Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

Tenecteplase versus Alteplase in Acute Ischemic Stroke: A Systematic Review and Meta-analysis.

Background: A number of clinical trials have compared tenecteplase (TNK) and alteplase for the management of acute ischemic stroke (AIS) and the results are inconsistent. Purpose: Present systematic review and meta-analysis is undertaken to analyse the efficacy and safety of TNK in AIS compared to alteplase. Summary: A thorough literature search was performed through the databases Embase, Cochrane Library, PubMed, and clinicaltrials.gov, for a period from inception to September 2022, with the keywords i.e., "tenecteplase" and "alteplase" and "acute ischemic stroke." Clinical trials published in English that compared the efficacy and safety of TNK to alteplase in AIS were included. The major outcomes of this meta-analysis were proportion of patients free from disability and functional independence at 90 days, early neurological improvement at 24 hours, all-cause mortality at 90 days, patients with intra cranial hemorrhage (ICH), and patients with severe disability at 90 days. A total of nine studies with 3,573 patients were included in the analysis. The proportion of patients with freedom from disability was comparable in both groups (relative risk [RR] = 1.04, 95 per cent CI = 0.92-1.17; p = .53). Similarly, proportion of patients with functional independence was comparable (RR = 1.12, 95 per cent CI = 0.96-1.31; p = .14). TNK group had a higher rate of early neurological recovery (RR = 1.56, 95 per cent CI = 0.96-2.54; p = .07). All-cause mortality at 90 days was comparable in both groups (RR = 0.97; 95 per cent CI = 0.72-1.29; p = .82). The proportion of patients with ICH was higher in TNK group (RR = 1.14, 95 per cent CI = 0.77-1.68; p = .52). The proportion of patients with severe disability was less in TNK group (RR =0.84, 95 per cent CI = 0.53-1.32; p = .44). Key Message: TNK was similar to alteplase in terms of efficacy and safety. The patients in TNK group showed early neurological improvement but were simultaneously at higher risk of ICH. The TNK can be an alternative to alteplase if the benefits outweigh the risks.

Lung carcinoma presenting as monocular painless blindness.

To discuss a very rare presentation of lung malignancy which results in visual disturbance as first and only clinical manifestation. Case report. We report a case of otherwise asymptomatic 32-year-old, nonsmoker female presenting with painless loss of vision in the right eye and photophobia in the left eye, owing to secondaries in choroid from lung carcinoma. Patient was worked up after admission in our hospital to ascertain the cause of blindness and subsequently revealed lung malignancy with widespread metastasis involving multiple organ systems. Despite widespread malignant involvement patient was completely asymptomatic and active except for visual disturbances. This case further emphasized the necessity of prompt and priority-based evaluation of patients for lung carcinoma whenever doubtful intraocular lesions are noted, regardless of age or smoking status. It seems that these cases represent a distinct subset of lung malignancy.

Inverse Design of Photonic Surfaces via High throughput Femtosecond Laser Processing and Tandem Neural Networks.

This work demonstrates a method to design photonic surfaces by combining femtosecond laser processing with the inverse design capabilities of tandem neural networks that directly link laser fabrication parameters to their resulting textured substrate optical properties. High throughput fabrication and characterization platforms are developed that generate a dataset comprising 35280 unique microtextured surfaces on stainless steel with corresponding measured spectral emissivities. The trained model utilizes the nonlinear one-to-many mapping between spectral emissivity and laser parameters. Consequently, it generates predominantly novel designs, which reproduce the full range of spectral emissivities (average root-mean-squared-error < 2.5%) using only a compact region of laser parameter space 25 times smaller than what is represented in the training data. Finally, the inverse design model is experimentally validated on a thermophotovoltaic emitter design application. By synergizing laser-matter interactions with neural network capabilities, the approach offers insights into accelerating the discovery of photonic surfaces, advancing energy harvesting technologies.

Olanzapine-Samidorphan for Schizophrenia: A Systematic Review and Meta-Analysis.

Background and Objective: United States Food and Drug Administration (USFDA) recently approved a novel combination of olanzapine-samidorphan (OLZSAM) for managing olanzapine-associated adverse events (weight gain) in adult patients with schizophrenia and bipolar disorder. To opine about the safety and efficacy of OLZSAM, authors performed a systematic review and meta-analysis to convene justifiable evidence. Methods: A thorough literature search was performed through the databases Embase, Cochrane Library, PubMed, and clinicaltrials.gov, from inception to September 2022, with the keywords: 'olanzapine and samidorphan' and schizophrenia; and "ALKS3831" and "lybalvi." Clinical trials published in English that analyzed the efficacy and safety of OLZSAM were included. The significant outcomes included in this study were change from baseline (CFB) in Positive and Negative Syndrome Scale (PANSS) at the end of the study, the proportion of patients with weight gain at the end of the study, the proportion of patients with at least one adverse event, and the incidence of drug discontinuation due to adverse events. Results: The change in PANSS score at the end of the study was comparable among groups receiving OLZSAM and olanzapine alone: standardized mean difference (SMD) = 0.04; 95% CI = -0.09 to 0.17; p = 0.57. The OLZSAM group reported less incidence of weight gain: risk ratio (RR) = 0.91; 95% CI = 0.62-1.34; p = 0.63, and any adverse event: RR = 0.99; 95% CI = 0.90-1.09; p = 0.81. Drug discontinuation incidence was higher in the OLZSAM group: RR = 1.22; 95% CI = 0.84-1.79; p = 0.30. Conclusions: The combination OLZSAM showed comparable efficacy to olanzapine alone in schizophrenia patients, with relatively less incidence of weight gain and adverse events; however, the drug discontinuation due to adverse events was more in the OLZSAM group.

A bioinformatics approach to elucidate conserved genes and pathways in C. elegans as an animal model for cardiovascular research.

Cardiovascular disease (CVD) is a collective term for disorders of the heart and blood vessels. The molecular events and biochemical pathways associated with CVD are difficult to study in clinical settings on patients and in vitro conditions. Animal models play a pivotal and indispensable role in CVD research. Caenorhabditis elegans, a nematode species, has emerged as a prominent experimental organism widely utilized in various biomedical research fields. However, the specific number of CVD-related genes and pathways within the C. elegans genome remains undisclosed to date, limiting its in-depth utilization for investigations. In the present study, we conducted a comprehensive analysis of genes and pathways related to CVD within the genomes of humans and C. elegans through a systematic bioinformatic approach. A total of 1113 genes in C. elegans orthologous to the most significant CVD-related genes in humans were identified, and the GO terms and pathways were compared to study the pathways that are conserved between the two species. In order to infer the functions of CVD-related orthologous genes in C. elegans, a PPI network was constructed. Orthologous gene PPI network analysis results reveal the hubs and important KRs: pmk-1, daf-21, gpb-1, crh-1, enpl-1, eef-1G, acdh-8, hif-1, pmk-2, and aha-1 in C. elegans. Modules were identified for determining the role of the orthologous genes at various levels in the created network. We also identified 9 commonly enriched pathways between humans and C. elegans linked with CVDs that include autophagy (animal), the ErbB signaling pathway, the FoxO signaling pathway, the MAPK signaling pathway, ABC transporters, the biosynthesis of unsaturated fatty acids, fatty acid metabolism, glutathione metabolism, and metabolic pathways. This study provides the first systematic genomic approach to explore the CVD-associated genes and pathways that are present in C. elegans, supporting the use of C. elegans as a prominent animal model organism for cardiovascular diseases.

"Unravelling the impacts of climatic heat events on cardiovascular health in animal models".

Climate change has led to an increase in high ambient temperatures, causing extreme heat events worldwide. According to the World Meteorological Organization (WMO), July 2023 marked a historic milestone as the Earth reached its hottest recorded temperature, precisely hitting the critical threshold of 1.5 °C set by the Paris Agreement. This distressing development led to a stark warning from the United Nations, signaling the dawn of what they call "an era of global boiling". The increasing global temperatures can result in high heat stress which leads to various physiological and biochemical alterations in the human body. Given that cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality globally, heat events exacerbate this public health issue. While clinical and in-vitro studies have suggested a range of pathophysiological and biochemical mechanisms underlying the body's response to heat stress, the complex nature of organ-system level interactions makes precise investigation challenging. To address this knowledge gap effectively, the use of animal models exposed to acute or chronic heat stress can be invaluable. These models can closely replicate the multifaceted effects observed in humans during heat stress conditions. Despite extensive independent reviews, limited focus has been shed on the high heat-induced cardiovascular complications and their mechanisms, particularly utilizing animal models. Therefore, in this comprehensive review, we highlight the crucial biomarkers altered during heat stress, contributing significantly to various CVDs. We explore potential mechanisms underlying heat-induced cardiovascular dysfunction and damage, delving into various animal models. While traditional rodent models are commonly employed, we also examine less conventional models, including ruminants, broilers, canines, and primates. Furthermore, we delve into various potential therapeutic approaches and preventive measures. These insights hold significant promise for the development of more effective clinical interventions against the effects of heat stress on the human cardiovascular system.

Harmonization Risks and Rewards: Nano-QSAR for Agricultural Nanomaterials.

This comprehensive review explores the emerging landscape of Nano-QSAR (quantitative structure-activity relationship) for assessing the risk and potency of nanomaterials in agricultural settings. The paper begins with an introduction to Nano-QSAR, providing background and rationale, and explicitly states the hypotheses guiding the review. The study navigates through various dimensions of nanomaterial applications in agriculture, encompassing their diverse properties, types, and associated challenges. Delving into the principles of QSAR in nanotoxicology, this article elucidates its application in evaluating the safety of nanomaterials, while addressing the unique limitations posed by these materials. The narrative then transitions to the progression of Nano-QSAR in the context of agricultural nanomaterials, exemplified by insightful case studies that highlight both the strengths and the limitations inherent in this methodology. Emerging prospects and hurdles tied to Nano-QSAR in agriculture are rigorously examined, casting light on important pathways forward, existing constraints, and avenues for research enhancement. Culminating in a synthesis of key insights, the review underscores the significance of Nano-QSAR in shaping the future of nanoenabled agriculture. It provides strategic guidance to steer forthcoming research endeavors in this dynamic field.

Identification of potential regulatory mechanisms and therapeutic targets for lung cancer.

Lung cancer poses a significant health threat globally, especially in regions like India, with 5-year survival rates remain alarmingly low. Our study aimed to uncover key markers for effective treatment and early detection. We identified specific genes related to lung cancer using the BioXpress database and delved into their roles through DAVID enrichment analysis. By employing network theory, we explored the intricate interactions within lung cancer networks, identifying ASPM and MKI67 as crucial regulator genes. Predictions of microRNA and transcription factor interactions provided additional insights. Examining gene expression patterns using GEPIA and KM Plotter revealed the clinical relevance of these key genes. In our pursuit of targeted therapies, Drug Bank pointed to methotrexate as a potential drug for the identified key regulator genes. Confirming this, molecular docking studies through Swiss Dock showed promising binding interactions. To ensure stability, we conducted molecular dynamics simulations using the AMBER 16 suite. In summary, our study pinpoints ASPM and MKI67 as vital regulators in lung cancer networks. The identification of hub genes and functional pathways enhances our understanding of molecular processes, offering potential therapeutic targets. Importantly, methotrexate emerged as a promising drug candidate, supported by robust docking and simulation studies. These findings lay a solid foundation for further experimental validations and hold promise for advancing personalized therapeutic strategies in lung cancer.Communicated by Ramaswamy H. Sarma.

Motorized Power Spiral Enteroscopy (MSE): Is Routine Bougienage of the Upper Esophageal Sphincter (UES) Necessary?

Introduction Wire-guided bougienage of the upper esophageal sphincter (UES) was performed routinely before per-oral motorized power spiral enteroscopy (MSE). In the present study, we aimed to answer the clinical question of whether routine bougienage of UES is required. Methods This was a retrospective study that included 20 patients who underwent antegrade spiral enteroscopy for various indications. The feasibility and safety of anterograde MSE without prior bougie dilatation of the upper esophageal sphincter were assessed. The technical success rate (TSR), diagnostic yield, and adverse events (AEs) were also assessed. Results In 16 out of the 20 patients, a spiral enteroscope was taken directly across UES into the esophagus without a prior bougie dilatation. The spiral enteroscope could not be negotiated across UES only in one patient, and bougie dilatation was done. The technical success rate was 100%. The diagnostic yield was 80%. Four patients reported AEs. Conclusions MSE had a good technical success rate and diagnostic yield. Routine dilatation of the UES before the procedure may be unnecessary.

Formulation of Solid Lipid Nanoparticles Loaded with Rosiglitazone and Probiotic: Optimization and In-vitro Characterization.

INTRODUCTION: In the present study, solid lipid nanoparticles loaded with Rosiglitazone and probiotics were prepared via solvent emulsification diffusion. As a lipid and surfactant, Gleceryl monostearate and Pluronic -68 were used in the formulation process. METHOD: During characterization, it was determined that ingredient quantity variations significantly impacted Rosiglitazone loading capacity, particle size, polydispersity index, etc. In an optimized formulation of RSG-PB loaded SLNs, spherical particles with a mean particle size of 147.66±1.52 nm, PDI of 0.42±0.02, and loading capacity of 45.36±0.20 were identified. RESULT: Moreover, the developed SLNs had the potential to discharge the drug for up to 24 hours, as predicted by Higuchi's pharmacokinetic model. The SLNs were stable at 25°C/60%RH for up to 60 days. There was little to no change in particle size, PDI, or loading capacity. In addition, the number of probiotic bacteria was determined using the standard plate count procedure. Further, the antioxidant effect of the prepared formulation is evaluated using the DPPH assay method. CONCLUSION: This study concludes that the method used to fabricate RSG-probiotic-loaded SLNs is straightforward and yields favorable results regarding various parameters, including sustained release property, particle size, PDI, and percent drug loading stability. Furthermore, DPPH radical scavenging activity shows the high antioxidant potential of RSG-PB SLNs when compared to RSG and probiotics alone.

Severe Acute Liver Injury: First Manifestation of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a common multisystem disease characterised by a wide variety of presentation patterns and complex manifestations. As a lymphoid organ, the liver plays an important role in the immune response and is a target of autoimmune responses.1 SLE can affect the liver in approximately 25-60 % of patients during their disease course.2,3 Liver dysfunction and SLE can present with complicated differential diagnoses. Liver dysfunction in SLE is usually mild and rarely leads to advanced liver diseases such as cirrhosis and liver failure.4,5 Liver dysfunction in SLE is usually caused by non-SLE-related causes such as drug toxicity, fatty liver, alcoholism, and associated autoimmune hepatitis. However, primary liver involvement in SLE is also well-recognised. Patients with SLE who present with acute liver failure are rare. We report a rare case of SLE-associated acute severe liver injury along with a literature review.

Assessment of Potential Drug-drug Interactions (pDDIs) and Their Risk Factors Among Hospitalized Cardiac Patients in a Tertiary-care Center of Central India: A Retrospective Record-based Study.

Background: Patients with cardiovascular disorders (CVD) possess multiple comorbidities and are prone to be prescribed multiple drugs, thus predisposing them to various drug-drug interactions (DDIs). Objective: This study was carried out to assess the potential-DDIs (pDDIs) among the drugs prescribed to hospitalized patients with CVD and associated factors. Method: It was a retrospective study conducted with the help of the medical records department. Medical records of all the patients admitted to the cardiology department of our tertiary care center from January 1st, 2019, to December 31st, 2019, were included for analysis using Lexicomp, an up-to-date drug interaction screening tool. The pDDIs were divided into classes A, B, C, D, and X, and those belonging to classes D or X were considered clinically significant. Multiple logistic regression was used to analyze the association between the factors associated with and the occurrence of clinically significant pDDIs, with a P-value < .05 considered statistically significant. Results: Almost all the records reflected (335/338) at least 1 pDDI. A total of 4966 pDDIs were detected, of which the majority belonged to category C (75.3%), and 5.1% of pDDIs were clinically significant. The patients who were prescribed more than 10 drugs per day (OR = 2.46; 95% CI: 1.27-4.82; P = .008), prescribed parenteral formulation (OR = 1.84; 95% CI: 1.57-2.21; P < .0001), or had a diagnosis of acute coronary syndrome (OR = 2.33; 95% CI:1.1-5.12; P = .03) were associated with clinically significant pDDIs. Other factors, that is, female sex, use of fixed-dose combinations, and the triad of diabetes mellitus, hypertension, and dyslipidemia, were positively associated with clinically significant pDDIs. Conclusion: Even though every patient had at least 1 pDDI, the prevalence of clinically significant pDDIs was relatively less. Use of >10 drugs/day, parenteral formulation, patients with acute coronary syndrome were significantly associated with clinically significant pDDIs.

Conserved Cardiovascular Network: Bioinformatics Insights into Genes and Pathways for Establishing Caenorhabditis elegans as an Animal Model for Cardiovascular Diseases.

Cardiovascular disease (CVD) is a collective term for disorders of the heart and blood vessels. The molecular events and biochemical pathways associated with CVD are difficult to study in clinical settings on patients and in vitro conditions. Animal models play a pivotal and indispensable role in cardiovascular disease (CVD) research. Caenorhabditis elegans , a nematode species, has emerged as a prominent experimental organism widely utilised in various biomedical research fields. However, the specific number of CVD-related genes and pathways within the C. elegans genome remains undisclosed to date, limiting its in-depth utilisation for investigations. In the present study, we conducted a comprehensive analysis of genes and pathways related to CVD within the genomes of humans and C. elegans through a systematic bioinformatic approach. A total of 1113 genes in C. elegans orthologous to the most significant CVD-related genes in humans were identified, and the GO terms and pathways were compared to study the pathways that are conserved between the two species. In order to infer the functions of CVD-related orthologous genes in C. elegans, a PPI network was constructed. Orthologous gene PPI network analysis results reveal the hubs and important KRs: pmk-1, daf-21, gpb-1, crh-1, enpl-1, eef-1G, acdh-8, hif-1, pmk-2, and aha-1 in C. elegans. Modules were identified for determining the role of the orthologous genes at various levels in the created network. We also identified 9 commonly enriched pathways between humans and C. elegans linked with CVDs that include autophagy (animal), the ErbB signalling pathway, the FoxO signalling pathway, the MAPK signalling pathway, ABC transporters, the biosynthesis of unsaturated fatty acids, fatty acid metabolism, glutathione metabolism, and metabolic pathways. This study provides the first systematic genomic approach to explore the CVD-associated genes and pathways that are present in C. elegans, supporting the use of C. elegans as a prominent animal model organism for cardiovascular diseases.

Structure-based virtual screening and in vitro validation of inhibitors of cyclic dinucleotide phosphodiesterases ENPP1 and CdnP.

IMPORTANCE: In this paper, we describe novel inhibitors of cyclic dinucleotide phosphodiesterase enzymes from Mycobacterium tuberculosis (M.tb) (CdnP) and mammals (ENPP1). The phosphodiesterase enzymes hydrolyze cyclic dinucleotides, such as 2',3'-cyclic GMP-AMP and c-di-AMP, which are stimulator of interferon gene (STING) agonists. By blocking the hydrolysis of STING agonists, the cyclic GMP-AMP synthase (cGAS)-STING-IRF3 pathway is potentiated. There is strong evidence in tuberculosis and in cancer biology that potentiation of the cGAS-STING-IRF3 pathway leads to improved M.tb clearance and also improved antitumor responses in cancer. In addition to the identification of novel inhibitors and their biochemical characterization, we provide proof-of-concept evidence that our E-3 inhibitor potentiates the cGAS-STING-IRF3 pathway in both macrophage cell lines and also in primary human monocyte-derived macrophages.

Deep Learning Enables Rapid Identification of a New Quasicrystal from Multiphase Powder Diffraction Patterns.

Since the discovery of the quasicrystal, approximately 100 stable quasicrystals are identified. To date, the existence of quasicrystals is verified using transmission electron microscopy; however, this technique requires significantly more elaboration than rapid and automatic powder X-ray diffraction. Therefore, to facilitate the search for novel quasicrystals, developing a rapid technique for phase-identification from powder diffraction patterns is desirable. This paper reports the identification of a new Al-Si-Ru quasicrystal using deep learning technologies from multiphase powder patterns, from which it is difficult to discriminate the presence of quasicrystalline phases even for well-trained human experts. Deep neural networks trained with artificially generated multiphase powder patterns determine the presence of quasicrystals with an accuracy >92% from actual powder patterns. Specifically, 440 powder patterns are screened using the trained classifier, from which the Al-Si-Ru quasicrystal is identified. This study demonstrates an excellent potential of deep learning to identify an unknown phase of a targeted structure from powder patterns even when existing in a multiphase sample.