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Cancer remains a public concern and leading cause of death worldwide. Hepatocellular carcinoma, the most common form of liver cancer, is the third leading cause of cancer-related deaths. The number of cases is expected to double by 2040, according to GLOBOCAN 2020. Patients are usually diagnosed with advanced-stage HCC, which limits the number of effective treatment options. Oral-targeted therapies involving sorafenib and lenvatinib remain the first-line treatment option, which has recently been replaced by immunotherapy. Due to economic issues and ease of administration, the vast majority prefer oral systemic therapy. Sorafenib and lenvatinib, which belongs to tyrosine kinase inhibitors have few limitations of having large inter-individual variability in absorption, genetic polymorphisms, poor patient adherence to oral regimen limiting its long-term therapy. Therapeutic Drug Monitoring can overcome the limitations of TKIs and help individualise the dosage regimen with minimal adverse events. Therefore, this simple and rapid method using latest equipment enabled with ultra-high speed, high-sensitivity analysis (LCMS-8045) is expected to bring a change in clinical practice to improve the efficacy and safety of medication for optimal patient benefits.

IntroductionCoccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown.MethodsPhase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness.ObjectivesThe primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality.DiscussionThis trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed.

Introduction: Coccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown. Methods: Phase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness. Objectives: The primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality. Discussion: This trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed.

Neurological and psychiatric disorders occur in about 6 percent of the global population indicating a significant amount of people suffering from neurological disorder on a varying range in day to day life. On an extensive view, there is a critical requirement for the development of an alternative biomarker for these conditions. The thwart found in developing a biomarker is the difficulty in identifying a serum biomarker as these are mostly limited to the central nervous system (CNS). Serotonin being a neurotransmitter synthesized in the raphe nuclei of the brain could serve as an alternative biomarker. Here, the limitation is that it’s quickly metabolized by the mitochondrial enzyme MAO to 5-hydroxy indole acetic acid (5HIAA). This subsequent metabolite can be used for the analysis of serotonin levels in brain by analysing its concentration in the cerebrospinal fluid (CSF). Many theories suggest that the variations in serotonin level could lead to the development of many neurological and psychiatric disorders like Alzheimer’s disease (AD), schizophrenia, depression and so on. A decreased level is noticed in these patients but this could either be due to decreased production or increased reuptake of serotonin from the neuronal synapses. For instance, we know that a patient with depression shows a significant reduction in the levels of 5HIAA, due to the location of the raphe nuclei within regions of memory and cognition. Similarly, it does shows variation in AD and mild cognitive disorder. Evolving of 5HIAA as a biomarker, could be more delicate and enhanced strategy for monitoring these disorders.

Phospholipids of erythrocyte are found as bilayer with choline containing phospholipid like phosphatidyl choline and sphingomylein in the outer layer and amine containing phospholipid like phosphatidyl ethanolamine and phosphatidyl serine in the inner layer. This arrangement is known as phospholipid asymmetry. Lipid asymmetry is maintained throughout the entire life span of red blood cell and is disturbed when cells enter into the stage of apoptosis. We here discuss some of the conditions in which phospholipid asymmetry of erythrocyte is maintained and disturbed and the various detection methods to check the distortion phospholipid asymmetry of it. [ABSTRACT FROM AUTHOR]

Abstract: Forensic pathologists can help in the investigation of sudden unexpected deaths in co-operation with the officials responsible for the maintenance of law and order to administer justice. Sudden unexpected deaths form the subject of medicolegal investigation if they occur in apparently healthy individuals, wherein an autopsy would shed light regarding the cause of death. A 4 year retrospective review of autopsy files at the Department of Forensic Medicine, Kasturba Medical College, Mangalore, South India was undertaken for cases of sudden unexpected deaths due to acute haemorrhagic pancreatitis occurring between May 2004 and April 2008. A total of seven cases of acute haemorrhagic pancreatitis diagnosed at autopsy as the cause of sudden unexpected death during the study period are discussed herein. [Copyright &y& Elsevier]

Bioinformatics apply informatics technique to understand and organize the information associated with the molecules. It is an application to the field of medicine and biology. This includes computational tools and methods to manage, analyze and manipulate large sets of biological data. Bioinformatics was applied in the creation and maintenance of a database to store biological information. Bioinformatics is the application of statistics & computer science in the field of molecular biology. The main goal of bioinformatics is the determination of the sequence of entire human genome. The use of this genomic information helps the understanding human diseases and in identification of new molecules targets for drug discovery. It also helps to predict the molecular evolution by comparing the genomic sequences, the study of interactions between the components of biological systems. Over the past few decades rapid developments in genomic and other molecular research technologies and developments in information technologies have combined to produce a tremendous amount of information related to molecular biology. [ABSTRACT FROM AUTHOR]

Prospective prediction from the Australian Institute of Health and Welfare (AIHW) showed a likely incidence of 1 in 23 women diagnosed with gynaecological malignancy, where the incidence of relapse with a drug-resistant clone poses a significant challenge in dealing with it even after initial treatment. Glucose metabolism has been exploited as a therapeutic target under anti-metabolomic study, but the non-specificity narrowed its applicability in cancer. Novel updates over epigenetics as a target in gynaecological cancer offer a rational idea of using this in the metabolic rewiring in mutated glycolytic flux-induced drug resistance. This review focuses on the application of epigenetic intervention at a diagnostic and therapeutic level to shift the current treatment paradigm of gynaecological cancers from reactive medicine to predictive, preventive, and personalised medicine. It presents the likely epigenetic targets that can be exploited potentially to prevent the therapeutic failure associated with glucose metabolism-induced chemotherapeutic drug resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Multi-targeted drug therapy has received substantial attention for the treatment of diseases of multifactorial origin, such as neurodegenerative diseases. Manasamitra vatakam (MMV) is a traditional Ayurvedic formulation used to improve cognitive impairment and mental illness. Here we have used a unique method for leveraging the barrier properties of the intestinal and blood-brain barrier (BBB) to screen and identify the bioactive molecules against Alzheimer's disease (AD). The current method exemplifies a facile method to expedite drug discovery from traditional formulations., Aim of the Study: The present study aimed to identify the phytoconstituents of MMV that reach the brain tissue and to predict major bioactive constituents by computational docking studies., Materials and Methods: After oral administration of the formulation, brain samples from male Sprague Dawley rats were collected at different time intervals and analyzed by liquid chromatography-mass spectrometry (LC-MS) to identify the phytoconstituents. In silico molecular docking studies were carried out to analyze the binding affinity of the compounds to the target proteins of AD using Schrodinger Maestro. The molecular dynamic studies were carried out for all the docked complexes having higher docking scores., Results: 34 phytoconstituents were identified by LC-MS analysis of brain homogenates. In the in silico docking study, the phytoconstituents chrysin, convolvin, rutin, galangin, palmatoside G, isoliquiritigenin, quercetin, and naringenin showed higher docking score against the target proteins of AD. These compounds may serve as the primary bioactive compounds responsible for the neuroprotective activity of the herbal formulation. Furthermore, molecular dynamic studies indicated that the galangin-acetylcholinesterase enzyme complex has the highest stability among these eight compounds., Conclusion: The study, together with previous in vivo and in vitro efficacy results, suggests that BBB-permeable compounds with high binding affinities for the target proteins of AD might be responsible for the effectiveness of MMV against AD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Anju C NairSonu BennyAneesh TPMS SudheeshPK Lakshmi., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cyclin-dependent kinases (CDKs) are crucial proteins involved in key cellular processes, such as cell division and transcription. Their dysregulation plays a significant role in cancer development. Inhibiting cyclin-dependent kinase 9 (CDK9) impacts several survival pathways in cancer cells, presenting a promising therapeutic approach for various cancers. CDK9, in association with cyclin T1, forms the positive transcription elongation factor b (P-TEFb) complex, which phosphorylates the C-terminal domain (CTD) of RNA polymerase II (Pol II). This phosphorylation promotes the transition from transcription initiation to elongation. This review examines recent advancements in CDK9 modulators, with a particular emphasis on compounds currently in clinical trials., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

An old ideology of killing the cancer cells by starving them is the underlying concept of the Warburg effect. It is the process of aerobic glycolysis exhibited by the cancer cells irrespective of anaerobic glycolysis or mitochondrial oxidative phosphorylation following by their healthy counterparts. Dr Otto Heinrich Warburg proposed this abnormal metabolic behaviour of tumour cells in 1920. This phenomenon illustrates the metabolic switching in tumour cells from oxidative phosphorylation to aerobic glycolysis triggered by an injury to the mitochondrial respiration. A modernised perspective of the Warburg hypothesis termed the Reverse Warburg effect introduced in 2009, with a two-compartment model describing the metabolic symbiosis between cancer cells and its neighbouring stromal cells or cancer-associated fibroblasts. This theory is elucidating the aerobic glycolysis occurring in cancer-associated fibroblasts which leads to the generation and deposition of the lactate in tumour microenvironment along with its significance. The transportation of lactate to and from the cancer cell and extracellular space is facilitated by the lactate transporters called monocarboxylate transporters. This lactate generated irrespective of the hypoxic or aerobic conditions acts as a primary metabolic fuel for the cancer cells. Besides, it will create a tumour microenvironment that is favouring the progression and metastasis of malignancy through several means. Overall, the lactate produced through this metabolic reprogramming is supporting and worsening the conditions of cancer. The concept of the Reverse Warburg effect proposes a new anti-cancer treatment modality by preventing the generation and transport of lactate through the inhibition of monocarboxylate transporters and in turn, defeating the cancer disease by arresting the cancer cells along with silencing tumour microenvironment., (Copyright © 2020. Published by Elsevier Ltd.)