Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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These papers provide a preamble for a larger collection of contributions on ultrashort pulse laser generation and ultrashort pulse laser phenomena. Papers on ultrashort pulse phenomena include works on few cycle pulses, high-power generation, propagation in various media, to various applications of current interest. Undoubtedly, Coherence and Ultrashort Pulse Emission offers a rich and practical perspective on this rapidly evolving field.",isbn:null,printIsbn:"978-953-307-242-5",pdfIsbn:"978-953-51-4538-7",doi:"10.5772/543",price:159,priceEur:175,priceUsd:205,slug:"coherence-and-ultrashort-pulse-laser-emission",numberOfPages:700,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"e1bd25a76712d1cb8792820acf2ff001",bookSignature:"F. J. 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He is the author and editor of several well-known books on tunable lasers including Dye Laser Principles (Academic, New York, 1990) and Tunable Laser Optics (Elsevier Academic, New York, 2003). His most recent edited work is Tunable Laser Applications, 2nd Edition (CRC, New York, 2009).\r\nDr. Duarte has made key experimental and theoretical contributions to the field of narrow-linewidth tunable laser oscillators. These include original oscillator architectures and the generalized multiple-prism grating dispersion theory. He has also pioneered the use of Dirac’s quantum notation in the description of generalized N-slit interference and classical optics phenomena. Currently, his research focuses on further developments of dispersive narrow-linewidth laser oscillators and very large N-slit laser interferometers.\r\nDr. Duarte’s contributions are cited in some 130 laser and optics books including several classics. 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Razorback sucker
Map of the Colorado River drainage in western USA.
The management of razorback sucker in Lake Mohave began with a single goal, to replace a declining old population likely to become extirpated by the turn of the twentieth century with a young repatriated population [4]. This single goal was established in the early 1990s by the ad hoc Lake Mohave Native Fishes Workgroup (NFWG), an informal group of biologists from state and federal agencies, universities, and private entities. It was seen as a stop-gap measure to buy time until effective, long-term recovery actions could be developed and implemented. Nearly 30 years later, the management strategy has resulted in a genetically diverse repatriate population of approximately 2500 individuals [5], far fewer than the estimated 60,000 wild adults that resided in the lake in the late 1980s. However, without this repatriated population, razorback sucker would have disappeared from the reservoir, as the wild population is now functionally extirpated [5].
\nMap of Lake Mohave Arizona and Nevada, USA.
The management strategy for razorback sucker in Lake Mohave has always been adaptive. As is likely with any resource management program that has covered multiple decades, it had to adapt to changing environmental conditions, technological advancements, and periodic political intransigence. Today, adaptive management is at the cornerstone of federal policy regarding endangered species recovery plans [6]. Recently, the informal adaptive management strategy for razorback sucker in Lake Mohave (NFWG) has been replaced by the formal and well-documented adaptive management structure of the Lower Colorado River Multi-Species Conservation Plan (LCR MSCP). This plan seeks to conserve at least 26 plant and animal species in the lower Colorado River corridor while continuing to allow normal Colorado River water and power operations [7]. Applying adaptive management principles to endangered species recovery programs requires striking a delicate balance. The public and elected officials often demand an end date, an exact price in dollars, and time for a recovery program, which can run counter to the adaptive management approach because new data can change predicted outcomes of management practices.
\nThe number of razorback sucker in Lake Mohave was likely in the hundreds of thousands, if not millions in the 1960s and 1970s, but no attempt to estimate their abundance was made until the early 1980s [8]. By the late 1980s, the remnant population was estimated at 60,000 individuals [9]. This was the largest remaining population of razorback sucker in existence, but fish that had been aged through otolith examination were old, between 25 and 45 years old [10]. Most of these adults were representatives of successful cohorts produced in the first few years after impoundment of the reservoir, and no recruitment had been detected for 25 years. If this continued, the population was projected to disappear before the turn of the century [1, 11].
\nAlthough the immediate threat to the species within Lake Mohave was simple to identify, no simple solution was available. The complete removal of larval production from the entire reservoir through predation, mainly from introduced centrarchid species, was seemingly improbable, but multiple studies spanning several decades throughout the basin all pointed in the same direction [12, 13]. Data to support alternative hypotheses could not be produced. Resource limitation appeared promising and was carefully investigated but could not be clearly identified as a mortality factor [14, 15]; larval razorback sucker survived and grew inside protective enclosures placed in the reservoir, and razorback sucker grew to adults when placed in a nonnative free environment. Neither the political climate nor the technical knowhow was available at the time or is presently available to remove all nonnative fish species from the reservoir. Therefore, if the population and the species were to be perpetuated, assistance would have to take the form of stocking fish.
\nEarly attempts to produce juveniles took place in an isolated backwater adjacent to Lake Mohave at Yuma Cove where a large aggregation of fish was available during the spawning season [1]. The first attempt in January 1991 was to stock ripe fish captured from the reservoir (33 females and 67 males) directly into the backwater. Larvae were produced but no juveniles survived; at least none was detected, and no mortality factor was identified. A year later in January 1992, 28 females and 60 males were transferred from the lake into the backwater. Larvae again were produced and this time juveniles survived and nearly 300 were captured the following autumn. However, genetic evaluation indicated that the juveniles represented a relatively small number of parents, their variation was less than expected relative to the wild adult population, and this method of propagation was unlikely to preserve the population’s genetic diversity [5, 16, 17]. The next iteration in March 1993 involved manually spawning ripe fish on site and stocking about 200,000 embryos thus produced into the backwater. Unfortunately, water level in the backwater lowered unexpectedly and exposed the bottom where most fertilized ova had settled, killing them. Nonetheless, some larvae hatched and a small number of juveniles was captured. At the same time, a number of laboratory-reared fish (meta-larvae and juveniles averaging 26 mm long) were stocked into this and other backwaters around the lake. Survival of these fish was variable among sites, but recovery of fewer than 500 juveniles was inadequate to fulfil programmatic goals of stocking thousands of young fish.
\nThe real “aha” moment came with the suggestion to harvest naturally produced larvae directly from the lake and transfer them to protective custody in nonnative-free rearing sites including lakeside backwaters. Larvae were known to be phototactic [8] and easily captured, abundant, and likely to represent the genetic diversity of the wild adult population. Thus, in winter-spring 1994 began the methodical process of nighttime harvest with dip nets of larvae that were attracted to lights, rearing in safe places, and return to the lake as relatively large subadults or adults. One unique aspect of the program was the early use of passive-integrated transponder (PIT) tags. From the beginning, every attempt was made to implant all repatriated razorback sucker with a PIT tag prior to being released into the reservoir. Each tag contained a unique 10-digit hexadecimal code that was used to identify individual fish. With periodic refinements, the same basic protocol is followed today.
\nEarly indications were that the repatriation program was a success. By 1994, repatriated razorback sucker were captured in routine monitoring on the spawning grounds throughout the reservoir. To increase the capacity of the program, the NFWG partnered with golf courses in Boulder City, Nevada, Willow Beach National Fish Hatchery (a federal trout hatchery that was built on the shores of the reservoir downstream of Hoover Dam), and other entities. An average of more than 12,000 razorback sucker was repatriated annually from 1997 to 2005. In 1999, the repatriate population was estimated at more than 1000 fish, based on PIT tag recapture data [18]. However, from 1999 through 2004 the repatriate population appeared to plateau at about 1500 fish (estimates fluctuated between 1000 and 2500) regardless of the number stocked (Figure 3). It was clear that the repatriate population was not going to match the previous size of the wild population under the current program. Meanwhile, the wild population had declined from more than 60,000 in 1991 to less than 50 [5], and now is functionally extinct. Concerns over whether genetic diversity could be maintained long term with a population of only a few thousand [19] motivated research into the sources of post-stocking mortality.
\nWild (black triangles) and repatriate (gray diamonds) population estimates and 95% confidence intervals for razorback sucker in Lake Mohave. Estimates are single census mark-recapture estimates derived from captures during annual netting activities in March. The solid line and secondary axes represent the cumulative number of PIT tagged repatriated razorback sucker stocked into Lake Mohave.
Based largely on work in the Gila River, the program originally considered a 250-mm razorback sucker to be free from most predatory threats in Lake Mohave, as the main concerns were channel catfish
Estimated first-year survival for repatriated razorback sucker released into Lake Mohave based on total length (TL) when released. Survival estimates based on mark-recapture analysis of release and capture data in Lake Mohave from 1993 through 2004.
One of the early attempts to quantify the size-survival relationship for razorback sucker used PIT tag recapture data from annual census data. Sampling trips to monitor populations of native (and endangered) bonytail
Prior to the formal publication of the size-survival relationship, incremental increases in stocking sizes were implemented moving to 300 and 350 mm TL from 1999 to 2004. By 2006, the decision was made to produce fish that were nearly immune to predatory threats, which required raising razorback sucker over 500 mm TL. Raising large numbers of razorback sucker to 500 mm TL at the hatchery was going to take additional years of growth and experimentation. In the interim acoustic telemetry studies were performed with small numbers of razorback sucker at the potentially optimal stocking size of 500 mm TL and at the previously common release size of 380 mm TL to test the hypothesis. The results from these studies were unequivocal and confirmed the size-survival relationship, but survival also varied dramatically from year to year [22]. In addition, an acoustic tag that was implanted in a 520-mm TL razorback sucker was recovered from the stomach of a relatively average sized 13-kg striped bass by a fisherman [23], providing evidence that no size was completely safe from predation; the maximum length of razorback sucker is thought to be near a meter [24], but few individuals longer than 700 mm now are encountered [18, 20].
\nWhile razorback sucker were being held for additional years of growth at the hatchery, few fish were stocked; only about 500 repatriates were released from the hatcheries between November 2007 and October 2009. The 2007 population estimate, calculated after the 2008 March Roundup, had dropped to near 1000 adult repatriates. Although razorback sucker held at the hatcheries had not reached the target length of 500 mm TL, the NFWG determined that releasing fish at their current size was better than taking the risk that genetic diversity of the population would be compromised due to the low population size. Over the next 18 months, more than 20,000 razorback sucker were stocked from the hatchery system. Although the mean TL of all fish stocked was similar to previous stockings (360 mm), more than 800 razorback sucker at 450 mm TL or longer were released.
\nAlong with a shift in release size, a technological shift also occurred in 2006. PIT tagging all repatriates released into Lake Mohave had been conducted since the program began in 1992 with few exceptions. By 2006, PIT tag technology had progressed significantly. The 400-kHz tags used in Lake Mohave for the previous 14 years were being superseded by 134.2-kHz PIT tags. Some PIT tag readers could detect both tag frequencies, but the newer 134.2-kHz tags were becoming the dominant format in animal tagging. The 134.2-kHz tag had significant advantages over the older frequency. The 400-kHz tags were read by rubbing the PIT tag reader over the tag injection site, the new 134.2-kHz tags could be read from tens of centimeters away. Not only did this reduce handling time by making it easier during capture to identify fish, it was now possible to detect fish without handling them. After years of favoring methodological continuity over emerging technology, the shift was made to 134.2-kHz tags in 2006. All razorback sucker were now tagged with the new tag prior to repatriation, and any razorback sucker captured during monitoring activities without a tag was given the new tag. Due to the lack of stocking from 2006 through 2008, razorback sucker captured with 400-kHz tags were given a 134.2-kHz tag starting in 2008 (double tagging).
\nOversight of the management program also shifted by 2006. Prior to 2006, management of the program was guided by the NFWG. However, in 2005 the Lower Colorado River Multi-Species Conservation Plan was signed. This negotiated agreement between state water resource agencies of the lower Colorado River basin and the federal government is a 50-year agreement for continued operations and conservation actions for at least 26 native plant and animal species. The informal adaptive management approach of the NFWG was replaced with a formal adaptive management strategy when the LCR-MSCP was signed and became the de facto management doctrine for razorback sucker and other native fish species in the lower Colorado River. The LCR MSCP strategy for the conservation of razorback sucker in the lower Colorado River closely followed the concepts developed by Minckley et al. [25]. This paper acknowledged the limited success of the repatriation program, and advocated for a different approach to conserving razorback sucker long term: create self-recruiting populations in off-channel habitats free of nonnative fishes, while maintaining a genetically diverse population of adults in the mainstem Colorado River and its reservoirs. The Lake Mohave razorback sucker population continued to be important as the genetic repository of the species, and understanding the population dynamics of the off-channel and reservoir populations would be fundamental to the success of the program. Remote PIT scanning appeared to be the tool needed to acquire the data upon which to base science-driven management decisions.
\nThe increased reception range of the new 134.2-kHz PIT tag allowed for remote sensing of PIT tags, that is, identifying a tagged fish without capturing it. Elsewhere, portable PIT scanners were used to monitor behavior, movement, and habitat use of fishes in shallow waters of small streams [26, 27], and fish movement has also been monitored in larger streams using units permanently or semi-permanently mounted to the substrate or man-made structure [28, 29]. Initial testing of this technology in Lake Mohave relied on Biomark® flat-plate antennas and FS2001 radiofrequency identification (RFID) scanners. These units were able to detect both 400-kHz and 134.2-kHz tags. Although read range of 400-kHz PIT tags was only a few centimeters or less, razorback sucker were known to remain close to the substrate and the potential to remotely contact at least a portion of 400-kHz tagged fish was important given the small number of 134.2-kHz tagged razorback sucker released by 2008. These PIT scanning units could only be deployed in the calm, lotic waters of the reservoir because they required a floating component to contain the RFID readers and batteries. In 2008, the remote PIT-scanning units on Lake Mohave contacted 176 unique PIT tags and 194 were contacted in 2009 [30]. In 2010, the number of available 134.2-kHz tagged fish increased due to large stocking events. PIT scanning in the reservoir contacted 477 razorback sucker in that year, nearly twice as many as the number encountered during the March Roundup (286 razorback sucker) in the same year. It was clear that this technology would allow for a much larger proportion of the population to be contacted annually than the netting effort once the 134.2-kHz tagged fish made up the majority of the population. This increase in monitoring data also would not require additional handling or netting activities, which could impact survival or spawning behavior. However, the PIT scanners could not alleviate one monitoring issue. Razorback sucker were routinely observed in the swiftly flowing and turbulent riverine section of the reservoir downstream of Hoover Dam, but these fish were generally unmonitored. Trammel nets were ineffective in the fast-flowing river, and boat electrofishing was effective, but potentially harmful to the fish [31]. PIT scanning would likely be effective as well, but the floating systems could not be anchored well enough to remain in place in the river.
\nIn 2010, a PIT scanner design was proposed for use in the riverine sections of Lake Mohave based on systems described in Bond et al. [28]. The design was adapted to allow the unit to be completely self-contained without a floating or a shore-based component. The first fully submersible PIT scanners were developed and deployed in 2011 between Hoover Dam and Willow Beach. Sites of deployment were based on observations of spawning aggregates during the winter and spring months (January through April), and PIT scanner units were typically deployed between 12 and 24 h before being retrieved, downloaded, and redeployed with fresh batteries during week-long sampling trips. In that first year, 670 PIT tags from repatriated razorback sucker were contacted. By 2012, this number nearly tripled to 1832, more than twice the number contacted in the basin by PIT scanners (882). The total number scanned in the river alone nearly matched the 2012 population estimate of 1854. Combined, repatriate PIT scanning contacts in Lake Mohave exceeded the population estimate based on mark-recapture data from netting activities during the March Roundup.
\nOne purpose of extending PIT scanning to the riverine section below Hoover Dam was to determine if the fish in the river and in the basin were of the same population. It was assumed that razorback sucker moved throughout the reach between Davis and Hoover dams, and that population estimates based on netting activities on the spawning grounds in the basin were representative of the lake-wide population. Initial analysis of PIT scanning data from 2011 and 2012 in the basin and river did not support this assumption. More than 80% of the fish contacted in the riverine reach downstream of Hoover Dam had been released (stocked) there, and more than 80% of the fish contacted in the basin had been released in the basin. In year-to-year comparisons, fewer than 10% of the fish contacted in one reach were contacted in the other reach the subsequent year. The partial demographic isolation of the two subpopulations required a rethinking of population estimates and the overall stocking strategy.
\nBeginning in 2012, year-to-year population estimates based on PIT scanning data supplemented the annual estimates based on annual netting activities. Consistent with the partial demographic isolation demonstrated in the PIT scanning data, population estimates were divided into basin and river subpopulations. In the first few years, the sum of subpopulation estimates based on PIT scanning was similar to estimates from netting activities even though the river subpopulation was not effectively sampled by netting activities. This was likely due to the exclusion of 400-kHz tagged fish in PIT scanning and the lack of complete geographic coverage of the basin area with PIT scanners. Netting activities generally covered four primary spawning aggregates in the basin area: Halfway Wash, Tequila Cove, Yuma Cove, and Owl Point. The majority of PIT scanning in 2011 and 2012 was concentrated in Tequila Cove and Yuma Cove. These two sites had semi-permanent PIT scanners that scanned nearly continuously throughout the spawning season (November through April). As the geographic coverage in the basin improved, and the proportion of 134.2-kHz tagged fish increased, the subpopulation estimate for the basin alone approached the overall estimate based on netting activities. By 2014, each subpopulation was estimated at around 1500 fish each. The discovery of additional razorback sucker in the system was a positive development for the program. However, the river subpopulation did not contribute significantly to the repatriation program. This is because until recently all larvae collected in the lake for the repatriation program were collected more than 10 km downstream of Willow Beach, whereas the majority of the river subpopulation was reproducing upstream reproducing upstream of Willow Beach. Proportional representation of the riverine subpopulation in larval collections would require about half of the 20,000 larvae collected annually to be collected upstream of Willow Beach, and so the program must again adapt to this new paradigm.
\nThe original goal of replacing the wild adult population with a young repatriated population was based on solid scientific evidence available at the time it was formulated. Changes in the fish fauna and lower than expected adult survival resulted in a population of only a few thousand, maintained through annual stocking of more than 10,000 razorback sucker. The NFWG adapted to new data and technologies, and the NFWG recognized the futility of continuing the stocking program indefinitely although a small population of razorback sucker had been established and maintained. Alternative strategies to the repatriation program were under development as early as the late 1990s. The overall strategy for razorback sucker conservation in the lower Colorado River codified in journal publications [5, 25], the US Fish and Wildlife Service (USFWS) implementation plans [32], and the LCR MSCP is one of natural recruitment within protected off-channel habitats. These small populations would be managed with the exchange of adults with the populations maintained in the mainstem and its reservoirs and with each other to maintain genetic diversity. This would eliminate the need for hatcheries and massive stockings and permit nearly natural selective pressures to continue. The LCR MSCP conceptually is in agreement with this strategy, but its formal adaptive management structure spreads limited resources too thin and its political nature creates obstacles to implementation of new strategies when data are acquired.
\nThe basic concept of adaptive management is to treat current management practices as working hypotheses, and the results of such practices are evaluated through monitoring to provide information, which forms the basis of changes in subsequent management practices. The number of knowledge gaps identified by the LCR MSCP conceptual model for razorback sucker [33] that required additional research stretches scant resources to their limit, and does nothing for conserving the species in the short term. The immediate need of optimizing stocking regimes should take precedence over understanding the complete life cycle of the species, especially when most of that research requires experiments with life stages that cannot be found in the natural system. Razorback sucker as a species is still in crisis, the size of the one population with the genetic legacy is too low to secure that legacy. Does it therefore make sense to spend resources answering biological questions that at best will aid razorback sucker recovery which is decades off and likely will not happen at all if current trends continue?
\nOne example of the lack of focus since the LCR MSCP is the size at release for razorback sucker in Lake Mohave. After the release of large fish from the hatchery system from 2009 to 2011, an experiment that began prior to the LCR MSCP, the target released size returned to 300 mm TL. The only large fish released into Lake Mohave have been from lakeside backwaters. This has resulted in almost no razorback sucker stocked in the last 3 years from the hatchery being captured or contacted via PIT scanners. For comparison, out of the 806 fish longer than 450 mm TL that were released during the attempt to grow 500-mm TL fish, 417 were contacted by PIT scanners from 2011 through 2015. More than 22,000 razorback sucker were released in 2012 and 2013 (41 fish over 450 mm TL), and only 169 have been contacted more than 30 days after their release. The complete failure of recently stocked fish to recruit to the adult population has erased any gains in population size that were created from the large fish releases in 2009, 2010, and 2011.
\nEqually important, the political constraints cause actions that could benefit razorback sucker to not be performed. The LCR MSCP mandates the creation of 360 surface acres of backwater. The most successful backwaters in the system to date are the lakeside backwaters on Lake Mohave. Experiments designed to assess the genetic contribution of one razorback sucker generation to the next in backwater environments are currently being conducted in three lakeside backwaters on Lake Mohave. Two of these backwaters produce young of year razorback sucker annually, but must be harvested each year as the backwaters dry up during reservoir drawdowns. One lakeside backwater at Yuma Cove that is deep enough to retain water year-round has a healthy population of several hundred razorback sucker, some stocked, some self-recruited in the backwater. With the exception of Cibola High Levee Pond [25], there is currently no other location on the lower Colorado River that has proven as effective. However, the LCR MSCP does not give credit to the program for any off-channel habitat created in Lake Mohave, and unfortunately the lakeside backwaters will only be used for experiments or grow-out, and no new backwaters will be created on the reservoir.
\nThe real danger of an expensive management program for any endangered species is failure to produce tangible results. A perception that millions of tax dollars were spent without a return on the investment would likely reduce support for future programs. The endangered fish recovery program in the upper basin should be a warning sign for the LCR MSCP. Although the LCR MSCP is very specifically a conservation and not a recovery program, that distinction will likely not save it from public or political scrutiny if it is perceived a failure. A 30- or 50-year time span may seem like a long time to recover a species, but it is within the life span of a single razorback sucker. It is unreasonable to expect that our understanding of the causes of population decline for razorback sucker will reach the level of being able to reverse that decline within the life span of a single fish. The upper basin has had nearly three decades to reach that goal, yet not one population of razorback sucker in that region is doing better now than before the beginning of the program if impacts of stocking are excluded. Although stocking can reduce the probability of extinction, it does nothing to improve the probability of self-sustenance, which is a fundamental requirement of any successful recovery program.
\nThe ultimate fate of the razorback sucker population in Lake Mohave under the LCR MSCP is unknown, but if the NFWG had required that a complete understanding of razorback sucker life history and predator-prey interactions be obtained prior to stocking one fish, there would be no population to conserve. The NFWG was able to focus on a single goal, adapted to new information, and still failed to achieve its goal. The LCR MSCP is attempting to achieve multiple goals, with a 5-year planning cycle, a 54-member steering committee, and an expectation that “program-level adaptive management is not anticipated to occur often over the 50 year term because the HCP conservation direction was developed using the best available information” [34]. There recently has been a refocus on meeting a target release size of near 500 mm TL. If razorback sucker at or near 500 mm TL are released consistently, a substantial increase in the number of individuals in the population is expected. These actions will secure the razorback sucker in Lake Mohave for a number of years; however, conservation and recovery of the species in the lower Colorado River will require successful implementation of the backwater-based program concept [25, 32]. Such a plan already has proven its biological efficacy and we urge the LCR MSCP partners to move forward aggressively to identify, confront, and overcome political and logistical barriers and put that plan into practice.
\nChronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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In the current study, removal of heavy metal ions from water/wastewater and the use of response surface methodology (RSM) for experimental optimization were examined thoroughly. The objective of this work was to summarize the removal of heavy metal ions from water/wastewater using various chemical techniques and to emphasize the superiority of RSM in these studies.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Muharrem Ince and Olcay Kaplan Ince",authors:[{id:"258431",title:"Prof.",name:"Muharrem",middleName:null,surname:"Ince",slug:"muharrem-ince",fullName:"Muharrem Ince"},{id:"266549",title:"Dr.",name:"Olcay",middleName:null,surname:"Kaplan Ince",slug:"olcay-kaplan-ince",fullName:"Olcay Kaplan Ince"}]},{id:"67269",doi:"10.5772/intechopen.86213",title:"Polycyclic Aromatic Hydrocarbons (PAHs) and Their Influence to Some Aquatic Species",slug:"polycyclic-aromatic-hydrocarbons-pahs-and-their-influence-to-some-aquatic-species",totalDownloads:1256,totalCrossrefCites:7,totalDimensionsCites:17,abstract:"Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants generated primarily during the incomplete combustion of organic materials (e.g., coal, oil, petrol, and wood). Many PAHs have toxic, mutagenic, and/or carcinogenic functions. PAHs are highly lipid soluble which lead to a fast absorption by the gastrointestinal tract of marine mammals. They are immediately distributed in a vast variety of tissues with a notable tendency for localization in body fat. Metabolism of PAHs is obtained via the cytochrome P450-mediated mixed function oxidase system with oxidation or hydroxylation as the first step. PAHs are environmental contaminants that pose significant risk to health of fish. The effect of PAHs on fish is a topic of rising attention in a lot of countries. Different studies using the bile metabolites separated by high-performance liquid chromatography with fluorescence detection were presented. The aim is to compare the levels of PAH metabolites in fish from different areas and fish species. The major metabolite present in all fish was 1-hydroxypyrene. The data confirm the importance of 1-hydroxypyrene as the key PAH metabolite in fish bile and suggest that the European eel is an ideal species for monitoring PAHs.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Ayoub Baali and Ahmed Yahyaoui",authors:[{id:"288629",title:"Ph.D.",name:"Ayoub",middleName:null,surname:"Baali",slug:"ayoub-baali",fullName:"Ayoub Baali"},{id:"293206",title:"Prof.",name:"Ahmed",middleName:null,surname:"Yahyaoui",slug:"ahmed-yahyaoui",fullName:"Ahmed Yahyaoui"}]},{id:"66089",doi:"10.5772/intechopen.85159",title:"Water Resource Pollution by Herbicide Residues",slug:"water-resource-pollution-by-herbicide-residues",totalDownloads:1294,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"Herbicides are frequently used in the chemical control of weeds in various crops in Brazil and worldwide, so they are more frequently detected outside the application areas, contributing to the risk of environmental contamination. The importance of knowledge of the physicochemical properties of the environment and the pesticide used in the agricultural area is in order to understand its effects on terrestrial and aquatic ecosystems and the search for the prevention of future bioaccumulation potentials (bioconcentration and/or biomagnification) of molecules of pesticides in living nontarget organisms, minimizing their negative effects on the environment. The understanding of analytical techniques for measuring the quality of water resources as well as techniques for the remediation of contaminated water is essential to minimize the possible impacts caused by the application of pesticides to the environment.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Kassio Ferreira Mendes, Ana Paula Justiniano Régo, Vanessa Takeshita and Valdemar Luiz Tornisielo",authors:[{id:"162791",title:"Prof.",name:"Valdemar",middleName:null,surname:"Tornisielo",slug:"valdemar-tornisielo",fullName:"Valdemar Tornisielo"},{id:"197720",title:"Ph.D.",name:"Kassio",middleName:null,surname:"Ferreira Mendes",slug:"kassio-ferreira-mendes",fullName:"Kassio Ferreira Mendes"},{id:"258779",title:"Dr.",name:"Ana Paula",middleName:null,surname:"Justiniano Régo",slug:"ana-paula-justiniano-rego",fullName:"Ana Paula Justiniano Régo"},{id:"277330",title:"MSc.",name:"Vanessa",middleName:null,surname:"Takeshita",slug:"vanessa-takeshita",fullName:"Vanessa Takeshita"}]},{id:"70500",doi:"10.5772/intechopen.89601",title:"Challenges for Assessing Toxicity of Nanomaterials",slug:"challenges-for-assessing-toxicity-of-nanomaterials",totalDownloads:1129,totalCrossrefCites:4,totalDimensionsCites:11,abstract:"On the development of nano-world, nanotechnology provides enormous opportunities in daily routine products and further future sustainable innovations. The nanotechnology extends its benefits to various fields such as engineering, medical, biological, environmental, and communication. However, the exponential growth of nanomaterials production would lead to severe complications related to their hazardous effects to the human health and environment. Moreover, negative impact of nanomaterials toxicity on human health is one of the significant issues on exhausting nano-products. The most vulnerable situation is associated with the use of nanomaterials in the biomedical application. The several efforts have been ongoing to study the nanotoxicity and its interaction with the biomolecules. Nevertheless, it is hard to assess and validate the nanotoxicity in a biological system. This chapter aims to study the challenges in determining the toxicity of nanomaterials. The toxicity assessment and hurdles in determining the impact on biological systems are epoch making. In-vitro, in-vivo, and in-silico studies are summarized in this chapter in assessing the toxicity of engineered nanomaterials. The different approaches of toxicity assessment have their difficulties faced by researchers while characterizing nanomaterials in powder form, solution-based, and interacting with biological systems. The assessment tools and characterization techniques play a vital role in overcoming the challenges, while the cytotoxic assays involve nanoparticle shape, morphology, and size consideration.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Akanksha Gupta, Sanjay Kumar and Vinod Kumar",authors:[{id:"309802",title:"Dr.",name:"Vinod",middleName:null,surname:"Kumar",slug:"vinod-kumar",fullName:"Vinod Kumar"},{id:"311316",title:"Dr.",name:"Akanksha",middleName:null,surname:"Gupta",slug:"akanksha-gupta",fullName:"Akanksha Gupta"},{id:"311317",title:"Mr.",name:"Sanjay",middleName:null,surname:"Kumar",slug:"sanjay-kumar",fullName:"Sanjay Kumar"}]},{id:"69211",doi:"10.5772/intechopen.89299",title:"Formaldehyde Advantages and Disadvantages: Usage Areas and Harmful Effects on Human Beings",slug:"formaldehyde-advantages-and-disadvantages-usage-areas-and-harmful-effects-on-human-beings",totalDownloads:1330,totalCrossrefCites:0,totalDimensionsCites:7,abstract:"Formaldehyde, a simple but important member of aldehydes, is highly reactive due to its strong electrophilic properties. It is a colorless, pungent, low molecular weight poisonous gas that can rapidly pass into gaseous phase at room temperature, can burn, and can dissolve very well in water. Formaldehyde, which is found in the natural structure of the organism, is used in many places from industrial areas to household materials and from the production of coatings in dentistry to the determination of cadavers in laboratories. In addition to having such a wide range of uses, it has harmful effects on human health as it can react spontaneously with various cellular elements. In this review, which is based on various sources, detailed information about the definition, properties, usage areas, and harmful effects of formaldehyde will be given.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Nuriye Tuna Subasi",authors:[{id:"279801",title:"Dr.",name:"Nuriye Tuna",middleName:null,surname:"Subaşı",slug:"nuriye-tuna-subasi",fullName:"Nuriye Tuna Subaşı"}]}],mostDownloadedChaptersLast30Days:[{id:"68822",title:"Heavy Metal Removal Techniques Using Response Surface Methodology: Water/Wastewater Treatment",slug:"heavy-metal-removal-techniques-using-response-surface-methodology-water-wastewater-treatment",totalDownloads:2218,totalCrossrefCites:10,totalDimensionsCites:19,abstract:"Advanced water/wastewater treatment techniques including ion exchange separation, filtration separation, and adsorption are essential in the removal of nonbiodegradable toxic wastes from water. In the current study, removal of heavy metal ions from water/wastewater and the use of response surface methodology (RSM) for experimental optimization were examined thoroughly. The objective of this work was to summarize the removal of heavy metal ions from water/wastewater using various chemical techniques and to emphasize the superiority of RSM in these studies.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Muharrem Ince and Olcay Kaplan Ince",authors:[{id:"258431",title:"Prof.",name:"Muharrem",middleName:null,surname:"Ince",slug:"muharrem-ince",fullName:"Muharrem Ince"},{id:"266549",title:"Dr.",name:"Olcay",middleName:null,surname:"Kaplan Ince",slug:"olcay-kaplan-ince",fullName:"Olcay Kaplan Ince"}]},{id:"70615",title:"Few-Layered Hexagonal Boron Nitride: Functionalization, Nanocomposites, and Physicochemical and Biological Properties",slug:"few-layered-hexagonal-boron-nitride-functionalization-nanocomposites-and-physicochemical-and-biologi",totalDownloads:965,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Hexagonal boron nitride (h-BN) is an analogue of graphite called “white graphene.” In the structure of h-BN, B and N atoms substitute C atoms. The boron and nitrogen atoms are linked via strong B-N covalent bonds and form interlocking hexagonal rings. h-BN is used in different areas due to its interesting physical and chemical properties, e.g., in electronics as an insulator and in ceramics, resins, plastics, and paints. Therefore, boron nitride (BN) is also a popular inorganic compound in cosmetic industry (the highest BN concentration up to 25% can be found in eye shadow formulation). It is also widely used in dental cement production (for dental and orthodontic applications). Boron nitride seems to be suitable for biomedical applications; therefore, the cytotoxicity in vitro and in vivo observations of h-BN nanoplates and novel few-layered h-BN-based nanocomposites are still needed. The short-time studies confirm their low cytotoxicity and suggest that BN can be used as a novel drug delivery system; however, medical application needs additional verification in long-term studies.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Magdalena Jedrzejczak-Silicka, Martyna Trukawka, Katarzyna Piotrowska and Ewa Mijowska",authors:[{id:"186478",title:"Dr.",name:"Magdalena",middleName:null,surname:"Jedrzejczak-Silicka",slug:"magdalena-jedrzejczak-silicka",fullName:"Magdalena Jedrzejczak-Silicka"},{id:"231014",title:"Prof.",name:"Ewa",middleName:null,surname:"Mijowska",slug:"ewa-mijowska",fullName:"Ewa Mijowska"},{id:"312078",title:"MSc.",name:"Martyna",middleName:null,surname:"Trukawka",slug:"martyna-trukawka",fullName:"Martyna Trukawka"},{id:"312079",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Piotrowska",slug:"katarzyna-piotrowska",fullName:"Katarzyna Piotrowska"}]},{id:"69211",title:"Formaldehyde Advantages and Disadvantages: Usage Areas and Harmful Effects on Human Beings",slug:"formaldehyde-advantages-and-disadvantages-usage-areas-and-harmful-effects-on-human-beings",totalDownloads:1329,totalCrossrefCites:0,totalDimensionsCites:7,abstract:"Formaldehyde, a simple but important member of aldehydes, is highly reactive due to its strong electrophilic properties. It is a colorless, pungent, low molecular weight poisonous gas that can rapidly pass into gaseous phase at room temperature, can burn, and can dissolve very well in water. Formaldehyde, which is found in the natural structure of the organism, is used in many places from industrial areas to household materials and from the production of coatings in dentistry to the determination of cadavers in laboratories. In addition to having such a wide range of uses, it has harmful effects on human health as it can react spontaneously with various cellular elements. In this review, which is based on various sources, detailed information about the definition, properties, usage areas, and harmful effects of formaldehyde will be given.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Nuriye Tuna Subasi",authors:[{id:"279801",title:"Dr.",name:"Nuriye Tuna",middleName:null,surname:"Subaşı",slug:"nuriye-tuna-subasi",fullName:"Nuriye Tuna Subaşı"}]},{id:"66089",title:"Water Resource Pollution by Herbicide Residues",slug:"water-resource-pollution-by-herbicide-residues",totalDownloads:1293,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"Herbicides are frequently used in the chemical control of weeds in various crops in Brazil and worldwide, so they are more frequently detected outside the application areas, contributing to the risk of environmental contamination. The importance of knowledge of the physicochemical properties of the environment and the pesticide used in the agricultural area is in order to understand its effects on terrestrial and aquatic ecosystems and the search for the prevention of future bioaccumulation potentials (bioconcentration and/or biomagnification) of molecules of pesticides in living nontarget organisms, minimizing their negative effects on the environment. The understanding of analytical techniques for measuring the quality of water resources as well as techniques for the remediation of contaminated water is essential to minimize the possible impacts caused by the application of pesticides to the environment.",book:{id:"9407",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",title:"Biochemical Toxicology",fullTitle:"Biochemical Toxicology - Heavy Metals and Nanomaterials"},signatures:"Kassio Ferreira Mendes, Ana Paula Justiniano Régo, Vanessa Takeshita and Valdemar Luiz Tornisielo",authors:[{id:"162791",title:"Prof.",name:"Valdemar",middleName:null,surname:"Tornisielo",slug:"valdemar-tornisielo",fullName:"Valdemar Tornisielo"},{id:"197720",title:"Ph.D.",name:"Kassio",middleName:null,surname:"Ferreira Mendes",slug:"kassio-ferreira-mendes",fullName:"Kassio Ferreira Mendes"},{id:"258779",title:"Dr.",name:"Ana Paula",middleName:null,surname:"Justiniano Régo",slug:"ana-paula-justiniano-rego",fullName:"Ana Paula Justiniano Régo"},{id:"277330",title:"MSc.",name:"Vanessa",middleName:null,surname:"Takeshita",slug:"vanessa-takeshita",fullName:"Vanessa Takeshita"}]},{id:"79936",title:"Snake Venom",slug:"snake-venom",totalDownloads:145,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Venomous snakes belonging to the family Viperidae, Elapidae, Colubridae and Hydrophidae, produces snake venom in order to facilitate immobilization and digestion of prey, act as defense mechanism against threats. Venom contains zootoxins which is a highly modified saliva that is either injected via fangs during a bite or spitted. The modified parotid gland, encapsulated in a muscular sheath, present on each side of the head, below and behind the eye, have large alveoli which temporarily stores the secreted venom and later conveyed by a duct to tubular fangs through which venom is injected. Venoms are complex mixtures of more than 20 different compounds, mostly proteins and polypeptides, including proteins, enzymes and substances with lethal toxicity which are either neurotoxic or haemotoxic in action and exert effects on nervous/muscular impulses and blood components. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. Physiology research may be linked to development, aging, environment, regular and pathological processes, adaptation and evolution, exercise, or several other factors affecting, or involved with, animal physiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. 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