Prolyl‐4‐hydroxylase (PHD) inhibitors in clinical trials.
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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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Enabling Technologies and Emerging Applications",slug:"medical-internet-of-things-m-iot-enabling-technologies-and-emerging-applications",publishedDate:"February 27th 2019",bookSignature:"Hamed Farhadi",coverURL:"https://cdn.intechopen.com/books/images_new/6655.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"171143",title:"Dr.",name:"Hamed",middleName:null,surname:"Farhadi",slug:"hamed-farhadi",fullName:"Hamed Farhadi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11867",leadTitle:null,title:"Echocardiography",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tAlthough the diagnosis and overall survival of patients with various cardiac diseases have improved in the last years, there still remains a significant proportion of patients with unfavorable prognoses. The evaluation of these patients necessitates effective imaging techniques in both diagnosis and long-term follow-up. Even though Cardiac Magnetic Resonance imaging is currently the imaging modality of choice for tissue characterization, advanced echocardiography represents a modern alternative. Speckle tracking echocardiography can be used to assess myocardial deformation at both segmental and global levels. Since distinct myocardial pathologies affect deformation differently, information about the underlying tissue can be offered by strain imaging. Echocardiography advances also show promising results in the improvement of diagnostic accuracy, management, and follow-up and a major advantage of echocardiography over other imaging modalities is the ability to use it in real-time, in the cardiac catheterization laboratory, allowing for the performance of imaging immediately before, during, and after interventional procedures. Furthermore, the prevalence of adult congenital heart disease continues to grow due to advances in surgical and diagnostic techniques. Echocardiography has proven to be a useful tool in the diagnosis and follow-up of these patients, both after percutaneous and surgical procedures, and its utility has expanded significantly due to the development of better technology. In addition, stress echocardiography could be useful in the evaluation of several cardiac diseases and should be preferred over other imaging modalities due to the lower cost, wider availability, and radiation-free nature.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art novel imaging techniques by focusing on the most important evidence-based developments in this area.
Anemia is a common complication of chronic kidney disease (CKD) that often develops early in the course of the disease, and its frequency and severity increase with the decline of renal function [1]. This condition is associated with a decreased quality of life [2, 3], increased hospitalizations and comorbidities [4, 5], progression of renal dysfunction [6–8], enhanced cardiovascular complications [9, 10] and mortality [11–13]. The main cause for anemia in CKD patients is erythropoietin (EPO) deficit, due to decreased hormone production by the failing kidneys; other factors can also contribute to the development or worsening of CKD‐anemia, such as iron deficiency, inflammation and uremic toxins, among others [14].
\nEPO is a glycoprotein that presents several functions acting as a hormone, cytokine or growth factor on target cells that express the EPO receptors (EPOR), through different pathways. In the bone marrow, EPO controls cell proliferation, differentiation and death of erythroid cells.
\nDuring fetal life, the majority of EPO is produced by the liver; after birth there is a switch to renal production, and in the adulthood, 90% of this hormone is produced by the kidneys, whereas the liver is a secondary site of production [15]. EPO is also expressed in the brain, spleen, lung and testis, but its contribution to serum EPO levels is not clarified [16]. The kidney cells responsible for EPO production are still under debate, but several studies showed that renal EPO‐producing cells (REPC) include the peritubular fibroblast‐like interstitial cells in the inner cortex and in the outer medulla [17, 18], the proximal and distal convoluted tubules and cortical collecting ducts [19]. REPC are sensitive to changes in oxygen (O2) tension, and in conditions of hypoxia, the kidney responds increasing the number of REPC capable of producing EPO [20].
\nIn CKD, the severity of the disease defines the kidney capacity to produce EPO [21, 22]. Indeed, patients with GFR >30 mL/min/1.73 m2 are still able to induce a physiologic response to anemia, showed by the normal or even elevated serum EPO levels [23, 24]. Nevertheless, serum EPO levels may not be sufficient for the degree of anemia; actually, anemic patients with normal renal function may present a 10‐fold to 100‐fold increase in serum EPO levels [25, 26], to achieve correction of anemia.
\nThe kidney is the major site of EPO production in the adults; however, it is possible that extrarenal sites contribute for the marked rise in plasma EPO in end‐stage renal disease (ESRD) patients [27], as already showed in animal models of kidney injury [28, 29]. It was also reported that patients with anemia can switch EPO production from the kidney to the liver [30, 31], as can be shown by glycoform analysis of EPO. Indeed, the posttranslational EPO glycosylation is specific of the synthesizing cells, giving rise to different EPO glycoforms that can be used to localize EPO synthesis [30, 32].
\nHypoxia regulates the EPO gene through the hypoxia‐inducible factor (HIF) system [20]. This HIF system includes O2‐dependent HIF‐1α, HIF‐2α (also known as endothelial PAS domain‐containing protein 1) and HIF‐3α subunits, and the constitutively expressed HIF‐1β and HIF‐2β subunits (also known as aryl hydrocarbon receptor nuclear translocator). The HIF‐α subunits are hydroxylated in specific proline residues, by the prolyl‐4‐hydroxylase (PHD) proteins that require O2 as a co‐substrate (\nFigure 1\n). The hydroxylated HIF‐α subunit targets the von Hippel‐Lindau tumor suppressor protein (VHL) to be recognized by an ubiquitin ligase complement that will induce a rapid ubiquitination and proteasomal degradation of HIF‐α subunits. Under normoxia, HIF‐α subunits are almost undetectable, but in hypoxic conditions, the hydroxylation by PHD proteins is inhibited; thus, the HIF‐α accumulates in the cytoplasm, is translocated to the nucleus and binds to the HIF‐β subunit, forming a complex that recruits the coactivators P300/CBP and activates the transcription of several genes [20].
\nRegulation of hypoxia‐inducible system. (A) In conditions of normoxia, the HIF‐α subunits are hydroxylated, in specific proline residues by prolyl‐4‐hydroxylase (PHD) proteins, which recruit the von Hippel‐Lindau tumor suppressor protein (VHL) a signal for rapid ubiquitination and proteasomal degradation of HIF‐α subunits. PHD inhibitors are under development, as they might impair the degradation of the HIF‐α subunits, improving anemia. (B) Under hypoxic conditions, the PHD proteins are inhibited, and consequently, the HIF‐α subunits are not targeted by VHL protein for degradation, translocating to the nucleus and binding to the HIF‐β subunit, forming a complex that recruit the coactivators P300/CBP, leading to the transcription of several genes that will depend on the type of HIF‐α subunit (HIF‐1α or HIF‐2a) that binds to the target gene sequences. There is a crosstalk between hypoxia and inflammation, leading to the activation of the nuclear factor kappa beta (NF‐κB) pathway that can also induce HIF‐1α accumulation.
Several genes are regulated by the HIF‐1α and HIF‐2α subunits (\nFigure 1\n), but recent studies showed that HIF‐2α is the main regulator of EPO synthesis in the kidney and liver [33–35] and is also important for the regulation of several factors involved in iron homeostasis, as iron is an important element for hemoglobin (Hb) synthesis [36]. The HIF‐1α subunit activates the transcription of glucose metabolism, angiogenesis and fibrosis related genes to promote wound healing [37]. The role of HIF‐3α is still ambiguous and under current investigation. It is known that HIF‐3α presents several isoforms with different roles [38]; the up‐regulation of some HIF‐3α isoforms appears to act as a negative feedback mechanism to regulate HIF‐1α and/or HIF‐2α subunits; however, recent studies showed that HIF‐3α might share with HIF‐1α the regulation of some genes [39].
\nThis chapter reviews the HIF response to erythropoiesis‐stimulating agents (ESA) therapy focusing on its potential involvement in the development of ESA resistance, by enhancing kidney fibrosis and inflammation.
\nRenal hypoxia is well known as an important contributor for the progression of renal disease. A study conducted in a rat model of diabetic nephropathy reported that intrarenal hypoxia develops early in the course of the disease and precedes the alterations in circulating biomarkers of kidney damage [40]. Irrespective of the initial cause of CKD, the histopathological analysis of renal biopsies showed that fibrosis is the common final pathway [41]. The underlying mechanisms are still debatable.
\nGlomerular injury leads to a reduction in glomerular blood flow and consequently limits blood flow into peritubular capillaries, causing hypoxia and tubulointerstitial injury [42]. After an initial injury, the tubular cells will attempt to correct and repair the injury by recruiting and activating several cells, such as macrophages, fibroblasts and epithelial tubular cells that will release pro‐inflammatory cytokines and fibrosis factors, and contribute to excessive interstitial extracellular matrix (ECM) accumulation and expansion. Transforming growth factor beta (TGF‐β), a recognized pro‐fibrotic factor, appears to be central for fibroblast activation, proliferation and transdifferentiation, contributing to ECM deposition [43]. TGF‐β also presents immunomodulatory effects on macrophages and monocyte recruitment, leading to the production of inflammatory cytokines [44]. In early renal injuries, M2‐type macrophages are recruited to promote tissue remodeling; however, if the injury is continuous, more inflammatory monocytes will be recruited differentiating their phenotype into M1‐type macrophages, responsible for the release of pro‐inflammatory cytokines (such as tumor necrosis factor [TNF‐α], interferon [IFN]‐γ, interleukin (IL)‐1β and IL‐6) and cell apoptosis [45]. The release of these pro‐inflammatory cytokines leads to the activation of the nuclear factor kappa B (NF‐κB) pathway, thus amplifying the inflammatory process [44]. The continuous activation of this system will culminate with the formation of scar tissue or fibrosis. The presence of fibrotic tissue reduces the diffusion of O2, which will further aggravate the hypoxic environment.
\nAnemia caused by inadequate EPO production by the kidneys also contributes to renal hypoxia. However, the mechanisms underlying the reduced capacity for EPO production by the REPC are not well understood. It has been proposed that after renal injury, REPC can suffer a transdifferentiation, called epithelial to mesenchymal transition (EMT), into myofibroblasts, losing their capacity to synthesize EPO and increasing the synthesis of collagen, contributing to the expansion of ECM [46]. Nevertheless, this EMT phenomenon was never proved in humans. The residual capacity to increase serum EPO levels when subjected to hypoxic environment or high altitudes by renal patients, even those on dialysis [47], indicates that a dysregulation of the HIF system, more than a complete loss of REPC cells, could be responsible for the reduced EPO production. Moreover, the pharmacological inhibition of the PHD in CKD patients stimulates endogenous EPO production further supporting a deranged oxygen sensing [27]. A recent study in mice by Souma et al. [48] also strengthened this hypothesis, by showing that inflammatory cytokines and/or fibrosis factors suppress HIF activation through the over‐activation of PHD even under pathologic hypoxic conditions, and that the inhibition of PHD restores EPO production.
\nThe standard treatment for CKD‐anemia is based on pharmacological intervention, using ESA and/or iron supplementation, in order to correct and maintain Hb concentration in the range of 10–11.5 g/dL [49]. ESA are medicines produced by recombinant DNA technology with similar structure and biological activity of EPO. They differ from EPO by the different patterns of glycosylation that increases their half‐life.
\nThe use of ESA has beneficial effects by correcting anemia and their associated symptoms and improving patients’ quality of life [50, 51]. However, the effects of ESA on the progression of renal function are controversial. Some studies showed that after starting ESA therapy and correction of anemia, renal function declines at a slower rate, delaying the need for dialysis in pre‐dialysis patients [52–54]; in opposition, other studies reported that ESA do not significantly affect renal function [55, 56].
\nESA were designed to correct anemia, but some evidences showed that these drugs (and EPO) may act beyond hematopoiesis. Pleiotropic effects have been attributed to EPO and ESA, such as cytoprotection, anti‐apoptosis, anti‐inflammatory and angiogenesis [57]. These non‐hematopoietic actions appear to result from the activation of another EPOR, a heterodimeric receptor constituted by the EPOR homodimer complexed with CD131, the common beta receptor (βCR) that is involved in granulocyte macrophage colony‐stimulating factor, IL‐3 and IL‐5 signaling [58]. The two EPOR present different affinities for EPO; in erythroid cells picomolar concentrations of EPO are sufficient to trigger activation of the EPOR homodimer, whereas on other cells and tissues high local EPO concentrations are needed to activate EPOR heterodimer [59]. This receptor was detected in several cells and tissues, such as brain (neurons, astrocytes and microglia), kidney, female reproductive system organs, vascular endothelial cells, cardiomyocytes, lymphocytes and monocytes, among others [57].
\nThe slower progression of renal dysfunction observed in some CKD patients may result from renoprotection of ESA therapy. Several studies on acute kidney injury (AKI) reported that a single dose of recombinant human EPO (rHuEPO) reduces kidney dysfunction through anti‐apoptotic mechanisms and increases NO production, only in intact vessels [60]. ESA therapy also exerts renoprotective effects by reducing the production of pro‐inflammatory cytokines (e.g., IL‐1β and TNF‐α), acute phase proteins [e.g., C‐reactive protein (CRP)], pro‐fibrotic factors (e.g., TGF‐β) and oxidative stress [61]. However, these effects appear to be only achieved with low doses of ESA, as high doses increase hematocrit and may activate platelets, increasing their adhesion to the injured endothelium, contributing to hemorheologic changes [60]. Indeed, other side effects are associated with ESA therapy, namely hypertension [62] and thrombotic events [63].
\nDespite the benefits of ESA therapy, some concerns have emerged from studies reporting a high incidence of cardiovascular events and mortality in CKD patients treated with ESA [63, 64], independently of the type of ESA used [65, 66]. Since the introduction of ESA therapy, several clinical trials aimed to define the better Hb target/ESA dose associated with lower cardiovascular risk. Indeed, recent studies reported increased cardiovascular risk and death in patients treated with high ESA doses to achieve higher Hb levels [9, 67–69].
\nThe need for new drugs with lower associated cardiovascular risk opened a growing area of research. The most promising are the PHD inhibitors (\nTable 1\n) with several compounds already under evaluation in clinical trials. Some of these compounds showed to be well tolerated, corrected anemia in non‐dialysis CKD and incident dialysis patients without increasing blood pressure, and also reduced serum hepcidin levels [70–73]. However, regarding their effects in reducing cardiovascular events and slowing the progression of the renal disease, no data are still available from human studies. Yu et al. [22] showed that the administration of PHD inhibitors in a more advanced stage of CKD in the rat reduced renal fibrosis and protected renal function, whereas the administration in an early stage of CKD promoted renal fibrosis and exacerbated renal dysfunction. In another strategy to induce EPO production, the hydrodynamic gene transfer of a plasmid encoding for EPO in a rat model overexpressing TGF‐β showed that this therapy increased Hb levels but had no effect on kidney fibrosis or function [74].
\nPHD inhibitor | \nRoute administration | \nClinicalTrials.gov Identifier | \n
---|---|---|
Molidustat(BAY85‐3934) | \nOral | \n\n
| \n
Roxadustat(FG‐4592) | \nOral | \n\n
| \n
Vadadustat(AKB‐6548) | \nOral | \n\n
| \n
GSK1278863 | \nOral | \n\n
| \n
Prolyl‐4‐hydroxylase (PHD) inhibitors in clinical trials.
The majority of CKD patients respond adequately to the currently available ESA therapy, but 5–10% of them do not respond properly, developing hyporesponsiveness to these drugs [75]. According to the KDIGO guidelines [49], CKD patients can present initial or acquired ESA hyporesponsiveness; in primary hyporesponsiveness patients, after one month of treatment with adequate weight‐based ESA dose, the target Hb concentration is not achieved; in acquired ESA hyporesponsiveness, after effective treatment with stable ESA dose, achieving the target Hb concentration, the patient requires two consecutive increases (up to 50% beyond the stable dose) in ESA dose. Hyporesponsiveness (also widely referred as resistance) to ESA therapy is associated with a poor outcome, progression of renal disease, sudden death, infectious complications, sudden death and all‐cause mortality, mainly due to cardiovascular events in dialysis patients [76–79]. Several causes are associated with poor response to ESA therapy, including iron deficiency, inflammation, malnutrition and hyperparathyroidism, among others [80–82].
\nA pro‐inflammatory state is a hallmark of CKD, which is due to increased uremic toxins that induce the production of inflammatory cytokines. Additionally, active infections, the vascular access for hemodialysis (HD) procedure and surgery‐related inflammation (vascular surgery included) can also contribute to inflammation.
\nThe activation of inflammatory cells is also associated with increased oxidative stress, favoring alterations in red blood cells (RBC) membrane, namely increased phosphatidylserine exposure, increased membrane bound Hb and increased membrane protein band 3 aggregation, all markers for RBC phagocytosis by macrophages and, thus, for a premature RBC removal [83, 84]. Uremic toxins and pro‐inflammatory cytokines also inhibit erythropoiesis, through the inhibitory effect of IL‐1β, TNF‐α and IFN‐γ on early erythroid cell stages in the bone marrow [85]. The macrophages of the bone marrow can also be stimulated to increase local pro‐inflammatory cytokines, amplifying the effects of systemic inflammation [86]. In CKD patients, hepcidin synthesis is enhanced, due to the increase in Il‐6, contributing for the limited iron availability for erythropoiesis [87]. Indeed, CKD patients often present with replete or even higher iron stores, alongside with inflammation and anemia. A disturbance in the crosstalk between inflammation, iron metabolism and erythropoiesis may, therefore, favor ESA hyporesponsiveness. The best predictors for ESA response appear to be IL‐6 and CRP [88, 89]. Studies conducted by our group showed that HD patients with poorer response to ESA present higher levels of pro‐inflammatory cytokines [90, 91]; moreover, in studies using a rat model of chronic renal failure, we found that the severity of the inflammatory state was related to the reduction in the rHuEPO response [92].
\nHyporesponsive patients to ESA therapy will develop anemia, and as already referred, it will promote the progression of renal disease. Tissue hypoxia is amplified according to the severity of anemia that will reduce O2 availability to body tissues and organs. Within the kidney, the hypoxic environment leads to the activation of the HIF system, promoting the transcription of several target genes. In the hypoxic kidney, HIF‐1α is essentially expressed in tubular and glomerular epithelial cells, whereas HIF‐2α expression is limited to endothelial and interstitial cells [93]. The localization of these HIF‐α subunits is related to their target genes.
\nRenal biopsies from CKD patients showed that increased expression of HIF‐1α in tubular epithelial cells is correlated with the stage of renal disease [94]. It was reported that HIF‐α activation in CKD rats presents dynamic changes, as it is activated in early CKD stages and suppressed in the moderate and end‐stage of CKD [95]. Thus, the administration of PHD inhibitors may improve renal function in more advanced stages of CKD, while in earlier stages, the PHD inhibitors may increase renal fibrosis due to upregulation of the HIF‐1α subunit [22].
\nHIF‐1α subunit is involved in the activation of pro‐fibrotic genes (\nFigure 1\n), including the connective tissue growth factor (CTGF) gene [96]; indeed, the plasma levels of CTGF appear as a good marker for staging diabetic nephropathy progression [97]. CTGF is a potent pro‐fibrotic factor and a marker of renal fibrosis, increasing ECM production, promoting EMT, stimulating fibroblasts and potentiating TGF‐β signaling [94, 98]. CTGF and TGF‐β present similar effects, but TGF‐β also presents immunomodulatory actions [44], recruiting macrophages to reduce the injury; however, a continuous macrophage activation leads to excessive ECM accumulation and increased release of pro‐inflammatory cytokines promoting fibrosis. A study by Basu et al. [99] suggested that TGF‐β can in turn induce HIF‐1α activation, which would amplify cell collagen expression contributing to the progression of fibrosis.
\nThere is also a crosstalk between HIF‐1α and inflammation (\nFigure 1\n). Inflammation favor tissue hypoxia by several mechanisms including: impaired EPO response, iron mobilization and bone marrow erythropoiesis, reduced RBC lifespan and also increased demand for O2 by the inflammatory cells in order to increase pro‐inflammatory cytokines. However, it was also reported that NF‐κB can induce HIF‐1α activation due to the presence of responsive elements in the promoter of
The majority of the studies report a beneficial effect of ESA on renal fibrosis through several mechanisms [29, 102]. However, recently Gobe et al. [103] reported that in rat model of AKI the use of higher rHuEPO doses was associated with increased TGF‐β expression, oxidative stress and stimulation of fibroblasts and EMT, contributing to the progression of the disease and gradual development of CKD in the long term. In this study, the expression of HIF‐α subunits was not reported, as well as the linking between HIF activation and the alterations observed. Further studies regarding this issue are warranted.
\nDespite the underlying mechanism, a continuous inflammatory response favoring fibrosis and a disturbance in the HIF system creates a vicious cycle, contributing to the progression of renal disease and aggravation of renal anemia [92], and reducing the response to ESA therapy creating a scenario of hyporesponsiveness to EPO.
\nAnemia is a common complication in CKD patients that can be corrected by the treatment with ESA. However, the development of a hyporesponse to this therapy was associated with (i) the progression of the renal disease, due to the amplification of fibrosis and inflammation through a mechanism involving activation of HIF‐1α pathway; (ii) increased risks in the development of cardiovascular disorder events and all‐cause mortality in patients treated with higher doses, opened a new research field, focused on the design of more effective agents to control anemia in CKD patients, with less side effects. The use of PHD inhibitors is promising, but further is needed to confirm their effects in the reduction of cardiovascular events and progression of renal disease.
\nThis work received financial support from FCT/MEC through national funds and co‐financed by FEDER, under the Partnership Agreement PT2020 (UID/MULTI/04378/2013—POCI/01/0145/FERDER/007728, UID/NEU/04539/2013) and Norte Portugal Regional Coordination and Development Commission (CCDR‐N)/NORTE2020/Portugal 2020 (Norte‐01‐0145‐FEDER‐000024).
\nBoron (B) is an element that is found in ultratrace amounts in mammalian cells and consists of two stable isotopes, boron-10 (10B) and boron-11 (11B), with a natural abundance ratio (10B/11B = 19.9/80.1). The most important properties of boron compounds with respect to biological and medical sciences would be: (1) 11B atoms have a higher NMR sensitivity (16.5% for 11B and 2.0% for 10B relative to 1H NMR), thus permitting the detection of B-containing drugs themselves and analytes that react with B-containing probes in living systems [1]; and (2) the 10B nucleus possesses a high reactivity with thermal neutrons resulting in the generation of two radioactive species (4He and 7Li particles), which induce the excitation and ionization of molecules within short path lengths [2]. For the above reasons, boron compounds can be useful in biological applications for the treatment and diagnosis of cancer and other diseases [3].
In 1936, Locher proposed the concept of boron neutron capture therapy (BNCT) based on the aforementioned nuclear reaction between 10B and thermal neutrons [4]. Because the destructive effect of the two heavy particles (4He and 7Li particles) that are generated by the decomposition of 10B lies within 5–9 μm, which is close to the size of living cells, single-cell treatment would be possible by the achievement of cancer-specific delivery of 10B and irradiation with a sufficient intensity of thermal neutrons [5, 6, 7].
BNCT systems have been installed in clinical facilities as a method for the noninvasive treatment of certain types of cancers such as recurrent head and neck cancer and malignant gliomas [8]. The selective and efficient accumulation of boron into tumor tissues is one of the important clues for successful BNCT and, as described below, two boron compounds have been approved for use as BNCT drugs. In addition, monitoring the distribution of boron in patients is required for planning treatment protocols to determine the irradiation doses and positions of the patient [9].
In this review, we introduce the applications of boron compounds to 11B NMR (nuclear magnetic resonance)/MRI (magnetic resonance imaging) probes for the sensing of intracellular metal ions and BNCT agents for use in the treatment of cancer. The d-block metal ion probes take advantage of changes in the chemical shift in 11B NMR spectra due to the cleavage of the carbon-boron bond in phenylboronic acid-pendant cyclen (1,4,7,10-tetraazacyclododecane) and the decomposition of the
Biologically essential d-block metal ions such as zinc (Zn2+), copper (Cu2+), manganese (Mn2+), and iron (Fe2+) are involved in a variety of physiological processes in living systems as cofactors for various enzymes, intracellular second messengers, and related processes [10]. It was reported that a metal imbalance in cells and tissues causes a number of disorders such as Alzheimer’s disease, Parkinson’s disease, Willson’s disease, etc. [10]. Therefore, the development of fluorescence-based probes for the detection of these intracellular metal ions has contributed to our understanding of their functions and metabolism in living cells, while some limitations to detecting their emission from tissues remain due to their impermeability [10, 11, 12].
It is well known that MRI is one of the useful noninvasive methods for
It is well established that macrocyclic polyamine ligands such as 1,4,7-triazacyclononane ([9]aneN3)
The structures of 9-, 12-, and 15-membered macrocyclic polyamines
Bendel and coworkers reported that 11B NMR/MRI would be a potential technique for the imaging of boron agents in the body [24, 25]. However, a functional system for achieving this has not been established yet. In this context, we hypothesized that the sp2 boron in
The C–B bond hydrolysis of phenylboronic acid-pendant 12-membered tetraamine (cyclen) to produce inorganic boric acid.
X-ray crystal structures of (a)
The 11B NMR spectral change of
δ (ppm) | Δδ (ppm)b | time (h)c | δ (ppm) | Δδ (ppm)b | time (h)c | ||
---|---|---|---|---|---|---|---|
31.1 | – | – | Mn2+ | 20.6 | –10.5 | 48 | |
Zn2+ | 19.4 | –11.7 | 0.5 | Ni2+ | 19.8 | –11.3 | 2 |
Cu2+ | 19.5 | –11.6 | 1.5 | Cd2+ | 19.2 | –11.9 | 0.1 |
Fe2+ | 19.7 | –11.6 | 0.5 | Ca2+ | 31.7 | 0.6 | – |
Fe3+ | 30.8 | –0.3 | – | Mg2+ | 31.9 | 0.8 | – |
Co2+ | 19.6 | –11.5 | 1 |
11B NMR spectral change of
All data are referenced to external BF3·Et2O in CDCl3 (δ = 0 ppm).
Δδ = δ (
Approximate reaction time for the completion of C–B bond cleavage.
The intracellular uptake of boron in
In-cell 11B NMR spectra of
It is known that the reaction of the
Decomposition of
Decomposition of
Changes in the 11B NMR spectra of
Decomposition of
As shown in Figure 8, the oxidation potentials of
Summary of the oxidation potentials of
In addition, the chemical yields of B(OH)3 from
Proposed mechanism for the decomposition reaction (arrows indicate positively charged boron atoms, which are susceptible to attack by H2O or HO−).
11B MRI experiments were conducted by using an aqueous solution of B(OH)3 (10 mM) and Cu(bpy) (1 mM) in a larger vial (Sout) and a
11B MRI images differentiating B(OH)3 and
The detection of Cu2+ by a 11B NMR probe
11B MRI and 11B{1H} NMR (128 MHz) spectra of
As described in the Introduction, BNCT is one of the powerful cancer treatment methods utilizing two heavy particles, 4He and 7Li, which are produced from 10B by a neutron capture reaction [10B (n, α)7Li] and induce the damage of biomolecules such as DNA, RNA, and so on within a short range of 5–9 μm [4, 5, 6, 7, 8]. For this BNCT to be achieved, the development of cancer-specific 10B carriers is urgently needed. To date, only two boron compounds, namely disodium mercaptoundecahydrododecaborate (BSH)
Structures of representative BNCT agents.
Sulfoquinovosyl acylglycerol (SQAG)
Structures of (a) SQAG and SQAP derivatives and (b) 2-boryl-1,2-dideoxy-D-glucose derivatives.
The synthesis route for preparing SQAG analogues
The synthetic route of SQAP derivatives developed by Aoki et al.
The design and synthesis of 2-boryl-1,2-dideoxy-D-glucose derivatives
We therefore performed the regio- and stereoselective hydroboration of D-glucal
Synthesis of 2-boryl-1,2-dideoxy-D-glucose derivatives
It is known that natural polyamines play multiple roles in cellular functions, including gene expression and the stabilization of chromatin structure, and that the activated polyamine transport system and biosynthesis in cancer cells are related to the increase in polyamine concentrations and proliferation activity [40, 41]. Therefore, it is expected that polyamines would be desirable scaffolds for cancer selective and DNA-targeting boron delivery agents [42, 43].
Kimura and coworkers reported that Zn2+–cyclen complexes
Complexation of (a) Zn2+–cyclen
In this context, we designed and synthesized some novel DNA-targeting BNCT agents containing macrocyclic polyamine scaffolds such as [9]aneN3, [12]aneN4, and [15]aneN5 and their Zn2+ complexes, which contain phenylboronic acid units, as shown in Figures 17 and 18 [55, 56]. It was assumed that these boron-containing macrocyclic polyamine monomers
Structures of B-containing macrocyclic polyamine monomers and their Zn2+ complexes.
Structures of B-containing macrocyclic polyamine dimers
The results of biological studies suggested that the boron-containing macrocyclic polyamine monomers
BNCT effect of macrocyclic polyamine monomers
According to the results of biological evaluations and DNA interaction studies using double-stranded calf-thymus DNA, it was concluded that metal-free monomers would be efficiently taken up by cancer cells and then form complexes with intracellular Zn2+. Both the cationic metal-free macrocycles and their Zn2+ complexes would bind to DNA via electrostatic interactions between cationic macrocyclic polyamine moieties and anionic double-stranded DNA (
Proposed scheme for BNCT effect of
In this review, we summarize the current state of knowledge regarding the design and synthesis of 10B and/or 11B containing agents for biomedical applications such as 11B NMR probes and BNCT agents. We developed the d-block metal ion probes based on changes in 11B NMR signals due to the hydrolysis of C–B bond in
We believe that this review provides useful information for the future design and synthesis of novel boron-containing compounds and their applications for the treatment and diagnosis of cancer and other diseases, as well as in related research fields.
We wish to thank our collaborators and coworkers for their contributions to work described in this review. We appreciate Dr. Motoo Shiro (Rigaku Co. Ltd.), Prof. Reiko Kuroda (Chubu University), and Dr. Yasuyuki Yamada (Nagoya University) for their great assistance and helpful discussion. Financial supports from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, the Uehara Memorial Foundation, the Tokyo Ohka Foundation for the Promotion of Science and Technology, Kanagawa, Japan, the Tokyo Biochemical Research Foundation, Tokyo, Japan, Japan Society for the Promotion of Science (JSPS), and Tokyo University of Science are gratefully acknowledged.
The authors declare no conflict of interest.
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Adenoviruses are excellent vectors for delivering genes or vaccine antigens to the target host tissues and are being tested in several vaccine and gene therapy studies. Adenovirus-based vectors offer several advantages over other viral vectors such as broad range of tissue tropism, well-characterized genome, ease of genetic manipulation including acceptance of large transgene DNA insertions, inherent adjuvant properties, ability to induce robust transgene-specific T cell and antibody responses, non-replicative nature in host, and ease of production at large scale. However, several studies have highlighted major drawbacks to using adenovirus as vaccine and gene therapy vectors. These include pre-existing immunity in humans, inflammatory responses, sequestering of the vector to liver and spleen, and immunodominance of the vector genes over transgenes. In the same vein, recently discovered protein sequence homology and heterologous immunity between adenoviruses and hepatitis C virus have significant implications in the use of adenoviral vectors for vaccine development, especially for hepatitis C virus. This chapter focuses on the current scope and challenges in using adenoviral vector-based vaccines and gene therapies.",book:{id:"7286",slug:"adenoviruses",title:"Adenoviruses",fullTitle:"Adenoviruses"},signatures:"Shakti Singh, Rakesh Kumar and Babita Agrawal",authors:null},{id:"33318",doi:"10.5772/33285",title:"Baculovirus Enhancins and Their Role in Viral Pathogenicity",slug:"baculovirus-enhancins-and-their-role-in-viral-pathogenicity",totalDownloads:2450,totalCrossrefCites:1,totalDimensionsCites:14,abstract:null,book:{id:"1775",slug:"molecular-virology",title:"Molecular Virology",fullTitle:"Molecular Virology"},signatures:"James M. Slavicek",authors:[{id:"94745",title:"Dr.",name:"James",middleName:null,surname:"Slavicek",slug:"james-slavicek",fullName:"James Slavicek"}]},{id:"66740",doi:"10.5772/intechopen.85484",title:"Bacteriophages: Their Structural Organisation and Function",slug:"bacteriophages-their-structural-organisation-and-function",totalDownloads:2038,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Viruses are infectious particles that exist in a huge variety of forms and infect practically all living systems: animals, plants, insects and bacteria. Viruses that infect and use bacterial resources are classified as bacteriophages (or phages) and represent the most abundant life form on Earth. A phage can be described as a specific type of nano-machine that is able to recognise its environment, find a host cell, start infection, self-assemble and safeguard its genome until the next cycle of replication is initiated. Remarkable results have been obtained by combining cryo-EM, X-ray analysis and bioinformatics in structural studies of these nano-machines. In this review we will describe results of structural studies of phages that uncover their organisation in different conformations, thus facilitating our understanding of the functional mechanisms in supramolecular assemblies and helping us understand the usage of phages in medical treatments. Currently, antibiotic resistance is an enormous challenge that we face. The tailed phages could be used in place of antibiotics due to their high specificity to host cells, but more knowledge of their organisation and function is required.",book:{id:"6910",slug:"bacteriophages-perspectives-and-future",title:"Bacteriophages",fullTitle:"Bacteriophages - Perspectives and Future"},signatures:"Helen E. White and Elena V. Orlova",authors:[{id:"101052",title:"Prof.",name:"Elena",middleName:null,surname:"Orlova",slug:"elena-orlova",fullName:"Elena Orlova"},{id:"262804",title:"Dr.",name:"Helen",middleName:null,surname:"White",slug:"helen-white",fullName:"Helen White"}]},{id:"58406",doi:"10.5772/intechopen.72660",title:"A Historical Review of Ebola Outbreaks",slug:"a-historical-review-of-ebola-outbreaks",totalDownloads:1594,totalCrossrefCites:2,totalDimensionsCites:8,abstract:"Ebola Virus Disease (EVD) is a severe, often fatal illness in humans caused by the Ebola virus. Since the first case was identified in 1976, there have been 36 documented outbreaks with the worst and most publicized recorded in 2014 which ravaged three West African Countries, Guinea, Liberia and Serial Leone. The West African outbreak recorded 28,616 human cases, 11,310 deaths (CFR: 57–59%) and left about 17,000 survivors, many of whom have to grapple with Post-Ebola syndrome. Historically, ZEBOV has the highest virulence. Providing a historical perspective which highlights key challenges and progress made toward detecting and responding to EVD is a key to charting a path towards stronger resilience against the disease. There have been remarkable shifts in diagnostics, at risk populations, impact on health systems and response approaches. The health sector continues to gain global experiences about EVD which has shaped preparedness, prevention, detection, diagnostics, response, and recovery strategies. 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Adenoviruses are excellent vectors for delivering genes or vaccine antigens to the target host tissues and are being tested in several vaccine and gene therapy studies. Adenovirus-based vectors offer several advantages over other viral vectors such as broad range of tissue tropism, well-characterized genome, ease of genetic manipulation including acceptance of large transgene DNA insertions, inherent adjuvant properties, ability to induce robust transgene-specific T cell and antibody responses, non-replicative nature in host, and ease of production at large scale. However, several studies have highlighted major drawbacks to using adenovirus as vaccine and gene therapy vectors. These include pre-existing immunity in humans, inflammatory responses, sequestering of the vector to liver and spleen, and immunodominance of the vector genes over transgenes. In the same vein, recently discovered protein sequence homology and heterologous immunity between adenoviruses and hepatitis C virus have significant implications in the use of adenoviral vectors for vaccine development, especially for hepatitis C virus. This chapter focuses on the current scope and challenges in using adenoviral vector-based vaccines and gene therapies.",book:{id:"7286",slug:"adenoviruses",title:"Adenoviruses",fullTitle:"Adenoviruses"},signatures:"Shakti Singh, Rakesh Kumar and Babita Agrawal",authors:null},{id:"66740",title:"Bacteriophages: Their Structural Organisation and Function",slug:"bacteriophages-their-structural-organisation-and-function",totalDownloads:2035,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Viruses are infectious particles that exist in a huge variety of forms and infect practically all living systems: animals, plants, insects and bacteria. Viruses that infect and use bacterial resources are classified as bacteriophages (or phages) and represent the most abundant life form on Earth. A phage can be described as a specific type of nano-machine that is able to recognise its environment, find a host cell, start infection, self-assemble and safeguard its genome until the next cycle of replication is initiated. Remarkable results have been obtained by combining cryo-EM, X-ray analysis and bioinformatics in structural studies of these nano-machines. In this review we will describe results of structural studies of phages that uncover their organisation in different conformations, thus facilitating our understanding of the functional mechanisms in supramolecular assemblies and helping us understand the usage of phages in medical treatments. Currently, antibiotic resistance is an enormous challenge that we face. The tailed phages could be used in place of antibiotics due to their high specificity to host cells, but more knowledge of their organisation and function is required.",book:{id:"6910",slug:"bacteriophages-perspectives-and-future",title:"Bacteriophages",fullTitle:"Bacteriophages - Perspectives and Future"},signatures:"Helen E. White and Elena V. 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Bandeira and José Antonio Suárez",authors:[{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}]},{id:"67876",title:"The Unusual Linear Plasmid Generating Systems of Prokaryotes",slug:"the-unusual-linear-plasmid-generating-systems-of-prokaryotes",totalDownloads:1220,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Linear DNA is vulnerable to exonuclease degradation and suffers from genetic loss due to the end replication problem. Eukaryotes overcome these problems by locating repetitive telomere sequences at the end of each chromosome. In humans and other vertebrates this noncoding terminal sequence is repeated between hundreds and thousands of times, ensuring important genetic information is protected. In most prokaryotes, the end-replication problem is solved by utilizing circular DNA molecules as chromosomes. However, some phage and bacteria do store genetic information in linear constructs, and the ends of these structures form either invertrons or hairpin telomeres. Hairpin telomere formation is catalyzed by a protelomerase, a unique protein that modifies DNA by a two-step transesterification reaction, proceeding via a covalent protein bound intermediate. The specifics of this mechanism are largely unknown and conflicting data suggests variations occur between different systems. These proteins, and the DNA constructs they produce, have valuable applications in the biotechnology industry. They are also an essential component of some human pathogens, an increased understanding of how they operate is therefore of fundamental importance. Although this review will focus on phage encoded protelomerase, protelomerases found from Agrobacterium and Borellia will be discussed in terms of mechanism of action.",book:{id:"6910",slug:"bacteriophages-perspectives-and-future",title:"Bacteriophages",fullTitle:"Bacteriophages - Perspectives and Future"},signatures:"Sophie E. Knott, Sarah A. Milsom and Paul J. 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The severity of GBS can range from mild impairment with fast recovery to complete paralysis including severe respiratory or autonomic failure. Recovery may take months and even years and may be incomplete despite disease modifying treatment with IVIG or plasma exchange. Therefore, optimal supportive care and effective rehabilitation remain crucial. Multidisciplinary rehabilitation is recommended but may be challenging in the acute phase because of limited patient participation due to profound muscle weakness and severe pain. Inactive denervated muscles will inevitably undergo rapid degeneration resulting in wasting, weakness, and contractures as major long-term complications in severely affected patients. In this chapter, the current evidence of rehabilitation on the short- and long-term motor function in GBS is reviewed, including newly obtained experiences with neuromuscular electrical stimulation (NMES). Rehabilitation remains an area lacking well designed and controlled clinical studies and thus a clear lack of evidence-based guidelines.",book:{id:"8990",slug:"current-concepts-in-zika-research",title:"Current Concepts in Zika Research",fullTitle:"Current Concepts in Zika Research"},signatures:"Thomas Harbo and Henning Andersen",authors:[{id:"310593",title:"M.D.",name:"Thomas",middleName:null,surname:"Harbo",slug:"thomas-harbo",fullName:"Thomas Harbo"},{id:"318823",title:"Prof.",name:"Henning",middleName:null,surname:"Andersen",slug:"henning-andersen",fullName:"Henning Andersen"}]}],onlineFirstChaptersFilter:{topicId:"427",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",fullName:"Reda R. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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