Shaping the future of gastrointestinal cancers through metabolic interactions with host gut microbiota.

Gastrointestinal (GI) cancers represent a significant global health challenge, driving relentless efforts to identify innovative diagnostic and therapeutic approaches. Recent strides in microbiome research have unveiled a previously underestimated dimension of cancer progression that revolves around the intricate metabolic interplay between GI cancers and the host's gut microbiota. This review aims to provide a comprehensive overview of these emerging metabolic interactions and their potential to catalyze a paradigm shift in precision diagnosis and therapeutic breakthroughs in GI cancers. The article underscores the groundbreaking impact of microbiome research on oncology by delving into the symbiotic connection between host metabolism and the gut microbiota. It offers valuable insights into tailoring treatment strategies to individual patients, thus moving beyond the traditional one-size-fits-all approach. This review also sheds light on novel diagnostic methodologies that could transform the early detection of GI cancers, potentially leading to more favorable patient outcomes. In conclusion, exploring the metabolic interactions between host gut microbiota and GI cancers showcases a promising frontier in the ongoing battle against these formidable diseases. By comprehending and harnessing the microbiome's influence, the future of precision diagnosis and therapeutic innovation for GI cancers appears more optimistic, opening doors to tailored treatments and enhanced diagnostic precision.

Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators.

Conversion of pantothenate to phosphopantothenate in humans is the first dedicated step in the coenzyme A (CoA) biosynthesis pathway and is mediated by four isoforms of pantothenate kinase. These enzymes are allosterically regulated by acyl-CoA levels, which control the rate of CoA biosynthesis. Small molecule activators of the PANK enzymes that overcome feedback suppression increase CoA levels in cultured cells and animals and have shown great potential for the treatment of pantothenate kinase-associated neurodegeneration and propionic acidemias. In this study, we detail the further optimization of PANK pyridazine activators using structure-guided design and focus on the cellular CoA activation potential, metabolic stability, and solubility as the primary drivers of the structure-activity relationship. These studies led to the prioritization of three late-stage preclinical lead PANK modulators with improved pharmacokinetic profiles and the ability to substantially increase brain CoA levels. Compound 22 (BBP-671) eventually advanced into clinical testing for the treatment of PKAN and propionic acidemia.

Biomarkers in sepsis.

Sepsis is a life-threatening condition characterized by dysregulated host response to infection leading to organ dysfunction. Despite advances in understanding its pathology, sepsis remains a global health concern and remains a major contributor to mortality. Timely identification is crucial for improving clinical outcomes, as delayed treatment significantly impacts survival. Accordingly, biomarkers play a pivotal role in diagnosis, risk stratification, and management. This review comprehensively discusses various biomarkers in sepsis and their potential application in antimicrobial stewardship and risk assessment. Biomarkers such as white blood cell count, neutrophil to lymphocyte ratio, erythrocyte sedimentation rate, C-reactive protein, interleukin-6, presepsin, and procalcitonin have been extensively studied for their diagnostic and prognostic value as well as in guiding antimicrobial therapy. Furthermore, this review explores the role of biomarkers in risk stratification, emphasizing the importance of identifying high-risk patients who may benefit from specific therapeutic interventions. Moreover, the review discusses the emerging field of transcriptional diagnostics and metagenomic sequencing. Advances in sequencing have enabled the identification of host response signatures and microbial genomes, offering insight into disease pathology and aiding species identification. In conclusion, this review provides a comprehensive overview of the current understanding and future directions of biomarker-based approaches in sepsis diagnosis, management, and personalized therapy.

Protein Kinase C (PKC) in Neurological Health: Implications for Alzheimer's Disease and Chronic Alcohol Consumption.

Protein kinase C (PKC) is a diverse enzyme family crucial for cell signalling in various organs. Its dysregulation is linked to numerous diseases, including cancer, cardiovascular disorders, and neurological problems. In the brain, PKC plays pivotal roles in synaptic plasticity, learning, memory, and neuronal survival. Specifically, PKC's involvement in Alzheimer's Disease (AD) pathogenesis is of significant interest. The dysregulation of PKC signalling has been linked to neurological disorders, including AD. This review elucidates PKC's pivotal role in neurological health, particularly its implications in AD pathogenesis and chronic alcohol addiction. AD, characterised by neurodegeneration, implicates PKC dysregulation in synaptic dysfunction and cognitive decline. Conversely, chronic alcohol consumption elicits neural adaptations intertwined with PKC signalling, exacerbating addictive behaviours. By unravelling PKC's involvement in these afflictions, potential therapeutic avenues emerge, offering promise for ameliorating their debilitating effects. This review navigates the complex interplay between PKC, AD pathology, and alcohol addiction, illuminating pathways for future neurotherapeutic interventions.

Barriers and corridors: Assessment of gene flow and movement among red panda populations in eastern Himalayas.

Landscape features can impede dispersal, gene flow, and population demography, resulting in the formation of several meta-populations within a continuous landscape. Understanding a species' ability to overcome these barriers is critical for predicting genetic connectivity and population persistence, and implementing effective conservation strategies. In the present study, we conducted a fine-scale spatial genetic analysis to understand the contemporary gene flow within red panda populations in the Eastern Himalayas. Employing geometric aspects of reserve design, we delineated the critical core habitats for red pandas, which comprise 14.5 % of the landscape (12,189.75 Km2), with only a mere 443 Km2 falling within the protected areas. We identified corridors among the core habitats, which may be vital for the species' long-term genetic viability. Furthermore, we identified substantial landscape barriers, including Sela Pass in the western region, Siang river in the central region, and the Dibang river, Lohit river, along with Dihang, Dipher, and Kumjawng passes in the eastern region, which hinder gene flow. We suggest managing red panda populations through the creation of Community Conservation Reserves in the identified core habitats, following landscape-level management planning based on the core principles of geometric reserve design. This includes a specific emphasis on identified core habitats of red panda (CH-RP 5 and CH-RP 8) to facilitate corridors and implement meta-population dynamics. We propose the development of a comprehensive, long-term conservation and management plan for red pandas in the transboundary landscape, covering China, Nepal, and Bhutan.

Resectable Distal Duodenal Gastrointestinal Stromal Tumour Presenting with Features of Anaemia.

Although gastrointestinal stromal tumours (GISTs) are encountered all along the gastrointestinal tract, duodenal GISTs are uncommon and account for <5% of the cases. A 45-year-old woman presented chiefly with anaemia and associated symptoms, whom on further evaluation was found to have a non-metastatic GIST in the distal duodenum sparing the pancreas and major vasculature. Patient was undertaken for segmental duodenectomy with the help of advanced bipolar energy device (tumour occupying D3-D4 with 1 cm proximal margin and 15 cm jejunum) preserving the pancreas and ampulla with end-to-end duodenojejunostomy with an uneventful postoperative course and clear margins on histopathology. Thus, the patient underwent a less morbid procedure with satisfactory oncological outcome and early resumption of activity. This highlights the need to conduct more trials to gather high level evidence in favour of conservative resection and its oncological adequacy and impact on overall survival and recurrence.

Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Genetic assessment of captive breeding program of Indian Pangolin: implications for conservation and management.

BACKGROUND: Captive breeding programs play a vital role in conservation of threatened species, necessitating an understanding of genetic diversity among captive individuals to ensure long-term genetic viability, appropriate mate selection, and successful reintroduction to native habitats. METHODS AND RESULTS: We did not observe any recent genetic bottleneck, and population showed moderate genetic diversity. The estimated effective population size, representing individuals capable of contributing genetically to future generations, was estimated as 18.6 individuals (11.4-35.1 at 95% CI). Based on the genetic make-up and allelic diversity, we found seventeen pangolins (11 females and 6 males) were genetically unrelated and relatively more potent than others. CONCLUSION: In this study, we evaluated the captive breeding program of the Indian pangolin population at the Pangolin Conservation Breeding Centre in Nandankanan Zoological Park, Bhubaneswar, Odisha. We highlight the significance of genetic monitoring within the captive population of Indian pangolin for preserving genetic diversity and ensuring the long-term survival of the species. We established the genetic profiles of all 29 pangolins and identified 17 pangolins to be prioritized for enhanced breeding and future zoo exchange programs. We appreciate the zoo authorities for promoting genetic assessment of pangolin for better and more effective monitoring of the captive breeding of the endangered Indian pangolin.

Donor coordination to support universal health coverage in Malawi.

Development assistance is a major source of financing for health in least developed countries. However, persistent aid fragmentation has led to inefficiencies and health inequities and constrained progress towards Universal Health Coverage (UHC). Malawi is a case study for this global challenge, with 55% of total health expenditure funded by donors and fragmentation across 166 financing sources and 265 implementing partners. This often leads to poor coordination and misalignment between government priorities and donor projects. To address these challenges, the Malawi Ministry of Health (MoH) has developed and implemented an architecture of aid coordination tools and processes. Using a case study approach, we documented the iterative development, implementation and institutionalization of these tools, which was led by the MoH with technical assistance from the Clinton Health Access Initiative. We reviewed the grey literature, including relevant policy documents, planning tools and databases of government/partner funding commitments, and drew upon the authors' experiences in designing, implementing and scaling up these tools. Overall, the iterative use and revision of these tools by the Government of Malawi across the national and subnational levels, including integration with the government's public financial management system, was critical to successful uptake. The tools are used to inform government and partner resource allocation decisions, assess financing and gaps for national and district plans and inform donor grant applications. As Malawi has launched the Health Sector Strategic Plan 2023-2030, these tools are being adapted for the 'One Plan, One Budget and One Report' approach. However, while the tools are an incremental mechanism to strengthen aid alignment, success has been constrained by the larger context of power imbalances and misaligned incentives between the donor community and the Government of Malawi. Reform of the aid architecture is therefore critical to ensure that these tools achieve maximum impact in Malawi's journey towards UHC.

PSMA Avidity in the Heterotropic Ossification-An Incidental Finding on PSMA PET/CT.

ABSTRACT: The upregulations of prostate-specific membrane antigen (PSMA) antigen are used for the presence of prostate cancer. However, published literature shows incidentally detected PSMA uptake in various nonprostatic benign and malignant conditions, which led to questioning the specificity of PSMA-targeted PET. In present case, we highlighted the abnormal PSMA expression in the benign bone abnormality.

Revision of Malawi's Health Benefits Package: A Critical Analysis of Policy Formulation and Implementation.

OBJECTIVES: Health benefits packages (HBPs), which define specific health services that can be offered for free or at a reduced cost to fit within public revenues, have been recommended for over 30 years to maximize population health in resource-limited settings. However, there remain gaps in defining and operationalizing HBPs. We propose a combination of design and prioritization methods along with practical strategies to improve the implementation of future iterations of the HBP in Malawi. METHODS: For HBP development for Malawi's Third Health Sector Strategic Plan, we combined cost-effectiveness analysis with a quantitative, consultative multicriteria decision analysis. Throughout the process of development, we documented challenges and opportunities to improve HBP design and application. RESULTS: The primary and secondary HBP included 115 interventions. However, the definition of an HBP is just one step toward focusing limited resources, with functional operationalization as the most critical component. Full implementation of previous HBPs has been limited by challenges in aid coordination with the misalignment of nonfungible vertical donor funding for the HBP without accounting for the complexity and interconnectedness of the health system. Opportunities for improved application include creation of a complementary minimum health service package to guide overall resource inputs through an integrative approach. CONCLUSIONS: We believe that expanded participatory HBP methods that consider value, equity, and social considerations, along with a shift to providing integrated health service packages at all levels of care, will improve the efficiency of using scarce resources along the journey to universal health coverage.

Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders.

Misfolded and aggregated proteins build up in neurodegenerative illnesses, which causes neuronal dysfunction and ultimately neuronal death. In the last few years, there has been a significant upsurge in the level of interest towards the function of molecular chaperones in the control of misfolding and aggregation. The crucial molecular chaperones implicated in neurodegenerative illnesses are covered in this review article, along with a variety of their different methods of action. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones serve critical roles in preserving protein homeostasis. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones have integral roles in preserving regulation of protein balance. It has been demonstrated that aging, a significant risk factor for neurological disorders, affects how molecular chaperones function. The aggregation of misfolded proteins and the development of neurodegeneration may be facilitated by the aging-related reduction in chaperone activity. Molecular chaperones have also been linked to the pathophysiology of several instances of neuron withering illnesses, enumerating as Parkinson's disease, Huntington's disease, and Alzheimer's disease. Molecular chaperones have become potential therapy targets concerning with the prevention and therapeutic approach for brain disorders due to their crucial function in protein homeostasis and their connection to neurodegenerative illnesses. Protein homeostasis can be restored, and illness progression can be slowed down by methods that increase chaperone function or modify their expression. This review emphasizes the importance of molecular chaperones in the context of neuron withering disorders and their potential as therapeutic targets for brain disorders.

FDG PET-CT in Clinical Management of a Rare Case of Primary Hepatic Lymphoma: Role and Challenges.

The common differential diagnoses for multiple space-occupying hepatic lesions (SOL) are metastases, multifocal hepatocellular carcinoma, and abscess. Primary hepatic lymphomas are rare entities that present many challenges with regard to their management. Fluorodeoxyglucose positron emission tomography-computed tomography is extensively used for the staging and response assessment of lymphomas but it can be challenging and difficult to interpret in cases with isolated liver involvement. We hereby present the case of an 82-year-old lady who presented with multiple liver SOL.

Understanding the Therapeutic Approaches for Neuroprotection.

The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.

Free-ranging dogs are seriously threatening Himalayan environment: delineating the high-risk areas for curbing free-ranging dog infestation in the Trans-Himalayan region.

It is becoming more widely recognised that free-ranging dogs, which have a nearly global distribution, threatening native wildlife. Their increasing population and spread to new areas is of growing concern for the long-term viability of wildlife species. Hence, it is imperative to understand the factors responsible for their infestation and map areas where native species are most vulnerable. Using the random forests algorithm, we modelled the free-ranging dog infestation in the Trans-Himalayan region to pinpoint the high-risk areas where free-ranging dogs are threatening the native wildlife species. We found that the likelihood of free-ranging dog occurrence is most in valley regions and up to 4000 m, often in proximity to roads. Our results also indicated that free-ranging dog prefers areas with wildlife near to protected areas. The predictor variables, such as potential evapotranspiration of the coldest quarter, distance to protected areas, elevation, distance to roads, and potential evapotranspiration of the driest quarter, significantly influence the distribution of the free-ranging dogs. We found that within the Ladakh region of the Trans-Himalayan area, the high-risk zones for free-ranging dogs are located in and around Hemis National Park, Karakoram Wildlife Sanctuary, and Changthang Wildlife Sanctuary. While, in the Lahaul and Spiti region the high-risk areas encompass Pin Valley National Park, Inderkilla National Park, Khirganga National Park, Kugti Wildlife Sanctuary, and several other protected areas. We identified the potentially high-risk areas for implementing strategies to mitigate the possible impact of free-ranging dogs on native wildlife of the Himalayas. Hence, the identified high priority areas can be used for implementing actions for controlling the population growth and further preventing the infestation of the free-ranging dogs into the new areas.

Landscape genetics identified conservation priority areas for blue sheep (Pseudois nayaur) in the Indian Trans-Himalayan Region.

The trans-Himalayan region of India, although have xeric features, still supports a unique assemblage of biodiversity, including some of the charismatic and endemic species. In the present study, we studied blue sheep (Pseudois nayaur) across the distribution range in the Western trans Himalayas of India and found about 18,775 km2 area suitable for blue sheep. The explicit Bayesian based spatial and non-spatial population structure analysis assigned blue sheep into two genetic populations, i.e., Ladakh and Lahaul-Spiti. We found relatively high genetic divergence in blue sheep which is also supported by the low current flow in Circuitscape model. With the multiple evidences, we explain landscape resistance facilitated by the landscape heterogeneity, and large patches of unsuitable habitats forced population divergence and poor functional connectivity. We found that blue sheep population has been demographically stable in the past, but showed a slight decline within the last few decades. This study is the first range-wide attempt to exhibit landscape features in shaping the spatial distribution, genetic structure and demography patterns of blue sheep in Western Himalayas, and will be of use in the conservation and management planning of blue sheep.

Mid-Pleistocene Transitions Forced Himalayan ibex to Evolve Independently after Split into an Allopatric Refugium.

Pleistocene glaciations had profound impact on the spatial distribution and genetic makeup of species in temperate ecosystems. While the glacial period trapped several species into glacial refugia and caused abrupt decline in large populations, the interglacial period facilitated population growth and range expansion leading to allopatric speciation. Here, we analyzed 40 genomes of four species of ibex and found that Himalayan ibex in the Pamir Mountains evolved independently after splitting from its main range about 0.1 mya following the Pleistocene species pump concept. Demographic trajectories showed Himalayan ibex experienced two historic bottlenecks, one each c. 0.8-0.5 mya and c. 50-30 kya, with an intermediate large population expansion c. 0.2-0.16 mya coinciding with Mid-Pleistocene Transitions. We substantiate with multi-dimensional evidence that Himalayan ibex is an evolutionary distinct phylogenetic species of Siberian ibex which need to be prioritized as Capra himalayensis for taxonomic revision and conservation planning at a regional and global scale.

Empirical Data Suggest That the Kashmir Musk Deer (Moschus cupreus, Grubb 1982) Is the One Musk Deer Distributed in the Western Himalayas: An Integration of Ecology, Genetics and Geospatial Modelling Approaches.

Insufficient research has been conducted on musk deer species across their distribution range, primarily because of their elusive behaviour and the fact they occupy remote high-altitude habitats in the Himalayas above 2500 m. The available distribution records, primarily derived from ecological studies with limited photographic and indirect evidence, fail to provide comprehensive information on the species distribution. Consequently, uncertainties arise when attempting to determine the presence of specific taxonomic units of musk deer in the Western Himalayas. This lack of knowledge hampers species-oriented conservation efforts, as there need to be more species-specific initiatives focused on monitoring, protecting, and combatting the illegal poaching of musk deer for their valuable musk pods. We used transect surveys (220 trails), camera traps (255 cameras), non-invasive DNA sampling (40 samples), and geospatial modelling (279 occurrence records) to resolve the taxonomic ambiguity, and identify the suitable habitat of musk deer (Moschus spp.) in Uttarkashi District of Uttarakhand and the Lahaul-Pangi landscape of Himachal Pradesh. All the captured images and DNA-based identification results confirmed the presence of only Kashmir musk deer (KDM) (Moschus cupreus) in Uttarakhand and Himachal Pradesh. The results suggest that KMD inhabit a narrow range of suitable habitats (6.9%) of the entire Western Himalayas. Since all evidence indicates that only KMD are present in the Western Himalayas, we suggest that the presence of other species of musk deer (Alpine musk deer and Himalayan musk deer) was wrongly reported. Therefore, future conservation plans and management strategies must focus only on KMD in the Western Himalayas.