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Wappler, Klára Felszeghy, Mukesh Varshney, Raj D. Mehra, Csaba Nyakas and Zoltán Nagy",authors:[{id:"97286",title:"Dr.",name:"Zoltán",middleName:null,surname:"Nagy",fullName:"Zoltán Nagy",slug:"zoltan-nagy"},{id:"101636",title:"Dr.",name:"Edina A.",middleName:null,surname:"Wappler",fullName:"Edina A. 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Traditionally, the pharmacological arsenal for the treatment of Crohn’s Disease (CD) includes the aminosalicylates (sulfasalazine, mesalazine), immunosuppressants (e.g., azathioprine, 6-mercaptopurine, and methotrexate), corticosteroids (e.g., prednisone, hydrocortisone, methylprednisolone, and budesonide), and antibiotics. This therapeutic armamentarium, regarded as “conventional,” does not seem to interfere with the natural history of the disease, while improving the symptoms of many patients [1, 2, 3].
\nIn the last two decades, there has been a major paradigm shift in the treatment of IBD, with the introduction of biological drugs (monoclonal antibodies) [4, 5]. Biological drugs were the only class of drugs that alter the natural course of the disease, reducing the risk of hospitalizations, and surgeries [6]. However, insights into the importance of early and optimized therapy have prompted interest in a ‘treat to target’ approach to achieve good disease control. This strategy involves treating to a pre-defined target that is associated with optimal long-term outcomes. Regular monitoring of objective measures of disease is required, and treatment is optimized based on these findings to ensure the target is achieved and maintained.
\nThe natural course of inflammatory bowel disease is characterized by periods of remission and exacerbation and, over time, patients can develop irreversible damage such as stenosis and fistulas in Crohn’s disease shortening and lead pipe appearance of colon in UC. However, it has been shown that early diagnosis with identification of severity predictors factors [7] and the early initiation of treatment with biological drugs during the “opportunity window,” where symptoms are mainly derived from the diseases inflammatory activity in its initial phase, significantly reduces the rate of surgical complications, such as fistula stenosis in CD, as well as the need for colectomy in patients with UC who present severe acute colitis or chronic colitis refractory to corticoid, aminosalicylates, and immunosuppressive therapy [8, 9, 10].
\nThe current IBD treatment goals include not only symptoms control, mainly but also sustained control of inflammation, through the mucosal healing and complication prevention (fistulae, abscesses, stenoses, dysmotility, and dysplasia), which may lead to hospitalization, surgery and substantial impact in quality of life [1, 11, 12]
The “treat to target” strategy defines the therapeutic goals that professionals should aim for, although it is important to emphasize which treatment strategy should be adopted in order to achieve the desired outcome. With that purpose, in 2017 the effect of tight control management on Crohn’s disease (CALM) trial was published, a multicenter phase 3, randomized controlled trial designed to evaluate the safety and effectiveness of two treatment strategies in patients with CD scaling to biological therapy based on predefined criteria of treatment failure. The primary endpoint was the mucosal healing, defined by a CDEIS <4 score and the absence of deep ulcers at the end of 48 weeks, patients were randomized into two groups: the “tight control,” where therapy was scaled based on clinical evaluation and biomarkers (fecal calprotectin and CRP), and the clinical management group, in which only the symptom assessment was considered. It was observed that a significantly higher proportion of patients in the “tight control” group reached the primary endpoint compared to the clinical management group, showing that the escalation of biological therapy guided by targets in patients with early CD is associated with better clinical and endoscopic outcomes when there is an association of clinical evaluation and biomarkers for decision-making [13].
\nThe first group of biological medicines was composed by tumoral necrosis factor (TNF) antagonists, approved for use in Crohn’s disease patients in 1998. The currently available anti-TNFs for treatment of CD are infliximab, adalimumab, and certolizumab pegol (Figure 1).
\nTNF’s mechanisms of action - In the pathophysiology of Crohn’s disease, TNF is produced at high concentrations by a variety of cell types, presumably induced by endogenous or microbial stimuli. A cascade and network of cellular responses mediated by TNF are shown in the the diagram.
The infliximab (IFX), a chimeric monoclonal IgG1 antibody, was the first biological used in CD. In 1997, Targan et al. published a randomized controlled trial demonstrating the superiority of the drug in inducing clinical remission in moderate to severe CD compared to placebo. Four groups were defined, involving 108 patients, to receive doses of 5, 10, 20 mg/kg, or placebo. The primary outcome was clinical response after 4 weeks, defined by a decrease of 70 points, or more in CDAI score after a single infusion. It was observed that 81% of patients receiving 5 mg/kg, 50% of those who received 10 mg/kg, and 64% receiving 20 mg/kg achieved the goal, compared to only 17% in the placebo group (
With the efficacy of IFX in inducing clinical remission established, in order to evaluate its efficacy in maintain clinical response in CD, in 2002 the ACCENT I study was published, the most relevant publication related to IFX in CD; a multicenter study (US, Europe, and Israel), controlled trial involving 573 patients with moderate to severe Crohn’s disease (CDAI between 220 and 400). All patients received a dose of IFX 5 mg/kg and were assessed after 2 weeks. Of these, 325 (58%) had clinical response (CDAI decrease of 70 points or more at baseline) and were randomized at week 2 into 03 groups: 5, 10 mg/kg, and placebo. Following treatment regimen suggested by Present et al., doses were administered at weeks 0, 2, and 6, and subsequently administered every 8 weeks. The primary endpoint was clinical remission (CDAI <150 points) maintained after 30 and 54 weeks of initiating therapy. It was observed that those who responded to induction dose had higher remission rate at weeks 30 and 54. The maintenance of clinical remission rates at 54 weeks were significantly higher in the groups that received IFX 5 and 10 mg/kg (28.3 and 38.4%, respectively) compared with placebo (13.6%), showing the effectiveness of maintenance therapy with IFX. No statistical significance was observed in the difference between 5 and 10 mg/kg groups. In addition, in the placebo group, there was no mucosal healing at week 10, whereas patients receiving IFX in doses of 5 and 10 mg/kg, healing was observed in 31% of cases [16]. Following this line of reasoning, ACCENT II was published in 2004, a phase III randomized, double-blind, placebo-controlled study that included 306 patients with penetrating CD (enterocutaneous and perianal fistula), of which 282 were randomized at week 14 after the induction therapy (weeks 0, 2, and 6) for receiving infusions of 5 mg/kg or placebo every 8 weeks, aiming to evaluate the loss of IFX response in both groups after 54 weeks of treatment. It was observed that the time to loss of response was significantly higher in the IFX group over placebo (>40 weeks vs. 14,
In order to assess the IFX therapy effectiveness in induction and maintenance of clinical response in moderate to severe UC two phase III placebo-controlled studies were subsequently published: the ACT I and II. With a total of 364 patients involved in each study, they were randomized to receive placebo, 5 or 10 mg/kg at weeks 0, 2, and 6, followed by infusions every 8 weeks through weeks 46 (ACT I) and 22 (ACT II). The primary endpoint was to evaluate clinical response (defined as decrease of three points in Mayo score and, at least, one point in the sub-item for rectal bleeding) at week 8, having as secondary endpoints the clinical response or remission after corticosteroid withdrawal and mucosal healing at weeks 8, 30 in both studies, and at week 54 in ACT I. In this last study, only 37% of patients in placebo group had clinical response at week 8 versus 69% (
The pivotal studies mentioned consolidated IFX use as induction and maintenance therapy in CD and UC. However, in general, the clinical trials inclusion criteria are too restrictive, restricting the participation of most patients in daily clinical practice. One of the biggest real-life studies evaluating the effectiveness of treatment of CD with IFX was published in 2009 by Schnitzler et al. from Leuven group. Six hundred fourteen patients were evaluated with a median of 55 months follow-up, in which approximately 11% were primary non-responders. Of the 547 remaining, 63.3% of patients had sustained clinical benefit. Treatment was discontinued in 31.7% of cases due to complete remission, 12.8% due to adverse events, and 21.6% due to loss of response to the drug. This study demonstrated that good results can be obtained with IFX treatment in the real world, when the requirements of controlled studies are often not attained [19].
\nIn order to evaluate the safety profile and long-term repercussions of IFX treatment based on real life clinical experience, Sandborn et al. published in 2012 a study involving 492 CD patients treated between 1998 and 2002 at the Mayo Clinic and followed until 2009. It was shown that approximately 80% of patients showed clinical response to induction therapy, of which 25% with partial and 75% with complete response, in agreement with previously reported data [16, 17]. Dose escalation or shortening of the interval between infusions occurred in approximately 57% of patients who received maintenance dose with a cumulative probability of a therapeutic adjustment of 19% in the first year, 57% in 5 years, and 74% in 10 years of follow-up, reflecting that there is a loss of response over time. Note that 10% of the 182 patients who received maintenance therapy, discontinued its use because of loss of response. The cumulative probability of adverse events was around 35% in the first year, increasing to 86% after 10 years of therapy. Approximately 5% of patients developed cancer, with a cumulative probability of 9.1% in 10 years, though it was unclear if this increased incidence of cancer was related to the CD itself, the use of IFX or because this study was performed at a reference center with a specific profile of patients. The most common infectious complications were bacterial infection (intra-abdominal abscesses and pneumonia) and viral [20].
\nLong-term studies have demonstrated that, despite its effectiveness, IFX shows loss of response over time, with frequent need for dose escalation due to their immunogenicity. Then was raised the possibility of association of anti-TNF with immunosuppressive agents such as azathioprine (AZA) and 6-mercaptopurine, as synergists agents. In this context, the SONIC study was published in 2010 evaluating 508 patients with CD randomized to three different treatment strategies: IFX monotherapy, AZA monotherapy, or combination therapy with the two drugs. After 30 weeks of treatment, approximately 57% of patients treated with the combination therapy achieved corticosteroid free clinical remission (primary endpoint), compared to 44.4% in IFX monotherapy group (
The data presented above have reassured that IFX, marketed for over 20 years, are efficient and have a satisfactory safety profile, being considered as a first-line biological treatment of IBD, especially in the management of perianal Crohn’s disease and severe acute colitis. Moreover, it plays an important role in the management of extra intestinal manifestations and the prevention of postoperative recurrence [23].
\nAdalimumab, a fully humanized monoclonal antibody IgG1, was the second anti-TNF antibody released for treating IBD. The first paper published on the efficacy of ADA in induction of remission in CD was the CLASSIC I trial in 2006. Aiming the assessment of clinical response after 4 weeks of treatment (CDAI <150 points), 299 patients naïve to anti-TNF therapy were randomized to receive, respectively, at weeks 0 and 2, a dose of ADA 40/20, 80/40, 80/160 mg, or placebo. The results showed major clinical remission rate at a dose of 160/80 mg (36%) compared to placebo (12%,
In order to establish the efficacy of ADA in maintaining clinical response, CLASSIC II was subsequently published evaluating 55 patients from the CLASSIC I who were in clinical that were further randomized to three different treatment regimens: ADA 40 mg every other week, 40 mg weekly, or placebo until completing 56 weeks. In addition, 204 patients from CLASSIC I who were not in clinical remission were enrolled in an open label arm to use ADA 40 mg every other week. The primary endpoint was to evaluate the clinical remission (CDAI <150 points) among randomized patients and it was observed that 79% of patients receiving ADA every other week and 83% of those who received ADA weekly were in clinical remission against 44% in the placebo group (
In order to emphasize the sustained efficacy of ADA in CD therapy, in 2007 Colombel et al. published the CHARM trial, a phase III study involving 854 patients who initially were subjected to induction with ADA, of which 499 (58%) had initial clinical response (CDAI decrease in ≥70 basal line) and were randomized to maintenance therapy with ADA 40 mg every other week, 40 mg weekly, or placebo with assess of clinical remission (CDAI <150) after 26 and 56 weeks of therapy. Analyzing the randomized groups, it was noted that clinical remission was significantly greater in the groups using ADA than to placebo at week 56, with 41% in the group receiving the drug weekly, 36% in the group receiving every other week, and 12% in the placebo group (
In order to properly evaluate the effectiveness of ADA as a rescue therapy in patients with CD who have intolerance or loss of response to IFX, GAIN study was further published in 2006. Similarly to CLASSIC I, clinical remission was assessed at the end of 4 weeks after the randomization of 325 patients to receive induction therapy (160 and 80 mg at weeks 0 and 2) or placebo. It was observed that 21% of patients with ADA therapy reached the primary endpoint compared to only 7% in the placebo group (
The therapy with ADA in UC was described later, when, in 2010, ULTRA 1 was published evaluating the drug efficacy in induction of clinical remission in patients naive for biological drugs. The study included 390 patients randomized into three groups to receive ADA in induction regimen with 160/80 mg at weeks 0 and 2, followed by 40 mg at weeks 4 and 6; 80/40 mg at weeks 0 and 2, followed by 40 mg every other week and the placebo group. At the end of 8 weeks, approximately 19% of patients in group 160/80 mg showed clinical remission compared with 9.2% of patients in the placebo group (
To analyze the efficiency in the induction of remission and also the maintenance of clinical response ULTRA 2 was sequentially published, studying 494 patients with UC who were initially stratified by prior use or not of anti-TNF alpha and randomized for induction therapy with ADA 160/80 mg at weeks 0 and 2 followed by ADA 40 mg every other week or placebo. The primary endpoint was clinical remission at weeks 8 and 52. Analyzing the group as a whole, there was no statistically significant difference at week 8, however, at week 52, 17.3% of patients with ADA achieved clinical remission superior to placebo group (8.5%,
Even though data in pivotal studies for ADA in UC are not as robust, Tursi et al. published in 2018 the results of a real-life study involving 102 UC patients demonstrating drug efficacy and safety more consistently. The primary outcome was the induction and maintenance of remission, defined by a Mayo score ≤ 2. At 3 months, 54.9% of patients achieved clinical remission and during an average follow-up of 18 months, 56.6% of the patients were in this same situation. Secondarily, clinical response and mucosal healing was achieved by 89.2 and 76.7% of the patients, respectively. Only three patients underwent colectomy (two because of primary therapeutic failure and one for secondary loss) and one patient discontinued treatment due to leukopenia [30].
\nIn relation to real life experience in CD, Loftus et al. recently published the results of PYRAMID registry, evaluating the efficacy and safety of ADA in patients naive to biological therapy followed for 6 years. Taking into consideration the Physician’s Global Assessment (PGA) and clinical remission (Harvey Bradshaw index <5), 2057 patients were analyzed with an improvement baseline PGA from 7.5 to 3.9 in the first year and 3.3 in the sixth year. The rate of patients in clinical remission increased from 29 to 68% and 75% after 1 and 6 years, respectively. As related to adverse events, 11.1% of patients had severe infections and the incidence of malignancy was relatively low (1.9%) [31].
\nADA has demonstrated superiority to placebo for induction and maintenance of remission in patients with CD and UC. Its subcutaneous administration seems to be a more convenient approach to patients who prefer to self-administer. It is also considered a first-line agent in the management of moderate to severe CD and UC patients refractory to conventional therapy with a satisfactory safety profile.
\nCertolizumab pegol (CZP), a pegylated humanized Fab fragment of IgG1 was also studied in CD. Although the initial induction trial did not demonstrate statistically significant difference in clinical remission after 6 weeks of treatment compared to placebo
Since chronic inflammatory diseases usually have a higher incidence and prevalence in females, there is much discussion about what would be the best therapeutic strategy to be adopted during pregnancy, once treatment suspension may be associated with “flares” of the underlying disease with deleterious effects for both the mother and fetus, in addition to the fact that anti-TNF alpha present variables degrees of placental transfer that can influence the immune response of the newborn. Due to its molecular conformation devoid of the Fc region, which prevents recognition by the FcRn receptor and consequently the active placental transfer, certolizumab pegol was evaluated as a safe treatment option during pregnancy [34].
\nIn 2017, a prospective pharmacokinetic study (CRIB study) was published evaluating 16 patients with at least 30 weeks pregnancy who were treated with CZP (three of them with CD) to assess the degree of placental transfer to the fetus via the dosage of the serum level of the drug in the newborn plasma. Patients were required to receive the last dose of CZP within a maximum of 35 days before delivery to be included. It was observed that even with maternal plasma levels within the therapeutic range of CZP, 13 of the 16 neonates had no detectable levels of CZP in plasma and one shows minimum levels (0.09% concentration in maternal plasma), which hardly had any clinical consequences [34]. In accordance with previous studies, it was shown that CZP presents minimal to no placental transfer even when used in the third trimester of pregnancy, unlike IFX, or ADA [35]. In the same year, CRADLE study analyzed breast milk from 17 mothers who were treated with the CZP (five of them with CD), showing that the drug concentration in breast milk is minimal, with a relative dose transferred to the newborn well below the 10% limit considered safe. Besides that, adverse events in patients exposed to CZP were consistent with the known safety profile and newborns had an adverse event profile that could be expected in an untreated population of similar age [36].
\nThe CZP presents itself as another subcutaneously administered anti-TNF option for CD with a suitable safety profile, especially in women in the reproductive phase.
\nMain studies | Objective | Primary end point | Results | Conclusion |
---|---|---|---|---|
Assess the efficacy of IFX in inducing clinical response in patients with moderate to severe CD | Reduction of CDAI ≥ 70 points after 4 weeks of single induction dose | Placebo: 17% had clinical response IFX 5 mg/kg: 81% had clinical response IFX 10 mg/kg: 50% had clinical response IFX 20 mg/kg: 64% had clinical response | A single induction dose is superior to placebo to induce clinical response in patients with moderate to severe CD | |
ACCENT I | Assess the benefit of maintenance therapy with infliximab in patients with active CD who responded to a single initial infusion of infliximab | Clinical remission at week 30 (CDAI < 150) and time to loss of clinical response by week 54 | Placebo: 21% in remission at week 30; mean time to loss of response of 19 weeks IFX 5 mg/kg at weeks 2 and 6, followed by 5 mg/kg every 8 weeks: 39% in remission at week 30; mean time to loss of response of 38 weeks IFX 5 mg/kg at weeks 2 and 6, followed by 10 mg/kg every 8 weeks: 45% in remission at week 30; mean time to loss of response >54 weeks | Patients who initially responded to IFX are most commonly in remission at week 30 and 54, when a dose of IFX is maintained every 8 weeks |
ACCENT II | Assess the efficacy of maintenance treatment with IFX in the closure of fistulas in patients with CD having one or more fistulas who have responded to the induction therapy with IFX | Time to loss of response during 54 weeks of follow-up among patients who had a response at week 14 and were randomized | Placebo: mean time of 14 weeks to loss of response IFX: mean time to loss of response of over 40 weeks | Patients with penetrating CD responding to induction therapy are more likely to have a sustained clinical response to maintenance therapy over a 54-week period |
ACT I | Assess the efficacy of IFX in induction and maintenance therapy in patients with moderate to severe UC | Clinical response at week 8 and secondarily, clinical remission and mucosal healing at weeks 8, 30, and 54 (among other secondary end points) | Clinical response at week 8:
| Patients with moderate to severe UC treated with IFX at weeks 0, 2, and 6, followed by maintenance every 8 weeks, more commonly have a clinical response at weeks 8, 30, and 54 than those who received placebo |
ACT II | Assess the efficacy of IFX in induction and maintenance therapy in patients with moderate to severe UC | Clinical response at week 8 and secondarily, clinical remission and mucosal healing at weeks 8 and 30 (within other secondary end points) | Clinical response at week 8:
| Patients with moderate to severe UC treated with IFX at weeks 0, 2, and 6, followed by maintenance every 8 weeks, more commonly have a clinical response at weeks 8 and 30 than those receiving placebo |
SONIC | Comparatively assess the efficacy of IFX monotherapy, AZA monotherapy or combined therapy in patients with moderate to severe CD naïve for biological therapy | Clinical remission free of corticoid and, secondarily, mucosal healing at week 26 | Clinical remission at week 26:
| Patients with moderate to severe CD treated with IFX or IFX + AZA are more likely to achieve clinical remission free of corticosteroids than those treated with AZA alone |
SUCCESS | Comparatively evaluate the efficacy of IFX monotherapy, AZA monotherapy, or combined therapy in patients with moderate to severe UC naïve for biological therapy | Clinical remission free of corticoid and secondarily mucosal healing at week 16 | Clinical remission at week 16:
| Patients naive for biological drugs with UC treated with combined therapy are more likely to achieve clinical remission than those treated with monotherapy drugs. Combined therapy is associated with better mucosal healing rates when compared to AZA monotherapy |
CLASSIC I | Assess ADA’s efficacy in inducing clinical remission in patients with moderate to severe CD naive for biological therapy | Clinical remission at week 4 after initial induction therapy | Placebo: 12% of the patients achieved remission ADA 40/20 mg: 18% of the patients achieved remission 18% (p = 0.36) ADA 80/40 mg: 24% of the patients achieved remission (p = 0.06) ADA 160/80 mg: 36% of the patients achieved remission (p = 0.001) | The ADA was superior to placebo in clinical remission induction in patients naive for biological therapy with moderate to severe CD, with a dose of 160 mg at week 0 followed by 80 mg at week 2 as the recommended regimen |
CLASSIC II | Assess the efficacy and safety of ADA in maintenance therapy in patients with moderate to severe CD | Maintenance of clinical remission at week 56 in the group of patients randomized after responding to induction therapy | Placebo: 44% of the patients had clinical remission ADA 40 mg every other week: 79% of the patients maintained clinical remission ADA 40 mg weekly: 83% of the patients maintained clinical remission | ADA was more effective than placebo in maintain remission after 56 follow-up |
ULTRA I | Assess the effectiveness of ADA in clinical remission induction in patients with moderate to severe UC naive for biological therapy | Clinical remission at week 8 after initial induction therapy | Placebo: 9.2% of the patients achieved remission ADA 80/40 mg: 10% of the patients achieved remission (p = 0.833) ADA 160/80 mg: 18.5% of the patients reached remission (p = 0.031) | The 160/80 mg dose of ADA was effective and safe in inducing clinical remission in patients with moderate to severe UC who failed to corticoid or immunosuppressive therapy |
ULTRA II | Assess the efficacy and safety of ADA in maintenance therapy of patients with moderate to severe UC | Maintenance of clinical remission at week 8 and week 52 after induction therapy | Placebo: 9.3% at week 8 and 8.5% at week 52 ADA: 16.5% at week 8 and 17.3% at week 52 | ADA was effective and safe in maintaining clinical remission in patients with moderate to severe UC who failed to corticoid or immunosuppressive therapy |
CHARM | Assess the efficacy and safety of ADA in maintenance therapy in patients with moderate to severe CD who responded to induction therapy | Percentage of patients who responded to induction and achieved clinical remission at weeks 26 and 56 | Placebo: 17% at week 26 and 12% at week 56 ADA 40 mg every other week: 40% at week 26 and 36% at week 56 ADA 40 mg weekly: 47% at week 26 and 41% at week 56 | ADA maintenance therapy in patients with moderate to severe CD who responded to induction therapy was more effective than placebo in maintaining clinical remission after 56 weeks of follow-up |
GAIN | Assess the efficacy of ADA in inducing clinical remission in patients with moderate to severe CD who lost response or were intolerant to IFX | Clinical remission at week 4 after ADA induction therapy | Placebo: 7% achieved clinical remission at week 4 ADA: 21% achieved clinical remission in week 4 | ADA was more effective than placebo in inducing clinical remission in patients who lost or were intolerant to IFX |
PRECISE 2 | Assess the efficacy and safety of CTZ in inducing and maintaining response and clinical remission in patients with moderate to severe CD who have responded to induction therapy | Clinical response rates in patients with baseline CRP ≥10 mg/L at week 26 | Placebo: 36% of patients maintained clinical response CTZ: 62% of patients maintained clinical response | Among patients who responded to the initial induction dose, maintenance of CTZ was more effective in maintaining clinical response than placebo |
PURSUIT | Assess the efficacy of golimumab in maintaining clinical response in patients with moderate to severe UC who responded to induction therapy | Maintenance of clinical response at week 54 | Placebo: 31.2% of the patients maintained clinical response Golimumab 50 mg: 47% of the patients maintained clinical response Golimumabe 100 mg: 49.7% of the patients maintained clinical response | Golimumab maintenance therapy was more effective than placebo in maintaining clinical response after 54 weeks of follow-up |
Main studies with Anti-TNF in inflammatory bowel disease.
Golimumab (GOLI), a fully humanized antibody anti-TNF alpha administered subcutaneously, has been described as effective in induction of clinical response and remission in ulcerative colitis in 2014, with the publication of PURSUIT-SC. This study combined the analysis of a phase 2 study (used to evaluate the appropriate dose of induction therapy) and phase 3, demonstrating the superiority of the drug over placebo. After determining the doses of 200/100 and 400/200 mg at the weeks 2 and 0 as the most appropriate induction regimen, 761 patients were randomized 1:1:1 to receive said regimens or placebo. At the end of 6 weeks, it was observed that the groups randomized to receive the golimumab 200/100 and 400/200 mg had better clinical response (51 and 54.9%, respectively) than placebo (30.3%;
Having 464 patients who responded to induction therapy with GOLI in previous studies (PURSUIT-SC and PURSUIT-IV), PURSUIT-M evaluated the efficacy of the drug in maintaining clinical response. Patients were randomized to receive 50, 100 mg, or placebo every 4 weeks and evaluated after 52 weeks of treatment at week 54. As a result, 47% of patients receiving 50 mg and 49.7% of those who received 100 mg had sustained clinical response, while 31.2% of those receiving placebo had the same result (
Thus, GOLI is presented as another subcutaneous anti-TNF therapy option for ulcerative colitis. Due to its recent approval, more data on its long-term safety and real life experience are needed (Table 1).
\nAs stated above, the treatment of IBD with the advent of anti-TNF alpha and more recently, other classes of biological drugs (anti-integrin, anti-IL 12/23 etc.) has dramatically changed the natural history of the disease and the incidence of complications. However, no head to head studies directly compared the efficacy of different drugs. Lacking such data, the decision on which treatment regimen to be used is mainly based on reported clinical experience, proposed algorithms by clinical trials, patient preference and safety profile [38].
\nAlthough imperfect, indirect comparative analyses, such as network meta analyses are available evidence to assess efficacy of different drugs. In 2018, Singh et al., through a systematic review and network meta-analysis, compared the efficacy and safety of treatment with various biological drugs in CD in naive patients for biological therapy (first-line therapy) and in patients previously tested with some anti-TNF (second-line therapy). Comparing direct and indirect evidence from 18 randomized controlled trials (RCT’s) involving patients with moderate to severe CD, it was observed that anti-TNF alpha, particularly IFX and ADA, were the options with strongest evidence in the induction of clinical remission and response as well as maintenance therapy. Ustekinumab and vedolizumab appear to have similar efficacy in the first-line therapy and were not higher when compared to IFX or ADA. The CZP at the standardized dose has been reported as inferior to the other agents.
\nAs second-line therapy (non-RCT using IFX or CZP as a second biological drug was identified), in the specific subgroup of patients who lost response or were intolerant to IFX, ADA seems to be superior compared to other agents. It is noteworthy that, for patients with primary nonresponse to IFX, the effectiveness of the ADA is uncertain, scenario in which ustekinumab seems to gain prominence. The safety profile and the incidence of major adverse events were assessed in maintenance studies, not being seen clear superiority of one agent over the other, although the risk of adverse events appears to be low to IFX and ustekinumab. However, RCT’s involved in the analysis were not powered to determine this difference, so this result should be evaluated with caution. Vedolizumab, a gut-selective anti-integrin, has not been clearly associated with an increased risk of serious infections in RCT’s analysis and longitudinal cohorts. It is noteworthy that the risk factors most associated with severe infections were concomitant use of corticosteroids, narcotics and severe disease activity [38].
\nThe same group published a meta-analysis evaluating the therapy in UC, where, besides the efficacy of induction/maintenance of clinical remission and safety profile of the drug, mucosal healing was also assessed. Combining direct and indirect evidence of 14 RCT’s including 4212 patients with moderate to severe disease, the group concluded that, as first-line therapy, all evaluated agents (IFX, ADA, golimumab, and vedolizumab tofacitinibe) were superior to placebo, with IFX and vedolizumab considered the most effective in the inducing of clinical remission and mucosal healing. In general, ADA was considered the least effective agent for both outcomes. Comparing IFX to ADA, data obtained favor IFX for induction of remission, however, as maintenance therapy, it appears to be no significant difference between the two drugs [39]. Superiority of IFX can be associated with pharmacokinetics and bioavailability of the drug since its dosage is variable according to the weight of the patient, unlike ADA with a fixed dose.
\nAs second line therapy, tofacitinib (JAK-2 inhibitor) seems to be the best choice for induction of remission and mucosal healing. A direct meta-analysis further demonstrated that vedolizumab and ADA were not superior to placebo, conferring a low level of evidence to indicate these drugs as a therapeutic alternative in this scenario. Importantly however, the studies that assessed ADA included only patients who lost response or were intolerant to IFX as part of the patients treated with vedolizumab were not primary responders to IFX, which may be linked to a specific population with a more aggressive form of the disease, disadvantaging vedolizumab in this analysis. This information was not clear in studies with tofacitinib and no study using IFX or golimumab as a second biological drug was identified [39].
\nAs a maintenance therapy, because of differences in the design of studies, RCT’s involving IFX and ADA were considered separately from those involving golimumab, vedolizumab, and tofacitinib. As stated earlier, IFX and ADA appear to be equally effective in maintaining remission in naive treatment patients. The other drugs were also superior to placebo in patients who responded to induction therapy and did not seem to differ from each other. Regarding the safety profile, none of the options was significantly worse compared to placebo in the incidence of adverse events. Taking into account the incidence of serious infections, vedolizumab seems to be the safer drug, since there was no difference compared to placebo, while golimumab and tofacitinib were associated to higher risk of infection [39].
\nIn an innovative way, the preliminary results of VARSITY, the first head to head trial in IBD were presented in a specific event. It is a phase 3b double-dummy, controlled and randomized trial, comparing ADA and vedolizumab in the treatment of moderate to severe UC. With a total of 769 patients who had failed conventional therapy (25% had been exposed to any anti-TNF), which were randomized into four groups to receive vedolizumab vs. placebo or adalimumab vs. placebo, clinical remission (primary endpoint), and mucosal healing were assessed after 52 weeks. It has been observed that patients treated with vedolizumab achieved clinical remission rates of 31.3% and mucosal healing of 39.7%, significantly better than patients treated with ADA (22.5%
The use of TNF-alpha inhibitors and their combination with thiopurines has proved to be more effective in controlling severe forms of CD and UC compared to monotherapy [21, 22]. However the use of these drugs is associated to a higher risk of adverse events, particularly infections and malignancies [41, 42].
\nThe analysis of a cohort study involving a large number of patients [43], showed a higher risk of serious and opportunistic infections in combination therapy than with the use of anti-TNF or thiopurines alone. Comparing anti-TNF and thiopurines in monotherapy, there was a higher incidence of serious infections and mycobacterial infections associated with anti-TNF, however, there is no difference in the incidence of opportunistic infections in general, since thiopurines were associated with higher chance of viral opportunistic infections and anti-TNF to bacterial infections. It is noteworthy that the results of a previous meta-analysis showed an increased incidence of opportunistic infections by bacteria and mycobacteria in patients treated with the combination therapy compared to monotherapy with anti-TNF, inferring that the use of thiopurines adds an extra risk for developing infections [44]. There was a higher incidence of viral opportunistic infections when combination therapy was compared to monotherapy with anti-TNF, but it did not differ when compared to monotherapy with the thiopurines, suggesting that the risk of this complication in the combination therapy is due to the use of thiopurines [45].
\nIt should be considered that not only therapeutic option is linked with a higher risk of infectious complications, but also the patient’s age, disease severity, and concomitant use of corticosteroids, all those associated with a worse outcome [46].
\nClassically, therapy with thiopurines is associated with an increased risk of malignancy in patients with IBD, particularly non-Hodgkin’s lymphoma, hepatosplenic lymphoma associated with EBV, cervical cancer associated with HPV, urinary tract cancer, and non-melanoma skin cancer, both as monotherapy and in combination therapy with an anti-TNF agent [42]. However, the association between malignancy and anti-TNF alpha use remains uncertain. In prior meta-analysis involving 21 placebo-controlled trials including more than 5000 patients with CD, treatment with anti-TNF was not associated with an increased risk of cancer development [47].
\nThrough the analysis of the TREAT™ Registry database, a prospective cohort study that evaluated the outcomes of long-term treatment regimens in DC involving 6237 patients in with more than half used the IFX sometime in the follow-up, it was found that, in general, the incidence of cancers (benign or malignant) was similar between the group treated with IFX and with the other therapeutic options [48]. In this study, age, disease duration and smoking were associated with increased risk of cancer. In a more recent meta-analysis including 44 RCT’s and more than 14,000 patients, and the incidence of malignancy as a secondary outcome, it was not possible to conclude that the use of anti-TNF significantly affect the risk of cancer. However, the data were scarce and periods of exposure and follow-up were too short to allow conclusions [41]. The incidence of melanoma is described as higher in patients with IBD in general, however, some studies suggest a possible association with the use of anti-TNF [49] while others do not [50].
\nA recent French cohort gathered data from nearly 190,000 patients to assess risk of lymphoma in patients with IBD that used azathioprine and/or anti-TNF agents. Surprisingly, not only the use of thiopurines but also the use of anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma among patients exposed. The risk was greater in the combination therapy than either drug alone [51].
\nOther adverse events associated with anti-TNF therapy are described and should also be remembered. Since there are reported the reactivation of tuberculosis and hepatitis B virus after initiation of therapy, the pretreatment screening, in order to guide the treatment of latent tuberculosis and prophylaxis with antiretroviral, is indicated [52, 53]. In those patients who are in triple immunosuppression,
Although effective in the induction and maintenance of clinical remission and mucosal healing, the therapeutic fail of anti-TNF is not uncommon in IBD, occurring in patients which are considered as primary non-responders (10–40% approximately) or lose the response in the first year of treatment (24–46%), and those who have some adverse effect that lead to treatment interruption [24, 26]. An understanding of the factors involved in therapeutic failure, as the patient’s profile, the presentation of the disease and the relationship between the concentration of the drug and its interaction with the anti-drug antibodies (ADAbs), are useful tools to guide the best strategy to be followed [55].
\nanti TNF’s mechanisms of action are illustrated above. The inflammatory cascade triggered by TNFR is disrupted by anti TNF-mediated direct blockade, which prevents binding of sTNF and tmTNF to specific receptors. On the right are the results of tmTNF antagonization by the drug, which include cytotoxicity of the CDC (complement ? dependent cytotoxicity) or ADCC (antibody-dependent cellular cytotoxicity), as well as reverse signaling via tmTNF. The pharmacokinetics-related are illustrated at the bottom of the image.
The concentration of drug in the site of action is directly linked to the magnitude of the expected pharmacological response and its monitoring in specific scenarios can assist in therapeutic decision. For example, the patient may experience an inadequate response due to the low concentration of the drug secondary to increased clearance, differing completely from one that has inadequate response with therapeutic trough levels, suggesting mechanistic failure. In the first situation, dose escalation can be effective, while the second would most benefit from exchange to a medication with a distinct mechanism of action (Figure 2) [56].
\nBased on these assumptions, in 2017, the American Gastroenterological Association has published a technical review on the role of therapeutic drug monitoring (TDM) as an auxiliary tool in decision-making regarding treatment of IBD. In the absence of adequate response, the dosage of the trough level of the drug has been suggested as a first step (reactive approach): if the serum levels of anti-TNF are within the therapeutic range, it is characterized the failure to the mechanism of action and class exchange is possibly the best option. However, if serum levels are below the appropriate, dosage of ADAbs can bring additional information: if they are high, it is likely that the clearance of the drug is being immune-mediated, and it is plausible the exchange of medication for a drug of the same class, besides the association with immunomodulator. If the ADAbs level is undetectable or low, it is likely that the clearance is increased due to mechanisms not immune-mediated, such as severe inflammatory burden leading to rapid use of anti-TNF and/or excessive loss in feces (indicated by hypoalbuminemia, CRP, and high fecal calprotectin), which would allow the optimization of the dosage instead of changing the biological agent. This strategy seems to be more effective than making decisions empirically, despite the low level of evidence further described [56]. In patients with the disease in remission, the dosage of the trough level and ADAbs as an auxiliary tool in decision-making (proactive proposal) is still uncertain, with few studies that corroborate its effectiveness, mainly regarding cost savings [57, 58].
\nIn order to examine predictors of therapeutic failure to anti-TNF, PANTS study has been recently published, a randomized clinical trial involving patients with luminal CD naive for biological therapy who started treatment with IFX or ADA. Through regression logistic, it was identified that only low trough level in week 14 (IFX < 7 mg/L and ADA < 12 mg/L) was associated to the absence of primary response. Obesity, smoking, hypoalbuminemia, high levels of inflammatory markers, and the development of immunogenicity were associated with lower serum levels of the drug. It was also observed that low levels at week 14 were independently associated to non-clinical remission at week 54, and were associated with increased formation of ADAbs. The combination with immunomodulators (azathioprine or methotrexate) was associated with lower immunogenicity for both IFX and ADA, and in the group of patients with IFX, combination therapy was associated with higher clinical remission rate at week 54 compared to monotherapy with IFX, unlike ADA, which was not more effective in maintaining remission when associated with immunomodulators [55].
\nThe initiation of therapy with tumor necrosis factor inhibitors certainly was a milestone in the treatment of inflammatory bowel disease, drastically changing the natural course of the disease and offering better quality of life to treated patients. With an acceptable safety profile, anti-TNF agents are excellent therapeutic options in severe forms of the disease, with proven efficacy in both Crohn’s disease and ulcerative colitis. The association with immunomodulators, particularly to infliximab is associated with better outcomes. A lack of head to head trials that compares the biological drugs limits the assessment of superiority among them to indirect comparisons, making it crucial that such evidence come to light. Therapeutic drug monitoring seems to be useful tools in decision-making and can increase the therapeutic success rates obtained. However, in the face of current evidence, it has not yet been consolidated as a cost effective strategy.
\nFuture perspectives involving anti-TNF agents include the development of new molecules of this class. Currently, several new TNF-alpha inhibitors have been studied in patients with CD. The DLX 105 (esbat Tech) is an anti-TNF antibody that has been studied specifically in patients with fistulizing CD, trough a local injection in a phase II trial (ClinicalTrials.gov NCT01624376), but no results are available to date. Other two anti-TNF-alpha oral therapies, V565 (VHsquared) and OPRX-106 (Bio Protalix) are in the pipeline. The V565 is currently recruiting patients with moderate to severely active CD to a phase II study (NCT02976129) after favorable results in a phase Ib (NCT03010787). The OPRX-106 demonstrated efficacy in clinical improvement of biomarkers in a phase II study of patients with mild to moderate UC. It is worth to wait for these promising therapies, since the oral mode of administration may be more convenient for some patients [59, 60].
\nIn the era of the new mechanisms of action, this critical analysis consolidates the anti-TNF agents as viable therapeutic options in the current IBD therapeutic armamentarium.
\nIntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
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\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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2022",numberOfDownloads:2194,editors:[{id:"197557",title:"Dr.",name:"Trudy",middleName:null,surname:"Corrigan",slug:"trudy-corrigan",fullName:"Trudy Corrigan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11371",title:"Cerebral Circulation",subtitle:"Updates on Models, Diagnostics and Treatments of Related Diseases",isOpenForSubmission:!1,hash:"e2d3335445d2852d0b906bb9750e939f",slug:"cerebral-circulation-updates-on-models-diagnostics-and-treatments-of-related-diseases",bookSignature:"Alba Scerrati, Luca Ricciardi and Flavia Dones",coverURL:"https://cdn.intechopen.com/books/images_new/11371.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:341,editors:[{id:"182614",title:"Dr.",name:"Alba",middleName:null,surname:"Scerrati",slug:"alba-scerrati",fullName:"Alba 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Saleh and Amal I. Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/11120.jpg",editedByType:"Edited by",publishedDate:"June 23rd 2022",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10696",title:"Applications of Calorimetry",subtitle:null,isOpenForSubmission:!1,hash:"8c87f7e2199db33b5dd7181f56973a97",slug:"applications-of-calorimetry",bookSignature:"José Luis Rivera Armenta and Cynthia Graciela Flores Hernández",coverURL:"https://cdn.intechopen.com/books/images_new/10696.jpg",editedByType:"Edited by",publishedDate:"June 23rd 2022",editors:[{id:"107855",title:"Dr.",name:"Jose Luis",middleName:null,surname:"Rivera Armenta",slug:"jose-luis-rivera-armenta",fullName:"Jose Luis Rivera Armenta"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"362",title:"Food Technology",slug:"agricultural-and-biological-sciences-plant-biology-food-technology",parent:{id:"41",title:"Plant Biology",slug:"agricultural-and-biological-sciences-plant-biology"},numberOfBooks:4,numberOfSeries:0,numberOfAuthorsAndEditors:201,numberOfWosCitations:484,numberOfCrossrefCitations:335,numberOfDimensionsCitations:723,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"362",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"5824",title:"Herbicide Resistance in Weeds and Crops",subtitle:null,isOpenForSubmission:!1,hash:"610684c4b1e9d8525e35debe68dc35e2",slug:"herbicide-resistance-in-weeds-and-crops",bookSignature:"Zvonko Pacanoski",coverURL:"https://cdn.intechopen.com/books/images_new/5824.jpg",editedByType:"Edited by",editors:[{id:"175043",title:"Associate Prof.",name:"Zvonko",middleName:null,surname:"Pacanoski",slug:"zvonko-pacanoski",fullName:"Zvonko Pacanoski"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5610",title:"Wheat Improvement, Management and Utilization",subtitle:null,isOpenForSubmission:!1,hash:"4b36fae039d0da5bf49b2d6d20f5ff03",slug:"wheat-improvement-management-and-utilization",bookSignature:"Ruth Wanyera and James Owuoche",coverURL:"https://cdn.intechopen.com/books/images_new/5610.jpg",editedByType:"Edited by",editors:[{id:"15636",title:"Ms.",name:"Ruth",middleName:"Otinga",surname:"Wanyera",slug:"ruth-wanyera",fullName:"Ruth Wanyera"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5137",title:"Grain Legumes",subtitle:null,isOpenForSubmission:!1,hash:"9af17ac91fc66472889985bd48d3fdb3",slug:"grain-legumes",bookSignature:"Aakash Kumar Goyal",coverURL:"https://cdn.intechopen.com/books/images_new/5137.jpg",editedByType:"Edited by",editors:[{id:"97604",title:"Dr.",name:"Aakash K.",middleName:null,surname:"Goyal",slug:"aakash-k.-goyal",fullName:"Aakash K. Goyal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5066",title:"Abiotic and Biotic Stress in Plants",subtitle:"Recent Advances and Future Perspectives",isOpenForSubmission:!1,hash:"d37213a7dbc2b6704c13b7ee519b563b",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",bookSignature:"Arun K. Shanker and Chitra Shanker",coverURL:"https://cdn.intechopen.com/books/images_new/5066.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",middleName:null,surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:4,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"49274",doi:"10.5772/61368",title:"Reactive Oxygen Species and Antioxidant Enzymes Involved in Plant Tolerance to Stress",slug:"reactive-oxygen-species-and-antioxidant-enzymes-involved-in-plant-tolerance-to-stress",totalDownloads:4921,totalCrossrefCites:47,totalDimensionsCites:106,abstract:"Plants are continuously exposed to several stress factors in field, which affect their production. These environmental adversities generally induce the accumulation of reactive oxygen species (ROS), which can cause severe oxidative damage to plants. ROS are toxic molecules found in various subcellular compartments. The equilibrium between the production and detoxification of ROS is sustained by enzymatic and nonenzymatic antioxidants. Due to advances in molecular approaches during the last decades, nowadays it is possible to develop economically important transgenic crops that have increased tolerance to stresses. This chapter discusses the oxidative stress and damage to plants. In addition, it reports the involvement of antioxidant enzymes in the tolerance of plants to various stresses.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Andréia Caverzan, Alice Casassola and Sandra Patussi Brammer",authors:[{id:"176303",title:"Dr.",name:"Alice",middleName:null,surname:"Casassola",slug:"alice-casassola",fullName:"Alice Casassola"},{id:"176409",title:"Dr.",name:"Andréia",middleName:null,surname:"Caverzan",slug:"andreia-caverzan",fullName:"Andréia Caverzan"},{id:"176410",title:"Dr.",name:"Sandra",middleName:null,surname:"Patussi Brammer",slug:"sandra-patussi-brammer",fullName:"Sandra Patussi Brammer"}]},{id:"49289",doi:"10.5772/61442",title:"Abiotic and Biotic Elicitors–Role in Secondary Metabolites Production through In Vitro Culture of Medicinal Plants",slug:"abiotic-and-biotic-elicitors-role-in-secondary-metabolites-production-through-in-vitro-culture-of-me",totalDownloads:6998,totalCrossrefCites:40,totalDimensionsCites:106,abstract:"Plant secondary metabolites are having the great application in human health and nutritional aspect. Plant cell and organ culture systems are feasible option for the production of secondary metabolites that are of commercial importance in pharmaceuticals, food additives, flavors, and other industrial materials. The stress, including various elicitors or signal molecules, often induces the secondary metabolite production in the plant tissue culture system. The recent developments in elicitation of plant tissue culture have opened a new avenue for the production of secondary metabolite compounds. Secondary metabolite synthesis and accumulation in cell and organ cultures can be triggered by the application of elicitors to the culture medium. Elicitors are the chemical compounds from abiotic and biotic sources that can stimulate stress responses in plants, leading to the enhanced synthesis and accumulation of secondary metabolites or the induction of novel secondary metabolites. Elicitor type, dose, and treatment schedule are major factors determining the effects on the secondary metabolite production. The number of parameters, such as elicitor concentrations, duration of exposure, cell line, nutrient composition, and age or stage of the culture, is also important factors influencing the successful production of biomass and secondary metabolite accumulation. This chapter reviews the various abiotic and biotic elicitors applied to cultural system and their stimulating effects on the accumulation of secondary metabolites.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Poornananda M. Naik and Jameel M. Al–Khayri",authors:[{id:"176282",title:"Prof.",name:"Jameel M.",middleName:null,surname:"Al-Khayri",slug:"jameel-m.-al-khayri",fullName:"Jameel M. Al-Khayri"},{id:"176284",title:"Dr.",name:"Poornananda M.",middleName:null,surname:"Naik",slug:"poornananda-m.-naik",fullName:"Poornananda M. Naik"}]},{id:"49852",doi:"10.5772/62235",title:"Antioxidant Enzyme Activities and Abiotic Stress Tolerance Relationship in Vegetable Crops",slug:"antioxidant-enzyme-activities-and-abiotic-stress-tolerance-relationship-in-vegetable-crops",totalDownloads:3103,totalCrossrefCites:20,totalDimensionsCites:57,abstract:"Climatic changes can cause serious reductions in yield and crop quality. Under the threat of climatic changes, one of the precautions to cope is selection and development of resistant vegetable genotypes to abiotic stresses. Several physiological and biochemical reactions and different tolerance levels can occur according to plant species. When plants are subjected to environmental stresses such as salinity, drought, temperature extremes, herbicide treatment and mineral deficiency, the balance between the production of reactive oxygen species (ROS) and the quenching activity of antioxidants is upset, often resulting in oxidative damage. Since activated oxygen species can disrupt normal metabolism through oxidative damage to lipids, protein and nucleic acids, plants possess a number of antioxidant enzymes that protect them from these cytotoxic effects. To control the level of ROS and to protect cells under stress conditions, plant tissues contain several enzymes for scavenging ROS. The high levels of antioxidative enzyme activities were determined in the tolerant genotypes of tomatoes, eggplant, peppers, cucumbers, melons, squash, beans, okra, etc. to several abiotic stress factors. Both the whole plant and in vitro callus culture experiments gave similar results. Antioxidant enzymes can be useful for screening to determine the tolerant and sensitive plant genotypes against abiotic stresses.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Sebnem Kusvuran, Sevinç Kiran and S. Sebnem Ellialtioglu",authors:[{id:"139032",title:"Associate Prof.",name:"Sebnem",middleName:null,surname:"Kusvuran",slug:"sebnem-kusvuran",fullName:"Sebnem Kusvuran"},{id:"142251",title:"Prof.",name:"Sebnem",middleName:"Seküre",surname:"Ellialtioglu",slug:"sebnem-ellialtioglu",fullName:"Sebnem Ellialtioglu"},{id:"176220",title:"Dr.",name:"Sevinc",middleName:null,surname:"Uslu Kıran",slug:"sevinc-uslu-kiran",fullName:"Sevinc Uslu Kıran"}]},{id:"50953",doi:"10.5772/64020",title:"Pulse Proteins: From Processing to Structure-Function Relationships",slug:"pulse-proteins-from-processing-to-structure-function-relationships",totalDownloads:3712,totalCrossrefCites:32,totalDimensionsCites:56,abstract:"Interest in alternative protein sources to those derived from animal, soy and wheat is on the rise, as consumers are searching for lower cost, healthier alternatives without compromising product quality and safety. Pulses are rich in protein, carbohydrates, vitamins and minerals and are low in fat. Although pea proteins experience greater integration into the plant protein ingredient market than others, lentil, chickpea, bean and faba beans are not far behind. This review discusses approaches used for extracting pulse proteins used to produce protein products (concentrates/isolates), mechanism driving structure-function relationships as well as potential applications.",book:{id:"5137",slug:"grain-legumes",title:"Grain Legumes",fullTitle:"Grain Legumes"},signatures:"Ashish Singhal, Asli Can Karaca, Robert Tyler and Michael Nickerson",authors:[{id:"178314",title:"Dr.",name:"Michael",middleName:null,surname:"Nickerson",slug:"michael-nickerson",fullName:"Michael Nickerson"},{id:"184142",title:"MSc.",name:"Ashish",middleName:null,surname:"Singhal",slug:"ashish-singhal",fullName:"Ashish Singhal"},{id:"184143",title:"Dr.",name:"Asli",middleName:null,surname:"Can Karaca",slug:"asli-can-karaca",fullName:"Asli Can Karaca"},{id:"184144",title:"Dr.",name:"Robert",middleName:null,surname:"Tyler",slug:"robert-tyler",fullName:"Robert Tyler"}]},{id:"49690",doi:"10.5772/61957",title:"Role of ABA in Arabidopsis Salt, Drought, and Desiccation Tolerance",slug:"role-of-aba-in-arabidopsis-salt-drought-and-desiccation-tolerance",totalDownloads:3454,totalCrossrefCites:26,totalDimensionsCites:52,abstract:"The ability of plants to respond to environmental stimuli is essential to plant survival. Abscisic acid (ABA) is a phytohormone with roles at various stages of plant development. ABA also plays a major role in mediating physiological responses to environmental stresses such as salt, osmotic, and cold stress. Plant responses to environmental stress have been widely studied in the model plant Arabidopsis thaliana and ABA signaling mechanisms elucidated. In general, the adaptive responses of plants to various stress conditions can be either ABA-dependent or ABA-independent. Here we focus on the role of ABA in stress signaling and abiotic stress tolerance. We describe the intrinsic mechanisms that confer stress tolerance via ABA, as well as how ABA-regulated gene products play a role in salt and drought tolerance at different stages of the life cycle. In addition, the contribution of ABA to regulation of stomatal aperture and therefore desiccation tolerance will be discussed. Understanding ABA signaling mechanisms in abiotic stress provides avenues for improving plant performance.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"V. C. Dilukshi Fernando and Dana F. Schroeder",authors:[{id:"46453",title:"Dr.",name:"Dana",middleName:null,surname:"Schroeder",slug:"dana-schroeder",fullName:"Dana Schroeder"},{id:"176279",title:"Dr.",name:"V.C. Dilukshi",middleName:null,surname:"Fernando",slug:"v.c.-dilukshi-fernando",fullName:"V.C. Dilukshi Fernando"}]}],mostDownloadedChaptersLast30Days:[{id:"54624",title:"Past, Present and Future Molecular Approaches to Improve Yield in Wheat",slug:"past-present-and-future-molecular-approaches-to-improve-yield-in-wheat",totalDownloads:1865,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter addresses the development and use of molecular markers for yield enhancement in wheat. Since their key goal for breeding is to maximize yield, extensive efforts have been made toward the improvement of yield. Agronomic traits related to yield, yield-related, disease resistance, and abiotic stresses are considered to be quantitative traits (QTLs), also known as complex traits, because they are controlled by numerous genes and are affected by environmental factors. Researchers have been studying such traits in the past decades for the development of molecular markers which can be used in various wheat breeding studies mainly involving restriction fragment length polymorphism (RFLP), simple sequence repeat (SSR), single nucleotide polymorphism (SNP), random amplified polymorphic DNA (RAPD), and amplified fragment length polymorphism (AFLP). Furthermore, the advent of next-generation sequencing (NGS) has accelerated the discovery of agronomically important genes. All of the technologies have enabled great advances for increasing the productivity of wheat. Here, the past history of first-generation sequencing, present status of second-generation sequencing, and future potential of translational genomics linked to the yield will be discussed.",book:{id:"5610",slug:"wheat-improvement-management-and-utilization",title:"Wheat Improvement, Management and Utilization",fullTitle:"Wheat Improvement, Management and Utilization"},signatures:"Sue Kyung Kim, Jin-Ho Kim and Won-Cheoul Jang",authors:[{id:"193571",title:"Prof.",name:"Won-Cheoul",middleName:null,surname:"Jang",slug:"won-cheoul-jang",fullName:"Won-Cheoul Jang"},{id:"195977",title:"Mr.",name:"Jin-Ho",middleName:null,surname:"Kim",slug:"jin-ho-kim",fullName:"Jin-Ho Kim"},{id:"195978",title:"Dr.",name:"Sue Kyung",middleName:null,surname:"Kim",slug:"sue-kyung-kim",fullName:"Sue Kyung Kim"}]},{id:"55149",title:"Weed Resistance to Herbicides",slug:"weed-resistance-to-herbicides",totalDownloads:2461,totalCrossrefCites:5,totalDimensionsCites:9,abstract:"Unfortunately, herbicide resistance developed shortly after the introduction of the herbicides 2,4‐D in 1957. According the herbicide resistance mechanisms, all processes can be grouped as follows: target‐site resistance, non‐target‐site resistance, cross‐resistance and multiple‐resistance. Target‐site resistance is generally due to a single or several mutations in the gene encoding the herbicide‐target enzyme, which, in turn, decreases the affinity for herbicide binding to that enzyme. Non‐target‐site resistance is caused by mechanisms that reduce the amount of herbicidal active compound before it can attack the plant through the reduced absorption or altered translocation, increased herbicide sequestration or enhanced herbicide metabolism. Cross‐resistance means that a single‐resistance mechanism causes resistance to several herbicides with some mode of action. Multiple‐resistance is a situation where two or more resistance mechanisms are present within the same plant, often due to sequential selection by herbicides with different modes of action. Currently, herbicide resistance has been reported in 478 weed biotypes (252 weed species) in 67 countries. Many of those biotypes are resistant to acetolactate synthase (ALS) inhibitors, PS II inhibitors, ACC‐ase inhibitors and EPSPS inhibitors. Strategy for herbicide‐resistance weed management must involve all the available preventive, cultural, mechanical and chemical measures for effective, safe and cost‐effective weed control.",book:{id:"5824",slug:"herbicide-resistance-in-weeds-and-crops",title:"Herbicide Resistance in Weeds and Crops",fullTitle:"Herbicide Resistance in Weeds and Crops"},signatures:"Sava Vrbničanin, Danijela Pavlović and Dragana Božić",authors:[{id:"199349",title:"Prof.",name:"Sava",middleName:null,surname:"Vrbničanin",slug:"sava-vrbnicanin",fullName:"Sava Vrbničanin"},{id:"204972",title:"Dr.",name:"Danijela",middleName:null,surname:"Pavlovic",slug:"danijela-pavlovic",fullName:"Danijela Pavlovic"},{id:"204973",title:"Prof.",name:"Dragana",middleName:null,surname:"Bozic",slug:"dragana-bozic",fullName:"Dragana Bozic"}]},{id:"50953",title:"Pulse Proteins: From Processing to Structure-Function Relationships",slug:"pulse-proteins-from-processing-to-structure-function-relationships",totalDownloads:3712,totalCrossrefCites:32,totalDimensionsCites:56,abstract:"Interest in alternative protein sources to those derived from animal, soy and wheat is on the rise, as consumers are searching for lower cost, healthier alternatives without compromising product quality and safety. Pulses are rich in protein, carbohydrates, vitamins and minerals and are low in fat. Although pea proteins experience greater integration into the plant protein ingredient market than others, lentil, chickpea, bean and faba beans are not far behind. This review discusses approaches used for extracting pulse proteins used to produce protein products (concentrates/isolates), mechanism driving structure-function relationships as well as potential applications.",book:{id:"5137",slug:"grain-legumes",title:"Grain Legumes",fullTitle:"Grain Legumes"},signatures:"Ashish Singhal, Asli Can Karaca, Robert Tyler and Michael Nickerson",authors:[{id:"178314",title:"Dr.",name:"Michael",middleName:null,surname:"Nickerson",slug:"michael-nickerson",fullName:"Michael Nickerson"},{id:"184142",title:"MSc.",name:"Ashish",middleName:null,surname:"Singhal",slug:"ashish-singhal",fullName:"Ashish Singhal"},{id:"184143",title:"Dr.",name:"Asli",middleName:null,surname:"Can Karaca",slug:"asli-can-karaca",fullName:"Asli Can Karaca"},{id:"184144",title:"Dr.",name:"Robert",middleName:null,surname:"Tyler",slug:"robert-tyler",fullName:"Robert Tyler"}]},{id:"49289",title:"Abiotic and Biotic Elicitors–Role in Secondary Metabolites Production through In Vitro Culture of Medicinal Plants",slug:"abiotic-and-biotic-elicitors-role-in-secondary-metabolites-production-through-in-vitro-culture-of-me",totalDownloads:6998,totalCrossrefCites:40,totalDimensionsCites:106,abstract:"Plant secondary metabolites are having the great application in human health and nutritional aspect. Plant cell and organ culture systems are feasible option for the production of secondary metabolites that are of commercial importance in pharmaceuticals, food additives, flavors, and other industrial materials. The stress, including various elicitors or signal molecules, often induces the secondary metabolite production in the plant tissue culture system. The recent developments in elicitation of plant tissue culture have opened a new avenue for the production of secondary metabolite compounds. Secondary metabolite synthesis and accumulation in cell and organ cultures can be triggered by the application of elicitors to the culture medium. Elicitors are the chemical compounds from abiotic and biotic sources that can stimulate stress responses in plants, leading to the enhanced synthesis and accumulation of secondary metabolites or the induction of novel secondary metabolites. Elicitor type, dose, and treatment schedule are major factors determining the effects on the secondary metabolite production. The number of parameters, such as elicitor concentrations, duration of exposure, cell line, nutrient composition, and age or stage of the culture, is also important factors influencing the successful production of biomass and secondary metabolite accumulation. This chapter reviews the various abiotic and biotic elicitors applied to cultural system and their stimulating effects on the accumulation of secondary metabolites.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Poornananda M. Naik and Jameel M. Al–Khayri",authors:[{id:"176282",title:"Prof.",name:"Jameel M.",middleName:null,surname:"Al-Khayri",slug:"jameel-m.-al-khayri",fullName:"Jameel M. Al-Khayri"},{id:"176284",title:"Dr.",name:"Poornananda M.",middleName:null,surname:"Naik",slug:"poornananda-m.-naik",fullName:"Poornananda M. Naik"}]},{id:"49669",title:"Drought Adaptation in Millets",slug:"drought-adaptation-in-millets",totalDownloads:3565,totalCrossrefCites:15,totalDimensionsCites:27,abstract:"Millets are major food and feed sources in the developing world especially in the semi-arid tropical regions of Africa and Asia. The most widely cultivated millets are pearl millet [Pennisetum glaucum (L.) R. Br.], finger millet [Eleusine coracana (L.) Gaertn], foxtail millet [Setaria italica (L.) P. Beauvois], Japanese barnyard millet [Echinochloa esculneta (A. Braun) H. Scholz], Indian Barnyard millet [Echinochloa frumetacea Link], kodo millet [Paspalum scrobiculatum L.], little millet [Panicum sumatrense Roth.ex.Roem. & Schult.], proso millet [Panicum miliaceum L.], tef [Eragrostis tef (Zucc.) Trotter] and fonio or acha [Digitaria exilis (Kippist) Stapf and D. iburua Stapf]. Millets are resilient to extreme environmental conditions especially to inadequate moisture and are rich in nutrients. Millets are also considered to be a healthy food, mainly due to the lack of gluten (a substance that causes coeliac disease) in their grain. Despite these agronomic, nutritional and health-related benefits, millets produce very low yield compared to major cereals such as wheat and rice. This extremely low productivity is related to the challenging environment in which they are extensively cultivated and to the little research investment in these crops. Recently, several national and international initiatives have begun to support the improvement of diverse millet types.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Zerihun Tadele",authors:[{id:"176084",title:"Dr.",name:"Zerihun",middleName:null,surname:"Tadele",slug:"zerihun-tadele",fullName:"Zerihun Tadele"}]}],onlineFirstChaptersFilter:{topicId:"362",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},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:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:315,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,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:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"23",title:"Education and Human Development",doi:"10.5772/intechopen.100360",issn:null,scope:"
\r\n\tEducation and Human Development is an interdisciplinary research area that aims to shed light on topics related to both learning and development. This Series is intended for researchers, practitioners, and students who are interested in understanding more about these fields and their applications.
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She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. She is the Assistant Director of the SEARCH Center at UCR and is a Faculty member in the Graduate Program in Neuroscience.",institutionString:null,institution:{name:"University of California, Riverside",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"89",title:"Education",coverUrl:"https://cdn.intechopen.com/series_topics/covers/89.jpg",isOpenForSubmission:!1,editor:{id:"260066",title:"Associate Prof.",name:"Michail",middleName:null,surname:"Kalogiannakis",slug:"michail-kalogiannakis",fullName:"Michail Kalogiannakis",profilePictureURL:"https://mts.intechopen.com/storage/users/260066/images/system/260066.jpg",biography:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool Education, University of Crete, and an Associate Tutor at School of Humanities at the Hellenic Open University. He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. He has published over 120 articles in international conferences and journals and has served on the program committees of numerous international conferences.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorTwo:{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorThree:null},{id:"90",title:"Human Development",coverUrl:"https://cdn.intechopen.com/series_topics/covers/90.jpg",isOpenForSubmission:!0,editor:{id:"191040",title:"Dr.",name:"Tal",middleName:null,surname:"Dotan Ben-Soussan",slug:"tal-dotan-ben-soussan",fullName:"Tal Dotan Ben-Soussan",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBf1QAG/Profile_Picture_2022-03-18T07:56:11.jpg",biography:"Tal Dotan Ben-Soussan, Ph.D., is the director of the Research Institute for Neuroscience, Education and Didactics (RINED) – Paoletti Foundation. Ben-Soussan leads international studies on training and neuroplasticity from neurophysiological and psychobiological perspectives. As a neuroscientist and bio-psychologist, she has published numerous articles on neuroplasticity, movement and meditation. She acts as an editor and reviewer in several renowned journals and coordinates international conferences integrating theoretical, methodological and practical approaches on various topics, such as silence, logics and neuro-education. She lives in Assisi, Italy.",institutionString:"Research Institute for Neuroscience, Education and Didactics, Patrizio Paoletti Foundation",institution:null},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:5,paginationItems:[{id:"82394",title:"Learning by Doing Active Social Learning",doi:"10.5772/intechopen.105523",signatures:"Anat Raviv",slug:"learning-by-doing-active-social-learning",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Active Learning - Research and Practice",coverURL:"https://cdn.intechopen.com/books/images_new/11481.jpg",subseries:{id:"89",title:"Education"}}},{id:"82310",title:"Knowledge of Intergenerational Contact to Combat Ageism towards Older People",doi:"10.5772/intechopen.105592",signatures:"Alice Nga Lai Kwong",slug:"knowledge-of-intergenerational-contact-to-combat-ageism-towards-older-people",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Social Aspects of Ageing - 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. 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He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. 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I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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