Anatomic AJCC-7 staging for CRC.
\r\n\tAdvances in mathematics, models, computational techniques, dynamic analysis, etc. are employed in Principal Component Analysis, where this book presents the more important.
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Colorectal cancers (CRC) are considered the third most commonly diagnosed cancers in the world. The incidence and mortality rates vary worldwide from lowest in Africa and Asia to highest in Australia, North America, and Europe. The etiology is mainly due to changes in dietary habits, from low-fiber ingestion to high-fat diet, increased body mass index (BMI), low physical activity, cigarette smoking, alcohol consumption, diabetes mellitus, ulcerative colitis, Crohn’s disease, some inherited syndromes (familial adenomatous polyposis syndrome and nonpolyposis colorectal cancer or Lynch syndrome (LS), MUTYH-associated and Turcot-associated polyposis syndromes, Peutz-Jeghers syndrome, Juvenile polyposis syndrome, and Cowden syndrome), in addition to radiation therapy for another abdominal cancer [1, 2, 3]. Early diagnosis is necessary to get full remission, and screening has proved to be fundamental in decreasing the mortality rate. The treatment of CRC is multidisciplinary and implies a collaboration of many therapeutic teams including surgical, chemotherapy, as well as radiotherapy experts. In the following chapter, we will be studying the different treatment modalities and strategies approved and administered worldwide, according to CRC stages.
The staging classification of CRC has been conceived according to collaboration between the Union for International Cancer Control (UICC) and the seventh edition of the American Joint Committee on Cancer (AJCC-7), taking into consideration the Dukes’ staging with its modifications by Astler-Coller (MAC) and Kirklin system (Table 1).
Stage | UICC/AJCC | Dukes | MAC | ||
---|---|---|---|---|---|
0 | Tis | N0 | M0 | — | — |
I | T1 | N0 | M0 | A | A |
T2 | N0 | M0 | A | B1 | |
II A | T3 | N0 | M0 | B | B2 |
B | T4a | N0 | M0 | B | B2 |
C | T4b | N0 | M0 | B | B3 |
III A | T1–T2 | N1–N1c | M0 | C | C1 |
T1 | N2a | M0 | C | C1 | |
B | T3–T4a | N1–N1c | M0 | C | C2 |
T2–T3 | N2a | M0 | C | C1–C2 | |
T1–T2 | N2b | M0 | C | C1 | |
C | T4a | N2a | M0 | C | C2 |
T3–T4a | N2b | M0 | C | C2 | |
T4b | N1–N2 | M0 | C | C3 | |
IV A | Any T | Any N | M1a | D | D |
B | Any T | Any N | M1b | D | D |
Anatomic AJCC-7 staging for CRC.
Tis, Tumor confined to the mucosa; T1, tumor invades the submucosa; T2, tumor invades the muscularis propria; T3, tumor invades subserosa or beyond, without invading other organs; T4, tumor invades nearby organs (T4a, without perforation of visceral peritoneum; T4b, with perforation of visceral peritoneum); N1, metastasis to one to three regional lymph nodes (RLNs) (N1a, metastasis to one RLN; N1b, metastasis to two to three RLNs; N1c, metastasis into areas of fat near lymph nodes but not the nodes themselves); N2, metastasis to four or more RLNs (N2a, metastasis to four to six RLNs; N2b, metastasis to seven or more RLNs); M1, distant metastases present (M1a, metastasis to distant organ, as the liver or lung, or distant set of lymph nodes; M1b, metastasis to distant organs, to distant set of lymph nodes, or to distant parts of the peritoneum as the lining of the abdominal cavity).
In stage 0 colorectal cancer, the tumor is still confined to the inner lining of the colon (T in situ). A surgical removal of the cancer is all that is needed. A polypectomy or a colonoscopic local excision is usually sufficient. Partial colectomy is required in case of bigger tumors.
Malignant polyps are adenomas that have been identified histologically, after endoscopic excision, to be adenocarcinomas which have invaded through the muscularis mucosa into the basic submucosa (pT1) [4]. They can occur sporadically or as part of a polyposis syndrome. They can be classified endoscopically by their size and morphology and histologically as favorable (low risk) and unfavorable (high risk). In 1985, Haggitt reconceived the Japanese society classification and the Paris endoscopic classification into a new one taking into consideration the level of invasion depth (Table 2).
Level | Location of carcinoma |
---|---|
0 | Carcinoma in situ or confined to the mucosa. Not invasive |
I | Carcinoma invading through the muscularis mucosa into the submucosa but limited to the head of the polyp |
II | Carcinoma invading the level of the neck of the polyp |
III | Carcinoma invading in any part of the stalk of the polyp |
IV | Carcinoma invading into the submucosa of the bowel wall below the stalk of the polyp but above the muscularis propria |
Haggitt’s classification according to the level of invasion.
Despite the big advantage and wide use of Haggitt’s classification in assessing the quality of resection of endoscopic polypectomies, the sessile, flat, or depressed lesions yet were not successfully evaluated using this classification. In the early 1990s, Kikuchi succeeded in quantifying the grade of vertical and horizontal submucosal invasion, dividing the invasion into three levels (Table 3).
Submucosal level | Submucosal invasion |
---|---|
Sm1* | Characterizes lesions that are limited to the upper third of the submucosal layer |
Sm1a | Submucosal invasion under one fourth of tumoral width |
Sm1b | Submucosal invasion between one fourth and a half of the tumoral width |
Sm1c | Horizontal affection of the superior third of the submucosa over half of the tumoral width |
Sm2 | Characterizes lesions that are limited to the middle third of the submucosal layer |
Sm3 | Characterizes lesions that are limited to the lower third of the submucosal layer |
Kikuchi’s classification according to submucosal invasion level.
Sm1 lesions are further subdivided into three categories (a, b, and c) with regard to the degree of horizontal involvement of the upper submucosal layer (B), to the horizontal involvement of the total lesion (A). B/A ratios of 0.25, 0.25–0.5, and >0.5 correspond to a, b, and c, respectively.
Morphologically, polyps are known to be either pedunculated or sessile. Pedunculated polyps are usually attached to the colonic mucosa via a stalk of variable length, while sessile polyps are devoid of stalk, are flattened in shape, and overlay the mucosa with less separation of the adenomatous epithelium part from the underlying layers of the colon [5].
Histologically, polyps can be divided into low-risk versus high-risk features (Table 4) [4].
Low-risk features (favorable) | High-risk features (unfavorable) |
---|---|
Pedunculated (levels 1–3 according to Haggitt classification) | Tumor budding |
Well-differentiated adenocarcinoma | Poorly differentiated adenocarcinoma (grade 3) |
Free resection margin (2 mm) | Positive, indeterminate, or <1 mm resection margin |
En bloc resection | Piecemeal removal |
Neither lymphatic nor vascular invasion | Presence of either lymphatic or vascular invasion |
Submucosal invasion Sm < 1 mm | Submucosal invasion Sm* >1 mm |
Polyp classification according to histological criteria.
While Sm1a + b lesions have a very low risk for metastasis, the malignant potential increases with depth of submucosal invasion [6].
All of the aforementioned classifications are mandatory for accurate assessment of the degree of malignancy and aggressiveness of the resected polyp for rational clinical decision. Studies have shown polyps smaller than 5 mm in diameter, have negligible risk of malignancy, and are easily managed by standard techniques of endoscopic snare removal. Protruding polyps (Haggitt levels I, II, or III) with favorable histological features should be subjected to local excision or endoscopic polypectomy. Haggitt level IV lesions with favorable histology are considered low risk and can be favorably managed with endoscopic polypectomy provided margins are safe (>2 mm). Haggitt level IV protruding polyps and/or polyps exhibiting unfavorable features should be surgically excised due to the high incidence of lymph node metastasis. Excision can be performed either through traditional open approach or via more conservative laparoscopic techniques [7]. For sessile non-protruding polyps, a wider excision should be reconsidered requiring endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) [4]. Endoscopic mucosal resection is more specific for removal of sessile polyps limited to the mucosa and submucosa (Sm1a + b) and is typically used for complete excision of lesions up to 2 cm [8]. Endoscopic submucosal dissection is usually adopted for larger gastrointestinal lesions, where it more easily promotes the en bloc resection, yet it carries greater risk of perforation (31%) and late bleeding (15%) [9]. Lesions with a deep level of invasion (Sm1c, Sm2, or Sm3) or rectal lesions (specifically those of the distal third) showed higher incidence of lymph node metastasis 12–25% and should be treated by a definitive oncologic segmental resection due to the high risk of regional lymph node involvement.
Local recurrence is basically common in managed malignant polyps. Regular endoscopic follow-up is recommended to detect any disease recurrence; however, the duration of subsequent surveillance varies [10, 11]. In favorable histological criteria, protruding (levels I, II, or III), and noninvasive Sm1a + b polyps, it is recommended that a colonoscopy be carried out 3 months after the polypectomy [12, 13]. Further regular checkup is advised within 1, 3, and 5 years [14]. In malignant pedunculated polyps with unfavorable histological criteria, the risk of relapse or residual lesions reached 39% in treated patients. These patients are also found to have distant metastasis on follow-up, even 5 years after surgery [15]. Accordingly, in addition to the regular endoscopic surveillance, monitoring the serum level of carcinoembryonic antigen (CEA) and imaging techniques as computerized tomography or magnetic resonance imaging would enable early detection of disease recurrence. According to the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer’s guidelines, shorter follow-up intervals are recommended in case of senility, positive family history, or hereditary nonpolyposis colorectal cancer (HNPCC). Furthermore, endoscopic ultrasound or flexible sigmoidoscopy at 3- to 6-month intervals for the first 2 years after polypectomy can be considered for detecting early curable recurrences.
Stage I CRC includes T1 and T2, where cancer is still limited to and has not yet invaded the layers of the colon into other nearby organs. T1 cancers are usually parts of polyps that were discussed hereinabove. For T2 cancers, the standard of care consists of partial colectomy with regional lymph node dissection. A laparoscopic-assisted colectomy can be an acceptable choice for patients who are not candidates for open colectomy.
Stage I adenocarcinoma of the rectum is relatively rare, and a surgical removal of the cancer is usually curable. For the low-risk stage I rectal cancer, both endoscopic resection and transanal excision can be used. Transanal endoscopic microsurgery (TEM) is a transanal operation suitable for small tumors and not too far from the anus. It involves wide excision of all layers of the invaded rectum with the surrounding tissue to secure negative margins. If the cancer is located in the upper part of the rectum, a low anterior resection (LAR) is recommended, where the incision takes part across the abdomen to remove the affected rectum along with some surrounding tissue and lymph nodes, and followed by anorectal anastomosis. If the cancer occupies the lower part of the rectum (alongside the anus), an abdominoperineal resection (APR) with permanent colostomy is advised, when the distance between tumor and anus is too short to allow safe anastomosis. No additional therapy is needed after these operations, unless the surgeon finds the cancer with high-risk features. Then, an adjuvant concomitant chemoradiotherapy is appropriate with 5-fluorouracil (5-FU) or capecitabine [16].
Regular follow-up testing after the end of treatment aims at seizing any early disease recurrence. Colonoscopy should be repeated 1 year after therapy completion. In case of normal results, the next checkup should be after 3 years and then after 5 years. In case of finding any advanced adenoma (polyps with ruffled structure, larger than 1 cm, or with high-grade dysplasia), colonoscopy should be repeated within 1 year [17].
The role of adjuvant chemotherapy remains undetermined in stage II CRC. Surgical intervention should aim at a wide resection of the tumor with the involved bowel segment, all together with cutting out of the lymphatic system draining that part. The resection should include at least 5 cm colon segment of either side of the resected tumor. For adequate tumor staging (II or III), and to determine and eliminate any possible lymph node metastases (pN), at least 12 lymph nodes should be excised and subjected to histological analysis. Partial colectomy may be the only needed treatment for low- and medium-risk stage II CRC patients. High-risk patients should be subjected to chemotherapy if one of the following risk factors was identified:
High pT4 stage (T4 or tumor invading into adherent organs)
Suboptimal lymph node resection (less than 12)
Presence of lymphovascular or perineural invasion
Bowel obstruction or perforation
Poorly differentiated histology
High carcinoembryonic antigen (CEA) marker level
Positive margins
Various additional risk factors are being implied in assessing the additive benefit to the high-risk factors in stage II colorectal cancer using adjuvant chemotherapy.
One of the most promising risk factors is the microsatellite instability (MSI)/mismatch repair (MMR), which is regarded as a good prognostic factor. Microsatellites are short, tandemly repeated DNA sequences in the genome that are susceptible to errors of DNA replication in the presence of a defective mismatch repair (MMR) system. They are detected in about 15% of all colorectal cancers and can be used to determine stage II patients who are at very low risk of recurrence and with low benefit of adjuvant chemotherapy [18, 19]. Moreover, it has been established in a multivariate analysis that microsatellite instability was significantly associated with survival advantage independently of any other prognostic factors (hazard ratio (HR) 0.42; 95% confidence interval 0.27–0.67; p < 0.001) [20].
Another potential predictive colorectal marker is the allelic deletion of chromosome 18q, or the loss of heterozygosity (LOH) of chromosome 18, which is considered as a bad prognostic factor. The 18q loci hold several genes that are highly related to apoptosis and carcinogenesis. Patients (stage II or III) presenting 18qLOH were found to have less disease-free survival and overall survival than those with retained chromosome 18 (DFS 44% versus 64%, p = 0.002; OS 50% versus 69%, p = 0.005) [21].
Another prognostic marker in CRC is the expression of guanylyl cyclase C (GCC) in resected lymph nodes. GCC is a protein that is usually expressed by intestinal cells but universally overexpressed in colorectal cancer. GCC is an intestinal tumor-suppressing receptor which regulates epithelial homeostasis. Silencing of GCC contributes to tumorigenesis by reflecting dysregulation of the cell cycle and DNA repair [22]. The presence of GCC in resected lymph nodes reflects the detection of prognostically important occult metastases [23].
The Kirsten rat sarcoma (
The tumor suppressor TP53, or genome guardian, is another important predictive prognostic factor in CRC. TP53 is the most commonly mutated gene in human cancers, and its prevalence in CRC comprises 34% of the proximal colon tumors where it is mostly related to lymphatic invasion and 45% of the distal colorectal tumors where it is majorly correlated with lymphovascular invasion [27]. Clinical studies have shown that CRC patients with mutant p53 are more 5-fluorouracil-based chemotherapy resistant and have poorer prognosis than those with wild-type p53 [28].
The transforming growth factor beta (TGF-β) signaling pathway plays a central but paradoxical role in the predisposition and progression of colorectal cancer. TGF-β acts as a potent tumor suppressor in normal intestinal epithelial cells by inhibiting cell proliferation and inducing apoptosis. However, mutations in the genes encoding for TGFB receptor 2 (TGFBR2), with high levels of microsatellite instability, promote colon tumorigenesis by perturbing the function of TGF-β signaling pathways and stimulating the proliferation and invasion of poorly differentiated and metastatic colon cancer cells [29, 30].
Thymidylate synthase (TS) is an enzyme implicated in the formation of thymidine, one of DNA nucleotides. It catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). This role in nucleotide metabolism has made TS an important target of many chemotherapeutic agents such as 5-FU and the new folate-based TS inhibitors (raltitrexed and pemetrexed). Elevated intracellular TS levels have been implicated in emerging resistance to fluoropyrimidines and other TS inhibitors due to the increase in transcription and translation roles of TS. Therefore, high TS expression in early-stage CRC patients is correlated to a poorer overall survival in both chemotherapy-treated and chemotherapy-untreated patients following surgery [31].
5-Fluorouracil remains the backbone chemotherapy in treating CRC. In MOSAIC study, patients with stage II or III disease were randomly assigned to receive adjuvant FOLFOX4 or 5-FU/leucovorin (LV). In stage II disease, no improvement in DFS or OS was noted in 899 patients upon adding oxaliplatin to 5-FU (DFS HR = 0.84, p = 0.258; OS HR = 1.00, p = 0.986). Moreover, in patients with high-risk stage II disease, the estimated 10-year overall survival was 75.4% in FOLFOX arm versus 71.7% in 5-FU/leucovorin arm (p = .058) [19]. Similar results were obtained with the NSABP C-07 trial, where patients were randomized to receive either bolus 5-FU/LV alone or with oxaliplatin. While the addition of oxaliplatin to 5-FU/LV improved DFS, no benefit in OS was observed at all [32]. Furthermore, the QUASAR study investigated the role of adjuvant 5-FU in disease recurrence in “average-risk” patients (patients without any high-risk feature). As a result, 5-FU decreased the risk of recurrence compared to observation alone (relative risk (RR) for colon cancer = 0.78, p = 0.004; RR for rectal cancer =0.68, p = 0.004). And, the risk of death was improved in treated patients (RR = 0.84; p = 0.046), with an absolute survival benefit of 3.6% [25]. A major predictive prognostic factor in stage II CRC is microsatellite instability. As known, microsatellites are repeated DNA sequences in the genome. They are very susceptible to errors in DNA replication and especially in case of a defective mismatch repair (MMR) system, where they really can substitute it [19]. In colon cancer, the high level of MSI is associated with mutations in the MMR system. Based on findings from over 7000 patients classified as MSI-high (MSI-H), MSI-low (MSI-L), or MSI-stable (MSS) colon cancers, those with MSI-H had a better prognosis compared to those with MSI-L or MSS tumors by 15% [33]. Another important predictive factor in stage II CRC is 18qLOH. Loss of heterozygosity of chromosome 18 is highly associated with decreased overall survival [21, 34, 35]. The ECOG 5202 trial aimed at stratifying patients according to the molecular prognostic factors, MSI and 18qLOH. The recommendations were for stage II patients with low-risk (MSI-H or with either MSS or MSI-L together with 18qLOH retention) observation without any treatment. However, for those with high-risk observation (either MSS or MSI-L with 18qLOH), chemotherapy with FOLFOX is suggested [19].
As a conclusion for stage II CRC adjuvant treatment, the following algorithm is reasonable (Table 5).
Low risk (with MSI-H or with either MSS or MSI-L and retention of 18qLOH) | Observation |
Average risk (with MSS) | Observation or fluoropyrimidine* as single agent (optional) |
High risk**: (with MSI-H and 18qLOH retention) (with MSS or MSS-L and 18qLOH) | Fluoropyrimidine as single agent FOLFOX or CAPOX*** |
Stage II CRC adjuvant treatment algorithm.
Fluoropyrimidines are a class of antimetabolites that are converted in the body to 5-fluorouracil. These include 5-fluorouracil, capecitabine, doxifluridine, tegafur, and carmofur.
The high-risk factors are mentioned hereinabove in the text.
FOLFOX denotes folinic acid/5-FU/oxaliplatin; CAPOX denotes capecitabine/oxaliplatin.
According to Johns Hopkins colorectal health team, radiotherapy can be used adjuvantly in case of pT4, where the lesion is fixed and adherent to the abdominal wall or bladder, as it provides a lower chance of recurrence. Similarly, in case of rectal cancer, neoadjuvant chemoradiotherapy is indicated in order to shrink the tumor size prior to surgery and to avoid colostomy if possible. Radiotherapy is indicated when the rectal tumor has invaded the wall of the bowel or has spread into adjacent lymph nodes. 5-Fluorouracil or capecitabine are being used concomitantly with radiotherapy to sensitize tumor cells to radiation. In addition, concomitant chemoradiotherapy is indicated when the margins of resection are positive. However, no significant differences in overall survival were reported till now. EORTC 22921 was one randomized trial of 1011 patients that assessed the role of adjuvant 5-FU after preoperative chemoradiation for patients with T3 or T4 resectable tumor. Patients were divided in four arms including preoperative radiotherapy with or without chemotherapy and preoperative radiotherapy with or without chemotherapy followed by adjuvant chemotherapy. The OS for a median follow-up of 10.4 years was similar in the four groups (48.4–52.9%). There were no differences either in DFS rates or in the cumulative incidence of distant metastases [36]. A number of treatment strategies have been recently studied by various clinical trials, yet still no conclusive decisions have been taken. The major aim remains the patient’s benefit from a better tumor resection with less side effects, longer survival, and minor recurrence rates.
Survivorship care is a follow-up that takes place after the end of treatment to provide a better disease control and a less recurrence morbidity. A thorough physical examination with a tumor marker CEA should be performed systematically every 3–6 months for 2 years. In case of normal results, the frequency can be reduced to 6 months for an additional 3 years. Radiological imaging including CT scans or MRIs is indicated once a year for a total of 5 years. Colonoscopy is also suggested at an interval of 1 year after treatment and then after 3 and 5 years if results are normal.
Stage III colon cancer is characterized by tumor of any size (T1–T4) with metastasis to regional lymph nodes. A partial colectomy to remove the involved part of the colon along with adjacent lymph nodes, followed by adjuvant chemotherapy (not beyond 8 weeks of surgery), is considered the standard of care for this stage. However, in rectal cancer, tumor size (T3–T4, with invasion through intestinal muscular layer) with clinical positive lymph nodes is suggestive for neoadjuvant chemoradiotherapy and followed by adjuvant chemotherapy for a lower risk of recurrence rate. The European Society for Medical Oncology (ESMO) guidelines recommended in 2013 a stratification of the risk factors for disease recurrence of rectal cancer according to the following items identified by pretreatment MRI. These included the tumor invasion depth (T staging), the number of metastatic lymph nodes (N staging), the distance to anus, invasion of mesorectal fascia (MRF), and extramural vascular invasion (EMVI). Four risk groups were stratified (ultralow-, low-, medium-, and high-risk groups). Surgery alone was the choice for the ultralow-risk group, while neoadjuvant chemoradiotherapy with adjuvant chemotherapy was the best choice for the medium- and high-risk groups; the low-risk group showed a beneficial effect of adding chemoradiotherapy or chemotherapy [37]. These findings are compatible with the NCCN guidelines which recommended neoadjuvant chemoradiotherapy and adjuvant chemotherapy for those patients with high risk of local recurrence, including stage II (T3–T4, with tumor invading through the intestinal muscle layer) and stage III (positive lymph nodes) [17].
After a wide surgical resection with anastomosis, the standard chemotherapy protocol is approved to be oxaliplatin and 5-FU/folinic acid (FOLFOX4 or FLOX). In the MOSAIC study, the addition of oxaliplatin to 5-FU/LV (FOLFOX) showed a significantly increased DFS at 6 years, with a reduction in the risk of recurrence of 23% compared with the control arm (5-FU/LV), with an OS absolute gain of 4.2%. Similar results were obtained in the NSABP C-07 study, either in DFS at 3 years or in terms of reduction in the risk of recurrence. As a result of these studies, FOLFOX has been adopted adjuvantly on a biweekly basis, for a period of 12 cycles. In case of contradiction to oxaliplatin, 5-FU/LV administered intravenously according to de Gramont, AIO, or Mayo Clinic regimen, or oral fluoropyrimidines (capecitabine) are comparable in benefit. Other drugs such as topoisomerase I inhibitor (irinotecan) or anti-VEGFR agent (bevacizumab) or
In neoadjuvant rectal treatment, 5-fluorouracil remains the standard chemotherapeutic agent to be administered concomitantly with radiation. In ASCO 2011, NASBP R-04 firstly randomly compared the effect of capecitabine (an oral fluoropyrimidine) and 5-FU in preoperative concurrent chemoradiotherapy of rectal cancer. The results showed neither significant difference in pathological complete response (pCR) rate nor in third and fourth degree of adverse reaction rate [39]. Recently, in Germany, a randomized clinical phase III multicenter non-inferiority study showed no statistical difference of 3 years of DFS and local recurrence rate between capecitabine and 5-FU, concluding that capecitabine can substitute 5-FU as adjuvant or neoadjuvant chemotherapy for locally advanced rectal cancer [40]. The role of oxaliplatin in radiotherapy has been thoroughly examined as in many randomized studies as STAR-01, ACCORD 12/0405, NSABP R-04, and PETACC 6. Unfortunately, neither study succeeded in showing any significant increase of the pCR rate or downstage rate comparing to single drug (5-FU or capecitabine). In addition, ACCORD 12/0405 reported same OS (88%) in both combined two drugs (capecitabine with oxaliplatin) and single drug (capecitabine) [39, 41]. As a conclusion, single-agent fluoropyrimidine (5-FU or capecitabine) used concomitantly with pelvic radiotherapy remains the standard of care in stage III CRC.
Regular follow-up is highly advised in stage III CRC due to the high rate of recurrence. Detecting early relapse can be performed through a meticulous regular physical checkup with tumor marker CEA every 3 months for the first 2 years. A thoraco-abdomino-pelvic CT scan is required every 6 months for the first 2 years. A colonoscopy is advised in a 6-month period for the first year after treatment. The period of physical examination with CEA can be elongated for a 6-month period for the following 3 years in case of normal results. The CT scan period can be lengthened to 1 year for the following 5 years, and the colonoscopic evaluation can be further extended to once every 3 years in case of normal previous results.
Almost 20–30% of the newly diagnosed CRC patients present with distant metastatic disease at the time of initial presentation. And, up to 50% of the early-stage CRC patients will eventually relapse with metastatic disease. Metastasis can occur in different organs and most commonly to the liver (50–60% of the cases). The lungs are less frequent (10–20%) and are more common in rectal than in colon cancer. Other less often places are the peritoneum, ovaries, adrenal glands, bones, and brain. In case of locally recurrent disease or with resectable metastases, the standard of care remains curative surgical intervention. Chemoradiotherapy or chemotherapy alone can also be considered an acceptable approach in case of rendering a tumor resectable. For non-resectable tumors and/or disseminated metastatic disease, systemic chemotherapy stays the main therapeutic approach. Fluoropyrimidines (5-FU and capecitabine) are the mainstay in all protocols used in metastatic colorectal cancer (mCRC). For nearly 40 years (mid-1950 to 1996), 5-FU was the only agent approved for mCRC treatment. Later on, different cytotoxic agents appeared, as the topoisomerase I inhibitor (irinotecan) and the third-generation platinum analog (oxaliplatin), which both led to considerable advances in mCRC treatment along with fluoropyrimidines. Targeted monoclonal antibodies, such as VEGF inhibitor (bevacizumab) and EGFR inhibitor wild-type
Various randomized clinical trials have been designed to determine the efficacy of oxaliplatin versus irinotecan together with 5-FU/LV or capecitabine. The most well-known trial was the GERCOR C97-3 study conducted by Tournigand and coworkers [42] in France which investigated 5-FU/LV (46-hour infusion) and oxaliplatin (FOLFOX6) compared with 5-FU/LV and irinotecan (FOLFIRI) in mCRC. A similar efficacy was observed in both arms with respect to overall response rate (ORR, 56% versus 54%, respectively), median time to tumor progression (8.5 versus 8.1 months), and median OS (20.6 versus 21.5 months). Similar results were obtained by CALGB Cooperative Group (CALGB 80203) and the Hellenic Cooperative Oncology Group in Greece. Based on these results, both FOLFOX and FOLFIRI have been approved for first-line treatment in mCRC. A meta-analysis of six clinical studies was conducted by Guo et al. [43] to investigate the clinical efficacy of the oral capecitabine (Xeloda) plus irinotecan (XELIRI) versus FOLFIRI regimen in the first-line treatment of mCRC. The results showed no significant differences in terms of ORR, PFS, or OS between the two arms. Another important randomized study to compare XELOX non-inferiority with respect to FOLFOX6 in the first-line treatment of mCRC was conducted by Ducreux and coworkers [44]. No differences were observed between both arms in terms of the clinical efficacy endpoints of ORR (42% versus 46%, respectively), PFS (8.8 versus 9.3 months, respectively), and OS (19.9 versus 20.5 months, respectively). Based on these and many other studies, it has been established that both protocols FOLFOX and FOLFIRI can be safely substituted by oral XELOX and XELIRI in terms of clinical efficacy (PFS and OS).
It is has been proven that doublet chemotherapy has superior clinical efficacy over single-agent fluoropyrimidine chemotherapy. However, a new question emerged: is triplet chemotherapy with 5-FU, oxaliplatin, and irinotecan can provide improved clinical efficacy over doublet chemotherapy? To answer this question, the Gruppo Oncologico Nord Ovest (GONO) of Italy conducted the first randomized phase III study to compare 5-FU/LV, oxaliplatin, and irinotecan (FOLFOXIRI) with FOLFIRI in the front-line setting [45]. After a median follow-up of 5 years, the final analysis confirmed the superiority of the FOLFOXIRI regimen over FOLFIRI, in terms of improved ORR, PFS, and median OS [46]. However, there was significantly higher grade 2/grade 3 neurotoxicity (19% versus 0%) and grade 3/grade 4 neutropenia (50% versus 28%) compared with FOLFIRI, the matter that limits the use of this regimen to relatively more fit patient population (ECOG performance status 0–1).
In order to understand the role of targeted therapy in treating mCRC, we should first perceive their mode of action on a molecular level. Bevacizumab (Avastin®) is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A), which stimulates angiogenesis in a variety of diseases, including cancer [47]. In 2004, bevacizumab has been approved in the United States for use in combination with standard chemotherapy for metastatic colon cancer. The CALGB/SWOG 80405 phase III randomized study compared the potential benefit of cetuximab and bevacizumab added to conventional chemotherapy (FOLFOX or FOLFIRI) [48]. In contrast to the FIRE study that showed identical ORR and PFS, but a 3.7-month improvement in OS toward the cetuximab arm, CALGB/SWOG 80405 study showed no significant difference at all either in PFS (10.4 versus 10.8 months) or in OS (29.9 versus 29.0 months) in patients treated with cetuximab compared with bevacizumab. Recently, Venook and coworkers investigated the potential effect of primary tumor location on the clinical efficacy of patients treated on CALGB/SWOG 80405 study. It was strange to report that there was a significant improvement in OS (p < .0001) for patients with left-sided tumors compared with right-sided tumors (33.3 versus 19.4 months). For the bevacizumab arms, the OS was maintained high in both groups (left-sided tumors versus right-sided tumors) and significantly higher for left-sided primary tumors (31.4 versus 24.2 months). However, in the cetuximab arms, the OS in left-sided tumors was 19.3 months (which was 36.0 months) and only 16.7 months for right-sided tumors. These findings highlighted the importance of sidedness as an important predictive marker and in determining response to anti-EGFR antibody in mCRC [49].
Cetuximab (Erbitux®) and panitumumab (Vectibix®) are both monoclonal antibodies that inhibit the epidermal growth factor receptor (EGFR). Both drugs were approved by the FDA to treat mCRC that exhibit
Due to the poor prognosis factor of the BRAF V600E-mutated gene, many trials tried to establish a standard treatment for BRAF-mutated mCRC. Vemurafenib is a BRAF enzyme inhibitor, which interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway, in case where BRAF possesses V600E mutation. In 2017, it has been approved by the FDA for the treatment of late-stage melanoma with BRAF V600E-mutated gene. In 2010, a phase I trial for solid tumors including colorectal cancer was launched to study the effect of vemurafenib (PLX4032) on mCRC patients with mutant BRAF. Unfortunately, the results were not as promising as they were in malignant melanoma, with median PFS of 3.7 months [56]. Loupakis and coworkers studied in a retrospective exploratory analysis of a phase II trial the effect of FOLFOXIRI regimen with bevacizumab on BRAF-mutated mCRC patients. Data found PFS and OS of 11.8 and 24.1 months, respectively [57]. Two limitations were reported in the study: the first was that only patients older than 70 were included, or those who fit (ECOG PS 0) 71–75 old patients, and the second was the rarity of BRAF-mutant patients (8% of the population). In TRIBE phase III study, FOLFOXIRI regimen was studied either with bevacizumab or alone as first-line treatment mCRC, and the median OS was 31 versus 25.8 months in favor of the combination. However, in the mutant BRAF subgroup, the median OS was 13.4 months [58, 59]. According to ASCO recommendations in 2017, FOLFOXIRI with or without bevacizumab should be considered in patients with a BRAF mutation and good performance status.
The programmed death-ligand 1 (PD-L1) with its receptor programmed cell death protein 1 (PD-1) is T-cell surface checkpoint protein that plays a major role in suppressing the immune system, promoting self-tolerance by downregulating T-cell inflammatory activity, and leading to carcinogenesis [60]. In the recently updated 2017 NCCN guideline, two novel anti-PD-1 antibodies, nivolumab (Opdivo®) and pembrolizumab (Keytruda®), have been indicated as treatment options for patients with unresectable MSI-H- or MMR-deficient CRC, although not yet FDA approved for mCRC [17]. This was based on the interim results of two ongoing studies: KEYNOTE-016, a phase II study of pembrolizumab as monotherapy in MSI-H-/MMR-deficient tumors, and CheckMate 142, a study of nivolumab versus nivolumab combination with ipilimumab, another monoclonal antibody, in recurrent or mCRC. This decision has been taken into account due to the impressive durable response in both studies [61, 62].
Ziv-aflibercept (Zaltrap®), a novel anti-VEGF, is a recombinant fusion protein that consists of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human immunoglobulin (IgG) 1 [63]. In 2012, it has been approved by the FDA for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen treatment. A randomized double-blind placebo-controlled global multicenter phase III VELOUR trial randomized two groups: one to receive FOLFIRI with ziv-aflibercept and the other FOLFIRI with placebo. A statistically significant improvement in OS was observed in patients in the FOLFIRI plus ziv-aflibercept group compared with the FOLFIRI plus placebo group [HR 0.82 (95% CI, 0.71–0.94), p = 0.0032, stratified log-rank test]. The median OS was 13.5 versus 12.06 months, and the median PFS was 6.9 versus 4.7 months, respectively, in the ziv-aflibercept group compared with the placebo group [64].
Regorafenib (Stivarga®), a new oral anti-angiogenic drug, is an oral multi-kinase inhibitor which targets angiogenic, stromal, and oncogenic receptor tyrosine kinase (RTK). It inhibits many membrane-bound and intracellular kinases that are involved in normal cellular functions and pathologic processes, mainly the VEGFR2-TIE2 tyrosine kinase receptors. In 2012, it has been approved by FDA for the treatment of mCRC patients which have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with the anti-VEGF therapy bevacizumab and, if KRAS wild type, with an anti-EGFR therapy. The approval was based on the results of an international randomized (2:1), double-blind, placebo-controlled CORRECT trial. The patients were randomized to get either oral regorafenib or placebo. A statistically significant prolongation in overall survival was observed in regorafenib arm [hazard ratio (HR) 0.77 (95% CI 0.64–0.94), p = 0.0102]. The median survival time was 6.4 versus 5 months in favor of the regorafenib group (phase III, 2011; FDA, 2012) [65].
Ramucirumab (Cyramza®) is a fully human monoclonal antibody (IgG1), which works by blocking the binding of VEGF to its receptor VEGFR2, hence preventing the downstream effect of VEGF in angiogenesis. Recently, it has been approved by FDA for use in combination with FOLFIRI for the treatment of patients with mCRC whose disease has progressed on a first-line regimen containing bevacizumab, oxaliplatin, and fluoropyrimidine [66]. A randomized double-blind multinational trial divided patients into FOLFIRI plus ramucirumab-receiving group and FOLFIRI plus placebo. A statistically significant improvement in OS was observed in patients who received FOLFIRI plus ramucirumab compared with those who received FOLFIRI plus placebo [median overall survival 13.3 versus 11.7 months; HR 0.85 (95% CI 0.73–0.98), p = 0.023, stratified log-rank test]. The DFS was also in favor of ramucirumab arm (5.7 versus 4.5 months) [67].
Trifluridine/tipiracil (TFD/TPI) (Lonsurf®) is a new combination drug approved in 2015 for the treatment of mCRC. It is a combination of two active components: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor, which prevents trifluridine rapid metabolism, hence increasing its bioavailability. In 2015, it has been approved by the FDA for use in patients with mCRC who have been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy and an anti-epidermal growth factor receptor (EGFR) therapy, if RAS wild type [68]. Based on a pivotal phase III study (RECOURSE) to assess the efficacy and safety of TFD/TPI compared with that of placebo in a large international population, the outcomes were in favor of TFD/TPI arm, in terms of median OS (7.1 versus 5.3 months) and median PFS (2.0 versus 1.7 months) [69].
In case of recurrence, surgical option for liver or lung metastases should be considered in the first place followed by adjuvant chemotherapy, albeit others prefer to administer neoadjuvant chemotherapy for 2–3 months before any metastasectomy. In non-resectable tumors and disseminated metastasis, chemotherapy remains the mainstay in treating disease recurrence. It should be based on non-previously used protocols, i.e., if FOLFOX was used in previous treatment modalities, FOLFIRI should be the right option, and if both FOLFOX and FOLFIRI have been used, the choice shifts toward XELOX or XELIRI. Another alternative is to use infusional 5-FU or oral capecitabine as monotherapies. Other possibilities are the use of newly approved drugs as ziv-aflibercept with FOLOIRI, ramucirumab plus FOLFIRI, oral regorafenib, trifluridine/tipiracil, and nivolumab or pembrolizumab in case of MSI-H or dMMR. According to the last NCCN guideline in 2017, adjuvant Stereotactic Body Radiation Therapy (SBRT) should be considered in some localized lung or liver lesions. Moreover, the hepatic arterial infusion (HAI) pump therapy can be used as a substitute to systemic chemotherapy in unresectable CRC liver metastases, where it demonstrated significant tumor response rates [70]. Chemoembolization or embolization via radioactive beads is another way to treat liver metastases through the hepatic artery in chemorefractory colorectal tumors [71]. In case of peritoneal carcinomatosis, a novel strategy has emerged combining cytoreductive peritonectomy with hyperthermic intraperitoneal chemoperfusion (HIPEC), with a median survival of 3 years [72]. Many other options are being studied to be used as palliative treatment in advanced metastatic disease, such as external-beam radiotherapy, photodynamic therapy, cryotherapy, and radiofrequency ablation, in addition to oncothermia and many others under trials to palliate and manage the disease burden (Table 6).
Locally recurrent disease, with resectable metastases | Colectomy + metastasectomy | |
Locally recurrent disease (T4) | Chemoradiotherapy or chemotherapy alone followed by colectomy | |
Non-resectable tumors and/or disseminated metastatic disease | Chemotherapy | FOLFOX or FOLFIRI (substitutable by XELOX or XELIRI) |
FOLFOXIRI (ECOG good performance status and BRAF V600E mutation) | ||
Targeted therapy* | Bevacizumab (for right-sided tumors) | |
bevacizumab or cetuximab, or panitumumab (for left-sided tumors and wild-type | ||
Bevacizumab (for left-sided tumors and mutant-type KRAS and NRAS genes) | ||
Disease recurrence | Nivolumab or pembrolizumab as monotherapy (for MSI-H or dMMR) | |
FOLFIRI + ziv-aflibercept | ||
FOLFIRI + ramucirumab | ||
Regorafenib as monotherapy | ||
Trifluridine/tipiracil as monotherapy | ||
Clinical trials |
Metastatic CRC treatment algorithm.
Targeted therapy should be added to chemotherapy, unless otherwise mentioned.
Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant disorder that increases the risk of many types of cancer, including endometrial, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, skin, and particularly colon cancer [73]. It is considered the most common hereditary colorectal diseases and accounts for 1–3% of all CRC. It is associated with inherited mutation in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. This defect in MMR genes leads to tumor DNA microsatellite instability (MSI) and promotes carcinogenesis [74]. For this reason MSI profiling with immunohistochemistry testing for DNA mismatch repair has been considered essential in diagnosing Lynch syndrome (LS). The revised Bethesda guidelines have endorsed the testing for MSI, for families at high risk, in any of the following situations in CRC diagnosed in patients <50 years of age, the presence of Lynch-associated tumors, and MSI-H identified in patients <60 years old, identifying Lynch-related tumors in one or more first-degree relative and in patients <50 years of age and identifying Lynch-related tumors in two or more second-degree relatives regardless of age [75, 76]. The mainstay in the treatment of Lynch syndrome is colectomy. However, due to the risk of developing synchronous or metachronous secondary tumors, subtotal colectomy with ileorectal anastomosis should be considered in young patients [76]. Recently, three kinds of chemotherapy have been investigated for the treatment of LS: 5-FU with leucovorin, oxaliplatin, and irinotecan. Most studies showed no benefit of chemotherapy in such patients, just one small study on stage IV CRC reported one complete response and three partial responses with MSI-H tumors compared to MSI-L/MSS tumors [77]. The use of acetylsalicylic acid (aspirin) as chemoprevention by patients with LS is highly supported to reduce the risk of CRC [78]. The Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) trial was conducted to study aspirin chemoprevention that has colorectal cancer as the primary endpoint. The initial findings did not show any significant difference in colorectal adenoma or cancer formation up to 4 years. In 2010, after a longer follow-up (56 months), the results showed a significant decrease in the incidence of CRC and LS-related cancers between the aspirin (600 mg) and placebo groups. Prescription of aspirin for people at high risk was recommended, but the optimum dose and duration of treatment remain to be established, hopefully in CAPP3 [79]. The colonoscopic surveillance in Lynch syndrome is recommended from the age of 20–25 years and repeated at 1–2 years of interval.
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21, and characterized by the presence of numerous adenomatous polyps in the colon and rectum. It is responsible for about 1% of all CRC cases, and, often, extracolonic manifestations can take place as in Gardner syndrome (sebaceous cysts, epidermoid cysts, fibromas, desmoid tumors, osteomas, dental anomalies and congenital hypertrophy of the retinal pigment epithelium (CHRPE)), Turcot syndrome (brain tumors), gastric and duodenum polyps, soft tissue tumors, and thyroid cancers. FAP can be subdivided into classical FAP, attenuated FAP (AFAP), and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) [80]. Clinical diagnosis can be based on the number of polyposis, where more than 100 adenomas can be counted in case of FAP, from 10 to 99 in case of AFAP, and gastric polyps restricted to the body and fundus of the stomach (gastric fundic gland polyposis) in case of GAPPS [81]. Identification of a heterozygous germline pathogenic variant in APC should be confirmed by a molecular genetic testing for a definitive diagnosis. Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is recommended in case of diffuse spreading out of the polyps with severe familial phenotype presence. Total colectomy with ileorectal anastomosis (IRA) is advised in case of scarce adenomas with a mild familial phenotype presence. In AFAP, endoscopic polypectomy can be considered in case of reduced polyposis number. In GAPPS, gastrectomy is recommended since gastric carcinoma is detected in 13% of GAPPS. Regular yearly endoscopic surveillance should be taken into account to detect any disease recurrence. In families with classic FAP, endoscopic evaluation should begin at age of 12–14 years and be continued lifelong in mutation carriers. Regular physical examination and screening via CT scans or MRI for extracolonic manifestations should also start early in life or as soon as colorectal polyposis is diagnosed [82].
MUTYH-associated polyposis (MAP) is another inheritable form of FAP that is caused by autosomal recessive mutations of the MUTYH gene [83]. It accounts for about 10–20% of all polyposis patients [2]. Clinically, in MAP patients, between 20 and 99 adenomas should be present upon endoscopy [84]; however, a molecular genetic testing is necessary to differentiate between APC and MUTYH mutations [85]. In case of reduce polyposis number, endoscopic polypectomy can be sufficient. In case of polyp dissemination all around the colic frame, IPAA is the treatment of choice, and if the rectum is intact, IRA can be used to conserve it [85, 86]. Regular annual checkup by endoscopy should be maintained in all families presenting MAP disorder [87].
The dream of one day expanding humanity’s presence into the solar system will require advanced propulsion systems that provide high levels of thrust and efficient use of fuels. Thrust will be needed to leave Earth’s gravitation field and to establish stable orbits when approaching other planets and returning home. Many of the missions that will one day be of interest to human explorers will require travel to locations that are far away from the sun, so dependence on solar power will not be an option, and prepositioning enough chemical propellant to allow freedom of movement and the ability to return to Earth will be too expensive.
\nA wide range of studies, including the National Aeronautics and Space Administration’s (NASA) recent Design Reference Architecture (DRA) 5.0 Study [1], have shown that nuclear power can enable exploration of the solar system. Nuclear thermal propulsion (NTP) and nuclear electric propulsion (NEP) are technologies that can provide the necessary thrust and power densities to enter and leave gravity wells of planets, moons, and large asteroids, and they do not need external sources of power to generate propulsion. Heat produced through fission is all that is needed to add energy to a propellant and produce thrust.
\nSpace nuclear reactors rely on nuclear fuels that include a range of fissionable compounds. Uranium oxide (UO2), uranium nitride (UN), uranium carbide (UC and UC2), and uranium oxycarbide (UCO) are ceramic materials that have been studied by various space reactor technology development activities. Each of these materials has advantages and disadvantages related to use in space reactors, but they are all capable of achieving the extremely high temperatures that will be needed to move humans and equipment from Earth to other parts of the solar system.
\nThe function of a rocket engine is to provide a force \n
The efficiency of an engine is determined by the force produced by a unit of mass flow rate, which is frequently defined in terms of “specific impulse.” Specific impulse is given by \n
This equation illustrates how \n
Another important aspect of rocket engine operations is that propellant exhaust velocity \n
where \n
As a result, \n
Comparison of rocket propulsion system characteristics.
Nuclear thermal propulsion systems can use a range of fluids for thrust and reactor cooling. Examples include hydrogen, ammonia, methane, octane, carbon dioxide, water, and nitrogen [3]. Specific impulse is lower for higher molecular weight fluids, but the heavier fluids require less storage capacity, and they could be mined, or synthesized, on interplanetary trips.
\nNuclear engine design requires iterative consideration of reactor neutronic thermal hydraulic and structural characteristics combined with engine system-level performance analysis [4]. Effective design and analysis sequences involve establishing a preliminary core design that meets the fundamental neutronic performance requirements of start-up criticality and reactor control. Fuel element designs using fixed fuel compositions and uranium enrichments are developed early in the design process, and then the preliminary design is used to determine neutron and gamma energy deposition characteristics that feed an integrated thermal hydraulic/structural analysis of the core’s internal components. Once acceptable neutronic and thermal/structural performance is achieved, overall engine performance is evaluated to determine how well the design satisfies mission requirements. The analysis sequence is then revised as necessary to optimize engine performance characteristics to support specific mission profiles.
\nEngine performance can be improved by various methods of controlling propellant flow through the reactor core and varying fuel compositions. For example, enrichment zoning within the fuel elements, with lower enrichments in high-power regions of the core, can be effective at flattening reactor power profiles and producing more uniform propellant exit temperatures. The cost of these design complications is often slightly reduced core reactivity that can have an impact on engine performance (i.e., specific impulse), but compensation for the reactivity loss is often possible through careful consideration of performance enhancements outside of the reactor fuel (e.g., propellant orificing, reductions in reactor mass, and the use of materials with low neutron absorption characteristics).
\nA wide variety of fast spectrum and thermal spectrum reactor designs have been developed for use in space propulsion systems. Fast spectrum reactors rely on high-energy (i.e., “fast”) neutrons having average energies greater than 0.5 MeV to produce heat using materials that can fission after fast neutron absorption, while thermal spectrum reactors require the use of moderator materials to slow neutrons down to lower energies that are more readily absorbed. Fast reactors require fuel that is relatively rich in fissile material, while thermal reactors can operate with low-enriched uranium fuels.
\nBoth fast and thermal spectrum reactors are typically designed with reflectors made from materials such as beryllium that prevent neutron leakage from the reactor core without producing a significant amount of neutron absorption. In space reactors, axial reflectors are often placed above and below the reactor core and radial reflectors are often placed around the core to reflect neutrons that would otherwise escape from the core back into the reactor’s fuel. Control drums that are rotated to add enough reactivity to start up the reactor and make minor adjustments to its power profile are typically placed inside the radial reflector. A material with a high neutron absorption cross section (e.g., boron carbide, B4C) is placed on one side of the control drums to remove neutrons while the reactor is shut down. The drums are rotated to move the neutron absorption material farther away from the core in order to start up the reactor.
\nFuel depletion and fission product buildup during reactor operation are typically areas of concern for reactor design, but space reactor operating times are typically very short, so fuel burnup and fission product buildup are usually of little importance to NTP reactor designs.
\nNuclear thermal propulsion systems were studied extensively during the 1950s and 1960s, but they were considered to be too heavy and expensive for deployment. At the time, chemical rockets and solar power were more economical for near-Earth operations that were the focus of the world’s space agencies. However, recent interest in deep space exploration, and especially interest in sending astronauts to Mars, has reinvigorated NTP research for several reasons. First, the longer thrust duration than chemical rockets that can be produced with an NTP system could cut the travel time to Mars by 20–25%. The reduced travel time is important because it would reduce the amount of dose that astronauts would receive from cosmic radiation during the voyage. Second, the higher thrust would extend the available launch window for missions to Mars. Conventional chemical rocket engines can only be used to reach Mars during a 30-day window that opens every 26 months due to the relative positions of the planets, while nuclear propulsion systems can provide enough thrust to leave Earth’s orbit and reach Mars during more points during the orbital profiles of the two planets. Finally, NTP systems could extend the amount of time during which a mission to Mars could be aborted and still allow astronauts to safely return to Earth. Chemical rocket fuel needed for the return trip from Mars to Earth would likely need to be sent to Mars in advance of a crewed mission, so astronauts would have to reach Mars in order to return to Earth after their initial supply of fuel is consumed, if chemical rockets were used for the mission. An NTP system, on the other hand, would be able to turn around and return to Earth before reaching Mars, if the mission had to be aborted.
\nSeveral successful research and development programs focused on space reactor fission power technologies have been established over the past 60 years. The earliest, and most extensive of these efforts, were the Rover and Nuclear Engine for Rocket Vehicle Application (NERVA) programs that were sponsored by the US Atomic Energy Commission (AEC) between 1958 and 1971 [5]. A total of 13 research reactors and 6 nuclear engines were built and tested under the Rover/NERVA programs at the AEC’s Nevada Test Site (NTS) Nuclear Rocket Development Station (NRDS) and other facilities located across the country [6]. The Rover reactor development and testing efforts were led by the Los Alamos Scientific Laboratory (LASL), and the NERVA reactors were designed and built by Westinghouse Electric Corporation (Astronuclear) and Aerojet-General Corporation following a 1961 design competition. The Kiwi (1955–1964), Phoebus (1964–1969), and Peewee (1969–1972) series of reactors were developed and tested under Rover to demonstrate the basics of nuclear rocket technology and to study characteristics of high-temperature nuclear fuels and long-life fuel elements. The NERVA NRX and XE engines were also built between 1964 and 1969 and tested at NRDS to study the complexities of nuclear engine start-up, full-power operation, and shutdown. A list of the best performance parameters achieved during the Rover/NERVA programs is presented in Table 1 [7].
\nParameter | \nReactor (test date) | \nPeak performance achieved | \n
---|---|---|
Power | \nPHOEBUS 2A (July 1968) | \n4100 MWt | \n
Peak fuel temperature | \nPEEWEE (November 1968) | \n2750 K | \n
Specific impulse | \nPEEWEE (November 1968) | \n848 s | \n
Maximum restarts | \nXE’ (June 1969) | \n28 | \n
Accumulated time at full power | \nNF-1 (June–July 1972) | \n109 min | \n
Continuous operation | \nNRX-A6 (December 1967) | \n62 min | \n
Maximum performance results achieved during the Rover/NERVA programs.
Early work in the Rover/NERVA program was performed with uranium carbide (UC or UC2) and uranium dioxide (UO2) fuel particles embedded into graphite. The effects of fission product interaction with the graphite matrix quickly led to the use of pyrolytic graphite-coated UO2 particles in the Rover/NERVA fuel designs. The pyrolytic carbon contained fission products produced during reactor operations before the fission products could cause dislocations in the graphite structural materials. The pyrolytic carbon layer also protected the UO2 particles from oxidation during fabrication and handling of the fuel.
\nA major drawback associated with using graphite in space reactors is that graphite converts to methane (CH4) under hydrogen exposure, and the conversion causes the graphite to corrode. During the Rover/NERVA programs, the graphite matrix used in the reactor fuel was protected from corrosion through application of a high-temperature niobium carbide (NbC) coating. However, the use of the NbC coating leads to issues associated with “mid-band corrosion,” which was higher corrosion rates in the center third of the reactor fuel elements where power density was high. The corrosion was found to be caused by cracking of the NbC coatings used in the fuel’s hydrogen coolant channels due to a mismatch between the thermal expansion coefficient of the NbC coating and the thermal expansion coefficient of the fuel matrix. The NbC coatings were eventually replaced with zirconium carbide (ZrC) coatings because of zirconium carbide’s superior resistance to fission product diffusion at high temperatures.
\nThe search for solutions to the corrosion problem also led to the development of {(U, Zr) C, graphite} composite fuel. The coefficient of thermal expansion for the composite fuel was 6–6.5 \n
Carbide material systems have several favorable features applicable to NTP reactors including:
Relatively small neutron absorption cross sections
High melting points
Thermal stability
Low volatility
High fuel densities
High moderation ratios
Low material densities (<10 g/cm3)
However, the complex fuel designs used in the early Rover/NERVA tests were challenged by the mechanical loads, thermal stresses, and high radiation fields found in NTP reactors. The intense operational conditions contributed to the formation of stress fractures in the fuel coatings and surfaces and the cracking encouraged increased hydrogen penetration into the fuel that produced fuel degradation.
\nThe Small Nuclear Rocket Engine (SNRE) was the last engine design studied by Los Alamos National Laboratory (LANL) under the Rover/NERVA program. The SNRE was a nominal 16,000 lbf thrust engine that was originally intended for short run-time, unmanned missions, and the SNRE stage design was constrained to fit within the payload volume of the planned space shuttle. The reactor’s core design used hexagonal fuel elements and hexagonal structural support elements (i.e., tie tubes), and the number of elements could be varied to support different thrust requirements. Higher thrust designs for SNRE meet or exceed performance characteristics identified in the DRA 5.0 study, so SNRE would be suitable for use in human missions to Mars.
\nThe GE-710 [8] high-temperature gas reactor (HTGR) and the Argonne National Laboratory (ANL) nuclear rocket engine programs [9] focused on development of ceramic-metal (cermet) fuels consisting of uranium ceramic material (e.g., uranium dioxide [UO2] or uranium nitride [UN]) embedded in a refractory metal matrix (e.g., tungsten). To ensure good bonding between the kernels and the matrix, the kernels were coated with a thin layer of the matrix metal (i.e., tungsten [W] or molybdenum [Mo]). In addition, the coolant flow channels of the cermet fuel were coated with either tungsten or niobium.
\nThe GE-710 program ran from 1962 to 1968 with the objective of performing reactor tests of a closed-loop system (i.e., an engine system that recycled engine propellant) that used neon as a coolant, and an open-loop system (i.e., an engine system that expelled the reactor coolant to produce thrust) that used hydrogen as the reactor coolant. Final program goals focused on longer-term operation (approximately 10,000 h) at fuel temperatures in the 2000–2250 K range. Major achievements during the GE 710 program included down selection to either W-UO2 or Mo-UO2 cermet fuels, significant development of fabrication and brazing techniques for cermet fuel elements, development of sintering methods for fabrication of high-density fueled cermets, and initiation of in-pile testing. Molybdenum was also investigated as a substitute for the tungsten matrix, but the lower strength of Mo caused increased fuel swelling at high burnups due to fission gas buildup. The loss of Mo due to vaporization at high temperatures during electron beam welding and during thermal cycling was also undesirable.
\nThe W-UO2 cermets tested under the GE-710 HTGR program were cold pressed and sintered into segments of approximately 12.7 mm lengths. Tungsten powder composed of 1–2 \n
After sintering, the GE-710 fuel segments were machined into a hexagonal shape. Coolant channels with 0.914 mm (0.036 in) diameters were drilled into the segments, and then 0.203 mm (0.008 in) wall thickness coolant tubes were sealed into place on one end of the segments by tungsten inert gas (TIG) welding. A header was brazed to the other end prior to complete element assembly, and a tantalum (Ta) spacer plate was used adjacent to the header to protect the fuel from the braze material. The segments were placed into a 0.381 mm (0.015 in) wall thickness cladding, and the fuel was bonded to the cladding using a high-temperature, high-pressure autoclaving process. Autoclaving was typically carried out at a pressure of 10.3 megapascals (MPa) (1494 pounds per square inch [psi]) and 1922 K for 1 h, although an alternate hot-gas pressure process was also used at 68.9 MPa (9993 psi) and 2022 K for 2–3 h.
\nDissociation of UO2 into free uranium and hyperstoichiometric UO2 or oxygen during the sintering process had a detrimental effect on fuel fabrication. Fuel performance issues arose from UO2 dissociation because an increase in excess oxygen within the fuel led to an increase in fuel swelling, and the excess oxygen could react with the W matrix to form WO2 stringers in the matrix grain boundaries. Free uranium was also detrimental to fuel dimensional stability and caused negative reactions with the cladding materials that were used. There was little to no mobility of free uranium below the fuel particle melting temperature range (1422–1644 K), but uranium formed a two-phase mixture that produced fuel swelling above the melting temperature range.
\nChallenges associated with dissociation of UO2 were first addressed by the addition of thorium oxide (ThO2) as a stabilizing compound, but testing showed that ThO2 only delayed free uranium migration. A more suitable solution to UO2 dissociation was found to be the addition of substoichiometric UO2 combined with the ThO2 stabilizer since substoichiometric UO2 retained a single phase as temperatures increased. Dissociation and free uranium migration became an issue only during thermal cycling, and oxygen to uranium ratios of 1.984–1.988 were found to have the best performance during thermal cycling tests [10].
\nDifferences in the coefficient of thermal expansion between the fuel, matrix, and cladding also presented themselves during the development program. During bonding of the cladding to the fuel, the cladding material expanded two times more than the matrix material, resulting in compression at the interface when the fuel was cooled. Alloying with 3 wt% rhenium (Re) in the tungsten matrix increased the low-temperature ductility of the matrix.
\nThe most promising clad materials used in the GE-710 program were elemental tantalum, tantalum alloys (T-111 and tantalum-10 weight percent tungsten [Ta-10W]), and a tungsten-30 weight percent rhenium-30 weight percent molybdenum (W-30Re-30Mo) alloy. Tantalum was selected as the initial cladding material because the material was readily available, and it had sufficient compatibility with the W-UO2 cermet fuel. However, tantalum clad performance was limited by free uranium that formed reaction voids in the cladding. The voids formed because repeated cycling of the fuel allowed uranium metal to precipitate out of single-phase UO2−x. The uranium migrated through the W matrix grain boundaries and into the Ta cladding, and leak paths developed as the uranium metal re-oxidized to form UO2. The T-111 cladding material was attractive because the alloy maintains a fine-grained structure that limits uranium movement until grain growth occurs above 1922 K. However, the alloy has a high oxygen permeability that results in reaction void formation. The W-30Re-30Mo alloy used in the later stages of the GE-710 program was found to have low oxygen permeability, low sensitivity to gas impurity absorption, high strength, high melting point, and good ductility. Unfortunately, high bond stresses caused by thermal expansion mismatch between the W-30Re-30Mo clad and the fuel matrix occurred during thermal cycling. An anneal heat treatment was used to overcome the bond stresses, but the treatment caused re-precipitation of the sigma phase at grain boundaries which led to clad weakness. Volatilization of Mo at high temperatures also increased sigma phase formation and reduced clad strength.
\nIrradiation tests performed under the GE-710 program included tests of UO2 and ThO2-stabilized UO2 fuel samples in the Idaho National Laboratory’s (INL) Engineering Test Reactor (ETR). Matrix materials used in the samples included W, W-Re, and Mo with Ta-10W, W-30Re-30Mo, and niobium (Nb) cladding. Approximately half of the samples evaluated in the ETR testing campaign developed fission gas leakage. Further testing was performed in the Low-Intensity Test Reactor (LITR) at the Oak Ridge National Laboratory (ORNL) using W and W-Re matrix material with W-30Re-30Mo and W-25Re-3Mo cladding. The results of the test were similar to the ETR results. However, a third series of tests in the Oak Ridge Research (ORR) reactor with basically the same matrix-cladding combinations showed significant improvements that were achieved by reducing the density of UO2 in the fuel to provide void space for fission product gas accumulation.
\nFuel failure modes observed during the GE-710 testing included [7]:
Loss of oxygen from UO2 at high temperatures followed by the formation of substoichiometric UO2, free uranium, and uranium penetration of the cladding wall during thermal cycling.
Volume expansion, and eventual cracking of the W-UO2 fuel matrix, during very high-temperature operation after significant thermal cycling.
Void formation between the cermet fuel and the fuel cladding during fabrication and early operation.
Fission product damage/release after 4000–7500 h of operation at 1870–2270 K in fuel specimens sintered to 95% or greater theoretical densities.
Preferential vaporization of Mo and other lower melt point materials out of the clad at temperatures above 2470 K. Molybdenum was found to be a poor candidate for alloying because Mo vapor pressure becomes significant at temperatures above 2470 K.
Physical mechanisms determined to have caused the failure mechanisms included:
Transparency of Ta and Ta alloy materials to oxygen at intermediate and high temperatures.
Volume expansion and cracking caused by incompatibility of coefficients of thermal expansion between tungsten and UO2 in the fuel matrix. The incompatibility caused fuel particles to pull apart from the tungsten matrix at high temperatures and after multiple thermal cycles.
Void formations caused by difficulties with achieving good seals between metal alloy cladding, internal metal alloy coolant tubes, and the cermet fuel material.
Insufficient permeation of alloy-clad material into the cermet during autoclaving, leaving weaknesses that developed into voids.
Fission product damage to the cermet, and eventually the cladding material, caused by accumulated buildup of pressure, lattice stresses, and dislocation weaknesses under irradiation.
Sintering to lower theoretical densities of 84–90% created a significant improvement in sample performance. An increase in burnup capability (i.e., fissions/cm3) by almost a factor of 10 was achieved by simply giving the fission products additional room for expansion without exerting stresses in excess of the tungsten matrix capability at elevated temperatures.
\nThe ANL nuclear rocket program focused on developing two reference reactor designs; the ANL200 and ANL2000 reactors were 200 MWt and 2000 MWt fast spectrum thermal propulsion systems that were designed to produce 44.5 kN (10,000 lbf) and 445 kN (100,000 lbf) of thrust.
\nMost of the ANL program’s work was focused on design and testing of the ANL2000 system. The reactor consisted of an array of 163 hexagonal fuel elements that were assembled into an approximately cylindrical core with a diameter of 66 cm (26 in). The fuel elements were made from a 93% enriched tungsten-urania cermet fuel that was clad with 0.76 mm (0.03 in) of a tungsten-rhenium (W-25Re) alloy. The elements had a total length of 130 cm (51.56 in) and a fueled length of 87 cm (34.25 in). The core was supported from an Inconel Inco-718 grid plate that was bolted to the reactor vessel at the cold end of the core, and a cylindrical beryllium-oxide axial reflector containing 12 control drums was mounted at the inlet end of the core. A preheater consisting of stainless steel-UO2 fuel elements at the inlet side of the reactor was also included in the reactor design.
\nThe ANL2000 development program’s performance goals were to reach a fuel temperature of at least 2770 K in order to produce an Isp of 821–832 s, achieve 10 hours of operation with at least 25 thermal cycles, and limit fuel loss to less than 1%. All of the program’s goals were achieved before the program was terminated; however, neither of the ANL program’s reference reactor designs were built or tested before the program was cancelled.
\nThe primary fuel evaluated under the ANL program was UO2 embedded in a tungsten matrix. The fuel choice was similar to the GE-710 program, but gadolinia was used to stabilize the ANL fuel, in contrast to the ThO2 that was used in the GE-710 program. Three fuel fabrication methods were investigated under the program: cold pressing and sintering of W-UO2 wafers, isostatic sintering of long fuel elements, and hot pneumatic compaction.
\nThe cold pressing and sintering technique led to fabrication of approximately 6.3 mm (0.02 in) thick W-UO2 wafers that were stacked to form a fuel column. Fuel grading was used in the stacks to optimize physics and thermodynamics of the core. The fuel fabrication method required a high strength cladding since the cladding provided structural support. The isostatic sintering method allowed for single-step fabrication of fuel elements that were approximately 45.7 cm (18 in) long. The process minimized concerns over coolant channel alignment tolerances because individual fuel wafers did not have to be stacked to form an element. Finally, the hot pneumatic pressing method was used to demonstrate the fabrication of fuel formed from UO2 fuel kernels that were CVD coated with tungsten. A fuel loading of 60 vol% of 93% enriched UO2 inside a W or W-Re matrix was used for all of the program’s fuel samples.
\nSimilar to the GE-710 program, stabilizers were added to the ANL program fuels to inhibit UO2 dissociation, but the stabilizers investigated under the ANL program included gadolinium (GdO1.5), dysprosium (DyO1.5), yttrium (YO1.5), and MoO3. Ten mole percent of stabilizer was added to the UO2 for all investigations.
\nThe fuel fabrication process that gave the best results was a powder metallurgical process that produced near net shape fuels with cold isostatic pressures, followed by sintering at approximately 1500 K and chemical vapor deposition (CVD) of cladding on the coolant channels, even though deposition of uniform CVD coatings was difficult in the 1960s. The gadolinia stabilized fuel showed excellent retentivity at 2770 K for up to 45 hours and 180 cycles in non-nuclear tests performed in two hydrogen loops. Other tests showed that flowing hydrogen at temperatures exceeding 2700 K had essentially no impact on fuel loss rates.
\nInduction brazing was investigated by the ANL program as a means for joining fuel sections. A Zr-Mo braze with a melt temperature above 1973 K was the most successful; however gas generated during brazing made it almost impossible to fabricate a leak-free joint. The problem was overcome by immersing fuel sections in liquid nitrogen with the section to be brazed left above the liquid pool. Brazing was carried out in five sections to avoid allowing the fuel section to reach a temperature where volatilization of impurities could occur.
\nHigh-temperature refractory brazing techniques were also developed under the ANL program. Solid-state diffusion bonding of W-25Re alloys using nickel as an interleaf material that forms an Ni-W-Re ternary has been demonstrated at temperatures as low as 1173 K (although a temperature of 1773 K is required to produce sufficiently strong bonding). Brazing of refractory metals is generally undesirable due to recrystallization of microstructures produced in the joint, but solid-state diffusion bonding avoids recrystallization through the use of low temperatures. Nickel may be an undesirable interleaf material for high-temperature NTP materials, but other interleaf materials may be identified with further investigation [11].
\nNuclear tests on the ANL cermet samples were performed in the Transient Reactor Test (TREAT) facility at INL. Eight cermet specimens, each with seven coolant channels and vapor-deposited tungsten cladding, were tested in the TREAT experiments. The test durations were typically 200–430 ms, although two samples were subjected to flat-top transients lasting 2–3 s. One of the tests failed, as fuel material was ejected from the sample, and the failure was attributed to fabrication issues, particularly tungsten coating thickness irregularities. The last two samples evaluated in the campaign were subjected to multiple transients at heating rates up to 16,000°C/s, a maximum temperature of 2870 K, and a power density of 30 MW/l. These samples showed no evidence of damage [7].
\nThe goal of fuel development under the Space Nuclear Thermal Propulsion (SNTP) Program was to develop a coated nuclear fuel particle with a diameter of approximately 500 \n
The particle bed reactor concept developed by Dr. James Powell and his team at Brookhaven National Laboratory (BNL) caught the attention of SDI program managers as a possible power source for a rapid intercept vehicle that could destroy ballistic missiles, because it had the potential to overcome limitations associated with high-power production. Interest in the PBR technology led to the creation of the Timberwind program in 1987 and creation of the SNTP program in 1991, after Timberwind was declassified and transferred to the US Air Force.
\nThe PBR fuel element designed for the SNTP program consisted of a large number of UC2 fuel particles packed between two porous cylinders called frits. The fuel elements were housed inside cylindrical moderator blocks made of beryllium or lithium hydride that slowed the reactor’s neutrons down to thermal energies that could sustain a fission chain reaction. Hydrogen served as both a coolant and propellant for the SNTP engine as it moved through the cold frit located on the outside of the fuel elements, flowed through the element particle beds to remove heat produced by the fission reaction, and then exited the fuel through the inner hot frit. The hydrogen then flowed axially down an annular channel located at the center of each of the core’s fuel elements and exited the core before expanding through the engine nozzle to produce thrust.
\nThe PBR concept promised significant reductions in system mass over solid core reactors due to the 20-fold increase in heat transfer surface area of the particle fuel elements compared to the prismatic fuel used in the Rover/NERVA program. PBRs also had a lower core pressure drop due to the shorter flow paths through the pebble beds. The small size of the particles helped to prevent cracking, because thermal gradients across the particles are relatively low, but the coatings used on the particles were found to be prone to high-temperature vaporization that was made worse by the high surface area to volume ratio of the particles.
\nThe SNTP program began working on the development of coated fuel particles based on the HTGR Program fuel design. These particles were known as the program’s baseline fuel. The baseline fuel development included the production of uranium-bearing fuel kernels using the internal gelation process. The fuel kernels were covered by pyrolytic carbon using chemical vapor deposition in a fluidized bed.
\nBabcock and Wilcox Inc. (B&W) developed the ability to produce ZrC outer coatings on microparticles with the assistance of LANL and General Atomics. B&W produced fuel particles consisting of UC2−x kernels coated with two layers of pyrocarbon and an outer layer of ZrC that supported the Particle bed reactor Integral Performance Element (PIPE) experiments that were performed in 1988 and 1989. The first pyrocarbon layer in the fuel particles was a porous layer that accommodated the mismatch in thermal coefficient of expansion between the fuel kernel and the outer ZrC layer. The second layer was dense pyrocarbon that protected the fuel kernel from attack by the halides used in the CVD process. The outer ZrC layer was used to delay corrosion of the fuel kernel after it was exposed to hydrogen propellant.
\nMore than 200,000 particles were tested in Sandia National Laboratory (SNL) Annular Core Research Reactor (ACRR) in four particle nuclear tests (PNT) [12]. Fuel temperatures achieved during the tests ranged from 1800 to 3000 K, and testing times ranged from 100 to 600 s. Baseline UC2−x fuel kernel performance is limited by its melting temperature of 2700–2800 K, but the PNT tests showed that the melting temperature of fabricated UC2−x kernels was actually closer to 2500 K. Molten UC2−x dissolved the particle carbon layers and attacked the ZrC outer layer during the tests, and a complete particle failure occurred about 5 min after kernel melting. It is possible that increasing the graphite layer thickness would delay the time to failure, but the increased particle size might weaken any fuel matrix that was used to contain the particles, so testing of increased graphite layer thicknesses was not performed by the SNTP program.
\nThe program pursued a dual fuel development path once it became clear that coated UC2-x kernels would not meet the program’s temperature requirements. Under the dual-path effort, BNL investigated the development of an infiltrated kernel (IK) fuel, and B&W investigated mixed-carbide fuel particles. BNL postulated that IK fuel could be formed when molten UC2−x distributes uniformly through a porous graphite matrix. The laboratory’s scientists reasoned that the molten uranium ceramic could be held within the graphite’s pores and protected from hydrogen corrosion by an appropriate high-temperature outer layer, since UC2−x is thermodynamically stable with respect to graphite and does not react with it even after melting. BNL demonstrated in 1992 at laboratory scale that molten UC2 could be infiltrated into porous graphite coupons to the desired uranium density and that spherical IK particles could be fabricated. The demonstration also showed that pyrolytic layers used in the baseline fuel design are unnecessary in the BNL IK fuel, so IK fuel has a higher uranium density and smaller particle size than the baseline SNTP fuel.
\nThe B&W mixed-carbide fuel design developed under SNTP was based on investigations that were performed at the end of the Rover/NERVA program. The fuel was formed as a mixture of refractory carbides such as ZrC, NbC, TaC, HfC, and UC. Uranium carbide has a theoretical melting temperature of 2798 K, but the refractory metal carbides have melting temperatures ranging from approximately 3700 K for ZrC to greater than 4200 K for TaC and HfC. Tantalum and Hf have relatively high neutron absorption cross sections, so only ternary mixtures of U-Zr-C and U-Nb-C were considered by the B&W fuel development program.
\nThe diagram shown in Figure 2 is an example of phase relationships for a mixed carbon fuel [13]. As illustrated in the figure, the melting temperature of mixed-carbide fuels decreases with increasing uranium content. The necessary uranium content for SNTP fuel was determined by fuel criticality conditions, and the B&W research identified a minimum required uranium mole fraction of 0.15, which equated to a melting temperature of approximately 3200 K. By the end of 1992, B&W measured the melting temperature of U-Zr-C as a function of uranium content; measured the plasticity of ZrC, NbC, and U-Zr-C at 3200 K; and produced a small amount of NbC-coated U-Zr-C kernels using an internal gelation manufacturing process and CVD coating.
\nUranium-carbon phase diagram [
Overall accomplishments of the SNTP program included:
Acquisition of technology and equipment that allowed production of nuclear fuel microparticles using the internal gelation process and coating of the particles with pyrolytic carbon and refractory metal layers using CVD
Production of baseline fuel particles that supported radiation and non-radiation testing
Development of a laboratory process for infiltrating porous graphite with uranium to produce infiltrated kernel particles
Modification of the internal gelation process that allowed for production of U-Zr-C particles
The Union of Soviet Socialist Republics (USSR) performed a significant amount of research and development on nuclear thermal propulsion fuels from the 1960s to the late 1980s. Reported work included:
Fabrication of a large number of samples
Non-nuclear hot hydrogen flow tests
Individual fuel element tests under rapid transient conditions in the Impulse Graphite Reactor (IGR)
Prototypic NTR operating condition testing in the IVG-1 and RA reactor
The USSR followed the NERVA program quite closely and chose to follow the mixed-carbide fuel path early in its fuel development program. (U, Zr) C fuel was used for the low-temperature portion of the USSR reactor design (i.e., propellant exit gas temperature ≤ 2500 K), and (U, Zr, Nb) C was used for the high-temperature portion of the reactor core (i.e., propellant exit gas temperatures up to 3100 K). Some work using Ta and Hf in place of Nb was also reported. There were claims that Ta and Hf could produce 200 K higher fuel temperatures, but there was concern over the higher neutron capture cross sections of these elements compared to Nb. Finally, carbon nitride fuels were developed under the USSR program, primarily for use with ammonia propellants.
\nThe USSR research program fabricated carbide fuels in a wide range of shapes, but the twisted ribbon geometry was the preferred fuel design. This geometry included long rods of fuel with many different cross-sectional shapes. The rods were twisted along their long axis and bundled together using wire wraps, or insertion into long canisters, to form fuel elements [14]. During the operation of the reactor, the propellant was directed through the bundles to transfer heat from the fuel. The twisted ribbon geometry provided a large surface area for heat transfer, and it could be fabricated in large volumes, although researchers from outside the USSR program were not allowed to observe the fabrication process.
\nTests were performed on the USSR nuclear thermal rocket fuel design over a period of 19 years on approximately 1550 fuel assemblies. The testing program included seven full-core tests and approximately 160 transient tests that were performed at the IGR between 1962 and 1978 [7]. The highest reported hydrogen exit gas temperatures from testing performed during that period ranged from 2800 to 3300 K. Reported power densities were as high as 20 MW/l, and uranium loss estimates were as low as 0.5–1.0% based on reactivity loss measurements [15]. Very little postirradiation examination data on the fuel samples has been reported.
\nThe GE-710 and ANL programs were established as backups to the Rover/NERVA program. The choice of evaluating refractory metal-based fuels as a secondary fuel type to the Rover/NERVA graphite fuel research resulted from the greater experience base associated with graphite fuel, graphite’s low thermal neutron absorption cross section, and the greater fabricability associated with graphite fuels.
\nGraphite was first used in nuclear reactors as a moderator, and large bars of polycrystalline graphite were used in many early reactors. A halogen purification process was developed to produce the high-purity graphite needed for natural uranium-plutonium production piles. More recently, graphite has been used as a fuel particle coating and as a matrix for fuel particles in high-temperature reactors [16].
\nThe term “graphite” refers to a wide range of materials made from carbon that have a variety of properties. For example, graphite can be used as both a thermal conductor and a thermal insulator, it can be made in very dense and very light forms, and it can be highly anisotropic or isotropic. Graphite also has a wide variety of uses in nuclear reactor applications. It can serve as a high-purity neutron moderator, and it can be used in control rods and shielding with the addition of boron.
\nThe variety of properties associated with nuclear grade graphite means that it can be difficult to obtain graphite that has specific properties within narrow limits that are consistent from batch to batch. New sources of graphite often have unknown property variations.
\nGraphite production processes are often proprietary, but the general method of manufacturing crystalline graphite includes [17]:
Raw petroleum coke is calcined at 1300°C, milled, sized, and mixed at about 165°C with a coal-tar pitch.
The mixture is cooled to 110°C and extruded.
The extrusion is cooled to room temperature to form a “green body” and placed in a baking furnace supported by a permeable pack of sand and carbon.
A large volume of gas evolves from pyrolysis of the pitch during baking to 800°C and the carbon body shrinks about 5 vol%.
The material is then graphitized in an electric furnace at 2500–3000°C. Some further gas is vaporized during graphitization, but the principle physical change involves transformation from amorphous carbon into crystalline graphite.
There are many variations that can affect final material properties. For example, the baked carbon can be impregnated with pitch to increase density and strength, carbon black can be added to improve density and strength, and the graphitized body can be heated in a halogen-containing environment to remove trace impurities.
\nPyrolitic carbon is made from decomposition of hydrocarbon gasses. For free-standing bodies, the carbon is usually deposited on a graphite substrate at temperatures from 1400°C to 2400°C. Material orientation, density, and other properties can be varied by changes in gas pressure, temperature, and other conditions. Subsequent heat treatment at higher temperatures can improve crystallinity, and small samples heat treated to 3000–3600°C (3273–3873 K) have shown electrical properties that are close to the properties of single crystals. Larger samples with near-single-crystal properties can be made by heating pyrolytic graphite above 2500°C (2773 K) under a compressive stress. Fuel particles are typically coated with pyrolytic carbon in a fluidized bed with the carbon coatings being applied to thicknesses of up to about 100 \n
Carbon is a relatively light atom, so graphite is an efficient moderator. Slowing down power is the logarithmic energy change of a neutron when it collides with a moderator, and a nuclear graphite with a density of 1.65 g/cm3 has a slowing down power of 0.063 cm−1. Light water has the highest slowing down power of 1.5 cm−1, and only several other materials such as beryllium (Be), beryllium oxide (BeO), and deuterium oxide used in heavy water reactors (D2O) have higher slowing down power than graphite. Graphite also absorbs fewer thermal neutrons than any other material except D2O.
\nGraphite is relatively weak at low temperatures, with a compressive strength of only a few thousand psi. However, its high-temperature strength is very good compared to other materials. Graphite’s strength increases with temperature and reaches a maximum at about 2500°C (2773 K). A typical polycrystalline nuclear graphite with a tensile strength of 2000 psi at room temperature has a strength of about 4000 psi at 2500°C (2773 K). Graphite’s high-temperature strength, good nuclear properties, and low cost are the primary reasons for its extensive use in high-temperature gas-cooled and nuclear propulsion reactors.
\nCarbide fuels such as UC and UC2 have advantages over more widely studied oxide fuels. The most important advantage is their higher thermal conductivity, which approaches the value found in metallic uranium. Higher thermal conductivity lowers peak centerline fuel temperatures, which in turn allows for higher linear heat generation and larger diameter fuel rods. Carbide fuels also have higher uranium densities than UO2, which allows for design of more compact reactors [15].
\nMixed carbides such as uranium-zirconium carbide solid solution ([U, Zr] C) fuels have higher melting temperatures than UC. Research into mixed-carbide fuel fabrication has taken place in the USA and former Soviet Union to support space nuclear power applications. Three major carbide fuel designs were investigated under Rover/NERVA:
UC2 particles with pyrolytic carbide coatings and dispersion in graphite
Composites of (U, Zr) C and graphite with the carbide forming a continuous web structure within the fuel
Solid solution (U, Zr) C
All of the fuel designs, except the solid solution design, used protective ZrC coatings. Only 28 solid solution fuel elements were tested under Rover/NERVA, so effectiveness of the fuel design was not fully evaluated.
\nA solid solution is formed when two metals are completely soluble in their liquid and solid states. Complete solubility means homogeneous mixtures of two or more kinds of atoms are formed in the solid state. The more abundant atomic form is referred to as the solvent, and the less abundant atomic form is referred to as the solute. For example, brass is a solid solution of copper (64%) and zinc (36%) so that copper is the solvent and zinc is the solute.
\nThere are two types of solid solutions: substitutional solid solutions and interstitial solid solutions. Substitutional solid solutions, which can be either ordered or disordered, are formed when solvent atoms in the parent metal’s crystal structure are replaced by solute atoms. For example, copper atoms may substitute for zinc atoms without disturbing zinc metal’s face-centered cubic (FCC) crystal structure. For complete solid solubility, the two elements should have the same type of crystal structure, and for extensive solid solubility, the difference in atomic radii between the two elements should be less than 15% [18]. Solid solubility is favored when the two elements have lesser chemical affinity, since compounds form when chemical affinity is high. Generally, compounds that are separated in the periodic table have higher chemical affinity, so elements that are close together tend to form solid solutions.
\nIn interstitial solid solutions, solute atoms enter holes in the solvent atom crystal structure in interstitial solid solutions. Atoms that have atomic radii less than 1 Å tend to form interstitial solid solutions. Carbon, nitrogen, oxygen, and hydrogen are example interstitial solid solution solutes. Intermetallic compounds are formed when one metal (e.g., magnesium) has chemical properties that are strongly metallic and another metal (e.g., antimony, tin, or bismuth) has chemical properties that are only weakly metallic. Intermetallic compounds have higher melting temperatures than either of their parent metals. The higher melting point indicates a strong chemical bond in the intermetallic compound.
\n\nTable 2 lists melting points and carbon to metal ratios (C/M) for several monocarbides that have been investigated for use in space reactors [19]. Solid solution carbides are expected to be able to operate for short periods of time at propellant exit temperatures as high as 3200 K and for many hours at exit temperatures of 2600–3000 K. The life-limiting phenomenon for the solid solutions appears to be vaporization at surface temperatures greater than 2900 K.
\nBinary alloy | \nMelting temperature (K) | \nCarbon to metal ratios | \n
---|---|---|
NbC | \n3873 ± 25 K | \n0.79 | \n
TaC | \n4258 K | \n0.89 | \n
UC | \n2803 K | \n1.00 | \n
ZrC | \n3813 K | \n0.87 | \n
Melting temperatures and carbon to metal ratios of various monocarbides [19].
The highest melting temperatures for most monocarbides occur at C/M ratios that are less than one, and pseudo-binary and pseudo-ternary carbides have their highest melting temperatures for single-phase solid solutions. The melting point for single-phase solid solution carbides has been shown to be 100–700 K higher than the melting temperature for carbides that have formed a separate carbon phase (e.g., [U, Zr] Cx + C) [20, 21]. Figure 3 shows the solidus curves for ternary mixed carbides of (U, Zr, Nb) C from [20]. This study showed higher melting temperatures for ternary mixtures than for binary carbides of ZrC or NbC with an equal amount of UC.
\nSolidus curves for ternary mixed carbides of (U, Zr, Nb) C [
Carbon to metal ratios were carefully controlled in the Rover/NERVA Nuclear Furnace (NF-1) tests to prevent formation of second phases that significantly reduced melting temperatures of the carbide fuels. A C/M ratio of 0.88–0.95 was targeted for NF-1, (U, Zr) C fuel elements for a proposed maximum operating temperature of 3200 K [22].
\nFabrication of carbide fuel elements was completed in several steps under Rover/NERVA. First, a mixture of ZrC, UO2, ZrO2, graphite flour, and binder was prepared and extruded. Free carbon was removed from the extrusion by leaching with hot flowing hydrogen. The fuel elements were then impregnated with zirconium to varying degrees using a CVD process to produce a single-phase solid solution carbide element that was substoichiometric in carbon. Extrusion of these elements produced severe die wear because of the carbide content, so 19 mm (0.75 in) wide hexagonal elements containing 19 coolant channels could not be directly fabricated through extrusion. Instead, the hexagonal elements were manufactured by first extruding cylindrical fuel forms and machining them to a hexagonal geometry.
\nAll three of the carbide fuel constituents can be mixed, cold pressed, and sintered to fabricate a fuel pin, but mixing all of the components at once makes it difficult to control C/M ratio and prevent the formation of a second carbon phase. Carbide particles also tend to be coarse and require long sintering times at high temperatures in order to produce a homogeneous material.
\nThe major problem with the use of graphite and other carbon-based fuels (e.g., UC, UC2, [U, Zr] C) in high-temperature space reactor applications is mass loss produced by a number of interrelated and competing physical processes [23]. These processes include the formation of carbon liquids, loss by vaporization, extensive creep, and corrosion during hydrogen exposure. Maximum mass losses typically occurred in moderate-temperature regions of the core (<2000 K). The amount of hydrogen corrosion that occurs is dependent on:
Reactor operational duration
Number of fuel duty cycles
Local material temperatures
Local hydrogen gas flow conditions
Fuel location in the reactor
Reactor power density
Compatibility of the fuel and coatings
There are four major coupled reactions and/or healing processes associated with hydrogen corrosion:
Exposure to hydrogen gas
Nonuniform loading and/or cycling of the fuel
Radiation exposure
Creep
The first process is directly associated with chemical corrosion, while the remaining processes affect the amount of cracking that occurs in the fuel, which affects the fuel surface area that is exposed to hydrogen.
\nCarbon-based fuel materials can experience mass loss by two mechanisms when exposed to hot hydrogen: vaporization (or sublimation) of material constituents at temperatures above carbide vaporization temperatures, and chemical reaction of carbon constituents with hydrogen to form hydrocarbon gas species such as methane (CH4) and acetylene (C2H2). Vaporization occurs at varying rates in the moderate- to high-temperature regions of U-Zr-C fuel, but it is the predominant mass loss mechanism at temperatures greater than 2900 K. Little chemical reaction between hydrogen and carbide materials takes place at temperatures below approximately 1500 K, but chemical reaction losses predominate below the vaporization temperature of carbide materials (i.e., temperatures between 1500 K and 2900 K). The formation of CH4 becomes increasingly unstable at low to moderate hydrogen pressures and temperatures greater than 1500 K, since C2H2 is the more stable compound under these conditions, but the opposite relationship is true for higher pressures [24].
\n\nFigure 4 shows the recession rate of U0.1 Zr0.9 C compared to other compounds as a function of temperature and illustrates the fact that the diffusion rates of carbon and uranium can be substantial at high temperatures. Changes in surface chemical conditions in U-Zr-C materials likely encourage the release of free carbon, since surface composition changes tend to enhance the diffusion of carbon and uranium to the fuel surface because of shifts in the U/Zr/C ratio. These changes were noted during start-up of the Rover/NERVA reactors and were determined to be a predominant contributor to corrosion mass loss. Corrosion mass loss may also degrade fuel surface properties so that particles, such as fuel grains and grain agglomerations, become loosened and erode into the hydrogen gas stream.
\nRecession rate of U0.1 Zr0.9 C compared to other uranium compounds and refractory carbide materials [
The presence of hydrocarbons in the propellant stream tends to decrease the release rate of carbon from downstream fuel surfaces [26]. This effect may be a partial explanation for the lower corrosion rates that were observed in higher-temperature regions of the Rover/NERVA fuel elements. Another partial explanation for the lower corrosion rates may be the healing of surface defects due to material creep at high temperatures. This healing process may reduce hydrogen intrusion into the high temperature fuel regions, but the healing effect may be reduced by radiation damage. Radiation damage can also reduce the thermal conductivity of the fuel, which can produce locally high thermal stresses and corresponding mismatches between stresses in fuel coatings and the fuel substrates. These mismatches in turn encourage the formation of surface coating cracks that enhance hydrogen penetration into the fuel and offset any beneficial effect produced by creep healing.
\nAnother major hydrogen corrosion initiator is nonuniform loading and thermal cycling of the fuel. Nonuniform loadings and material expansion effects were considered to be a major cause of reduced corrosion in higher-temperature fuel regions due to closing of surface cracks [24]. Nonuniform mechanical loading can be produced by:
The presence of preload stresses during fuel fabrication and application of material coatings. The Rover/NERVA reactors were often designed with tie tubes that had substantial preloads that offset the axial loads produced by high hydrogen pressure differences.
The presence of nonuniform or unsteady pressures and nonuniform axial temperature distributions. Varying pressure profiles are always present during NTP transient operations, such as during reactor start-up and shutdown.
Residual stresses produced by fuel cycling. For example, fuel can undergo creep at high temperatures, which may lead to high induced tensile and compressive stresses during fuel cooldown.
It was initially believed during the Rover/NERVA program that radiation effects would be minimal in carbon-based fuels because of carbon’s resistance to radiation and the low operation time for NTP systems. This belief turned out to be unfounded because of the high-power densities that are required in NTP reactors. Post-test examinations of the Rover/NERVA reactors showed that radiation damage caused reductions in thermal conductivity and ductility, and these reductions caused cracking that allowed hydrogen to enter the fuel [22].
\nNASA is once again exploring the feasibility of building and operating nuclear fission systems for use in deep space science and exploration missions. The primary objective for the feasibility studies is to identify systems that can be used to support human missions to Mars, but missions to the outer solar system and beyond are also under consideration. The major barrier to demonstrating a high-performance nuclear propulsion system is developing a fuel that can survive the extreme operating conditions that will be required during space flight missions. The fuel operational characteristics that will need to be satisfied during reactor operations include:
Minimizing high-temperature hydrogen corrosion
Minimizing brittle fracture behavior at low temperatures
Minimizing fuel creep and vaporization at high temperatures
Minimizing radiation damage that impairs fuel performance
Managing high transient thermal and mechanical stresses on the fuel during reactor start-up
Rapid heat transfer from the fuel to the propellant
Matching coefficients of thermal expansion for different materials used in the fuel to avoid fuel constituent separation during reactor operation
High uranium loading to allow for use of low-enriched uranium fuel
Low fuel and reactor system mass to minimize launch costs
Limiting fuel dissociation and constituent migration during reactor operation
Limiting cracking of fuel and coatings to minimize hydrogen ingress into the fuel during reactor operations.
As a result of these restrictive requirements, it is likely that whatever fuel is selected will have to operate close to its thermal and mechanical failure limits. There will be little margin for error in system operation, so a significant amount of research and testing will be needed before a safe and reliable system can be built and operated. The majority of future work associated with developing space reactor propulsion and power generation reactors will be associated with designing, building, and operating the equipment and experiments that will build on past testing programs and lead to fuel and reactor qualification and public acceptance.
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Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"58638",doi:"10.5772/intechopen.72823",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1956,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"66619",doi:"10.5772/intechopen.85692",title:"Contribution of the Microbiome as a Tool for Estimating Wine’s Fermentation Output and Authentication",slug:"contribution-of-the-microbiome-as-a-tool-for-estimating-wine-s-fermentation-output-and-authenticatio",totalDownloads:1094,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Wine is the alcoholic beverage which is the product of alcoholic fermentation, usually, of fresh grape must. Grape microbiome is the source of a vastly diverse pool of filamentous fungi, yeast, and bacteria, the combination of which plays a crucial role for the quality of the final product of any grape must fermentation. In recent times, the significance of this pool of microorganisms has been acknowledged by several studies analyzing the microbial ecology of grape berries of different geographical origins, cultural practices, grape varieties, and climatic conditions. Furthermore, the microbial evolution of must during fermentation process has been overstudied. The combination of the microbial evolution along with metabolic and sensorial characterizations of the produced wines could lead to the suggestion of the microbial terroir. These aspects are today leading to open a new horizon for products such as wines, especially in the case of PDO-PGI products. The aims of this review is to describe (a) how the microbiome communities are dynamically differentiated during the process of fermentation from grape to ready-to-drink wine, in order to finalize each wine’s unique sensorial characteristics, and (b) whether the microbiome could be used as a fingerprinting tool for geographical indication, based on high-throughput sequencing (HTS) technologies. Nowadays, it has been strongly indicated that microbiome analysis of grapes and fermenting musts using next-generation sequencing (NGS) could open a new horizon for wine, in the case of protected designation of origin (PDO) and protected geographical indication (PGI) determination.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Dimitrios A. Anagnostopoulos, Eleni Kamilari and Dimitrios Tsaltas",authors:[{id:"180885",title:"Associate Prof.",name:"Dimitris",middleName:null,surname:"Tsaltas",slug:"dimitris-tsaltas",fullName:"Dimitris Tsaltas"},{id:"203761",title:"MSc.",name:"Dimitris",middleName:null,surname:"Anagnostopoulos",slug:"dimitris-anagnostopoulos",fullName:"Dimitris Anagnostopoulos"},{id:"271801",title:"Ms.",name:"Elena",middleName:null,surname:"Kamilari",slug:"elena-kamilari",fullName:"Elena Kamilari"}]},{id:"67444",doi:"10.5772/intechopen.86443",title:"Somatic Variation and Cultivar Innovation in Grapevine",slug:"somatic-variation-and-cultivar-innovation-in-grapevine",totalDownloads:1036,totalCrossrefCites:4,totalDimensionsCites:9,abstract:"Paradoxically, continuous vegetative multiplication of traditional grapevine cultivars aimed to maintain cultivar attributes in this highly heterozygous species ends in the accumulation of considerable somatic variation. This variation has long contributed to cultivar adaptation and evolution under changing environmental and cultivation conditions and has also been a source of novel traits. Understanding how this somatic variation originates provides tools for genetics-assisted tracking of selected variants and breeding. Potentially, the identification of the mutations causing the observed phenotypic variation can now help to direct genome editing approaches to improve the genotype of elite traditional cultivars. Molecular characterization of somatic variants can also generate basic information helping to understand gene biological function. In this chapter, we review the state of the art on somatic variation in grapevine at phenotypic and genome sequence levels, present possible strategies for the study of this variation, and describe a few examples in which the genetic and molecular basis or very relevant grapevine traits were successfully identified.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Pablo Carbonell-Bejerano, Carolina Royo, Nuria Mauri, Javier Ibáñez and José Miguel Martínez Zapater",authors:[{id:"287215",title:"Prof.",name:"Jose Miguel",middleName:null,surname:"Martinez Zapater",slug:"jose-miguel-martinez-zapater",fullName:"Jose Miguel Martinez Zapater"},{id:"287226",title:"Dr.",name:"Javier",middleName:null,surname:"Ibáñez",slug:"javier-ibanez",fullName:"Javier Ibáñez"},{id:"300441",title:"Dr.",name:"Pablo",middleName:null,surname:"Carbonell-Bejerano",slug:"pablo-carbonell-bejerano",fullName:"Pablo Carbonell-Bejerano"},{id:"300442",title:"Dr.",name:"Carolina",middleName:null,surname:"Royo",slug:"carolina-royo",fullName:"Carolina Royo"},{id:"300444",title:"Dr.",name:"Nuria",middleName:null,surname:"Mauri",slug:"nuria-mauri",fullName:"Nuria Mauri"}]},{id:"59216",doi:"10.5772/intechopen.73132",title:"Potential for Use of the Residues of the Wine Industry in Human Nutrition and as Agricultural Input",slug:"potential-for-use-of-the-residues-of-the-wine-industry-in-human-nutrition-and-as-agricultural-input",totalDownloads:1259,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The use of underutilized resources, with the aim of increasing productivity and creating wealth, will increasingly deserve the attention of the wine sector. The treatment of agricultural by-products will increasingly enter the priority agenda of the agribusiness sector, with a view to its use, the environment’s re-cleanliness and, in many cases, whenever possible, for both purposes. Solid waste from the process of grape industrialization, when not adequately disposed, is aggressive to the environment. Such residues release significant amounts of liquid effluents when disposed in the soil, and this liquid contains high content of nutrients, organic matter, and other elements that can change the environment, especially of streams and sources, causing the death of aquatic beings. However, if properly used, they can be used as raw materials for other purposes. The solid residues of industrially processed grapes, which may have some potential economic interest, are pomace, seeds, liquid (lees), and other materials. In this context, this chapter presents the description of these by-products and their potential for use.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Renato Vasconcelos Botelho, Gabriela Datsch Bennemann,\nYohandra Reyes Torres and Alessandro Jefferson Sato",authors:[{id:"64335",title:"Prof.",name:"Renato",middleName:"Vasconcelos",surname:"Botelho",slug:"renato-botelho",fullName:"Renato Botelho"},{id:"208714",title:"MSc.",name:"Gabriela",middleName:null,surname:"Datsch Bennemann",slug:"gabriela-datsch-bennemann",fullName:"Gabriela Datsch Bennemann"},{id:"208715",title:"Dr.",name:"Yohandra",middleName:null,surname:"Reyes Torres",slug:"yohandra-reyes-torres",fullName:"Yohandra Reyes Torres"},{id:"208716",title:"Dr.",name:"Alessandro Jefferson",middleName:null,surname:"Sato",slug:"alessandro-jefferson-sato",fullName:"Alessandro Jefferson Sato"}]}],mostDownloadedChaptersLast30Days:[{id:"58638",title:"Occurrence and Analysis of Sulfur Compounds in Wine",slug:"occurrence-and-analysis-of-sulfur-compounds-in-wine",totalDownloads:1953,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"Sulfur compounds play an important role in the sensory characteristics of wine. These molecules can derive from the grape, in which the non-volatile forms are usually present as glycosylated molecules, the metabolic activities of yeast and bacteria, the chemical reactions taking place during the wine aging and storage, and the environment. The sulfur compounds include molecules positively correlated to the aromatic profile of wine, namely the volatile thiols, and are responsible for certain defects, imparting notes described as cabbage, onion, rotten egg, garlic, sulfur and rubber. Due to the low concentration of these molecules in wine, their high reactivity and the matrix complexity, the analytical methods which enable their detection and quantification represent a challenge. The solid phase microextraction (SPME) technique has been developed for sulfur compounds associated with off-flavors. The analysis of volatile thiols usually requires a derivatization followed by gas chromatography (GC)-MS or UPLC-MS methods. Besides the sulfur-containing aromas, another sulfur compound that deserves mention is the reduced glutathione (GSH) which has been widely studied due to its antioxidant properties. The analysis of GSH has been proposed using a liquid chromatography technique (HPLC or UPLC) coupled with fluorescence, MS and UV detectors.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Daniela Fracassetti and Ileana Vigentini",authors:[{id:"207271",title:"Dr.",name:"Daniela",middleName:null,surname:"Fracassetti",slug:"daniela-fracassetti",fullName:"Daniela Fracassetti"},{id:"220967",title:"Dr.",name:"Ileana",middleName:null,surname:"Vigentini",slug:"ileana-vigentini",fullName:"Ileana Vigentini"}]},{id:"57497",title:"Recovering Ancient Grapevine Varieties: From Genetic Variability to In Vitro Conservation, A Case Study",slug:"recovering-ancient-grapevine-varieties-from-genetic-variability-to-in-vitro-conservation-a-case-stud",totalDownloads:1767,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"A great number of varieties have been described in grapevine; however, few of them are currently in use. The increasing concern on varietal diversity loss has encouraged actions for recovering and preserving grapevine germplasm, which represents valuable resources for breeding as well as for diversification in grapevine-derived products. On the other hand, it is expected that this important crop, which is distributed in warm areas worldwide, will suffer the climate changes. Therefore, it is also convenient the identification of intravarietal variability and the recovery of accessions well adapted to particular environments. In this chapter, we will contribute to highlight the importance of recovering ancient materials, the usefulness of SSR markers to determine their molecular profile, the importance to analyze their virus status, and the possibilities that offer biotechnological tools for virus sanitation and in vitro storage as a complement of field preservation. In this context, we have evaluated different grapevine accessions and developed in vitro culture protocols for micropropagation, sanitation, and storage grapevine cultivars. In this work, we report the results obtained for the historic variety “Valencí Blanc” (or “Beba”) and the historic and endangered variety “Esclafagerres” (“Esclafacherres” or “Esclafacherris”).",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Carmina Gisbert, Rosa Peiró, Tania San Pedro, Antonio Olmos,\nCarles Jiménez and Julio García",authors:[{id:"207745",title:"Dr.",name:"Carmina",middleName:null,surname:"Gisbert",slug:"carmina-gisbert",fullName:"Carmina Gisbert"},{id:"207748",title:"Dr.",name:"Rosa María",middleName:null,surname:"Peiró",slug:"rosa-maria-peiro",fullName:"Rosa María Peiró"},{id:"207749",title:"Ms.",name:"Tania",middleName:null,surname:"San Pedro Galán",slug:"tania-san-pedro-galan",fullName:"Tania San Pedro Galán"},{id:"207750",title:"Dr.",name:"Antonio",middleName:null,surname:"Olmos",slug:"antonio-olmos",fullName:"Antonio Olmos"}]},{id:"58633",title:"The Evolution of Polyphenols from Grapes to Wines",slug:"the-evolution-of-polyphenols-from-grapes-to-wines",totalDownloads:2021,totalCrossrefCites:5,totalDimensionsCites:13,abstract:"Polyphenols play an important role in the quality of wines, due to their contribution to the wine sensory properties: color, astringency and bitterness. They act as antioxidants, having positive role in human health. They can be divided into non-flavonoid (hydroxybenzoic and hydroxycinnamic acids and stilbenes) and flavonoid compounds (anthocyanins, flavan-3-ols and flavonols). Anthocyanins are responsible for the color of red grapes and wines, hydroxycinnamic and hydroxybenzoic acids act as copigments, stilbenes as antioxidants and the flavan-3-ols are mainly responsible for the astringency, bitterness and structure of wines, being involved also in the color stabilization during aging. This chapter will focus on the chemical structures of the main polyphenols, their identification and quantification in grapes and wines by advanced analytical techniques, highlighting also the maceration and aging impact on the polyphenols evolution. The factors influencing the phenolic accumulation in grapes are also reviewed, emphasizing as well the relationship between phenolic content in grapes versus wine. Polyphenolic changes during the wine making process are highlighted along with the main polyphenol extraction methods and analysis techniques. This research will contribute to the improvement in the knowledge of polyphenols: their presence in grapes, the relationship with wine quality and the influence of the external factors on their evolution.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Violeta-Carolina Niculescu, Nadia Paun and Roxana-Elena Ionete",authors:[{id:"187102",title:"Dr.",name:"Roxana",middleName:null,surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"206056",title:"Dr.",name:"Violeta",middleName:"Carolina",surname:"Niculescu",slug:"violeta-niculescu",fullName:"Violeta Niculescu"},{id:"207020",title:"Mrs.",name:"Nadia",middleName:null,surname:"Paun",slug:"nadia-paun",fullName:"Nadia Paun"}]},{id:"67760",title:"Production and Marketing of Low-Alcohol Wine",slug:"production-and-marketing-of-low-alcohol-wine",totalDownloads:1299,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Moderate wine consumption may be associated with specific health benefits and a healthy lifestyle. However, increased amounts of ethanol are cytotoxic and associated with adverse health outcomes. Alcohol reduction in wine might be an avenue to reduce alcohol related harm without forcing consumers to compromise on lifestyle and benefit from positive aspects of moderate consumption. The aim of this review is to give an overview of viticultural and pre and post fermentation methods to produce low-alcohol wine, and to summarize the current evidence on the consumer acceptance and behaviour related to low-alcohol wine. Strategies for the labelling and marketing of wines with reduced alcohol content are discussed.",book:{id:"8054",slug:"advances-in-grape-and-wine-biotechnology",title:"Advances in Grape and Wine Biotechnology",fullTitle:"Advances in Grape and Wine Biotechnology"},signatures:"Tamara Bucher, Kristine Deroover and Creina Stockley",authors:[{id:"289140",title:"Dr.",name:"Creina",middleName:null,surname:"Stockley",slug:"creina-stockley",fullName:"Creina Stockley"},{id:"289141",title:"Dr.",name:"Tamara",middleName:null,surname:"Bucher",slug:"tamara-bucher",fullName:"Tamara Bucher"},{id:"289142",title:"Ms.",name:"Kristine",middleName:null,surname:"Deroover",slug:"kristine-deroover",fullName:"Kristine Deroover"}]},{id:"57946",title:"Microbiological, Physical, and Chemical Procedures to Elaborate High-Quality SO2-Free Wines",slug:"microbiological-physical-and-chemical-procedures-to-elaborate-high-quality-so2-free-wines",totalDownloads:1613,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Sulfur dioxide (SO2) is the most preservative used in the wine industry and has been widely applied, as antioxidant and antibacterial agent. However, the use of sulfur dioxide implicates a range of adverse clinical effects. Therefore, the replacement of the SO2 content in wines is one of the most important challenges for scientist and winemakers. This book chapter gives an overview regarding different microbiological, physical, and chemical alternatives to elaborate high-quality SO2-free wines. In the present chapter, original research articles as well as review articles and results obtained by the research group of the Wine Technology Center (VITEC) are shown. This study provides useful information related to this novel and healthy type of wines, highlighting the development of winemaking strategies and procedures.",book:{id:"6077",slug:"grapes-and-wines-advances-in-production-processing-analysis-and-valorization",title:"Grapes and Wines",fullTitle:"Grapes and Wines - Advances in Production, Processing, Analysis and Valorization"},signatures:"Raúl Ferrer-Gallego, Miquel Puxeu, Laura Martín, Enric Nart, Claudio\nHidalgo and Imma Andorrà",authors:[{id:"207221",title:"Dr.",name:"Raúl",middleName:null,surname:"Ferrer-Gallego",slug:"raul-ferrer-gallego",fullName:"Raúl Ferrer-Gallego"},{id:"208597",title:"Dr.",name:"Miquel",middleName:null,surname:"Puxeu",slug:"miquel-puxeu",fullName:"Miquel Puxeu"},{id:"208598",title:"Dr.",name:"Laura",middleName:null,surname:"Martín",slug:"laura-martin",fullName:"Laura Martín"},{id:"208599",title:"Mr.",name:"Enric",middleName:null,surname:"Nart",slug:"enric-nart",fullName:"Enric Nart"},{id:"208600",title:"Dr.",name:"Claudio",middleName:null,surname:"Hidalgo",slug:"claudio-hidalgo",fullName:"Claudio Hidalgo"},{id:"208601",title:"Dr.",name:"Imma",middleName:null,surname:"Andorrà",slug:"imma-andorra",fullName:"Imma Andorrà"}]}],onlineFirstChaptersFilter:{topicId:"1410",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81659",title:"State-of-the-Art Knowledge about 2,4,6-Trichloroanisole (TCA) and Strategies to Avoid Cork Taint in Wine",slug:"state-of-the-art-knowledge-about-2-4-6-trichloroanisole-tca-and-strategies-to-avoid-cork-taint-in-wi",totalDownloads:27,totalDimensionsCites:0,doi:"10.5772/intechopen.103709",abstract:"Cork stoppers have been used for many centuries to seal wine in various vessels. Therefore, corks have become a traditional part of wine packaging in many countries and still play an important role for the entire wine industry. Nowadays, there is a wide option of bottle cork stoppers on the market, such as natural corks, agglomerated and technical stoppers (1 + 1), etc. These cork closures have a number of advantages, including positive sustainable and ecological aspects. Natural cork material can also be responsible for cork taint, which imparts musty/moldy or wet cardboard off-odors to the wine. However, corks are not the only source of cork taint in wine, as will be shown in the present chapter. Over the past decades, a number of compounds have been detected that can contribute to the cork taint. Among them, haloanisoles play a major role, in particular 2,4,6-trichloroanisole (TCA), which has been shown to be responsible for 50–80% or more of musty defect cases in wine. Currently, the cork and wine industries have developed a number of tools and technologies to effectively prevent cork tait in wine or to remove it if the wine is already contaminated. These practical as well as analytical questions about the TCA defects are the subject of the actual chapter.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Andrii Tarasov, Miguel Cabral, Christophe Loisel, Paulo Lopes, Christoph Schuessler and Rainer Jung"},{id:"78620",title:"Table Grapes: There Is More to Vitiviniculture than Wine…",slug:"table-grapes-there-is-more-to-vitiviniculture-than-wine",totalDownloads:141,totalDimensionsCites:0,doi:"10.5772/intechopen.99986",abstract:"Table grapes are fruits intended for fresh human consumption due to their sensory attributes and nutritional value. The objective of this chapter is to review the existing knowledge about table grapes, including a description of different varieties, with particular emphasis on the new highly appreciated seedless varieties. Following an introductory note on the world distribution and production of table grapes, also considering the impact of climate change, selected varieties of table grapes will be characterized in terms of their physiology, postharvest features, and consumer preferences. A morphological description of each variety, with emphasis on grape skin, grape rachis and grape cluster will be included. A final note on the drying of table grapes into raisins, and the most appropriate varieties for drying, will be given. The major changes occurring throughout the growth, development, and ripening phases of table grapes production will be discussed, regarding both physical (skin color and skin and pulp texture) and chemical (phenolic compounds, sugar content and acidity) parameters, as well as growth regulators.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Ana Cristina Agulheiro-Santos, Marta Laranjo and Sara Ricardo-Rodrigues"},{id:"79500",title:"New Insights about the Influence of Yeasts Autolysis on Sparkling Wines Composition and Quality",slug:"new-insights-about-the-influence-of-yeasts-autolysis-on-sparkling-wines-composition-and-quality",totalDownloads:94,totalDimensionsCites:0,doi:"10.5772/intechopen.101314",abstract:"Sparkling wines elaborated using the traditional method undergo a second fermentation in the bottle. This process involves an aging time in contact with the lees, which enriches the wine in various substances, especially proteins, mannoproteins and polysaccharides, thanks to the autolysis of the yeasts. As a result of this yeast autolysis, sparkling wines benefit from better integration of carbon dioxide and a clear sensory improvement, especially in the case of long aging. This chapter synthetizes the main results that our research group has obtained about the influence of yeasts autolysis on sparkling wines composition and quality during last years, making special emphasis on the capacity of the lees to release proteins and polysaccharides as well as on their capacity to consume oxygen and thus protect the sparkling wines from oxidation.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Pere Pons-Mercadé, Pol Giménez, Glòria Vilomara, Marta Conde, Antoni Cantos, Nicolas Rozès, Sergi Ferrer, Joan Miquel Canals and Fernando Zamora"},{id:"79110",title:"Microbial Decontamination by Pulsed Electric Fields (PEF) in Winemaking",slug:"microbial-decontamination-by-pulsed-electric-fields-pef-in-winemaking",totalDownloads:80,totalDimensionsCites:0,doi:"10.5772/intechopen.101112",abstract:"Pulsed Electric Fields (PEF) is a non-thermal technique that causes electroporation of cell membranes by applying very short pulses (μs) of a high-intensity electric field (kV/cm). Irreversible electroporation leads to the formation of permanent conductive channels in the cytoplasmic membrane of cells, resulting in the loss of cell viability. This effect is achieved with low energy requirements and minimal deterioration of quality. This chapter reviews the studies hitherto conducted to evaluate the potential of PEF as a technology for microbial decontamination in the winemaking process for reducing or replacing the use of SO2, for guaranteeing reproducible fermentations or for wine stabilization.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Carlota Delso, Alejandro Berzosa, Jorge Sanz, Ignacio Álvarez and Javier Raso"},{id:"78993",title:"pH Control and Aroma Improvement Using the Non-Saccharomyces Lachancea thermotolerans and Hanseniaspora spp. Yeasts to Improve Wine Freshness in Warm Areas",slug:"ph-control-and-aroma-improvement-using-the-non-saccharomyces-lachancea-thermotolerans-and-hanseniasp",totalDownloads:90,totalDimensionsCites:0,doi:"10.5772/intechopen.100538",abstract:"Lachancea thermotolerans is a yeast species that works as a powerful bio tool capable of metabolizing grape sugars into lactic acid via lactate dehydrogenase enzymes. The enological impact is an increase in total acidity and a decrease in pH levels (sometimes >0.5 pH units) with a concomitant slight reduction in alcohol (0.2–0.4% vol.), which helps balance freshness in wines from warm areas. In addition, higher levels of molecular SO2 are favored, which helps to decrease SO2 total content and achieve better antioxidant and antimicrobial performance. The simultaneous use with some apiculate yeast species of the genus Hanseniaspora helps to improve the aromatic profile through the production of acetyl esters and, in some cases, terpenes, which makes the wine aroma more complex, enhancing floral and fruity scents and making more complex and fresh wines. Furthermore, many species of Hanseniaspora increase the structure of wines, thus improving their body and palatability. Ternary fermentations with Lachancea thermotolerans and Hanseniaspora spp. sequentially followed by Saccharomyces cerevisiae are a useful bio tool for producing fresher wines from neutral varieties in warm areas.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Antonio Morata, Carlos Escott, Iris Loira, Juan Manuel Del Fresno, Cristian Vaquero, María Antonia Bañuelos, Felipe Palomero, Carmen López and Carmen González"},{id:"78970",title:"Alternatives to CU Applications in Viticulture. How R&D Projects Can Provide Applied Solutions, Helping to Establish Legislation Limits",slug:"alternatives-to-cu-applications-in-viticulture-how-r-d-projects-can-provide-applied-solutions-helpin",totalDownloads:180,totalDimensionsCites:2,doi:"10.5772/intechopen.100500",abstract:"Copper (Cu) and its based preparations have been used for over 200 years to control fungi and bacterial diseases in cultivated plants. Downy mildew caused by the obligate biotrophic oomycete Plasmopara viticola is one of the most relevant and recurrent diseases of grapevines. Recently, the use of Cu is being limited by some regulations because of its high impact at different levels (health and environmental problems). Due to its accumulation in soil, this metal causes a little controversy with the principles of sustainable production. Therefore, international legislation and initiatives have recently been arisen to start limiting its use, with the main goal to replace it. In this framework, some alternatives have been tested and others are recently being developed to replace, at least partially, the use of Cu in viticulture. Many of them, are being developed and tested under the scope of research and development EU funded projects. To not compromise sustainability targets in viticulture, results from these R&D projects need to be considered to assess the present risks of using Cu in viticulture and to better support establishing limits for its applications, considering soils vulnerability, while no sustainable alternatives are available in the market.",book:{id:"10901",title:"Grapes and Wine",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg"},signatures:"Mario De La Fuente, David Fernández-Calviño, Bartosz Tylkowski, Josep M. Montornes, Magdalena Olkiewicz, Ruth Pereira, Anabela Cachada, Tito Caffi, Giorgia Fedele and Felicidad De Herralde"}],onlineFirstChaptersTotal:16},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics, and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.",coverUrl:"https://cdn.intechopen.com/series/covers/13.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:10,editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. 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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}}]}},subseries:{item:{id:"41",type:"subseries",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"