Evidence-Based Unani Pharmacotherapeutics for the Treatment of Non-Alcoholic Fatty Liver Disease: A Mechanistic Review.

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a global health crisis, affecting a quarter of the world's population, and is anticipated to become a leading cause of liver transplantation and hepatocellular carcinoma by 2030. Conventional pharmacotherapy for NAFLD remains imperfect. In this context, Unani medicine offers a promising alternative for managing NAFLD. Objective: This review aims to compile information on Unani medications used for the treatment of NAFLD, aiming to provide evidence of their efficacy and delve into the mechanisms through which these Unani drugs exert their therapeutic effects in NAFLD. Methods: A comprehensive exploration of classical Unani literature was conducted, referencing well-established texts to extract pertinent information regarding NAFLD and its treatment in Unani Medicine. Electronic databases, including PubMed, Science Direct, and Google Scholar, were systematically searched to gather information on the efficacy of Unani drugs in the treatment of NAFLD. Results: Unani medicine offers a rich repository of single herbs and compound formulations. There is a description of about 32 single herbs and 18 compound formulations for the treatment of NAFLD. These drugs act due to their Musakhkhin (calorific), Mudirr (diuretics), Mufattih (deobstruent), Muqawwῑ-i-Jigar (hepatoprotective), and Muhallilat (anti-inflammatory) action. The bioactive components present in these drugs possess antioxidant, hypolipidemic, anti-inflammatory, hypoglycemic, and hepatoprotective activities. These actions of Unani drugs closely align with the multifaceted nature of NAFLD pathogenesis, and thus effective in the treatment of NAFLD. Conclusion: The findings led us to conclude that the use of Unani medicines can improve clinical outcomes in NAFLD, as demonstrated by various clinical and experimental trials. However, further clinical trials are essential to provide a safe and effective option for addressing this prevalent liver condition.

Epigenetic regulation of tumor immunity.

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumor-immune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy.

Factor Xa inhibitors versus low-molecular-weight heparin for preventing coagulopathy following COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Background: Hospitalized patients with COVID-19 have shown a significant occurrence of thromboembolism and a heightened risk of death. It remains unclear whether factor Xa inhibitors are superior to enoxaparin in this context. Hence, there is a need for a direct comparison to assess the preventive effects and safety of factor Xa inhibitors versus enoxaparin in hospitalized COVID-19 patients. Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) or retrospective studies that compared the effectiveness or safety of factor Xa inhibitors and enoxaparin in preventing thromboembolism in hospitalized patients with COVID-19. Embolic incidence, incidence of bleeding, and all-cause mortality were among the outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95 percent CIs. Results: The analysis included six RCTs and two retrospective studies containing 4048 patients. Meta-analysis showed a statistically significant reduction among patients on factor Xa inhibitors compared with low-molecular-weight heparin (LMWH) in the embolic incidence [risk ratio (RR) 0.64 (95%, CI 0.42, 0.98); P=0.04, I2=12%]. Upon subgroup analysis by type of study design, no significant reductions were noted in patients on factor Xa inhibitors in RCTs (RR: 0.62; 95% CI: 0.33-1.17; P=0.14) or observational studies (RR: 0.53; 95% CI: 0.23-1.26; P=0.15) when compared with enoxaparin Factor Xa inhibitors were not significantly associated with incidence of bleeding [RR 0.76 (95% CI 0.36, 1.61); P=0.47, I2=0%] or all-cause mortality (RR: 0.81; 95% CI: 0.48-1.36; P=0.43). Consistent results were obtained upon subgroup analysis by the type of study design. Conclusion: Factor Xa inhibitors are more effective than enoxaparin in preventing thromboembolism among patients with COVID-19 who are not acutely ill and are hospitalized. Additional rigorous RCTs comparing factor Xa inhibitors with enoxaparin are warranted.

Bladder-resident bacteria associated with increased risk of recurrence after electrofulguration in women with antibiotic-recalcitrant urinary tract infection.

Background: Antibiotic-recalcitrant recurrent urinary tract infection (rUTI) is has become increasingly observed in postmenopausal women. Therefore, when standard antibiotic therapies have failed, some elect electrofulguration (EF) of areas of chronic cystitis when detected on office cystoscopy. EF is thought to remove tissue-resident bacteria that have been previously detected in the bladder walls of postmenopausal women with rUTI. We hypothesized that increased bladder bacterial burden may be associated with incomplete rUTI resolution following EF. Methods: Following IRB approval, bladder biopsies were obtained from 34 consenting menopausal women electing EF for the advanced management of rUTI. 16S rRNA FISH was performed using both universal and Escherichia probes and tissue-resident bacterial load was quantified. Time to UTI relapse after EF was recorded during a six-month follow-up period and the association of bladder bacterial burden and clinical covariates with UTI relapse was assessed. Results: We observed bladder-resident Escherichia in 52% of all participants and in 92% of participants with recent E. coli UTI. Time-to-relapse analysis revealed that women with high bladder bacterial burden as detected by the universal probe had a significantly ( p =0.035) higher risk of UTI within six months of EF (HR=3.15, 95% CI: 1.09-9.11). Interestingly, bladder-resident Escherichia was not significantly associated ( p =0.26) with a higher risk of UTI relapse (HR= 2.14, 95% CI: 0.58-7.90). Conclusions: We observed that total bladder bacterial burden was associated with a 3.1x increased risk of rUTI relapse within six months. Continued analysis of the relationship between bladder bacterial burden and rUTI outcomes may provide insight into the management of these challenging patients.

Genome analyses of colistin-resistant high-risk blaNDM-5 producing Klebsiella pneumoniae ST147 and Pseudomonas aeruginosa ST235 and ST357 in clinical settings.

BACKGROUND: Colistin is a last-resort antibiotic used in extreme cases of multi-drug resistant (MDR) Gram-negative bacterial infections. Colistin resistance has increased in recent years and often goes undetected due to the inefficiency of predominantly used standard antibiotic susceptibility tests (AST). To address this challenge, we aimed to detect the prevalence of colistin resistance strains through both Vitek®2 and broth micro-dilution. We investigated 1748 blood, tracheal aspirate, and pleural fluid samples from the Intensive Care Unit (ICU), Neonatal Intensive Care Unit (NICU), and Tuberculosis and Respiratory Disease centre (TBRD) in an India hospital. Whole-genome sequencing (WGS) of extremely drug-resitant (XDR) and pan-drug resistant (PDR) strains revealed the resistance mechanisms through the Resistance Gene Identifier (RGI.v6.0.0) and Snippy.v4.6.0. Abricate.v1.0.1, PlasmidFinder.v2.1, MobileElementFinder.v1.0.3 etc. detected virulence factors, and mobile genetic elements associated to uncover the pathogenecity and the role of horizontal gene transfer (HGT). RESULTS: This study reveals compelling insights into colistin resistance among global high-risk clinical isolates: Klebsiella pneumoniae ST147 (16/20), Pseudomonas aeruginosa ST235 (3/20), and ST357 (1/20). Vitek®2 found 6 colistin-resistant strains (minimum inhibitory concentrations, MIC = 4 µg/mL), while broth microdilution identified 48 (MIC = 32-128 µg/mL), adhering to CLSI guidelines. Despite the absence of mobile colistin resistance (mcr) genes, mechanisms underlying colistin resistance included mgrB deletion, phosphoethanolamine transferases arnT, eptB, ompA, and mutations in pmrB (T246A, R256G) and eptA (V50L, A135P, I138V, C27F) in K. pneumoniae. P. aeruginosa harbored phosphoethanolamine transferases basS/pmrb, basR, arnA, cprR, cprS, alongside pmrB (G362S), and parS (H398R) mutations. Both strains carried diverse clinically relevant antimicrobial resistance genes (ARGs), including plasmid-mediated blaNDM-5 (K. pneumoniae ST147) and chromosomally mediated blaNDM-1 (P. aeruginosa ST357). CONCLUSION: The global surge in MDR, XDR and PDR bacteria necessitates last-resort antibiotics such as colistin. However, escalating resistance, particularly to colistin, presents a critical challenge. Inefficient colistin resistance detection methods, including Vitek2, alongside limited surveillance resources, accentuate the need for improved strategies. Whole-genome sequencing revealed alarming colistin resistance among K. pneumoniae and P. aeruginosa in an Indian hospital. The identification of XDR and PDR strains underscores urgency for enhanced surveillance and infection control. SNP analysis elucidated resistance mechanisms, highlighting the complexity of combatting resistance.

Regional variations in antimicrobial susceptibility of community-acquired uropathogenic Escherichia coli in India: Findings of a multicentric study highlighting the importance of local antibiograms.

Objectives: Evidence-based prescribing is essential to optimize patient outcomes in cystitis. This requires knowledge of local antibiotic resistance rates. Diagnostic and Antimicrobial Stewardship (DASH) to Protect Antibiotics (https://dashuti.com/) is a multicentric mentorship program guiding centers in preparing, analyzing and disseminating local antibiograms to promote antimicrobial stewardship in community urinary tract infection. Here, we mapped the susceptibility profile of Escherichia coli from 22 Indian centers. Methods: These centers spanned 10 Indian states and three union territories. Antibiograms for urinary E. coli from the outpatient departments were collated. Standardization was achieved by regional online training; anomalies were resolved via consultation with study experts. Data were collated and analyzed. Results: Nationally, fosfomycin, with 94% susceptibility (inter-center range 83-97%), and nitrofurantoin, with 85% susceptibility (61-97%), retained the widest activity. The susceptibility rates were lower for co-trimoxazole (49%), fluoroquinolones (31%), and oral cephalosporins (26%). The rates for third- and fourth-generation cephalosporins were 46% and 52%, respectively, with 54% (33-58%) extended-spectrum ß-lactamase prevalence. Piperacillin-tazobactam (81%), amikacin (88%), and meropenem (88%) retained better activity; however, one center in Delhi recorded only 42% meropenem susceptibility. Susceptibility rates were mostly higher in South, West, and Northeast India; centers in the heavily populated Gangetic plains, across north and northwest India, had greater resistance. These findings highlight the importance of local antibiograms in guiding appropriate antimicrobial choices. Conclusions: Fosfomycin and nitrofurantoin are the preferred oral empirical choices for uncomplicated E. coli cystitis in India, although elevated resistance in some areas is concerning. Empiric use of fluoroquinolones and third-generation cephalosporins is discouraged, whereas piperacillin/tazobactam and aminoglycosides remain carbapenem-sparing parenteral agents.

Use of Diabetes Technologies and Retinopathy in Adults With Type 1 Diabetes.

Importance: Diabetic retinopathy (DR) is a complication of diabetes that can lead to vision loss. Outcomes of continuous glucose monitoring (CGM) and insulin pump use in DR are not well understood. Objective: To assess the use of CGM, insulin pump, or both, and DR and proliferative diabetic retinopathy (PDR) in adults with type 1 diabetes (T1D). Design, Setting, and Participants: A retrospective cohort study of adults with T1D in a tertiary diabetes center and ophthalmology center was conducted from 2013 to 2021, with data analysis performed from June 2022 to April 2023. Exposure: Use of diabetes technologies, including insulin pump, CGM, and both CGM and insulin pump. Main Outcomes and Measures: The primary outcome was development of DR or PDR. A secondary outcome was the progression of DR for patients in the longitudinal cohort. Multivariable logistic regression models assessed for development of DR and PDR and association with CGM and insulin pump use. Results: A total of 550 adults with T1D were included (median age, 40 [IQR, 28-54] years; 54.4% female; 24.5% Black or African American; and 68.4% White), with a median duration of diabetes of 20 (IQR, 10-30) years, and median hemoglobin A1c (HbA1c) of 7.8% (IQR, 7.0%-8.9%). Overall, 62.7% patients used CGM, 58.2% used an insulin pump, and 47.5% used both; 44% (244 of 550) of the participants had DR at any point during the study. On univariate analysis, CGM use was associated with lower odds of DR and PDR, and CGM with pump was associated with lower odds of PDR (all P < .05), compared with no CGM use. Multivariable logistic regression adjusting for age, sex, race and ethnicity, diabetes duration, microvascular and macrovascular complications, insurance type, and mean HbA1c, showed that CGM was associated with lower odds of DR (odds ratio [OR], 0.52; 95% CI, 0.32-0.84; P = .008) and PDR (OR, 0.42; 95% CI, 0.23-0.75; P = .004), compared with no CGM use. In the longitudinal analysis of participants without baseline PDR, 79 of 363 patients (21.8%) had progression of DR during the study. Conclusions and Relevance: In this cohort study of adults with T1D, CGM use was associated with lower odds of developing DR and PDR, even after adjusting for HbA1c. These findings suggest that CGM may be useful for diabetes management to mitigate risk for DR and PDR.

Curcumin coating: a novel solution to mitigate inherent carbon nanotube toxicity.

Multi-walled Carbon Nanotubes (MWCNTs) are inert structures with high aspect ratios that are widely used as vehicles for targeted drug delivery in cancer and many other diseases. They are largely non-toxic in nature however, when cells are exposed to these nanotubes for prolonged durations or at high concentrations, they show certain adverse effects. These include cytotoxicity, inflammation, generation of oxidative stress, and genotoxicity among others. To combat such adverse effects, various moieties can be attached to the surface of these nanotubes. Curcumin is a known anti-inflammatory, antioxidant and cytoprotective compound derived from a medicinal plant called Curcuma longa. In this study, we have synthesized and characterized Curcumin coated-lysine functionalized MWCNTs and further evaluated the cytoprotective, anti-inflammatory, antioxidant and antiapoptotic effect of Curcumin coating on the surface of MWCNTs. The results show a significant decrease in the level of inflammatory molecules like IL-6, IL-8, IL-1ß, TNFα and NFκB in cells exposed to Curcumin-coated MWCNTs as compared to the uncoated ones at both transcript and protein levels. Further, compared to the uncoated samples, there is a reduction in ROS production and upregulation of antioxidant enzyme-Catalase in the cells treated with Curcumin-coated MWCNTs. Curcumin coating also helped in recovery of mitochondrial membrane potential in the cells exposed to MWCNTs. Lastly, cells exposed to Curcumin-coated MWCNTs showed reduced cell death as compared to the ones exposed to uncoated MWCNTs. Our findings suggest that coating of Curcumin on the surface of MWCNTs reduces its ability to cause inflammation, oxidative stress, and cell death.

Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

Epigenetic regulation of tumor-immune symbiosis in glioma.

Glioma is a type of aggressive and incurable brain tumor. Patients with glioma are highly resistant to all types of therapies, including immunotherapies. Epigenetic reprogramming is a key molecular hallmark in tumors across cancer types, including glioma. Mounting evidence highlights a pivotal role of epigenetic regulation in shaping tumor biology and therapeutic responses through mechanisms involving both glioma cells and immune cells, as well as their symbiotic interactions in the tumor microenvironment (TME). In this review, we discuss the molecular mechanisms of epigenetic regulation that impacts glioma cell biology and tumor immunity in both a cell-autonomous and non-cell-autonomous manner. Moreover, we provide an overview of potential therapeutic approaches that can disrupt epigenetic-regulated tumor-immune symbiosis in the glioma TME.

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications.

Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.

Case report: A rare case of dual primary synchronous malignancies of the breast and kidney in a 70 year female.

INTRODUCTION: Multiple primary cancers (MPCs) have attracted attention in medical research due to their increasing incidence. The coexistence of invasive breast carcinoma and clear cell carcinoma of the kidney, alongside a family history of cancer, highlights the multifactorial origins of MPCs, particularly their potential association with genetic factors. CASE PRESENTATION: A 70-year-old female initially sought medical attention for a two-year history of a right breast lump as her primary concerns centered on the long-standing lump. Clinical evaluations and imaging studies revealed an invasive breast carcinoma diagnosis, and simultaneously, an incidental mass in her left kidney was identified as clear cell carcinoma. DISCUSSION: Emphasis and further researh should be on the potential role of genetic factors in MPC development, necessitating comprehensive genetic evaluations. CONCLUSION: This study highlights the significance of customized treatment approaches for each malignancy, facilitating early detection, improved patient outcomes, and an enhanced understanding of MPCs.

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

Purpose: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients. Experimental Design: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic effects in vivo in UM liver metastasis models. Results: CLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell lines in vitro decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. Conclusion: Imipridones are a promising strategy for further testing and development in mUM.

SGLT2 inhibitors in heart failure with preserved ejection fraction.

Heart failure (HF) is a clinical syndrome due to either functional or structural impairment of the ventricular pump or filling, representing a major cause of global morbidity and mortality. Heart failure with preserved ejection fraction (HFpEF), characterized by a left ventricular ejection fraction (LVEF) of ≥50%, constitutes over half of the HF population, with a rising prevalence. Until recently, therapeutic options in treating HFpEF and reducing hospitalization and mortality remained limited. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promising results in this patient population. This review article explores current literature and significant clinical trials investigating the impact of sodium- SGLT2 inhibitors in patients with HFpEF.

Needle-free electronically-controlled jet injector treatment with bleomycin and lidocaine is effective and well-tolerated in patients with recalcitrant keloids.

OBJECTIVES: The treatment of recalcitrant keloids is challenging. Although intralesional bleomycin using conventional needle injectors (CNI) is effective, it has important drawbacks, such as the need for repetitive and painful injections. Therefore, we aimed to evaluate the effectiveness, tolerability and patient satisfaction of intralesional bleomycin with lidocaine administered with a needle-free electronically-controlled pneumatic jet-injector (EPI) in recalcitrant keloids. METHODS: This retrospective study included patients with recalcitrant keloids who had received three intralesional EPI-assisted treatments with bleomycin and lidocaine. Effectiveness was assessed using the Patient and Observer Scar Assessment Scale (POSAS) at baseline and four to six weeks after the third treatment. Additionally, treatment related pain scores numeric rating scale, adverse effects, patient satisfaction and Global Aesthetic Improvement Scale (GAIS) were assessed. RESULTS: Fifteen patients with a total of >148 recalcitrant keloids were included. The median total POSAS physician- and patient-scores were respectively 40 and 41 at baseline, and reduced with respectively 7 and 6-points at follow-up ( p < 0.001; p < 0.001). The median pain scores during EPI-assisted injections were significantly lower compared to CNI-assistant injections, (2.5 vs. 7.0, respectively ( p < 0.001)). Adverse effects were mild. Overall, patients were "satisfied" or "very satisfied" with the treatments (14/15, 93.3%). The GAIS was "very improved" in one patient, "improved" in nine patients and "unaltered" in four patients. CONCLUSIONS: EPI-assisted treatment with bleomycin and lidocaine is an effective, well tolerated, patient-friendly alternative for CNI in patients with recalcitrant keloid scars. Randomized controlled trials are warranted to confirm our findings and improve the clinical management of recalcitrant keloids.

Characterization of direct oral anticoagulants use in adult hematopoietic stem cell transplant recipients.

Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) treatment are of interest in oncology due to ease of administration and lack of need for therapeutic monitoring compared to other anticoagulants. Data supporting their use in patients with hematologic malignancies post-hematopoietic stem cell transplant (HCT) are limited. The purpose of the study is to characterize DOAC use in HCT patients. This multicenter, retrospective cohort analysis included allogeneic and autologous HCT recipients. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB)/minor bleeding and VTE recurrence. Of 126 patients, 91 (72.2%) patients received an autologous HCT, and 35 (27.8%) patients received an allo-HCT. No major bleeding occurred in either transplant recipient groups. In autologous HCT recipients, CRNMB/minor bleeding occurred in four (4.4%) patients and VTE recurrence occurred in one (1.1%) patient. For allogeneic HCT recipients, CRNMB/minor bleeding occurred in five (14.3%) patients and VTE recurrence occurred in two (5.7%) patients. For patients that experienced a CRNMB, five (100%) of the allogeneic HCT and two (50%) of the autologous HCT recipients were thrombocytopenic at the time of bleeding. Only 38.5% of patients who experienced a drug-drug interaction requiring DOAC dose adjustment received the appropriate dose adjustment. DOACs were associated with low rates of recurrent VTE and no major bleeding events, similar to published data on DOAC use in the general cancer patient population. This suggests that DOACs may be safe therapeutic options with proactive management of drug interactions and careful monitoring for bleeding events, especially in the allogeneic HCT population where minor bleeding rates were slightly higher.

De novo generation of dual-target ligands for the treatment of SARS-CoV-2 using deep learning, virtual screening, and molecular dynamic simulations.

De novo generation of molecules with the necessary features offers a promising opportunity for artificial intelligence, such as deep generative approaches. However, creating novel compounds having biological activities toward two distinct targets continues to be a very challenging task. In this study, we develop a unique computational framework for the de novo synthesis of bioactive compounds directed at two predetermined therapeutic targets. This framework is referred to as the dual-target ligand generative network. Our approach uses a stochastic policy to explore chemical spaces called a sequence-based simple molecular input line entry system (SMILES) generator. The steps in the high-level workflow would be to gather and prepare the training data for both targets' molecules, build a neural network model and train it to make molecules, create new molecules using generative AI, and then virtually screen the newly validated molecules against the SARS-CoV-2 PLpro and 3CLpro drug targets. Results shows that novel molecules generated have higher binding affinity with both targets than the conventional drug i.e. Remdesivir being used for the treatment of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Trends and advances in pre- and post-harvest processing of linseed oil for quality food and health products.

Linseed is an ancient crop used for diverse purposes since the beginning of civilization. In recent times, linseed has emerged as a superfood due to its high content of health-promoting omega-3 fatty acids and other bioactive compounds. Among primary health effects, it has potential to manage hypertension, diabetes, osteoporosis, atherosclerosis, cancer, arthritis, neurological, cardiovascular diseases including blood cholesterol levels, constipation, diarrhea, and autoimmune disorders etc. due to the presence of omega-3 fatty acid, lignans, high dietary fibers, and proteins, whereas, secondary health effects comprise of relieving from various skin disorders. Due to these health-beneficial properties, interest in linseed oil necessitates the intensification of research efforts on various aspects. These include cultivation technology, varietal and genetic improvement, post-harvest processing, profiling of nutrients and bioactive compounds, pre-clinical and clinical studies, etc. The present review discussed the advances in linseed research including pre- and post-harvest processing. However, focus on the bioactive compounds present in linseed oil and their health effects are also presented. Linseed cultivation, pre- and post-harvest processing aspects are covered including climatic, edaphic, agronomic factors, type of cultivar and storage conditions etc, which impact the overall oil yield and its nutritional quality. Various emerging applications of linseed oil in functional food, nutraceutical, pharmaceutical, and cosmeceutical preparations were also presented in detail. Further, recommendations were made on linseed oil research in the field of genetics, breeding germplasm resources and genome editing for exploring its full applications as a nutrition and health product.

LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma.

Glioblastoma (GBM) is a hypoxic and "immune-cold" tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3ß-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8+ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.