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Unlocking Neurodegeneration: Scaffold-Derived Blockers of MAO-B and AChE Inspired by Bryophyllum pinnatum: A Structural Exploration

This study evaluates the potential of Bryophyllum pinnatum ligands as treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) by targeting acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), enzymes linked to these neurodegenerative disorders. Utilizing Schrödinger Suite and Maestro 12.8 for computer-aided drug design, ligands from B. pinnatum and standard drugs were docked into the active sites of AChE and MAO-B. Further analysis included ADMET screening and MM/GBSA calculations, with pharmacophore modeling to align compounds with reference ligands. The study identified 4 and 6 promising compounds as MAO-B and AChE inhibitors, respectively. Pinoresinol was identified as the most promising candidate, exhibiting optimal binding, favorable blood-brain barrier permeability, and pharmacophoric features similar to those of the standard drug. These findings suggest the neuroprotective capabilities of B. pinnatum ligands, recommending further in vivo and in vitro testing to confirm their therapeutic efficacy
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Dosing Time-Dependency of the Arthritis-Inhibiting Effect of Tofacitinib in Mice

Rheumatoid arthritis (RA) has a 24-hour rhythm with a characteristic symptom of morning stiness, which causes pain in the joints from late night to early morning. We previously revealed that higher therapeutic eects were obtained in RA patients and RA animal models when the dosing time of anti-rheumatic drugs was chosen according to the 24-hour rhythms of cytokine and in- ammatory reaction. In this study, we evaluated whether dosing with the Janus-associated kinases inhibitor Tofacitinib while accounting for biological rhythms results in higher therapeutic ecacy
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Bioequivalence Studies of Two Formulations of Rivaroxaban 10 Mg Coated Tablets under Fasting Conditions and 20 Mg Coated Tablets Under Fed and Fast Conditions And its Pharmacokinetic Comparison In Healthy Subjects

Justificative: This trial was conducted in order to register a new generic product of Rivaroxaban. Objective: To evaluate the bioequivalence of rivaroxaban formulations manufactured by Eurofarma Laboratórios S/A and the reference drug, Xarelto (Bayer) under fasting and fed conditions. Methods: Three randomized, open label, balanced, 2 treatments, 4 periods, 2 sequences, single dose, full replicate, crossover studies in 48 healthy adult human subjects under fed and fasting conditions for rivaroxaban 10 mg and 20 mg. Rivaroxaban concentrations in plasma were determined using a validated HPLC-MS/MS method.
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Case Report: Pyoderma Gangrenosum in IBD Treated with Tofacitinib

Pyoderma gangrenosum is a rare ulcerating skin disease often presenting as an extra intestinal manifestation of IBD and is difficult to manage. Treatment options for pyoderma gangrenosum include steroids, calcineurin inhibitors and anti TNF agents. Here in, we report a case of recurrent Pyoderma gangrenosum with Ulcerative Colitis that was successfully managed with Tofacintib, a JAK inhibitor
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Anti-Infectives do not Impact Treatment Response to Immune Checkpoint Inhibitors: a Single Center Retrospective Analysis

Immune-checkpoint inhibitors (ICI) have provided groundbreaking advancements for a variety of malignancies. It has been of recent interest to identify predictive indicators of response to improve cancer management using immunotherapy. The intestinal microbiome has been recognized as a potential predictor of ICI anti- tumor activity. Antibiotics reduce diversity the overall composition of the gut microbiota, with effects seen as quickly as in a single day. Post-antibiotic dysbiosis recovery varies depending on type and duration of exposure. Preclinical studies in mice with advanced cancer treated with broad spectrum antibiotics have been associated with resistance to ICI treatment.
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Prevalence of Minority Mutations That Confer Multi-Drug Resistance Among Patients Failing a Nucleoside Reverse Transcriptase Inhibitor Based Regimen in Uganda

Background:The extensive use of antiretroviral therapy has favored the emergence of multiple patterns of drug resistance mutations. These mutations evolve over time and are only detected by the conventional Sanger sequencing technology when they exceed 20% at which time there may be cross resistance. Unfortunately, the controversy surrounding the significance of these minority drug resistance mutations is still overwhelming. Methods: Samples were obtained from patients who were failing on an NRTI based regimen between 2010 and 2019. For the subtype A and D analysis, 1000 patient samples were analyzed while the subtype C sub-analysis was comprised of 363 samples. Sanger based sequencing was performed as part of the standard of care. A subset of these samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off to determine the prevalence of minority multi-drug resistant variants. Results: Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. On the other hand, the Q151M mutation complex was significantly more predominant among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion: Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex more predominant among patients harboring subtype C viruses. Even in patients with a fully susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that if their early detection is missed, cross resistance is inevitable.
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Tofacitinib as a Therapeutic Option in the Treatment of Refractory Scleritis: A Case Report

This was a 50-year-old patient with recurrent bilateral nodular anterior scleritis refractory to several treatments, including immunosuppressants and anti Tnfα. She was assessed for the different causes of immune-mediated and infectious diseases, but nothing was found. Tofacitinib was started 5 mg twice a day, which led to the spacing of crises until their total disappearance. At present, the patient has been crisis-free for nine months. In conclusion, the use of Janus Kinase inhibitor (Tofacitinib) alone was effective in the treatment of refractory recurrent nodular anterior scleritis.
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Safety Concerns of Glaucoma Chemotherapy among G6PD Deficient Glaucoma Patients: A Pilot Study

The aim of this study was to assess the potential acute adverse effects associated with the use of anti-glaucoma medications among glaucoma patients with Glucose-6-Phosphate Dehydrogenase deficiency.
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How to select Tyrosine Kinase Inhibitor for the patients with newly diagnosed Chronic Myeloid Leukemia?

The clinical outcomes of chronic myeloid leukemia (CML) have been improved by tyrosine kinase inhibitors (TKIs). However, there is no established consensus for TKI selection in de novo CML. We investigated TKI treatment patterns in a real-world setting. Among 95 chronic-phase CML patients, 44% were initiated treatment with imatinib, 26% with dasatinib, and 30% with nilotinib. Our data suggest that imatinib remains applicable and that dasatinib has a favorable therapeutic effect, although pleural effusion can arise. Nilotinib was the most prevalent TKI as the treatment-associated adverse events were deemed more manageable than those associated with imatinib and dasatinib.
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Mechanisms of Resistance to Kinase Inhibitors and Strategies to Prevent the Development of Drug Resistance

Targeting mutant proteins and associated signaling pathways of driver oncogenes by small molecule kinase inhibitors (KIs) are a promising strategy of cancer therapy. However, despite the initial success of treatment, KIs often become ineffective as intrinsic and acquired resistance. This article reviews the English-language literature to explore the underlying mechanisms of drug resistance and to present a challenge for developing drugs to overcome resistance. Mechanisms of acquired resistance include 1) the selection of pre-existing subclones with other mutations, 2) the emergence of secondary mutations in the target kinase domain, 3) upregulation of kinases both within the same kinase family and their related kinase families, as well as activation of alternative bypass pathways, 4) epithelial-mesenchymal transition, 5) overexpression of pro-survival Bcl-2 family proteins and 6) drug efflux mechanisms. Currently available methods are to obtain tumor biopsy samples at recurrence or progression if the tumor lesion is accessible to a biopsy and to use the second- and third-generation KIs based on the individual need of each patient. Furthermore, recent computational challenges provide design principles to prevent the development of drug resistance. In conclusion, we provide an overview of the postulated resistance mechanisms and highlight the future direction of computational structure-based design of new potent KIs.
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Former Effective Immunotherapy without Adverse Events of Inoperable Epithelial Ovarian Cancers and a Prospect for the Immune Prophylaxis

Current cancer treatments by immune checkpoint blockades are limited due to severe adverse events caused by alteration of the immune system required for homeostasis of normal tissues. Common cancer chemotherapy alters the quality of patients’ lives. Platinum-based treatment can lead to severe neurotoxicity with chronic debilitation. Additionally, survival of patients with epithelial ovarian cancers (EOCs) has remained poor despite extensive cytoreductive surgery, high dose chemotherapy, checkpoint blockades and immunotherapies effective in some other types of cancer. The pathobiology of EOC cancer stem cells (CSCs) is not well understood. Observations demonstrate that EOCs exhibit in vivo two distinct CSC types - perivascular diploid CSCs dividing asymmetrically with the help of the host suicidal CD8+ T cells, and haploid CSCs at the cancer abdominal surface originating from meiosis I cytokinesis of bulk surface cancer cells. The perivascular CSCs contribute to the cancer cell bulk and, via left ovary venous blood, can cause EOC liver metastases. Haploid CSCs released from the bulk cancer surface cause the common pelvic and abdominal EOC spread. Former elimination of the host antibodies blocking T cell effectors by intermittent doses of cyclophosphamide exhibiting significant immunomodulatory anticancer effects, facilitation of the immune system reactivity against alloantigens of cancer cells by blood transfusions, and augmentation of anticancer immunity by bacterial toxins, resulted during the subsequent treatment-free period into rejection of inoperable EOCs without any adverse events during the treatnment. To help prevent cancer relapses, patients treated for advanced primary epithelial cancers should be considered as candidates for continuously stimulating immune anticancer activity by treatments such as daily metformin and weekly lentinan consumptions.
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DNA Polymerase as Therapeutic Intervention for Treating Patients with Multiple Sclerosis

In recent years, increasing evidence has pointed to the potential role of fibrinolysis in the pathogenesis of MS. Based on hypotheses describing the aggressive autoimmune responses observed in MS patients, a result of impaired between (t-PA and PA1-1) which are a key molecules in both fibrinolysis and extracellular proteolysis. The present study was done to investigate the therapeutic potential of polymerase enzyme in modulating the changes occurred between levels of Tissue- type plasminogen activator (t-PA) and its inhibitor (PAI-1) in patients with multiple sclerosis. A pilot study was carried out on a total of twenty-one patients (17 females, 4 males; aged 22-46 years) with demyelination suggestive of MS and clinically silent T2 brain lesions on magnetic resonance imaging (MRI).
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Pulmonary Adenocarcinoma Transforming into Small Cell Carcinoma: An Extreme Rarity

Primary small cell lung cancer (SCLC) showing epidermal growth factor receptor (EGFR) mutation is extremely rare. Transformation into SCLC has been reported as an evolution of lung adenocarcinoma acquiring resistance to EGFR tyrosine kinase inhibitors (TKI) and is considered to be a rare resistance mechanism of EGFR-TKI therapy.
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An Introduction to the Approaches of Novel Drug Delivery Systems for Acquired Immune Deficiency Syndrome (AIDS)

The currently available anti HIV agents have several drawbacks such as short half life, low bioavailability, poor CNS penetration and retention, hepatic first pass metabolism, undesirable side effects and frequent dosing regimen.
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IL-8 Regulates Epithelial-Mesenchymal Transition through pERK1/2 in AGS Cells

The aim of this project was to evaluate the influence of inflammatory cytokines IL-1β and IL-8 on gastric epithelial-mesenchymal transition in gastric epithelial cells.
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Editorial Board Members Related to inhibitor

Jack Ho WONG

Research Associate
School of Biomedical Sciences
Faculty of Medicine
The Chinese University of Hong Kong
Hong Kong

Xiaodong Ma

Associate professor
College of Pharmacy
Dalian Medical University
China

YARON NIV

Clinical Professor of Medicine
Tel-Aviv University
Israel

Robert R. Redfield

Professor
Department of Immunology and Microbiology
University of Maryland
United States

SANJEEV KUMAR SINGH

Professor
Department of Bioinformatics
Alagappa University
India

Jack Ho Wong

School of Biomedical Sciences
Chinese University of Hong Kong
Hong Kong

Khaldon Bodoor

Associate Professor
Department of Biotechnology and Genetic Engineering
Jordan University of Science and Technology
Jordan

Tzi Bun NG

Professor
School of Biomedical Sciences
Faculty of Medicine
The Chinese University of Hong Kong
Hong Kong

TZI BUN NG

Professor of Biochemistry
School of Biomedical Sciences
Chinese University of Hong Kong
China

Tao Liu

Children's Cancer Institute
University of New South Wales
Australia
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