Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8-35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1-43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8-51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

Clinical Effects of Yoga and Meditational Practices on the Holistic Health of Chronic Kidney Disease Patients: A Systematic Review.

As the world accelerates, sedentary and unhealthy lifestyles have an increasingly negative impact on human physical and emotional well-being. Millions of people globally are thought to have chronic kidney disease (CKD), which is frequently brought on by diabetes, hypertension, and glomerulonephritis. Over time, the illness gets worse and eventually results in irreversible renal failure. A person's life can be seriously affected by CKD in many different ways, including emotionally, socially, physically, and financially. Apart from physiological manifestations like anemia, discomfort, and exhaustion, CKD can also result in psychological problems like anxiety and depression, which can impair one's overall standard of life. Numerous studies have demonstrated the beneficial effects of yoga and meditation on people with chronic renal disease, enhancing their general health and quality of life. Because of therapeutic limitations, familial pressures, financial restraints, and symptoms of end-stage kidney disease, people with CKD frequently experience stress and anxiety. By reducing stress and anxiety, yoga and meditation can help individuals with chronic conditions maintain their health and improve their overall well-being. Recent research has found that yoga can improve blood pressure, sympathetic activity, and basal metabolic rate as well as reduce blood pressure and blood sugar levels by balancing the autonomic nervous system. Furthermore, studies have demonstrated that yoga helps CKD patients live healthier lives by lowering stress, anxiety, and sadness. Healthcare professionals can help patients with chronic renal disease manage their symptoms and enhance their general health and well-being by adding yoga and meditation into their treatment regimens. Modifying lifestyle is essential for both the prevention and treatment of chronic renal disease. CKD often co-occurs with other age-related and sedentary lifestyles and poor diet-related chronic conditions. The dearth of targeted treatment for a large percentage of CKD patients led to the investigation of the therapeutic applications of yoga and meditation in this study. These affordable, non-invasive therapies provide a comprehensive approach to controlling CKD, benefiting both healthy individuals and those with CKD in terms of their physical and mental well-being.

PROTEIN L-ISOASPARTYL METHYLTRANSFERASE protects enolase dysfunction by repairing isoaspartyl-induced damage and is positively implicated in agronomically important seed traits.

The protein-repairing enzyme (PRE) PROTEIN L-ISOASPARTYL METHYLTRANSFERASE (PIMT) influences seed vigor by repairing isoaspartyl-mediated protein damage in seeds. However, PIMTs function in other seed traits, and the mechanisms by which PIMT affects such seed traits are still poorly understood. Herein, through molecular, biochemical, and genetic studies using overexpression and RNAi lines in Oryza sativa and Arabidopsis thaliana, we demonstrate that PIMT not only affects seed vigor but also affects seed size and weight by modulating enolase (ENO) activity. We have identified ENO2, a glycolytic enzyme, as a PIMT interacting protein through Y2H cDNA library screening, and this interaction was further validated by BiFC and co-immunoprecipitation assay. We show that mutation or suppression of ENO2 expression results in reduced seed vigor, seed size, and weight. We also proved that ENO2 undergoes isoAsp modification that affects its activity in both in vivo and in vitro conditions. Further, using MS/MS analyses, amino acid residues that undergo isoAsp modification in ENO2 were identified. We also demonstrate that PIMT repairs such isoAsp modification in ENO2 protein, protecting its vital cellular functions during seed maturation and storage, and plays a vital role in regulating seed size, weight, and seed vigor. Taken together, our study identified ENO2 as a novel substrate of PIMT, and both ENO2 and PIMT in turn implicate in agronomically important seed traits.

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity.

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.

The Arabidopsis F-box protein SKP1-INTERACTING PARTNER 31 modulates seed maturation and seed vigor by targeting JASMONATE ZIM DOMAIN proteins independently of jasmonic acid-isoleucine.

F-box proteins have diverse functions in eukaryotic organisms, including plants, mainly targeting proteins for 26S proteasomal degradation. Here, we demonstrate the role of the F-box protein SKP1-INTERACTING PARTNER 31 (SKIP31) from Arabidopsis (Arabidopsis thaliana) in regulating late seed maturation events, seed vigor, and viability through biochemical and genetic studies using skip31 mutants and different transgenic lines. We show that SKIP31 is predominantly expressed in seeds and that SKIP31 interacts with JASMONATE ZIM DOMAIN (JAZ) proteins, key repressors in jasmonate (JA) signaling, directing their ubiquitination for proteasomal degradation independently of coronatine/jasmonic acid-isoleucine (JA-Ile), in contrast to CORONATINE INSENSITIVE 1, which sends JAZs for degradation in a coronatine/JA-Ile dependent manner. Moreover, JAZ proteins interact with the transcription factor ABSCISIC ACID-INSENSITIVE 5 (ABI5) and repress its transcriptional activity, which in turn directly or indirectly represses the expression of downstream genes involved in the accumulation of LATE EMBRYOGENESIS ABUNDANT proteins, protective metabolites, storage compounds, and abscisic acid biosynthesis. However, SKIP31 targets JAZ proteins, deregulates ABI5 activity, and positively regulates seed maturation and consequently seed vigor. Furthermore, ABI5 positively influences SKIP31 expression, while JAZ proteins repress ABI5-mediated transactivation of SKIP31 and exert feedback regulation. Taken together, our findings reveal the role of the SKIP31-JAZ-ABI5 module in seed maturation and consequently, establishment of seed vigor.

Methionine sulfoxide reductase B5 plays a key role in preserving seed vigor and longevity in rice (Oryza sativa).

Oxidation of methionine leads to the formation of methionine S-sulfoxide and methionine R-sulfoxide, which can be reverted by two types of methionine sulfoxide reductase (MSR): MSRA and MSRB. Though the role of MSR enzymes has been elucidated in various physiological processes, the regulation and role of MSR in seeds remains poorly understood. In this study, through molecular, biochemical, and genetic studies using seed-specific overexpression and RNAi lines of OsMSRB5 in Oryza sativa, we demonstrate the role of OsMSRB5 in maintaining seed vigor and longevity. We show that an age-induced reduction in the vigor and viability of seeds is correlated with reduced MSR activity and increased methionine sulfoxide (MetSO) formation. OsMSRB5 expression increases during seed maturation and is predominantly localized to the embryo. Further analyses on transgenic lines reveal the role of OsMSRB5 in modulating reactive oxygen species (ROS) homeostasis to preserve seed vigor and longevity. We show that ascorbate peroxidase and PROTEIN l-ISOASPARTYL METHYLTRANSFERASE undergo MetSO modification in seeds that affects their functional competence. OsMSRB5 physically interacts with these proteins and reverts this modification to facilitate their functions and preserve seed vigor and longevity. Our results thus illustrate the role of OsMSRB5 in preserving seed vigor and longevity by modulating ROS homeostasis in seeds.

Motivation and preparedness of first semester medical students for a career in medicine.

PURPOSE: To determine motivation of medical students towards a medical career, and their knowledge of and preparation for it. METHODS: After ethical committee approval, students admitted in 2009, who volunteered, were administered an anonymous questionnaire. Descriptive analysis was done. RESULTS: Of 150 students admitted, 103 (68.7%) submitted completed questionnaires. Fifty-seven students (55%) got admission after > or = 2 attempts; 65 (63%) decided on a medical career before class ten. Accurate knowledge about the curriculum was poor even though many had a family member in the health field and were encouraged to take up medicine. Only half had sought guidance from a medical person; most had never undergone career preparation activity. CONCLUSION: Students are early deciders and highly motivated to join medicine. Family is a strong motivator and could encourage career preparation activities. Policy makers could design interventions to inform school students before they make the critical decision to join medicine.

Comparison of cardiac autonomic functions among postmenopausal women with and without hormone replacement therapy, and premenopausal women.

The aim of present study was comparison of cardiac autonomic status during different phases of reproductive life in women - in premenopausal women between proliferative and secretory phase, in postmenopausal women and in postmenopausal women receiving hormone replacement therapy (HRT). The study included 30 premenopausal women (Group 1) who were assessed in both proliferative (Group 1A) and secretory phase (Group 1B) of menstrual cycle, 30 postmenopausal women (Group 2) and 30 postmenopausal women on HRT (Group 3). Various autonomic function tests were done to assess parasympathetic and sympathetic functions. Results were obtained by ANOVA followed by Tukey test. The postmenopausal women (Group 2) showed increased sympathetic and decreased parasympathetic tone compared to premenopausal women (Group1). The women on HRT (Group 3) showed parasympathetic dominance and decrease in sympathetic activity compared to postmenopausal women (Group 2). Across the menstrual cycle, increased parasympathetic activity was seen in secretory phase while no change was observed in the sympathetic activity in the two phases.