Search

An enveloped double-stranded DNA monkeypox virus (MPXV) is a causative agent of the zoonotic viral disease, human monkeypox (HMPX). MPXV belongs to the genus Orthopoxviridae, a family of notorious smallpox viruses, and so it shares similar clinical pathophysiological features. The recent multicountry HMPX outbreak (May 2022 onwards) is recognized as an emerging global public health emergency by the World Health Organization, shunting its endemic status as opined over the past few decades. Re-emergence of HMPX raises concern to reassess the present clinical strategy and therapeutics as its outbreak evolves further. Keeping a check on these developments, here we provide insights into the HMPX epidemiology, pathophysiology, and clinical representation. Weighing on its early prevention, we reviewed the strategies that are being enrolled for HMPX diagnosis. In the line of expanded MPXV prevalence, we further reviewed its clinical management and the diverse employed preventive/therapeutic strategies, including vaccines (JYNNEOS, ACAM2000, VIGIV) and antiviral drugs/inhibitors (Tecovirimat, Cidofovir, Brincidofovir). Taken together, with a revised perspective of HMPX re-emergence, the present report summarizes new knowledge on its prevalence, pathology, and prevention strategies. [ABSTRACT FROM AUTHOR]

Summary: Reduced‐intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo‐HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)‐matched sibling or unrelated donor allo‐HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0·01. There were no significant differences between regimens in risk for non‐relapse mortality (NRM) (P = 0·54), relapse/progression (P = 0·02) or progression‐free survival (PFS) (P = 0·14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo‐HCT (HR = 0·28; 95% CI = 0·10–0·73; P = 0·009), but beyond 11 months post allo‐HCT it was associated with a significantly higher risk of mortality, (HR = 2·46; 95% CI = 0·1.32–4·61; P = 0·005). Four‐year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0·64), respectively. These data confirm the choice of RIC for allo‐HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo‐HCT (possibly due to late NRM events). [ABSTRACT FROM AUTHOR]

The Sundarbans, abutting the Bay of Bengal is home to about 7.2 million people; about 2.7 million in Bangladesh and the rest in India. Due to global warming the region is experiencing rise in sea surface temperature and sea level, increasing frequency of severe storms, and consequently, net land loss. What choices do communities and administrations have in the region? (i) Abandon and retreat, (ii) enhance resilience, or (iii) anticipate and facilitate transitions. This paper attempts to answer this question on the basis of a generic adaptation decision framework (GADF). The problem of climate vulnerability of the Indian Sundarbans is superimposed on the GADF to help administrations rationalize between choices. The threat of climate change-induced displacement in the ecoregion is real and the paper recommends a functional alliance between Bangladesh and India to bilaterally address environmental security issues, implying guarding against environmental degradation, and consequently, social disorder and conflict. [ABSTRACT FROM AUTHOR]

The article discusses a chemoimmunotherapy review for diffuse large B cell lymphoma (DLBCL) patients with hepatic and/or renal dysfunction in 2013-2016. Topics covered include the potential excellent outcomes for such patients if chemoimmunotherapy with appropriated dose adjustments in selected patients is quickly initiated, the possible quick reversal of lymphoma-related organ dysfunction, and the non-dose reduction or withdrawal of cyclophosphamide.

Diabetic cardiomyopathy (DCM) is a chronic complication in individuals with diabetes and is characterized by ventricular dilation and hypertrophy, diastolic dysfunction, decreased or preserved systolic function and reduced ejection fraction eventually resulting in heart failure. Despite being well characterized, the fundamental mechanisms leading to DCM are still elusive. Recent studies identified the involvement of small non-coding small RNA molecules such as microRNAs (miRs) playing a key role in the etiology of DCM. Therefore, miRs associated with DCM represents a new class of targets for the development of mechanistic therapeutics, which may yield marked benefits compared to other therapeutic approaches. Indeed, few miRs currently under active clinical investigation, with many expressing cautious optimism that miRs based therapies will succeed in the coming years. The major caution in using miRs based therapy is the need to improve the stability and specificity following systemic injection, which can be achieved through chemical and structural modification. In this review, we first discuss the established role of miRs in DCM and the advances in miRs based therapeutic strategies for the prevention/treatment of DCM. We next discuss the currently employed chemical modification of miR oligonucleotides and their utility in therapies specifically focusing on the DCM. Finally, we summarize the commonly used delivery system and approaches for assessment of miRNA modulation and potential off-target effects. [ABSTRACT FROM AUTHOR]

Allogeneic blood or marrow transplantation (alloBMT) may lead to long-term disease control in patients with multiple myeloma (MM). However, historically, the use of alloBMT in MM has been limited by its high nonrelapse mortality (NRM) rates, primarily from graft-versus-host disease (GVHD). We previously demonstrated that post-transplantation cyclophosphamide (PTCy) decreases the toxicities of both acute and chronic GVHD after alloBMT. Here, we examine the impact of PTCy in patients with MM undergoing alloBMT at Johns Hopkins Hospital. From 2003 to 2011, 39 patients with MM underwent bone marrow or peripheral blood alloBMT from HLA-matched related/unrelated or haploidentical related donors after either myeloablative or nonmyeloablative conditioning. Post-transplantation GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4 with or without mycophenolate mofetil and tacrolimus. Engraftment was detected in 95% of patients, with neutrophil and platelet recovery at a median of 15 and 16 days, respectively. The cumulative incidences of acute grades 2 to 4 and grades 3 and 4 GVHD were .41 and .08, respectively, and no cases of grade 4 acute GVHD were observed. The cumulative incidence of chronic GVHD was .13. One patient succumbed to NRM. All cases of chronic GVHD involved extensive disease and 60% of these patients received systemic therapy with complete resolution. After alloBMT, the overall response rate was 62% with complete, very good partial, and partial response rates of 26%, 21%, and 15%, respectively. The median progression-free survival was 12 months and was associated with the depth of response but not cytogenetic risk. The estimated cumulative incidence of relapse was .46 (95% confidence interval [CI], .3 to .62) at 1 year and .56 (95% CI, .41 to .72) at 2 years. At last follow-up, 23% of patients remain without evidence of disease at a median follow-up of 10.3 years after alloBMT. The median overall survival was 4.4 years and the 5-year and 10-year overall survival probabilities were 49% (95% CI, 35% to 67%) and 43% (95% CI, 29% to 62%), respectively. The use of PTCy after alloBMT for MM is feasible and results in low NRM and GVHD rates. The safety of this approach may allow the development of novel post-transplantation maintenance strategies to improve long-term disease control. [ABSTRACT FROM AUTHOR]

Quercetin-Magnesium complex is one of the youngest alkaline rare earth metal (Magnesium) complexes with flavonoids (Quercetin) in organo-metalic family. Earlier studies describe the details of the complex formation, characterization and antioxidant study of the complex but toxicity profile is still under darkness. The present study was taken up to investigate the oral acute toxicity, 28 days repeated oral sub-acute toxicity study and genotoxicity study of Quercetin-Magnesium complex in Swiss albino mice. Quercetin-Magnesium complex showed mortality at a dose of 185 mg/kg in the Swiss albino mice. In 28 days repeated oral toxicity study, Quercetin-Magnesium complex was administered to both sex of Swiss albino mice at dose levels of 150, 130 and 100 mg/kg body weight respectively. Where 150 mg/kg dose shows increased levels of white blood cells and changes in total protein, serum creatinine and blood urea nitrogen. Histopathological study of Quercetin-Magnesium complex shows minor structural alteration in kidney at 150 mg/kg dose. No observed toxic level found in 130 mg/kg or below doses. No genotoxic effect found in any doses of the complex. Therefore 130 mg/kg or below dose level could be better for further study. [ABSTRACT FROM AUTHOR]

Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana). Thirteen PD-L1+ cases were further analyzed for gene copy number variations (CNV) by NGS and for PD-L1/JAK2/PD-L2 co-amplification using fluorescent in-situ hybridization assay (FISH). PD-L1 positivity (≥5% positive cancer cells, IHC) was present in 32/77 (42%) and 33/71 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance between the two anti-PD-L1 clones was high with only three (4%) discrepant cases. The strongest and consistent (10/11 cases) expression was observed in cHL and primary mediastinal B-cell lymphomas (3/3). Diffuse large B-cell lymphomas (DLBCL) were frequently positive (13/26) irrespective of subtype. Follicular (1/8), peripheral T-cell (3/11) and mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/CLL and marginal zone lymphomas were consistently negative (3/3). Co-amplification/CNVs of PD-L1/JAK2/PD-L2 were observed in 3 cases of DLBCL and cHL, respectively. Of note, all three cHL-amplified cases were positive by FISH, but not by NGS. Since only a fraction of the IHC positive lymphoma cases were positive by FISH and NGS assays, other mechanisms are involved in PD-L1 upregulation, especially in DLBCL. FISH assay may be more suitable than NGS assay for determination of PD-L1 alterations in cHL. [ABSTRACT FROM AUTHOR]

Quercetin (3,3′,4′,5,7-pentahydroxyflavone) one of the most abundant dietary flavonoids, has been investigated in the presence of magnesium (II) in methanol. The complex formation between quercetin and magnesium (II) was examined under UV–visible, Infra-red and 1 H NMR spectroscopic techniques. The spectroscopic data denoted that quercetin can reacts with magnesium cation (Mg +2 ) through the chelation site in the quercetin molecule. The free radical antioxidant activity of the complex with respect to the parent molecule was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. It was observed that the free radical scavenging activity of quercetin was increased after complexation of magnesium (Mg +2 ) cation. [ABSTRACT FROM AUTHOR]

Background: Pediatric risk of mortality (PRISM III) score is used across the globe to predict the mortality of hospitalized children by an objective method based on 17 variables measured during first 24 h of admission in pediatric intensive care unit (PICU). Aims and Objectives: We have done this study to evaluate the cause, management and outcome of PICU admissions and also to find out the statistical significance of PRISM III score in predicting mortality. Materials and Methods: This observational prospective study was conducted for a period of 1 year in the PICU of a district Medical College of West Bengal among children 1-12 years age. They were divided into 4 groups according to the PRISM III scores of 1-10, 11-20, 21-30, and >30 and outcome in all the groups were recorded and analyzed. Results: Respiratory (25%), neurological (20.1%), and infectious (17.3%) etiology were major cause of PICU admission. About 17.4% patients needed mechanical ventilation, 31.2% Continuous Positive Airway Pressure and 66% patients inotropic support. Out of 144 cases, 117 discharged and 27 expired. Percentage of death is 100%, 44.4%, 21.6%, and 4.6% among child with PRISM III score of >30, 21-30, 11-21, and =10, respectively. Significant increase in mortality noted with increase in number of organ failures. Specificity and positive predictive value increases with higher PRISM III score and sensitivity and negative predictive value is more with low PRISM III score. Conclusion: PRISM III score can be used as a triage tool in limited resource settings for early initiation of intense management to high risk and salvageable cases. [ABSTRACT FROM AUTHOR]

Introduction: Kawasaki Disease (KD) is an acute self-limiting systemic vasculitis involving medium and small-sized arteries. It may soon replace rheumatic fever to become the most common cause of acquired heart disease in Indian children. Coronary Artery Aneurysm (CAA) which can develop in 15-25% of untreated children remains the most dreaded complication of KD. Predicting the risk of CAA and taking timely measures can help in reducing the fatality of the condition. Aim: To study the spectrum of cardiovascular complications in patients with KD and also to assess associated risk factors for developing CAA in the patients under study. Materials and Methods: This prospective clinical study was carried out in the Paediatric Medicine Ward, Burdwan Medical College and Hospital, West Bengal, Eastern India, from 1st January, 2020 to 31st May, 2021. Total 52 children diagnosed with KD, aged between one month to 12 years, were included and followed-up for six months. Data regarding demographic variables, duration of fever, Intravenous Immunoglobulin (IVIG) resistance, hepatomegaly, neutrophilia, thrombocytopenia, haematocrit, Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), hepatic transaminases (alanine transaminase, aspartate amino-transferase), hyponatremia, hypoalbuminemia, and N-terminal-brain natriuretic peptide (NT-proBNP) were collected. Univariate and multivariate regression analyses were done using these variables for assessment of risk factors. Results: In the present study, out of 52 children, 28 (53.85%) were males and 24 (46.15%) were females with mean age of 3.74±2.55 years. Cardiovascular complications were observed in 27 (51.92%) patients, of whom 19 (35.54%) had CAA. Duration of fever =10 days, IVIG resistance, thrombocytopenia, low hematocrit, Alanine Transaminase (ALT) ≥100 U/L, hypoalbuminemia, and raised NT-proBNP were proven to be significant risk factors for development of CAA on univariate analysis. Thrombocytopenia and raised NT-proBNP came across as significant on binary logistic regression analysis. Conclusion: In this study, one or more types of cardiovascular abnormalities were present in 51.92% cases. Seven risk factors were identified to be significant in development of CAA on univariate analysis and among them two were proven significant in binary logistic regression. [ABSTRACT FROM AUTHOR]

Lymphocyte infiltration into the intestinal tract in inflammatory bowel disease (IBD) is mediated by interaction between α4 integrin and its specific ligands. Development of monoclonal antibodies against α4 integrin allowed targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, vedolizumab, alicaforsen AJM300, rhuMAb β7, CCX282-B, and PF-00547,659 are few of monoclonal antibodies that have shown high promise in trials with the potential for more attractive benefit:risk ratio than currently available therapies. In this review, an attempt is made to underline the therapeutic potential and the safety of anti-adhesion molecule treatment in IBD. [ABSTRACT FROM AUTHOR]

Background: Hepatic dysfunction is a known complication in neonates with hypoxic ischemic encephalopathy (HIE). Aims and Objectives: We conducted this study to compare hepatic function between normal and asphyxiated newborn and whether the changes in liver function vary with the grade of HIE. Materials and Methods: This observational analytical cross-sectional study was done in a rural medical college of eastern India for 1 year with 51 HIE (17 each in HIE I, II, and III group) and 51 healthy neonates as control. Biochemical parameters of liver function such as alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), total serum bilirubin (TSB), serum albumin, and prothrombin time (PT) were measured in both groups between 48 and 72 h of birth. Results: We found that TSB, liver enzymes, and PT ware significantly elevated and serum albumin reduced in HIE group in comparison to control group. However, TSB, PT, and serum albumin does not differ much among three stages of HIE. By contrast, liver enzymes increases significantly among three stages of HIE, and also, there is significant difference in ALT, AST, and ALP between survivor and non-survivor of HIE babies. Conclusion: Hence, liver function test may serve as an useful early marker of perinatal asphyxia when the history of birth asphyxia is lacking and it can also be used as a prognostic indicator as there is more rise of liver enzymes from low to high grade of HIE and from survived to expired HIE babies. [ABSTRACT FROM AUTHOR]

Identifying the group that acts as the proton storage/loading site is a challenging but important problem for understanding the mechanism of proton pumping in biomolecular proton pumps, such as bacteriorhodopsin (bR) and cytochrome c oxidase. Recent experimental studies of bR propelled the idea that the proton storage/release group (PRG) in bR is not an amino acid but a water cluster embedded in the protein. We argue that this idea is at odds with our knowledge of protein electrostatics, since invoking the water cluster as the PRG would require the protein to raise the pKa of a hydronium by almost 11 pKa units, which is difficult considering known cases of pKa shifts in proteins. Our recent quantum mechanics/molecular mechanics (QM/MM) simulations suggested an alternative "intermolecular proton bond" model in which the stored proton is shared between two conserved Glu residues (194 and 204). Here we show that this model leads to microscopic pKa values consistent with available experimental data and the functional requirement of a PRG. Extensive QM/MM simulations also show that, independent of a number of technical issues, such as the influence of QM region size, starting X-ray structure, and nuclear quantum effects, the "intermolecular proton bond" model is qualitatively consistent with available spectroscopic data. Potential of mean force calculations show explicitly that the stored proton strongly prefers the pair of Glu residues over the water cluster. The results and analyses help highlight the importance of considering protein electrostatics and provide arguments for why the "intermolecular proton bond" model is likely applicable to the PRG in biomolecular proton pumps in general. [ABSTRACT FROM AUTHOR]

Context: Liver disease is a serious ailment and the scenario is worsened by the lack of precise therapeutic regimens. Currently available therapies for liver ailments are not apposite and systemic toxicity inhibits their long term use. Medicinal plants have been traditionally used for treating liver diseases since centuries as the toxicity factor appears to be on the lower side. Objective: Several phytochemials have been identified which have significant hepatoprotective activity with minimal systemic adverse effects which could limit their long term use. The scenario calls for extensive investigations which can lead to development of lead molecules for hepatoprotective molecules of future. This review deals with the biological activity, mode of action and toxicity and forthcoming application of some of these leads. Methods: These generally have strong antioxidative potential and cause induction of antioxidant enzymes like superoxide dismutase, reduced glutathione and catalase. Additional mechanisms of hepatoprotection include stimulation of heme oxygenase-1 activity, inhibition of nitric oxide production, hepatocyte apoptosis and nuclear factor-κκB activation. Results and conclusion: Out of the several leads obtained from plant sources as potential hepatoprotective agents, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside, phyllanthin, hypophyllanthin, and glycyrrhizin have been established as potent hepatoprotective agents. The hepatoprotective potential of several herbal medicines has been clinically evaluated. Significant efficacy has been seen with silymarin, glycyrrhizin and Liv-52 in treatment of hepatitis, alcoholic liver disease and liver cirrhosis. [ABSTRACT FROM AUTHOR]

Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases. Neurodegenerative diseases are characterized by progressive dysfunction and death of neurons. Oxidative stress is associated with dysfunction of the mitochondria and endoplasmic reticulum, inducing apoptosis and protein misfolding in neurons. Decreased activities of antioxidant enzymes like SOD, catalase, glutathione, glutathione peroxidase in neurodegenerative states signifies role of reduced antioxidant potential in neurodegeneration. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include Hsp70, heme oxygenase-1, thioredoxin and sirtuins. Cellular signalling pathways and molecular mechanisms that mediate hormetic responses typically involve antioxidant enzymes and transcription factors such as Nrf-2 and NF κκB. Vitagenes, either individually or by acting in concert, contribute to counteract the ROS mediated damage. In this review the importance of oxidative stress and the potential use of antioxidants in the prevention and treatment of neurodegenerative disorders are discussed. [ABSTRACT FROM AUTHOR]

Despite their efficacy in myeloma, corticosteroids have acute and chronic toxicities. Newer agents with significant anti-myeloma activity permit the development of steroid-free regimens. We designed a Phase II clinical trial to study the toxicity and efficacy of a steroid-free combination of bortezomib and thalidomide as a first-line treatment in patients with symptomatic myeloma. Patients received bortezomib 1·3 mg/m on days 1, 4, 8 and 11 every 21 d and thalidomide 150 mg/d for a maximum of eight cycles. Amongst 27 evaluable patients, the overall response was 81·5% with 25·8% near complete response or greater. The response rate was comparable to most other two drug combinations for upfront therapy but lower than that obtained with the use of three drugs. The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%), fatigue (7%) and anaemia (7%). Peripheral neuropathy completely resolved in 80% of the patients upon completion of therapy, but not in the remaining 20% of patients. No venous thromboembolic events were observed even in the absence of prophylactic anticoagulation. The median progression-free survival was 16·8 months (95% confidence interval 8·7-21·6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3-year overall survival was 74%. This study demonstrates: (i) the efficacy of a steroid-free regimen; (ii) mostly reversible treatment-related peripheral neuropathy; and (iii) the absence of venous thrombotic events. [ABSTRACT FROM AUTHOR]

Current advances in understanding of the pathogenesis of inflammatory bowel disease have encouraged the development of many new therapies targeted at specific and non-specific mediators of the inflammatory bowel disease inflammatory pathway. Crohn's disease and ulcerative colitis, two common inflammatory bowel diseases likely result from interaction of multiple genetic and environmental risk and protective factors, deregulation of mucosal immunity in gut and breakdown of delicate balance of proinflammatory and anti-inflammatory cytokines. Immunobiologic agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-κB), and others are being assessed and will open exciting perspectives on development of therapies for inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Abstract: Several key observations providing evidence for the cancer stem cell hypothesis and insights into the unique biology of these cells have come from the study of multiple myeloma. These include evidence that cancer cells may be functionally heterogeneous in spite of their genetic homogeneity and that malignant progenitors share many biological features with normal adult stem cells including drug resistance and regulatory processes governing self-renewal. We review studies that have examined clonogenic cells in multiple myeloma, highlight controversies regarding the cell of origin in multiple myeloma, and discuss potential targeting strategies. [Copyright &y& Elsevier]

As stringent tests for the molecular model and computational protocol, microscopic pKa calculations are performed for the key residue, Glu286, in cytochrome c oxidase (CcO) using a combined quantum mechanical/molecular mechanical (QM/MM) potential and a thermodynamic integration protocol. The impact of the number of water molecules in the hydrophobic cavity and protonation state of several key residues (e.g., His334, CUB-bound water, and PRDα3) on the computed microscopic pKa values of Glu286 has been systematically examined. To help evaluate the systematic errors in the QMIMM-based protocol, microscopic pKa calculations have also been carried out for sites in a soluble protein (Asp70 in T4 lysozyme) and a better-characterized membrane protein (Asp85 in bacteriorhodopsin). Overall, the results show a significant degree of internal consistency and reproducibility that support the effectiveness of the computational framework. Although the number of water molecules in the hydrophobic cavity does not greatly influence the computed pKa of Glu286, the protonation states of several residues, some of which are rather far away, have more significant impacts. Adopting the standard protonation state for all titratable residues leaves a large net charge on the system and a significantly elevated pKa for Glu286, highlighting that any attempt to address the energetics of proton transfers in CcO at a microscopic level should carefully select the protonation state of residues, even those not in the immediate neighborhood of the active site. The calculations indirectly argue against the deprotonation of His334 for the proton pumping process, although further studies that explicitly compute its pKa are required for a more conclusive statement. Finally, the deprotonated Glu286 is found to be in a stable water-mediated connection with PRDα3 for at least several nanoseconds when this presumed pumping site is protonated. This does not support the proposed role of Glu286 as a robust gating valve that prevents proton leakage, although a conclusive statement awaits a more elaborate characterization of the Glu286-PRDα3 connectivity with free energy simulations and a protonated PRDα3. The large sets of microscopic simulations performed here have provided useful guidance to the establishment of a meaningful molecular model and effective computational protocol for explicitly analyzing the proton transfer kinetics in CcO, which is required for answering key questions regarding the pumping function of this fascinating and complex system. [ABSTRACT FROM AUTHOR]

The positions of protons are not available in most high-resolution structural data of biomolecules, thus the identity of proton storage sites in biomolecules that transport proton is generally difficultto determine unambiguously. Using combined quantum mechanical! molecular mechanical computations, we demonstrate that a pair of conserved glutamate residues (Glu 194/204) bonded by a delocalized proton is the proton release group that has been long sought in the proton pump, bacteriorhodopsin. This model is consistent with all available experimental structural and infrared data for both the wild-type bacteriorhodopsin and several mutants. In particular, the continuum infrared band in the 1,800to 2,000-cm[sup-1] region is shown to arise due to the partially delocalized nature of the proton between the glutamates in the wild-type bacteriorhodopsin; alternations in the flexibility of the glutamates and electrostatic nature of nearby residues in various mutants modulate the degree of proton delocalization and therefore intensity of the continuum band. The strong hydrogen bond between Glu 194/204 also significantly shifts the carboxylate stretches of these residues well <1,700 cm[sup-1]1, which explains why carboxylate spectral shift was not observed experimentally in the typical >1,700-cm[sup-1] region upon proton release. By contrast, simulations with the proton restrained on the nearby water cluster, as proposed by several recent studies [see, for example, Garezarek K, Gerwert K (2006) Functional waters in intraprotein proton transfer monitored by FuR difference spectroscopy. Nature 439:109], led to significant structural deviations from available X-ray structures. This study establishes a biological function for strong, low-barrier hydrogen bonds. [ABSTRACT FROM AUTHOR]

Psoriasis is one of the most common human skin diseases and is considered to have key genetic contributions. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is reversible with appropriate therapy with the possibilities of recurrence. The trigger of the keratinocyte response is thought to be the activation of the cellular immune system with T cells, dendritic cells and various immune related cytokines and chemokines being implicated in pathogenesis. Immunosuppressants like cyclosporine and methotrexate were used earlier in the treatment of psoriasis, however their use was associated with severe adverse effects due to down regulation of immune system. The most recent advances in therapies for psoriasis target specific immune components of psoriasis and promise to have high therapeutic efficacy with low adverse effects. This review focuses on the novel therapies aimed to specifically modulate the dysregulated immune system with minimal adverse effects. [ABSTRACT FROM AUTHOR]

A proportion of patients with diffuse large B cell lymphoma (DLBCL) will fail to achieve durable remission to standard chemoimmunotherapy treatment with R-CHOP or dose- adjusted R-EPOCH regimens [1]. This benefit may be offset by an increased rate of relapse, however, leading to no significant differences in overall survival (OS) between patients receiving myeloablative conditioning (MAC) regimens and those receiving RIC regimens. 333, 1995, 1540-1545 3 E. Van Den Neste, N. Schmitz, N. Mounier, Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study. [Extracted from the article]

The relationship between the behaviour at melting and the range and softness of interatomic potentials is explored using Monte Carlo simulations of bulk Morse and Lennard-Jones systems. The range parameter of the Morse interaction is tuned to mimic the variation seen in atomic systems. from metallic systems with soft, long-range interactions to van der Waah solids with short-range. strongly repulsive potentials. An umbrella sampling procedure is used to determine the melting point by constructing Landau free energy curves; the accuracy and finite-size effects associated with this approach are estimated for the Lennard-Jones system by comparison with existing results in the literature. The melting temperature as well as the strength of the first-order transition for Morse solids is shown to increase as the range and softness of the interatomic interactions decrease. The phase transition properties are largely determined by the behaviour of the pair interaction near equilibrium separation. The height of the barrier separating the two phases. as determined from the Landau free energy curve, is shown to be correlated with the crystal liquid interfacial free energy. [ABSTRACT FROM AUTHOR]

Most hypersensitivity reactions to insect stings are immediate, ranging from transient local reactions of little medical consequence to fatal anaphylaxis. Rarely, some patients have delayed reactions after a period of apparent normality which manifest as systemic features which can be life-threatening. A 3-year-old boy was attacked by a swarm of bees, estimated to be about 200 in number. There was an immediate cutaneous reaction which was treated at a local hospital. After 9 days, he presented with oliguria, dark-coloured urine, pedal oedema, hypertension and acute kidney injury (AKI). He was managed conservatively with fluid restriction, control of blood pressure and peritoneal dialysis, and renal function returned to normal gradually over the following 9 days. The delayed-onset AKI and other laboratory abnormalities suggested a immune-mediated type III hypersensitivity reaction leading to renal insufficiency. After improvement of initial hypersensitivity reactions, patients with bee stings should be followed up in order to detect any late-onset complications which might be life-threatening. [ABSTRACT FROM AUTHOR]

BACKGROUND: The informCLL registry is the largest prospective, US-based observational registry of patients who received treatment for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the era of novel agents. OBJECTIVE: To report baseline characteristics, prognostic biomarker testing, and treatment patterns in routine clinical practice for patients enrolled in the informCLL registry. METHODS: From October 2015 to June 2019, the informCLL registry enrolled eligible patients aged ≥18 years with CLL or SLL who had initiated FDA-approved treatment for CLL or SLL within ≥45 days of enrollment. Based on the index treatment at enrollment, patients were classified into 5 groups: ibrutinib (single-agent or combination), chemoimmunotherapy, chemotherapy, immunotherapy, and other novel agents. RESULTS: The informCLL registry enrolled 1461 patients; 855 (59%) patients were treatment-naïve and 606 (41%) had relapsed or refractory disease; the median age was 71 years, 64% of the patients were male, and 88% had ECOG performance status of 0/1. For patients with staging performed (N = 852), 51% had Rai stage III/IV. Most (93%) enrolling sites were community-based practices. The median time from diagnosis to index treatment for untreated patients was 18.6 months and 84.27 months for patients with relapsed or refractory disease. The median follow-up was 14.9 months for untreated patients and 15.3 months for patients with relapsed or refractory disease. Overall, prognostic biomarker testing was infrequent: fluorescence in situ hybridization testing was performed in 28% of patients, testing for TP53 mutation in 11%, and testing for IGHV mutation was 12%. Of patients who had prognostic biomarker testing, 24% (100/415) had deletion 17p, 27% (43/162) had TP53 mutation, and 71% (121/171) had wild-type IGHV. Overall, the most common treatment was ibrutinib (46%), and 87% started ibrutinib at the recommended dose of 420 mg daily. For patients continuing ibrutinib therapy, 75% did not require dose modifications. At 12 months or 24 months, 77% (307/401) and 68% (126/184) of patients continued ibrutinib therapy, respectively. For patients who completed chemoimmunotherapy regimens, bendamustine plus rituximab (BR) and fludarabine, cyclophosphamide, and rituximab (FCR) were the most common chemoimmunotherapy regimens received; 80% and 85% of patients who received BR and FCR, respectively, received <6 cycles. Only 6% of patients had index treatment of other novel agents. CONCLUSION: Results from the informCLL registry allow for a prospective assessment of CLL treatment pat - terns in the era of novel agents. Ibrutinib was the most common index treatment received, and most ibrutinibtreated patients continued therapy at 2 years of follow-up; 33% of patients received chemoimmunotherapy. Prognostic biomarker testing was infrequent, especially for TP53 and IGHV mutational status, indicating that prognostic marker testing results may not always guide treatment selection for patients with high-risk disease. [ABSTRACT FROM AUTHOR]

Differentiated Thyroid carcinoma (DTC) with distant skeletal metastases is associated with a very poor prognosis and are unfortunately resistant to radioiodine therapy (RIT). Surgical removal of the metastases in such selected cases is a beneficial adjunct to RIT. We report two cases of DTC with sternal metastases whom we successfully managed with surgical resection of the sternal lesion with reconstruction of the chest wall defect using titanium mesh implant and myocutaneous flap. [ABSTRACT FROM AUTHOR]

Human soluble epoxide hydrolase (sEH), a dual-functioning homodimeric enzyme with hydrolase and phosphatase activities, is known for its pivotal role in the hydrolysis of epoxyeicosatrienoic acids. Inhibitors targeting sEH have shown promising potential in the treatment of various life-threatening diseases. In this study, we employed a range of in silico modeling approaches to investigate a diverse dataset of structurally distinct sEH inhibitors. Our primary aim was to develop predictive and validated models while gaining insights into the structural requirements necessary for achieving higher inhibitory potential. To accomplish this, we initially calculated molecular descriptors using nine different descriptor-calculating tools, coupled with stochastic and non-stochastic feature selection strategies, to identify the most statistically significant linear 2D-QSAR model. The resulting model highlighted the critical roles played by topological characteristics, 2D pharmacophore features, and specific physicochemical properties in enhancing inhibitory potential. In addition to conventional 2D-QSAR modeling, we implemented the Transformer-CNN methodology to develop QSAR models, enabling us to obtain structural interpretations based on the Layer-wise Relevance Propagation (LRP) algorithm. Moreover, a comprehensive 3D-QSAR analysis provided additional insights into the structural requirements of these compounds as potent sEH inhibitors. To validate the findings from the QSAR modeling studies, we performed molecular dynamics (MD) simulations using selected compounds from the dataset. The simulation results offered crucial insights into receptor–ligand interactions, supporting the predictions obtained from the QSAR models. Collectively, our work serves as an essential guideline for the rational design of novel sEH inhibitors with enhanced therapeutic potential. Importantly, all the in silico studies were performed using open-access tools to ensure reproducibility and accessibility. [ABSTRACT FROM AUTHOR]

The objective of the study aims to evaluate the combined protective effects of coenzyme Q10 and magnesium sulphate on isoproterenol induced myocardial damage in rats. CoenzymeQ10 (50 mg/kg) and magnesium sulphate (10 mg/kg) were administered orally to wistar rats in individual or in combination for 30 days. At the end of this period, rats were administered isoproterenol (85 mg/kg i.p.) intraperitonially for two consecutive days to induce myocardial injury. After induction, rats were anaesthetized and plasma was collected to analyze various biochemical parameters. Further, immunohistochemistry and histopathology of the heart tissue was performed. Induction of rats with isoproterenol resulted in a marked (p<0.001) elevation of infarct size , level of serum marker enzymes (AST, ALT, LDH and CK- MB), lipid peroxidation , protein expression of alpha- smooth muscle actin (α SMA) along with alterations in histopathology. Pretreatment with combination of coenzyme Q10 (CoQ10) and magnesium sulphate (MgSO4) exhibited a significant (p<0.001) decrease in serum marker enzyme, infarct size , lipid peroxidation , protein expression of α- smooth muscle actin (α-SMA) and showed preservation of cardiomyocytes histo-architecture when compared with individual treated groups. This study demonstrated the synergistic cardio protective effect of coenzymeQ10 (CoQ10) and magnesium Sulphate (MgSO4) in isoproterenol induced myocardial damage in rats demonstrated that the oral pretreatment with CoQ10 and Magnesium sulphate were associated with moderate protection against ISO-induced cardio toxicity and cardiac hypertrophy. The mechanism might be associated with the enhancement of antioxidant defense system. The present results can form the basis that combination of CoQ10 and magnesium sulphate proved to be a potential therapeutic agent for pharmacological management of ischemic heart disease. It could provide experimental evidence to support the rationality of combinatorial use in the prevention of the onset and progression of myocardial injury. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.Methods: PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m2 and intravenous cyclophosphamide 300 mg/m2 daily for 3 days) followed 2-7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8+ and CD4+ CAR+ T cells for a total target dose of 100 × 106 CAR+ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103.Findings: Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.Interpretation: These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.Funding: Juno Therapeutics, a Bristol-Myers Squibb company. [ABSTRACT FROM AUTHOR]

[Display omitted] • N-succinylated chitosan (NCS), mangiferin (MGF) are conjugated into a nanohybrid. • The NCS-MGF conjugate particle size is measured as 100 ∼ 200 nm. • FT-IR and COSY analyses revealed hydrogen-hydrogen coupling between NCS and MGF. • The blood glucose lowered > 67% on 28 days treatment with NCS-MGF. • The NCS-MGF lowered plasma cholesterol > 37% and serum triglycerides > 61%. Mangiferin (MGF), from Mangifera indica is well reported for its hypoglycemic activity and hypolipidemic activity. However, MGF suffers therapeutic limitation due to poor solubility causing disparaging bioavailability. Herein to address this problem, we have incorporated MGF in alginate grafted N-succinylated chitosan (NSC) nanomatrix. Characterization by molecular docking, FT-IR and 2D-NMR (COSY) has revealed that MGF could reinforce interaction with NSC. The OH and CH 2 OH groups of MGF may set interactions with pyranosic OH, CH 2 OH, NH 2 (or NH-succinyl and COOH-succinyl) of NSC. The NSC-MGF nanoconjugate revealed a spherical particle geometry of 100 ∼ 200 nm size. The encapsulated MGF showed 100% release in vitro. In vivo, NSC-MGF nanoconjugate revealed blood glucose lowering from 300 mg/dL to ∼ 90 mg/dL as well as ∼ 37% lowering of total plasma cholesterol. This is well comparative to the earlier reports which acknowledged only 1 ∼ 36% lowering of plasma cholesterol with MGF. Furthermore, NSC-MGF lowered serum trigyceride to ∼ 61%, while in earlier studies, only 10 ∼ 40% serum triglycerides reduction was found with solitary MGF. [ABSTRACT FROM AUTHOR]

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is an exceedingly rare extra-nodal variant of diffuse large B-cell lymphoma (DLBCL) with an aggressive natural history that often manifests as red cutaneous tumour lesions on the lower extremities. Additionally, with the chemoresistant nature of PCDLBCL-LT and the relatively poor prognosis, many patients experience disease relapse and thus, novel treatment paradigms are needed for salvage therapy. PET/CT 13 months after starting therapy shows continued CR, and the patient remains in remission clinically at 20 months. After four cycles of therapy, an interim PET/CT scan demonstrated a CR with no hypermetabolic uptake to indicate active, recurrent, or metastatic disease. [Extracted from the article]

Background: Aggressive large B‐cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. Methods: The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression‐free survival (PFS) were calculated with Kaplan‐Meier methods. Baseline characteristics were compared with Fisher exact tests. Results: Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3‐5, 43% vs 47%; P =.50), frontline chemotherapy (98% vs 96%; P =.68), or the incidence of relapsed/refractory disease (40% vs 38%; P =.74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P >.99) or chimeric antigen receptor T‐cell therapy (16% vs 19%; P >.99). Enrollment in clinical trials was comparable (17% vs 14%; P =.64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P =.01). The 2‐year OS rates were 81% and 76% for minorities and Whites, respectively (P =.27); the 2‐year PFS rates were 62% and 65%, respectively (P =.78). Conclusions: This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline‐concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages. Although other studies have shown worse outcomes for minorities with aggressive large B‐cell lymphoma, this study demonstrates similar survival in White and minority patients. The authors attribute the equitable outcomes to equal access to guideline‐conforming care and novel treatment options, which may have been attainable by overcoming barriers via the aid of nurse navigation. [ABSTRACT FROM AUTHOR]

Introduction: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent‐behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. Methods: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high‐dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non‐intensive (n = 131). Results: There was no difference in progression‐free (PFS; P =.224) or overall survival (OS; P =.167) in deferred patients who received non‐intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P =.015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. Conclusions: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy. [ABSTRACT FROM AUTHOR]

• MDSC subset distribution distinguishes three DLBCL immunotypes. • Standard chemoimmunotherapy reduces monocytic MDSC blood counts in DLBCL. • Persistence of polymorphonuclear MDSC after treatment worsens the patient's prognosis. The revised International Prognostic Index (R-IPI) is an important prognostic tool in diffuse large B cell lymphoma (DLBCL); however, outcomes can vary markedly within R-IPI groups, and additional prognostic markers are needed. We conducted a prospective observational study to evaluate the circulating immature myeloid (IM) cell subsets and cytokine profiles of 31 patients with newly diagnosed DLBCL before and after chemoimmunotherapy. Among circulating IM cells, myeloid-derived suppressor cells (MDSCs) were the predominant cell type (73.8% ± 26%). At baseline, circulating monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) were predominantly mutually exclusive. Patients with DLBCL clustered into three distinct immunotypes according to MDSC levels and subtype predominance: M-MDSChigh, PMN-MDSChigh, and MDSClow. The M-MDSChigh immunotype was associated with the germinal center B cell–like (GCB) subtype and elevated serum IL-8 and MIP-1α levels. PMN-MDSChigh was associated with the non-GCB subtype and elevated IL-8, MCP-1, IP-10, TNFα, and IL-1Ra levels. Standard chemoimmunotherapy partially reduced M-MDSC distribution across the MDSClow and M-MDSChigh groups. By contrast, among the MDSClow and PMN-MDSChigh groups, PMN-MDSCs persisted after treatment. Two high-risk patients with non-GCB DLBCL and MDSClow immunotype experienced early disease recurrence within 12 months of treatment completion. This study demonstrates that distinct types of MDSCs are associated with subtypes of DLBCL. MDSC levels are dynamic and may be associated with disease status. Persistence of PMN-MDSCs among high-risk patients with DLBCL may be associated with early relapse. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemic state. The α-glucosidase and α-amylase are considered two major targets for the management of Type 2 DM due to their ability of metabolizing carbohydrates into simpler sugars. In the current study, cheminformatics analyses were performed to develop validated and predictive models with a dataset of 187 α-glucosidase and α-amylase dual inhibitors. Separate linear, interpretable and statistically robust 2D-QSAR models were constructed with datasets containing the activities of α-glucosidase and α-amylase inhibitors with an aim to explain the crucial structural and physicochemical attributes responsible for higher activity towards these targets. Consequently, some descriptors of the models pointed out the importance of specific structural moieties responsible for the higher activities for these targets and on the other hand, properties such as ionization potential and mass of the compounds as well as number of hydrogen bond donors in molecules were found to be crucial in determining the binding potentials of the dataset compounds. Statistically significant 3D-QSAR models were developed with both α-glucosidase and α-amylase inhibition datapoints to estimate the importance of 3D electrostatic and steric fields for improved potentials towards these two targets. Molecular docking performed with selected compounds with homology model of α-glucosidase and X-ray crystal structure of α-amylase largely supported the interpretations obtained from the cheminformatic analyses. The current investigation should serve as important guidelines for the design of future α-glucosidase and α-amylase inhibitors. Besides, the current investigation is entirely performed by using non-commercial open-access tools to ensure easy accessibility and reproducibility of the investigation which may help researchers throughout the world to work more on drug design and discovery. [Display omitted] • α-glucosidase and α-amylase are considered two major targets for diabetes treatment. • 2D- and 3D-QSAR models were developed with diverse inhibitors of these targets. • 2D-QSAR models highlighted important structural requirements for higher inhibition. • 3D-QSAR hinted possible interactions with the proteins to guide future design. • The current work is entirely dependent on non-commercial open-access tools. [ABSTRACT FROM AUTHOR]

• PTP1B is a crucial target for drug development and is associated with diabesity. • PTP1B regulates both insulin end leptin signalling pathways. • 71 natural sources and 32 synthetic analogues were examined for T2DM therapy. • Numerous natural and synthetic agents have been proven to inhibits the PTP1B enzyme. • Protein-inhibitor interactions against PTP1B is also summarized. Diabetes mellitus (DM), especially type 2 diabetes mellitus (T2DM), is the most disruptive metabolic disorder globally affecting human health. To effectively manage this medical condition, the quest for a new medication to treat T2DM continues. The emergence of medication resistance to the insulin and leptin receptors leads to significant concerns. The compounds which can tackle this resistance issue may be helpful in the therapeutic management of T2DM. Protein tyrosine phosphatase 1B (PTP1B) is a promising therapeutic target for treating T2DM. Diverse natural bioactive and synthetic molecules have offered great opportunities for developing lead molecules with significant inhibitory action in in vitro and in vivo against PTP1B. Numerous PTP1B inhibitors have recently been found from natural sources or synthesized by organic synthesis and shown effectiveness for treating T2DM. This review comprehensively updates the latest research findings in developing potent natural and synthetic PTP1B inhibitors over the past six years, including structural features of PTP1B, classification of inhibitors, biological effects, and protein-inhibitors interaction modalities. These studies will be highly helpful for the medicinal chemists working in this field to design and develop novel selective PTP1B inhibitors as anti-diabetic agents in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.Methods: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044.Findings: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells.Interpretation: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.Funding: Juno Therapeutics, a Bristol-Myers Squibb Company. [ABSTRACT FROM AUTHOR]

• Bloodless autologous hematopoietic cell transplantation may be safely performed. • Prime hemoglobin with erythropoiesis-stimulating agents before transplant. • Thrombopoietin agonists may be considered to optimize transplant success. Bloodless autologous hematopoietic cell transplantation is associated with risks of severe bleeding and profound anemia. RBC or platelet transfusions are often used to prevent these hematologic complications. However, in patients such as Jehovah's Witnesses who refuse major blood components, the lack of transfusion support is not an absolute contraindication to an autologous hematopoietic cell transplant. Pennsylvania Hospital performed the world's first bloodless hematopoietic cell transplant more than 15 years ago and has gradually improved its technique with a sizable patient population. Erythropoiesis-stimulating agents were successfully employed as part of their pretransplant regimen to prevent severe anemia. Thrombopoietin agonists' potential role in bloodless transplant is also currently being explored. Although there is limited literature, available reports in combination with physiologic reasoning may support the use of these growth factors to promote transplant success. These agents offer potential benefit and may be of utility in minimizing complications of a bloodless transplant. In this review, we summarize the available literature and offer insight into how we may incorporate growth factors to allow bloodless autologous hematopoietic cell transplantation to be an available option to patients who may otherwise be denied. [ABSTRACT FROM AUTHOR]

• We found a lower incidence of chronic GVHD in RIC haploidentical versus matched sibling donor transplantation for Hodgkin lymphoma. • We found a decreased relapse in PTCy-based haploidentical versus matched sibling donor transplantation for Hodgkin lymphoma. Classic Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of 2 reduced-intensity conditioning (RIC) HCT platforms in cHL: T cell–replete related donor haploidentical (haplo) HCT with a post-transplant cyclophosphamide (PTCy)-based approach versus an MSD/calcineurin inhibitor (CNI)-based approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008 and 2016 using either a haplo-PTCy (n = 139) or MSD/CNI-based (n = 457) approach. Overall survival (OS) was the primary endpoint. Secondary endpoints included acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no significant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR], 1.07; 95% confidence interval [CI],.79 to 1.45; P =.66) or PFS (HR,.86; 95% CI,.68 to 1.10; P =.22). Haplo/PTCy was associated with a significantly higher risk of grades II to IV aGVHD (odds ratio [OR], 1.73, 95% CI, 1.16 to 2.59; P =.007), but the risk of grades III to IV aGVHD was not significantly different between the 2 cohorts (OR,.61; 95% CI,.29 to 1.27; P =.19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR,.45; 95% CI,.32 to.64; P <.001), and a significant reduction in relapse risk (HR,.74; 95% CI,.56 to.97; P =.03). There was a statistically nonsignificant trend toward higher NRM with a haplo/PTCy approach (HR, 1.65; 95% CI,.99 to 2.77; P =.06). Haplo/PTCy-based approaches are associated with lower incidences of cGVHD and relapse, with PFS and OS outcomes comparable with MSD/CNI-based approaches. There was a leaning toward higher NRM with a haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable with MSD/CNI-based allo-HCT. [ABSTRACT FROM AUTHOR]

Highlights • Hemorrhagic cystitis occurs more frequently following haploidentical donor transplantation compared with matched related donor transplantation. • This higher frequency occurs despite the receipt of identical graft-versus-host disease prevention. • The grater susceptibility appears related to the inherent immune deficiency of HLA mismatch. ABSTRACT Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P =.01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients. [ABSTRACT FROM AUTHOR]

Highlights • CYP3A5 polymorphisms did not impact i.v. tacrolimus exposure post-transplant. • CYP3A4 and ABCB1 polymorphisms impacted i.v. tacrolimus exposure post-transplant. • ABCB1 2677TT genotype was associated with increased risk of tacrolimus toxicity. • C YP3A4 and ABCB1 C2677T genotyping may help individualize i.v. tacrolimus dosing. • Pharmacogenomic guidelines should acknowledge differences in i.v. versus oral tacrolimus. Abstract Pharmacogenetics influences oral tacrolimus exposure; however, little data exist regarding i.v. tacrolimus. We investigated the impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on i.v. tacrolimus exposure and toxicity in adult patients receiving an allogeneic hematopoietic stem cell transplant for hematologic malignancies. Germline DNA was extracted from buccal swabs and genotyped for CYP3A4, CYP3A5, and ABCB1 polymorphisms. Continuous i.v. infusion of tacrolimus.03 mg/kg/day was initiated on day +5 post-transplant, and steady-state blood concentrations were measured 4days later. We evaluated the association between phenotypes and prevalence of nontherapeutic target concentrations (below or above 5 to 15 ng/mL) as well as tacrolimus-related toxicities. Of 63 patients, 28.6% achieved the target concentration; 71.4% were >15ng/mL, which was more common in CYP3A4 intermediate/normal metabolizers (compared with rapid) and those with at least 1 ABCB1 C2677T loss-of-function allele (P <.05). ABCB1 C2677T was significantly associated with concentrations >15ng/mL (odds ratio, 6.2; 95% confidence interval, 1.8 to 23.6; P =.004) and tacrolimus-related toxicities (odds ratio, 7.5; 95% confidence interval, 1.6 to 55.2; P =.02). ABCB1 C2677T and CYP3A4 are important determinants of i.v. tacrolimus exposure, whereas ABCB1 C2677T also impacts tacrolimus-related toxicities in stem cell transplants. [ABSTRACT FROM AUTHOR]

Background: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically.Methods: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose.Results: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.Conclusions: The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .). [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL. [ABSTRACT FROM AUTHOR]