Mutations have been reported at
\r\n\tThere will be a chapter on secondary causes of sexual dysfunction disorders related to diabetes, cardiovascular disease, and obesity. A chapter on remedial measures to enhance sexual activity and maintain human relationships will be discussed. As there is a growing number of cancer survivors a chapter on cancer-related sexual dysfunction will be welcomed for including it.
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Dr. Sheriff has authored five books including a textbook on medical biochemistry with additional interest in human sexology. He had editorials written in the British Journal of Sexology, Journal of Royal Society of Medicine, Postgraduate Medicine, and Scientist. 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Understanding the mechanisms underlying both the sensitivity and the resistance of tumor cells to anticancer agents first requires understanding the global view of the cancer genome (genetic, genomic, and epigenetic alterations) to identify driver events that decisively influence the viability and clinical behavior of a given tumor. This knowledge, together with an understanding of the mechanism of action of drugs, will lead to the identification of novel targets and the development of targeted therapeutics in the appropriate patient subpopulation.
By 1982, mutations and chromosomal translocations had been established as key genetic mechanisms that are capable of driving cancer. Then, the
One of the first pivotal discoveries of activating mutations was within
The historical timelines for discovery of driver translocation, mutation and amplification.
Oncogenesis results from mutations or alterations of genes that regulate cell functions such as proliferation, growth, invasion, angiogenesis, metastasis, death, energy metabolism, genome stability, and replication. Simple mutations can be induced in DNA by exposure to a variety of mutagens, such as radiation and chemicals, or by spontaneous errors in DNA replication and repair. Genes with mutations that cause cancer can be grouped into two classes: oncogenes and tumor suppressor genes.
Oncogenes are the mutant form of proto-oncogenes, a class of normal cellular protein-coding genes that promote the growth and survival of cells. Oncogenes encode proteins such as:
Growth factors (e.g.,
Growth factor receptors (e.g.,
Intracellular signal transduction factors (e.g.,
Cell cycle factors (e.g.,
Transcription factors that control the expression of growth promoting genes (e.g.,
Inhibitors of programmed cell death machinery (e.g.,
Tumor suppressor genes, which control cell growth, can be grouped into two classes: gatekeeper and caretaker tumor suppressor genes. Gatekeeper tumor suppressor genes (e.g.,
Activation of proto-oncogenes (activating mutations) can occur either by large-scale alterations, such as gain/amplification, insertion, or chromosome translocation, or by small-scale mutations, such as point mutation. Inactivation of tumor suppressor genes (inactivating mutations) can occur either by small-scale mutation or by large-scale alterations, such as loss of region of tumor suppressor gene or whole chromosome.
Small-scale mutations can be grouped into the following classes on the basis of the effect of the mutation on the DNA sequence:
Deletion of multiple codons (three bases) may affect protein function or stability.
A frameshift mutation—not of a multiple of three bases (codon)—is likely to result in premature termination with loss of function.
A large deletion—partial- or whole-gene deletion—is likely to result in premature termination with loss of function or expression.
Insertion of 3 nucleotides (a codon) or of multiple codonsmay affect protein function or stability.
A frameshift mutation, which occurs when either <3 or >3 nucleotides are inserted, is likely to result in premature termination with loss of function.
A large insertion, which is partial-gene duplication, is likely to result in premature termination with loss of function. Whole-gene duplication may have an effect because of increased gene dosage.
A dynamic mutation, which is the expansion of a dinucleotide or a trinucleotide repeat, may alter gene expression or may alter protein stability or function.
Whereas mutations in coding DNA have a phenotypic effect, mutations in non-coding DNA are less likely to have a phenotypic effect, except when the mutation occurs in a regulatory sequence such as a promoter sequence and miRNAs. Mutations exert their phenotypic effect through either gain of function or loss of function. Loss-of-function mutations result in either reduced activity or complete loss of the gene product. Gain-of-function mutations can result in either an increased level of expression or the development of a new function of the gene product.
Important progress has been made in developing new technologies for identifying mutations. One of these is next-generation sequencing. This technology enables the identification of copy number changes, chromosomal alterations such as translocations and inversions, and point mutations.
Recent advances in molecular oncology and discoveries in genetic alterations have yielded new treatment strategies that target specific molecules and pathways in the cancer cell and thereby shed light on personalized therapy. In the past, treatment decisions were based on pathologic results. Now, diagnostic or therapeutic decisions are often also based on genetics/genomic alterations. Currently, the genomic view effectively guides cancer treatment decisions and predicts therapeutic response. Early clinical success was achieved with all-
G719A12 | M117R13 | G12C5, 12 | E542K4, 5, 6, 28, 29 | K642E13, 22 | M244V10 | R132C2, 5, 8, 9, 19,20, 21, 27 | V617F8, 19, 20 |
G719C12 | I326T4 | G12R12 | E545K4, 5, 6, 9, 12, 28, 29 | L576P13 | L248V10 | R132H1,2, 9, 21, 26, 27 | K539L19 |
G719S12 | K439Q12 | G12S5, 12 | E545Q4 | W557R13 | G250E10 | R132S2, 9, 26 | N542E543del19 |
T790M12 | K439T12 | G12A5, 9, 12 | E545A4 | V559A13 | Q252H10 | R132G2, 9, 26 | F537-K539delinsK19 |
L858R4, 12 | T440P12 | G12D5, 12 | E545G4, 5, 29 | V560D22 | Y253F10 | R132L2, 9, 26 | H538-K539delinsL19 |
L858Q12 | V459L12 | G12V5, 12 | E545V4 | D816H13, 22 | Y253H10 | R132V2, 9 | F537-I546dupF547L19 |
L858L21 | G469A14 | G13C5, 12 | Q546K4, 6 | F504L13 | E255K10 | R132G2 | E543del19 |
D761Y12 | R462I5 | G13R12 | Q546E4 | S502-Y503insFA13 | E255V10 | V71I14, 24 | H538QK539L19 |
L747S12 | I463S5 | G13S12 | Q546P4 | K550N13 | D276G10 | G123R24 | I540-E543delinsMK19 |
T854A12 | G464E5, 11, 17 | G13A12 | Q546R4, 6 | Y553N13 | E279K10 | G97D9,25 | F547V19 |
P782L21 | G464V5, 11, 17 | G13D5, 12, 14 | Q546L4 | 556insL13 | V299L10 | H538DK539LI540S19 | |
F788L21 | G464R5, 11, 17 | Q61K10, 12, 13 | D549N4 | K558N13 | F311L10 | F537-F547dup19 | |
R748K21, 22 | G466A6, 12, 13 | Q61L5, 10, 12 | H1047L4, 6, 29 | G565V13 | T315I10 | I540-N542delinsS19 | |
L747–S752del | G466E12, 13 | Q61R12, 13 | H1047R4, 5, 6, 9, 28, 29 | N566D13 | T315A10 | V294M13 | V536-F547dup19 |
E746-A750del4, 17, 28 | G466R12, 13 | Q61H5, 10, 12, 14 | Q1064R6 | V569G13 | F317L10 | R172K2, 9 | V536-I546dup19 |
S752-I759del4 | G466V 12, 13 | A146T5, 14 | A1066V6 | R634W13 | F317V10 | R172M2, 9 | |
L707S25 | F468C5 | Y64D14 | Y1021C6 | V654A13 | F317C10 | R172G2, 9 | |
T710A25 | G469A3,5, 10, 11, 12, 13,16 | L19F14 | G12-R19del6 | N655K13 | M351T10 | R172S2 | |
E711V25 | G469E3,5, 10, 11, 12, 13,16 | K117N14 | R38H6 | D816H13 | E355G10 | R172W2, 9 | |
E749K25 | G469R3,5, 10, 11, 12, 13,16 | E63K14 | R88Q4, 5, 6, 9 | D816V2, 13 | F359V10 | R140Q2, 9, 19, 20 | Y592A2 |
E762G25 | G469S3,5, 10, 11, 12, 13,16 | K147N28 | G106A6 | D820V13 | F359C10 | R140W2 | |
A767T25 | G469V3,5, 10, 11, 12, 13,16 | G12F10, 12 | E109del6 | D820Y13 | V379I10 | R140L2, 26 | Y599F2 |
K745R28 | K475E13 | V344G6 | N822I13 | L384M10 | F691L2 | ||
G735S24 | N581S5 | E309NfsX106 | N822K2, 13 | L387M10 | |||
R108K9 | E586K17 | E453K4,6 | Y823D13 | H396R10 | |||
T263P9 | D587A5 | M1043V6, 9 | A829P13 | H396P10 | D835N2 | ||
A289V9 | D594G5, 13, 16, 23 | M1043I6 | I841V13 | F486S10 | D835Y2 | ||
G598V9 | D594K5, 13, 16, 23 | E81K6 | S864F13 | E459K | D835A2 | ||
L861Q9 | D594V5, 13, 16, 23 | H1048R6 | V120F29 | D835E2 | |||
R680G9 | F595L5, 11 | G1049R6 | V560D22 | D835H2 | |||
G136A9 | G596R5 | E418K6 | Y503-F504insAY22 | D835V2 | |||
G136C9 | L597Q11, 12, 13, 17 | C420R6 | Y570-L576del22 | D835F2 | |||
G323A9 | L597R11, 12, 13, 17 | H701P6 | A599T15 | I836F2 | |||
A787C9 | L597S11, 12, 13, 17 | LWGIHLM10del9 | V833L10,30 | I836S2 | |||
C866A9 | L597V11, 12, 13, 17 | P18del9 | P577S10,30 | M837P2 | |||
G865A9 | T599I5 | N345K9 | V825A10,30 | Y842H2 | |||
C866T9 | T599-ins(T-T)13 | C420R9 | L576P30 | Y842D2 | |||
G971T9 | V600D3, 4, 5, 7, 9, 11, 12, 13, 17, 22, 23, 24 | E562K 30 | |||||
G988A9 | V600E3, 4, 5, 7, 9, 11, 12, 13, 17, 22, 23, 24 | N564S30 | |||||
D1006Y14 | V600G3, 4, 5, 7, 9, 11, 12, 13, 17, 22, 23, 24 | D816V2,10, 17 | |||||
M178I28 | V600K3, 4, 5, 7, 9, 11, 12, 13, 17, 18, 19, 23 | D816H2, 10, 17, 26 | |||||
I475V28 | V600M3, 4, 5, 8, 9, 11, 12, 13, 17, 22, 23, 24 | D816I10 | |||||
S492R25 | V600R | D816G10 | |||||
F712S25 | V600-K605 ins13 | D816F10 | |||||
T725T25 | K601E5, 13, 22 | V825A2 | |||||
V742V21,25 | K601N5, 13, 22 | D816Y2, 17, 26 | |||||
F795S25 | R682Q6 | R634R30 | |||||
G796S25 | A728V1 | D820G19 | |||||
G796V21 | V825I19 | ||||||
T751I21 | E839K19 | ||||||
R748K21 | I957T19 | ||||||
R836R25 | P31L19 | ||||||
T847I4 | R956Q19 | ||||||
Q820R21 | T22A19 | ||||||
E804G21 | G961S19 | ||||||
L828M21 | K642E13 | ||||||
F856Y21 | V559D22 | ||||||
F856L21 | W557R22 | ||||||
A839V21 | V559G22 | ||||||
G863D12, 21 | V559D13, 22 | ||||||
V851I12, 21 | V540L2 | ||||||
I821T21 | M541L2 | ||||||
I789I21 | |||||||
H870N21 | |||||||
V834A21 | |||||||
T725M17 | |||||||
L858R17 | |||||||
R832C17 | |||||||
A868D17 | |||||||
T852M17 | |||||||
T725A17 | |||||||
L703P17 | |||||||
S720F17 | |||||||
N700S17 | |||||||
R836S17 | |||||||
G721S17 | |||||||
L703P17 | |||||||
K708G17 | |||||||
P772-H773insV12 | |||||||
R108K9 | |||||||
L62R9 | |||||||
V651M9 | |||||||
R222C9 | |||||||
T263P9 | |||||||
A289T9 | |||||||
A289V9 | |||||||
A597P9 | |||||||
G598V9 | |||||||
C620Y9 | |||||||
S703F9 |
Mutations have been reported at
In a normal cell, ABL protein is located in the nucleus, but in cancer cells the BCR-ABL fusion protein is found in the cytoplasm and is constitutively active (Goldman and Melo 2008). Studies have shown that
The discovery of this oncogenic fusion protein led to the development of imatinibmesylate. Imatinib, an ABL kinase inhibitor, was the first therapeutically successful treatment for CML and gained U.S. Food and Drug Administration approval in 2001. However, a substantial proportion of patients with CML developed resistance to imatinib because of mutation in
T315I is the most common imatinib-resistant mutation in
One of the discoveries of mutations affecting cancer prognosis is
MEK inhibitors suppress ERK signaling in all normal and tumor cells. In contrast, the RAF inhibitor vemurafenib inhibits the ERK pathway and cell proliferation only in tumor cells with mutant
Mutated
Shortly after
This finding was followed by the identification of activating point mutations and small insertions/deletions in
One of the mechanisms by which resistance to erlotinib or gefitinib develops in 50% of relapsed patients is acquisition of a resistant mutation in exon 20 (T790M) in
Gefitinib and erlotinib are first-generation, reversible EGFR inhibitors. Currently being developed are second-generation irreversible EGFR inhibitors, which inhibit EGFR kinase activity even when the T790M mutation is present. Neratinib (HKI-272) (Li, Shimamura et al. 2007; Wong, Fracasso et al. 2009; Sequist, Besse et al. 2010) and afatinib (BIBW 2992) (Eskens, Mom et al. 2008; Li, Ambrogio et al. 2008; Yap, Vidal et al. 2010) are dual inhibitors against EGFR and HER2, and PF-00299804 is a multi-inhibitor against EGFR, ERBB2, and ERBB4 (Engelman, Zejnullahu et al. 2007). For
Shortly after the discovery of
The discovery of the somatic gain-of-function mutation (V617F) in Janus kinase 2 (
An activating mutation of
Other kinase activating mutations have been found in the oncogene c-
Another recent breakthrough was the discovery of translocations or other chromosomal rearrangements between ETS transcription factors (
Drugs targeting some of these mutations are now either undergoing clinical testing or have protocols in the approval process. The discovery of base mutations through systematic DNA sequencing has provided decisive genetic evidence that these same pathways play crucial roles in tumorigenesis and maintenance and has also opened up new avenues for the deployment of targeted therapeutics. We are just starting to understand the genetic mechanisms that lead to the development of cancer and play a role in treatment.Hence, we are still at the beginning of the road map to targeted therapy. We still need to discover all activating mutations or other chromosomal rearrangements, inactivating mutations, and epigenetic alterations in the genome that drive cells to tumorigenesis for each type and subtype of cancer, and we need to identify resistant and sensitive mutations to find the correct targets for the development of new selective therapeutic agents, and use combination of selective therapeutic agents.
Translational science provides the opportunity to apply advances in science directly to patient care. In oncology, new and important scientific information is moving forward at an enterprise level. Managing data for translational science requires a sophisticated informatics infrastructure that can harmonize multiple datasets on subjects in all areas that influence outcome. Medical history, stage of disease, disease location, surgery, pathology genomic/proteomics imaging, radiation therapy, and medical oncology are equally important in determining outcome both in tumor control and normal tissue function post-therapy. In this chapter, we describe opportunities moving forward to enhance our knowledge and application of science to patient care.
The primary mechanism for oncology clinical development over the past 50 years has been in the planning and execution of clinical trials. The oncology clinical trial program in the National Cancer Institute (NCI) began as small groups of clinical investigators driven by the common need to potentially improve the care of subjects undergoing cancer therapy. The groups quickly grew into larger organizations of adult and pediatric oncologists, which included representation from all oncology disciplines in surgery, medical oncology, and radiation therapy. By 1980, pediatrics was recognized as its own discipline and the Pediatric Oncology Group (POG) was established by the merger of the pediatric divisions of the former Cancer and Leukemia Group B (CALGB) and SWOG. In 1995, imaging was recognized as its own discipline and the American College of Radiology Imaging Network (ACRIN) was established to meet the growing need of imaging acquisition and imaging science in clinical trials. Although each of the established groups housed radiation oncology as a discipline committee, the Radiation Therapy Oncology Group (RTOG) was established to promote radiation oncology as a discipline with a pathway to evaluate radiation technology and comprehensive radiation therapy. In its halcyon moment, there were 10 cooperative groups each with its own statistical data center and tissue bank resource center. The cooperative groups have been responsible for generating many of the most important publications on oncology care over the past 60 years and have become the model for validating progress in oncology. Core services in imaging and radiation therapy were established to manage specified needs in cooperative group clinical trial management. These included the Radiological Physics Center (RPC) and the Quality Assurance Review Center (QARC) as well as the American College of Radiology (ACR). As radiation oncology matured into an image-directed discipline, the radiation oncology quality assurance centers assumed a greater responsibility into collecting images used to develop target volumes of choice for radiation therapy treatment planning. In pediatrics, the images were not siloed as segregate entities between radiology and radiation therapy but applied symbiotically to all investigators for target definition and assessment of response in a single data review system. This enhanced the synergism between radiologists and radiation oncologists in the care of children [1]. In 2007, a recommendation was made by a group designed to review and assess the cooperative group mechanism and functions. The recommendation was to decrease the number of the individual cooperative groups and consolidate core services including tissue banks, data management centers, and process review of quality assurance [2]. The pediatric groups had merged into the Children’s Oncology Group (COG) and as the restructuring started to mature, COG was positioned to be one of the five funded groups. The transition was completed by 2014. SWOG (formerly South West Oncology Group) chose to remain a single entity. The National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG) merged as an administrative entity now known as NRG Oncology. The Cancer and Leukemia Group B (CALGB), American College of Surgeons Oncology Group (ACOSOG), and the North Central Cancer Treatment Group (NCCTG) formed the Alliance for Clinical Trials in Oncology and the Eastern Cooperative Oncology Group (ECOG) merged with the American College of Radiology Imaging Network (ACRIN) to form the ECOG-ACRIN Cancer Research Group. Each of the groups maintains an operation center as well as a statistical and data management center with NRG having more than one center. Tissue banking overlaps between the groups. The image acquisition and management and radiation therapy quality assurance are managed by the Imaging and Radiation Oncology Core (IROC), which was constituted by the existing imaging and radiation therapy quality assurance centers. These centers include the Radiologic Physics Center (RPC), the Quality Assurance Review Center (QARC), the Wright Imaging Center at Ohio State, and the American College of Radiology (ACR) core quality assurance centers in imaging and radiation oncology [1, 3].
The integration of the cooperative groups established an economy of scale for the NCI clinical trials program. The five NCTN groups house a significant amount of data. These data include outcome data, tissue banks data, and IROC hosting invaluable information important for clinical trial outcome analysis. These data libraries house the largest volume of oncology-related information in the world. Because the data are acquired on clinical trials, the datasets and outcome information are the best in the world for consistency in data acquisition and management and completeness of the information. They are among the best resources in the world for performing outstanding translational science research and comparing institutional translational science against validated datasets. Currently, the data are fragmented and siloed within the multiple remaining statistical centers, tissue banks, and IROC. Moving salient trial information into a single or synergistic data system would be an important objective promoting translational science. Hundreds of thousands of complete datasets are readily available in these systems, which can be used to promote individual work and serve to validate work of translational scientists for the next generation of clinical trials. This is the goal of big data acquisition and data management of this information. Each subject on study has pathology, imaging, therapy, and data for outcome analysis. Validated datasets with consistent and uniform acquisition of information will permit accurate assessment of trial outcome and provide quantitative significance to the work. The potential for successful application of this effort is within our reach, the challenge is to define a pathway to achieve the goals of the work.
Problem solving in oncology is challenging. To move the field forward with strong translational science and apply balanced judgments for disease management, the information acquired for review must be robust to appropriately power the study question and have the quality needed to be certain that the conclusions are accurate and can be validated. Oncology data management can be challenging if the information under review is incomplete and unvalidated, resulting in inaccurate conclusions established in outcome analysis. The database must also undergo self-renewal as process improvements become standard for evaluating outcome imaging to validate patterns of failure and pathology to review change in biomarker status relative to disease progression. Tools for biomarker identification, imaging, radiation oncology, and applied medical oncology are under constant revision and databases for translational science need constant maintenance to insure accuracy and applicability. Future strategic translational science objectives are clear and unambiguous. The more complete and accurate the information acquired, the more successful science can be applied to the bedside. In the next section, we will describe challenges in clinical trial outcome interpretation when information is incomplete.
Hodgkin lymphoma is a unique disease than can affect children, adolescents, and adults of all ages. Chemotherapy has become the initial and primary therapy for this disease with choice of agents and duration of therapy based on stage at presentation, subject medical status, and response to induction therapy. The use of radiation therapy remains under continued refinement and influenced by both response to chemotherapy and volume of tumor at presentation. Pediatric Oncology Group protocol 8725 evaluated what would be today called intermediate and advanced stage subjects. In this study, subjects were treated with eight cycles of hybrid chemotherapy (ABVD-MOPP). After completion of chemotherapy, subjects were randomized to observation or to receive radiation therapy to all sites of disease identified on imaging at presentation. In the original Journal of Clinical Oncology publication, there was no difference in outcome in subjects who received radiation therapy [4]. Retrospective analysis of the study required imaging at presentation and before radiation therapy. The results revealed that subjects who received study-compliant radiation therapy had a survival rate that was 10% superior to those who received chemotherapy only. For the subjects treated in a manner not compliant to study guidelines (deviation), the survival was identical to those who received chemotherapy alone. In other words, subject outcome with chemotherapy was not improved using consolidation radiotherapy in a non-study-compliant manner. Most study deviations were secondary to excluding original disease from the treatment field [4, 5].
Because of the study deviation rate, the next series of clinical trials in Hodgkin lymphoma required that the radiation therapy fields be reviewed pre-radiation therapy at the Quality Assurance Review Center (QARC/now IROC). The trials evaluated early stage subjects with therapy titration secondary to response after two cycles of chemotherapy and subjects with intermediate risk disease. With pre-treatment review of radiation therapy objects, compliance to study was outstanding. However, the images at presentation and response were collected by QARC to (1) confirm response and (2) define radiation therapy treatment fields. The images were reviewed retrospectively for response confirmation and the central review agreed only 50% of the time with the site assessment, demonstrating the need to define response in a consistent manner if clinical trials were going to be designed to either titrate or augment therapy based on response to treatment [6].
COG AHOD0031 was the first clinical trial in the world to use central review of imaging objects to assess response to treatment and to review radiation therapy treatment objects in real time. The real time review of objects was imbedded into the trial design structure. The image review and the review of radiation therapy treatment objects were completed at QARC with immediate feedback to site and COG statistical center, which in turn triggered both secondary and tertiary points of randomization with therapy titration based on good to complete response and therapy augmentation if response was incomplete (Figure 1). The trial accrued more than 1700 subjects. The completeness of the database, including outcome images, have generated many secondary projects including response in bone with PET, radiomics of response to chemotherapy in pulmonary parenchyma and pleural effusions, and patterns of failure on protocol therapy [8, 9, 10]. The data management process involved in COG trials has established the infrastructure for translational science. Pathology objects are housed in tissue banks and outcome information is housed at the statistical center; nevertheless, this information could be made available as needed for secondary projects to be completed. One of the goals moving forward is to have all this information available in a single format. This will be discussed in greater length in The Cancer Imaging Archive (TCIA) section.
Real-time imaging and radiation therapy object reviews on AHOD0031. This image is under the creative commons attribution license [
The advantage to the data management system housed at IROC for COG is the current ability to now manage clinical trials for many subsets of subjects with Hodgkin lymphoma in a nimble manner with international involvement. With digital data transfer tools, information can be reviewed in real time to effectively manage adaptive trials in a facile manner. Very young subjects, older subjects with medical co-morbidities, CD30 therapies, and immunotherapy are now under study with real-time review of response coupled with biomarker analysis [11]. Expanding this strategy to a global and quantitative function is how translational science can be applied on an enterprise basis. Creating a central resource of all cancer research information and objects for investigators would enhance next generation science.
Clinical trials have been the infrastructure to process improvements in care for breast cancer patients. The NSABP (National Surgical Adjuvant Breast and Bowel Project) clinical trial B-06 confirmed the use of radiation therapy in the definitive management of breast cancer. Clinical trials have optimized chemotherapy in this disease, conformed the utility of hormonal therapy, and provided us the platform to titrate therapies including surgery. The advantages of clinical trials in breast cancer are self-evident [12, 13]. Likewise, clinical trials in breast cancer also reflect the problems associated with limited data acquisition and how unintentional omission of data acquisition negatively influences translational science.
The former CALGB conducted a series of well-designed clinical trials intended to evaluate the role of chemotherapy dose escalation with Adriamycin and Cytoxan with the sequential additional of Taxol in node positive subjects [13]. These trials performed in sequence predated the routine use of Her-2-Neu-directed therapy in this disease. Likewise, these trials in development predated the confirmation that radiation therapy provided a survival advantage for node positive breast cancer subjects treated with chemotherapy. The decision was made by the principal investigator not to either collect or inquire how local care to the breast and lymph nodes was applied and accomplished. The decision was made in this direction because there was no unambiguous information available at the time of trial development that local care or local control affected survival; therefore, the utility of data collection was not thought to be of consequence and did not merit the cost or effort. Evidence to the contrary was made public in 1997 when two separate clinical trials were published together, both demonstrating a survival advantage when node positive subjects were treated with radiation therapy on an adjuvant basis [14, 15]. This made clinical trial interpretation challenging because subject outcome relative to type, duration, and specific chemotherapy could not be solely assigned to the chemotherapy delivered. Many of the subjects on these series of studies also received radiation therapy to dose and volumes that were non-uniform and site/investigator specific.
To attempt and address this situation, Sartor and colleagues from QARC (now IROC Rhode Island) attempted to collect radiation therapy treatment information in a retrospective manner by contacting institutions about specific subjects. This was partially effective, however limited in execution because of several reasons. This effort was not the intention or part of the data management of the studies; therefore, site investigator enthusiasm to support the effect was non-uniform. The second issue was one that is now more visible in more modern clinical trials as to collect this information, institutional review boards (IRB) began to insist that subjects on study be re-consented for this effort. Accordingly, this became a significant barrier to project completion [16].
These trials accrued more than 3000 subjects and were well powered to achieve the objectives of the study. However, only less than one-third of the radiation therapy information could be collected and often the information received was incomplete. The information received clearly indicated that without protocol guidelines, dose and volumes treated were significantly heterogeneous and when treated, subjects received therapy that was non-uniform relative to dose and volume and conclusions would have been difficult to validate. There was a trend for subjects who received Taxol to also have received radiation therapy, imposing a question as to which therapy, or both, provided a care advantage.
A second issue foreshadowed a problem now seen in current breast cancer clinical trials. There were more than 300 local and or local regional failures in this study. If radiation therapy objects were collected and detailed information concerning the location and nature of the local failure, the application of the radiation oncology treatment fields, technique, and dose could be reviewed to better ascertain how radiation therapy can/should be applied along the chest wall and regional draining lymph nodes. The lack of information has led to a paralysis in our understanding of issues than remain today.
ACOSOG Z0011 (Z11) was a clinical trial designed to evaluate limited axillary surgery in subjects with breast cancer including those with limited nodal involvement. The objective was to validate that sentinel lymph node staging coupled with radiation therapy would be non-inferior to more comprehensive axillary surgery [17]. The trial asked for what is referred to as “tangential radiation therapy.” This would imply that the axillary volume was treated to a partial volume. In studies evaluating this point using anatomical guidelines superimposed on radiation therapy treatment fields, approximately 60% of the axilla would be included in a traditional field that would not extend superiorly to the axillary vein nor posteriorly to the latissimus muscle [18]. The study proved to be positive relative to limited axillary surgery. However, radiation therapy treatment objects were not collected as part of the study, giving the impression that partial volume RT to the axilla could be considered a new standard of care. Jolie and colleagues decided to review this point and with several colleagues including support from QARC (IROC), attempts were made to gather specific information as to how radiation therapy was delivered to subjects on study. The investigators encountered similar barriers to data acquisition relative to site enthusiasm and IRB approval. However, the investigators were able to determine that a significant number of subjects were treated with more comprehensive radiation therapy to extended volumes including regional lymph nodes that were not study directed. Therefore, conclusions concerning the application of radiation therapy to limited volumes of the axilla are premature [19].
If radiation therapy digital datasets and radiation dose were collected as part of the study, it is possible that interventional review pre-therapy could have been performed and the data set could have been more uniform. In this situation, outcome images could be applied to patterns of failure analysis and define outcome relative to axillary therapy with more security. This issue continues to haunt even the most current breast cancer trial attempting to discern the appropriate radiation therapy target volume in subjects with limited and more extended axillary surgery. This has influence in normal tissue outcome and despite nearly 50 years of clinical trials, it remains unanswered. If the datasets were complete, it is possible we might be closer to understanding how to apply therapy for both tumor control and optimal normal tissue function. This is of increasing importance as radiation therapy is now being asked to treat nodal regions with more limited surgery. If information acquired on study was more complete, we may be further along in our understanding of field placement. This also limits our ability to perform translational science including pathology biomarkers for local failure and other potential areas of interest to the oncology community. These are problems of omission of data acquisition and limit our ability to use these datasets to review information in retrospect and apply knowledge to the next generation of clinical trials.
There is much to be learned as issues of head and neck management are influenced by biomarkers and relationship to viral origin of disease. To be accurate in data assessment, pathology and imaging objects need to be complete to intercompare both staging and therapy execution/outcome. Non-uniform treatment execution can limit study success and utility of the dataset for translational science.
Tirapazamine gained prominence as a hypoxic cell sensitizer to radiation therapy with favorable phase 2 results. In the HeadSTART clinical trial, Tirapazamine was randomized with traditional chemoradiotherapy for locally advanced squamous cell carcinoma of the head/neck. In this study, both imaging and radiation therapy quality assurance objects underwent on treatment review at QARC for study compliance. Pre-treatment review was not utilized because the trial included many international partners and most of the involved sites credentialed for participation had primitive digital transfer tools at the time of clinical trial participation. The trial management committee determined that pre-therapy review would potentially be a barrier to accrual. Nearly 25% of the cases required radiation field adjustments to ensure that full dose was received to gross tumor as seen on central review. Of the 211 requests for field alteration, 116 chose not to adjust the fields and 95 chose to make the adjustment. In all cases, the potential for deviation was due to potential exclusion of gross tumor from full dose and protocol-compliant radiation. If the adjustment was made on treatment, subjects had reasonable survival; however, their survival was less than those who had a compliant plan de novo. If adjustments were not made, except for two cases, the trial management committee agreed with the assessment of the on-treatment reviewer. The trial committee asked the primary on-treatment reviewer to score all study deviations into two categories, clinically meaningful or not. Clinically meaningful deviations excluded gross tumor from full-dose radiation therapy. Subjects with clinically meaningful deviations had a significant decrease in survival while those whose deviations were not considered significant had an outcome identical to those whose plans were adjusted for compliance on treatment. Both groups had survival less than the subjects who had a compliant plan upfront. The most unfortunate aspect of this study is the deviation rate on trial over rode the point of randomization on the study, rendering the experimental arm uncertain, secondary to quality of the radiation therapy. Therefore, the cases become less helpful for translational science endeavors including pattern of failure analysis as the outcome was influenced by the quality of the data [20, 21].
Current studies in head and neck cancer place emphasis on the role of immunotherapy in both comparing the traditional platinum-based therapy coupled with non-inferiority objectives to evaluate toxicity. In these trials, investigators have matured in the coverage of gross tumor. However, there is new disparity on coverage of targets deemed of intermediate and low risk as investigators are empirically titrating volume treated to ameliorate mucosal discomfort and late effects to multiple normal tissue volumes. Therapeutic titration will influence toxicity profiles. If investigators are titrating volumes, modern protocols may unfairly favor toxicity profiles generated by new regimens in comparison to historical standard. Complete datasets including outcome imaging with patterns of failure will be important to compare both tumor control and toxicity moving forward.
These are important datasets as strategies in artificial intelligence and machine learning in radiology and radiation oncology need to be developed from accurate and complete datasets, especially as the origin of disease becomes multifactorial in origin. If objects are not targeted correctly or per protocol, it will be impossible to develop accurate artificial intelligence (AI) machine tools that can be applied for translational science moving forward.
Treatment of patients with lung malignancy is challenging as metrics for normal tissue function extend beyond the anatomical constraints that can be defined in radiation oncology planning images. Both tumor control and normal tissue function are influenced by dose to target and radiation dose to normal tissue, including volumes of parenchyma receiving low, intermediate, and high doses. One of the challenges moving forward is to ensure that volumes are drawn accurately to assess tumor control and cardio-pulmonary function. RTOG 0617 study evaluated the role of targeted therapy coupled with both low- and high-dose radiation therapy to tumor target. Radiation therapy treatment objects were submitted for review without diagnostic images to validate that what was drawn for treatment reflected all the tumor anatomy. It was assumed, perhaps accurately, that the planning CT would be sufficient to confirm that all disease was included in the intended target. Although the study did not show a benefit to high-dose radiation, the paradox was that in the early phase of the trial, the higher dose arm had statistically worse local control. One explanation is that gross tumor may not have been fully contoured in selected cases and possibly influenced trial outcome. As such, without primary imaging and outcome imaging, it is difficult to confirm the pattern of failure, possibly rendering these datasets less useful for secondary analysis. Complete datasets would be helpful to validate trial outcome and increase the utility of the data for secondary analysis and translational science [22].
Successful translational science requires that all relevant information be made readily available in an informatics format that can be queried in a facile manner. Incomplete datasets can lead to conclusions that may be inaccurate. Complete datasets will permit the facts to drive study outcome and investigators will feel the analysis is accurate. A senior clinical trial investigator once stated that the time to write your protocol is when you analyze your data as you finally begin to see the questions you should have both asked and anticipated in the design phase of the trial. This is why informatics platforms must have enterprise-level query function to help answer questions not anticipated in study design. Datasets from clinical trials potentially make the best tools for moving translational science forward as the (1) subjects are entered on trial for a specific purpose, (2) the stage and appropriateness for subject entry are confirmed with uniform standards, (3) information including pathology and imaging are collected and collated in a uniform manner, (4) subjects are treated in a uniform manner with treatment data available for review, and (5) outcome information is available including imaging to validate outcome as appropriate. These datasets permit evaluation of a potential new biomarker as (1) the information may be available in situ as a digital object and (2) additional tissue may be available as part of an exhaustible resource housed in a tissue bank. Nimble query function can permit intercomparison between subjects on the same trial or other subjects on different studies with similar demographics for analysis. This can potentially evaluate and compare those with similar biomarkers on different studies. The datasets become a rich resource for science. At the moment within both industry and the NCTN, the information is housed in disparate locations including statistical data centers that house subject demographics and outcome, IROC which houses images and radiation therapy treatment objects, and tissue banks which house both digital maps of known biomarkers and tissue help for additional studies when needed. As a result, efforts to perform secondary analysis on objects become challenging and often lost in process and sequential approvals for use. This can take considerable time and effort and often the scientific question is muted and defeated by processes designed for data protection.
To make science move forward at an enterprise level, this information needs to be housed in in a single platform designed to promote and support the modern scientist with nimble and comprehensive query function for robust data review. The next section will discuss how these objects are currently managed and present a strategy for modern science moving forward.
TCIA is an initiative of the National Institute of Health (NIH) and the National Cancer Institute (NCI) to address the need for enterprise database availability to promote translational science and to validate concepts and ideas against a strong database. The archive resides in the public domain and the objects are fully de-identified per government standards. The principal investigator of TCIA is Fred Prior, PhD, who is the chair of quantitative science at the University of Arkansas. Dr. Prior has long-standing expertise in database management and development of image datasets. He has applied his expertise to this effort coupled with co-investigators Joel Saltz, MD, PhD, and Ashish Sharma, PhD. Dr. Saltz is the chair of bioinformatics at Stony Brook University and an international expert in digital pathology and integrated database function. Dr. Sharma is at Emory University and is an informatics expert who helps move TCIA to enterprise function.
The digital archive houses imaging and outcome information that can be used for translational science. The current portfolio includes datasets from all cancer subtypes in adult oncology and will soon be updated with datasets from pediatric oncology. The information includes clinical information, imaging, radiation therapy datasets and treatment plans, pathology objects including genomics, and other supplemental information required for analysis. The current portfolio can be accessed through www.thecancerimagingarchive.net. TCIA is an important initiative as it makes information available to all interested scientists who can apply information directly to their projects of interest.
As TCIA moves forward, it will be essential to find mechanisms for enterprise-level data capture and uniform data formatting for all trials both within the NCTN and industry. Clinical trials within the NCTN will likely need to be designed in the future with data capture as part of the protocol and processes imbedded in the trial will need to be made uniform in the trial design to be uploaded to TCIA once the trial is complete and objects fully de-identified for the public archive. Investigators will want to be able to look at specific subjects’ subsets in clinical trials and evaluate both image and biomarker expression for subsets both within individual trials and intercompare with other trials for outcome analysis. This will be true in all adult and pediatric oncology subtypes. We are learning more each day about response-directed therapies and the relationship of response and disease progression relative to biomarkers. The informatics tools will need to be robust to accommodate this element of data exchange and evaluation. Digital pathology will play an increasingly important role including capture of profiles that are identified to date in a manner similar to oncotype for breast cancer. Tissue will need to be stored for the biomarker not yet identified. Digital capture makes identified objects inexhaustible while tissue is exhaustible, hence the reason we need to store and protect this invaluable resource. Radiation therapy treatment plans will need to be fused with images that define targets and correlate to images that review the pattern of failure. It will be through these mechanisms we will all mature in our understanding of disease processes and the success/failure of our applied therapies [23, 24].
Enterprise-level function of comprehensive clinical trial datasets is closer to reality than it has been in the past. The quality of the dataset will significantly influence the quality of our understanding of the applied information and how we use clinical information moving forward. Efforts need to be made to optimize existing datasets in the NCTN and industry to help move knowledge forward in a manner we can validate and trust.
CA 180803.
The authors declare no conflict of interest.
IntechOpen - where academia and industry create content with global impact
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\\n\\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\\n\\nBut, one thing we have in common is -- we are all scientists at heart!
\\n\\nSara Uhac, COO
\\n\\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\\n\\nAdrian Assad De Marco
\\n\\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\\n\\nDr Alex Lazinica
\\n\\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
\\n"}]'},components:[{type:"htmlEditorComponent",content:"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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According to a survey, 63% of deaths due to cancer are reported from developing countries. There are different conventional treatment modalities that are available to treat and manage cancer. However, new cancer treatment options are being explored continuously as over 60% of all current experimental trials worldwide are focusing on tumor cure. The success of treatment depends upon the type of cancer, locality of tumor, and its stage of progression. Surgery, radiation-based surgical knives, chemotherapy, and radiotherapy are some of the traditional and most widely used treatment options. Some of the modern modalities include hormone-based therapy, anti-angiogenic modalities, stem cell therapies, and dendritic cell-based immunotherapy. This chapter discusses different traditional and novel treatment modalities to combat different types of cancer.",book:{id:"6313",slug:"neoplasm",title:"Neoplasm",fullTitle:"Neoplasm"},signatures:"Zaigham Abbas and Sakina Rehman",authors:[{id:"214546",title:"Dr.",name:"Zaigham",middleName:null,surname:"Abbas",slug:"zaigham-abbas",fullName:"Zaigham Abbas"}]},{id:"64178",doi:"10.5772/intechopen.81517",title:"Zebrafish (Danio rerio) as a Model Organism",slug:"zebrafish-em-danio-rerio-em-as-a-model-organism",totalDownloads:2802,totalCrossrefCites:4,totalDimensionsCites:26,abstract:"Animals as model organisms, the silent sentinels, stand watch over the environmental health of the world. These are non-human animal species which can be used to understand specific biological processes and to obtain informations which can provide an insight into working of other organisms. Among the model organisms, the zebrafish (Danio rerio) is one of the best leading models to study developmental biology, cancer, toxicology, drug discovery, and molecular genetics. In addition, the zebrafish is increasingly used as a genetic model organism for aquaculture species and in toxicogenomics and also to generate zebrafish disease models for application in human biomedicines. This tiny fish is a versatile model organism for many fields of research because of its easy maintenance, breeding, and transparent body during early development.",book:{id:"7054",slug:"current-trends-in-cancer-management",title:"Current Trends in Cancer Management",fullTitle:"Current Trends in Cancer Management"},signatures:"Farmanur Rahman Khan and Saleh Sulaiman Alhewairini",authors:[{id:"221847",title:"Dr.",name:"Saleh",middleName:null,surname:"Alhewairini",slug:"saleh-alhewairini",fullName:"Saleh Alhewairini"},{id:"258210",title:"Dr.",name:"Farmanur Rahman",middleName:null,surname:"Khan",slug:"farmanur-rahman-khan",fullName:"Farmanur Rahman Khan"}]},{id:"61662",doi:"10.5772/intechopen.78271",title:"The Human Epidermal Growth Factor Receptor 2 (HER2) as a Prognostic and Predictive Biomarker: Molecular Insights into HER2 Activation and Diagnostic Implications",slug:"the-human-epidermal-growth-factor-receptor-2-her2-as-a-prognostic-and-predictive-biomarker-molecular",totalDownloads:1725,totalCrossrefCites:7,totalDimensionsCites:10,abstract:"The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor protein. HER2 gene amplification and receptor overexpression, which occur in 15–20% of breast cancer patients, are important markers for poor prognosis. Moreover, HER2-positive status is considered a predictive marker of response to HER2 inhibitors including trastuzumab and lapatinib. Therefore, reliable HER2 determination is essential to determine the eligibility of breast cancer patients to targeted anti-HER2 therapies. In this chapter, we aim to illustrate important aspects of the HER2 receptor as well as the molecular consequences of its aberrant constitutive activation in breast cancer. In addition, we will present the methods that can be used for the evaluation of HER2 status at different levels (protein, RNA, and DNA level) in clinical practice.",book:{id:"6813",slug:"cancer-prognosis",title:"Cancer Prognosis",fullTitle:"Cancer Prognosis"},signatures:"Daniela Furrer, Claudie Paquet, Simon Jacob and Caroline Diorio",authors:null},{id:"67964",doi:"10.5772/intechopen.87963",title:"Protein Tyrosine Phosphatases in Tumor Progression and Metastasis: Promoter or Protection?",slug:"protein-tyrosine-phosphatases-in-tumor-progression-and-metastasis-promoter-or-protection-",totalDownloads:946,totalCrossrefCites:4,totalDimensionsCites:6,abstract:"Reversible phosphorylation of proteins, executed by kinases and phosphatases, is the major posttranslational protein modification in eukaryotic cells, causing them to become activated or deactivated. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a broad number of diseases, including cancer. Few decades ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors. However, nowadays, accumulating evidence demonstrates that a misregulation of PTP activities plays a crucial and decisive role in cancer progression and metastasis. In this chapter, we will focus on the molecular aspects that support the crucial role of PTPs in cancer and in turn make them promising for prediction, monitoring, and rational appropriate therapy selection of individual patients.",book:{id:"8002",slug:"tumor-progression-and-metastasis",title:"Tumor Progression and Metastasis",fullTitle:"Tumor Progression and Metastasis"},signatures:"Carmen V. Ferreira-Halder, Stefano Piatto Clerici, Alessandra V. Sousa Faria, Patrícia Fernandes de Souza Oliveira, Helon Guimarães Cordeiro and Erica Akagi",authors:[{id:"61709",title:"Prof.",name:"Carmen",middleName:null,surname:"Ferreira",slug:"carmen-ferreira",fullName:"Carmen Ferreira"},{id:"307647",title:"MSc.",name:"Stefano",middleName:null,surname:"Piatto Clerici",slug:"stefano-piatto-clerici",fullName:"Stefano Piatto Clerici"},{id:"307648",title:"Ph.D. Student",name:"Alessandra",middleName:"V. S.",surname:"Faria",slug:"alessandra-faria",fullName:"Alessandra Faria"},{id:"307649",title:"MSc.",name:"Patrícia",middleName:null,surname:"Oliveira",slug:"patricia-oliveira",fullName:"Patrícia Oliveira"},{id:"307650",title:"MSc.",name:"Helon",middleName:null,surname:"Cordeiro",slug:"helon-cordeiro",fullName:"Helon Cordeiro"},{id:"307651",title:"Dr.",name:"Erica",middleName:null,surname:"Akagi",slug:"erica-akagi",fullName:"Erica Akagi"}]},{id:"55760",doi:"10.5772/intechopen.69397",title:"Exosomes and Their Role in Viral Infections",slug:"exosomes-and-their-role-in-viral-infections",totalDownloads:2396,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Exosomes are excretory nano-vesicles that are formed by the cell’s endocytic system and shed from the surface of almost all types of cells. These tiny extracellular vesicles, once thought to be “garbage bags for cells,” carry a wide variety of molecules of cellular origin, including proteins, lipids, and RNAs, that are selectively incorporated during the formation of exosomes. Exosomes are now known to play a central role in several important biological processes such as cellular communication, intercellular transfer of bioactive molecules, and immune modulation. Recent advances in the field have shown that a number of animal viruses can exploit the exosomal pathway by incorporating specific cellular or viral factors within exosomes, in order to modulate the cellular microenvironment and influence downstream processes such as host immunity and virus spread. In this chapter, we provide an overview of our current understanding of exosome biogenesis and how this normal physiological process is hijacked by some pathogenic viruses. Viral components that appear to be selectively incorporated into exosomes and the potential role of these exosomes in viral pathogenesis are discussed. Identifying viral signatures in exosomes and their mode of action is fundamental for any future diagnostic and therapeutic strategies for viral infections.",book:{id:"5793",slug:"novel-implications-of-exosomes-in-diagnosis-and-treatment-of-cancer-and-infectious-diseases",title:"Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases",fullTitle:"Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases"},signatures:"Gulfaraz Khan, Waqar Ahmed and Pretty S. Philip",authors:[{id:"199889",title:"Prof.",name:"Gulfaraz",middleName:null,surname:"Khan",slug:"gulfaraz-khan",fullName:"Gulfaraz Khan"},{id:"201764",title:"Mr.",name:"Waqar",middleName:null,surname:"Ahmed",slug:"waqar-ahmed",fullName:"Waqar Ahmed"},{id:"201766",title:"Ms.",name:"Pretty",middleName:null,surname:"Philip",slug:"pretty-philip",fullName:"Pretty Philip"}]}],mostDownloadedChaptersLast30Days:[{id:"60895",title:"An Overview of Cancer Treatment Modalities",slug:"an-overview-of-cancer-treatment-modalities",totalDownloads:3068,totalCrossrefCites:29,totalDimensionsCites:59,abstract:"Cancer is a global issue majorly affecting developing countries. According to a survey, 63% of deaths due to cancer are reported from developing countries. There are different conventional treatment modalities that are available to treat and manage cancer. However, new cancer treatment options are being explored continuously as over 60% of all current experimental trials worldwide are focusing on tumor cure. The success of treatment depends upon the type of cancer, locality of tumor, and its stage of progression. Surgery, radiation-based surgical knives, chemotherapy, and radiotherapy are some of the traditional and most widely used treatment options. Some of the modern modalities include hormone-based therapy, anti-angiogenic modalities, stem cell therapies, and dendritic cell-based immunotherapy. This chapter discusses different traditional and novel treatment modalities to combat different types of cancer.",book:{id:"6313",slug:"neoplasm",title:"Neoplasm",fullTitle:"Neoplasm"},signatures:"Zaigham Abbas and Sakina Rehman",authors:[{id:"214546",title:"Dr.",name:"Zaigham",middleName:null,surname:"Abbas",slug:"zaigham-abbas",fullName:"Zaigham Abbas"}]},{id:"64178",title:"Zebrafish (Danio rerio) as a Model Organism",slug:"zebrafish-em-danio-rerio-em-as-a-model-organism",totalDownloads:2801,totalCrossrefCites:4,totalDimensionsCites:26,abstract:"Animals as model organisms, the silent sentinels, stand watch over the environmental health of the world. These are non-human animal species which can be used to understand specific biological processes and to obtain informations which can provide an insight into working of other organisms. Among the model organisms, the zebrafish (Danio rerio) is one of the best leading models to study developmental biology, cancer, toxicology, drug discovery, and molecular genetics. In addition, the zebrafish is increasingly used as a genetic model organism for aquaculture species and in toxicogenomics and also to generate zebrafish disease models for application in human biomedicines. This tiny fish is a versatile model organism for many fields of research because of its easy maintenance, breeding, and transparent body during early development.",book:{id:"7054",slug:"current-trends-in-cancer-management",title:"Current Trends in Cancer Management",fullTitle:"Current Trends in Cancer Management"},signatures:"Farmanur Rahman Khan and Saleh Sulaiman Alhewairini",authors:[{id:"221847",title:"Dr.",name:"Saleh",middleName:null,surname:"Alhewairini",slug:"saleh-alhewairini",fullName:"Saleh Alhewairini"},{id:"258210",title:"Dr.",name:"Farmanur Rahman",middleName:null,surname:"Khan",slug:"farmanur-rahman-khan",fullName:"Farmanur Rahman Khan"}]},{id:"70898",title:"MicroRNA: A Signature for Cancer Diagnostics",slug:"microrna-a-signature-for-cancer-diagnostics",totalDownloads:975,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Various tools and techniques are being used for the diagnosis of cancer, but not a sole technique provides powerful result at the very early stages of cancer. This provides the need for type of tools which could detect cancer at early stages so that survival rate could be augmented. There are various diagnostic ways to identify cancer, but in each case, there are always circumstances to compromise on the sensitivity. In this framework, a new and more advanced approach of diagnosis for cancer is microRNA (miRNA). miRNAs are conserved regions among humans and animals, and their synthesis takes place in the nucleus and cytoplasm. There are several types of microRNAs that could be upregulated and downregulated in various cancers. A cancer cell could be identified by measurement of the expression pattern of miRNA. By examining the expression level for different types of cancers, miRNA can be used as biomarker for early detection of cancer in human beings.",book:{id:"9172",slug:"current-cancer-treatment",title:"Current Cancer Treatment",fullTitle:"Current Cancer Treatment"},signatures:"Ayesha Siddiqua, Sumaira Kousar, Amer Jamil, Riaz Tabassum, Tariq Mehmood and Nusrat Shafiq",authors:null},{id:"63685",title:"A Molecular Link between the Circadian Clock, DNA Damage Responses, and Oncogene Activation",slug:"a-molecular-link-between-the-circadian-clock-dna-damage-responses-and-oncogene-activation",totalDownloads:1405,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Circadian clocks enhance the efficiency and survival of living things by organizing their behavior and body functions. There has been a long history of research seeking a link between circadian clock and tumorigenesis. Studies of animal models and human tumor samples have revealed that the dysregulation of circadian clocks is an important endogenous factor causing mammalian cancer development. The core circadian clock regulators have been implicated in the control of both the cell cycle and DNA damage responses (DDR). Conversely, several intracellular signaling cascades that play important roles in regulation of the cell cycle and the DDR also contribute to circadian clock regulation. This review describes selected regulatory aspects of circadian clocks, providing evidence of a molecular link of the circadian clocks with cellular DDR.",book:{id:"7281",slug:"oncogenes-and-carcinogenesis",title:"Oncogenes and Carcinogenesis",fullTitle:"Oncogenes and Carcinogenesis"},signatures:"Yoshimi Okamoto-Uchida, Junko Izawa and Jun Hirayama",authors:[{id:"246364",title:"Prof.",name:"Jun",middleName:null,surname:"Hirayama",slug:"jun-hirayama",fullName:"Jun Hirayama"}]},{id:"67447",title:"Molecular Pathogenesis of Oral Squamous Cell Carcinoma",slug:"molecular-pathogenesis-of-oral-squamous-cell-carcinoma",totalDownloads:3824,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Oral carcinogenesis is a molecular and histological multistage process featuring genetic and phenotypic molecular markers which involves enhanced function of several protooncogenes, oncogenes and/or the deactivation of tumor suppressor genes, resulting in the over activity of growth factors and its cell surface receptors, which could enhance messenger signaling intracellularly, and/or leads to the increased production of transcription factors. Alone oncogenes are not responsible for carcinogenesis, genes having tumor suppressor activity, leads to a phenotypic change in cell which is responsible for increased cell proliferation, loss of cellular cohesion, and the ability to infiltrate local tissue and spread to distant sites. Understanding the molecular interplay of both onco and tumor genes will allow more accurate diagnosis and assessment of prognosis, which might lead the way for novel approaches to treatment.",book:{id:"8211",slug:"squamous-cell-carcinoma-hallmark-and-treatment-modalities",title:"Squamous Cell Carcinoma",fullTitle:"Squamous Cell Carcinoma - Hallmark and Treatment Modalities"},signatures:"Anshi Jain",authors:[{id:"280692",title:"Dr.",name:"Anshi",middleName:null,surname:"Jain",slug:"anshi-jain",fullName:"Anshi Jain"}]}],onlineFirstChaptersFilter:{topicId:"428",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82682",title:"Soft Tissue Tumors: Molecular Pathology and Diagnosis",slug:"soft-tissue-tumors-molecular-pathology-and-diagnosis",totalDownloads:10,totalDimensionsCites:0,doi:"10.5772/intechopen.104096",abstract:"Tumors of mesenchymal origin, also called soft tissue tumors, include tumor from muscle, fat, fibrous tissue, vessels and nerves, which are a group of heterogeneous neoplasms, and accounts for about 1% of all malignant tumors. They are uncommon tumors in routine practice, with complex tumorigenesis. Due to the recent advance in molecular pathology, we got a major achievement in the understanding of these tumors at the gene level, which makes the diagnosis and prognosis of this type of tumor more accurate and comfortable. This chapter will cover some molecular pathology and diagnosis of soft tissue and bone tumors.",book:{id:"11316",title:"Advances in Soft Tissue Tumors",coverURL:"https://cdn.intechopen.com/books/images_new/11316.jpg"},signatures:"Frank Y. Shan, Huanwen Wu, Dingrong Zhong, Di Ai, Riyam Zreik and Jason H. Huang"},{id:"82354",title:"Introductory Chapter: Soft Tissue Tumors of the Eye",slug:"introductory-chapter-soft-tissue-tumors-of-the-eye",totalDownloads:9,totalDimensionsCites:0,doi:"10.5772/intechopen.105735",abstract:null,book:{id:"11316",title:"Advances in Soft Tissue Tumors",coverURL:"https://cdn.intechopen.com/books/images_new/11316.jpg"},signatures:"Gloria Yum and Hilal Arnouk"},{id:"82233",title:"Effect of Metabolic Syndrome in Patients with Prostate Cancer (Review)",slug:"effect-of-metabolic-syndrome-in-patients-with-prostate-cancer-review",totalDownloads:10,totalDimensionsCites:0,doi:"10.5772/intechopen.105357",abstract:'The human prostate gland is an endocrine organ in which dysregulation of various hormonal factors plays a key role in the development of non-tissue transformation and leads to the formation of prostate cancer. Existing epidemiological data confirm the role of the components of the metabolic syndrome, namely obesity, hypercholesterolemia, diabetes, and hyperinsulinemia, in the development and/or progression of prostate cancer. Although the exact mechanisms underlying the relationship between metabolic syndrome and prostate cancer remain largely unknown, it has been shown that various \\"in vitro\\" and animal experiments with models of the metabolic syndrome contribute to survival, mitogenesis, metastasis, and treatment resistance pathways through various adaptive reactions, such as intracellular steroidogenesis and lipogenesis. Although the exact biopathophysiological mechanisms between metabolic syndrome and prostate cancer have yet to be studied, drugs that target specific components of the metabolic syndrome have also provided evidence for the relationship between metabolic syndrome, its components, and prostate cancer. The appearance of “in vitro” results and molecular genetic research data will bring us closer to using this knowledge to determine specific ways of cancer-specific survival and improve treatment outcomes in patients with this disease.',book:{id:"11316",title:"Advances in Soft Tissue Tumors",coverURL:"https://cdn.intechopen.com/books/images_new/11316.jpg"},signatures:"Maxim N. Peshkov, Galina P. Peshkova and Igor V. Reshetov"},{id:"82080",title:"The Clinical Usefulness of Prostate Cancer Biomarkers: Current and Future Directions",slug:"the-clinical-usefulness-of-prostate-cancer-biomarkers-current-and-future-directions",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.103172",abstract:"Worldwide, prostate cancer (PCa) is the leading cause of morbidity and cancer-related mortality in men. The pathogenesis of PCa is complex and involves abnormal genetic changes, abrogation of cell growth with heterogeneous progression and predictive subgroups. In the last two decades there have been the exploration and development of molecular and genetic biomarkers for PCa due to limitations of traditional serum biomarkers such as prostate specific antigen (PSA) in screening and diagnosis. These biomarkers could possibly differentiate between PCa and benign prostatic hyperplasia (BPH) patients, and healthy controls as well as assist with prognosis, risk stratification and clinical decision-making. Such molecular biomarkers include serum (PHI and 4K score), urine (PCA3 and SelectMDx), and tumor tissue (Oncoytype DX, Decipher and Prolarix). microRNAs (miRNAs) deregulation where there is increased or decreased expression levels, constitute prospective non-invasive molecular biomarkers for the diagnosis and prognosis of PCa. There are also other emerging molecular biomarkers such as exosomal miRNAs and proteins that are in various stages of development and clinical research. This review is intended to provide a wide-ranging appraisal of the literature on current and emerging PCa biomarkers with robust evidence to afford their application in clinical research and by extension routine clinical practice.",book:{id:"10661",title:"Cancer Bioinformatics",coverURL:"https://cdn.intechopen.com/books/images_new/10661.jpg"},signatures:"Donovan McGrowder, Lennox Anderson-Jackson, Lowell Dilworth, Shada Mohansingh, Melisa Anderson Cross, Sophia Bryan, Fabian Miller, Cameil Wilson-Clarke, Chukwuemeka Nwokocha, Ruby Alexander-Lindo and Shelly McFarlane"},{id:"81809",title:"Imaging of Benign Soft-Tissue Tumors",slug:"imaging-of-benign-soft-tissue-tumors",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.104320",abstract:"Soft-tissue tumors account for less than 4% of all tumors in adult patients and 7–10% of all tumors in pediatric age group. The majority of these tumors are benign in nature (more than 99%). Different imaging modalities play a significant role in the diagnosis, treatment, and follow-up of these tumors. In this chapter, we will try to cover the imaging appearances of different benign soft-tissue tumors and to demonstrate the differentiation features. In addition, we will demonstrate a systematic approach for the characterization of soft-tissue masses based on different imaging appearances.",book:{id:"11316",title:"Advances in Soft Tissue Tumors",coverURL:"https://cdn.intechopen.com/books/images_new/11316.jpg"},signatures:"Ahmed D. Abdulwahab"},{id:"80160",title:"Soft-Tissue Tumors of the Head and Neck Region",slug:"soft-tissue-tumors-of-the-head-and-neck-region",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.102026",abstract:"Fibroblastic and myofibroblastic neoplasms in the head and neck region are a rare group of tumors ranging from benign lesions to malignant lesions. Due to the difficult anatomy of the head and neck region, even neoplasms without metastatic potential can pose significant therapeutic challenges in this region. In this section, the most common soft-tissue neoplasms in the head and neck region will be discussed.",book:{id:"11316",title:"Advances in Soft Tissue Tumors",coverURL:"https://cdn.intechopen.com/books/images_new/11316.jpg"},signatures:"Ahmet Baki"}],onlineFirstChaptersTotal:12},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",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:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. 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Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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