CD38-RyR2 axis-mediated signaling impedes CD8+ T cell response to anti-PD1 therapy in cancer.

PD1 blockade therapy, harnessing the cytotoxic potential of CD8+ T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8+ T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8+ T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8+ T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8+ T cells, revealed that CD38-expressing CD8+ T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8+ T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8+ T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8+ T cells elevated intracellular Ca2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8+ T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.

Intratumoral PD1+CD38+Tim3+ CD8+ T Cells in Pre-BCG Tumor Tissues Are Associated with Poor Responsiveness to BCG Immunotherapy in Patients with Non-Muscle Invasive Bladder Cancer.

Intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) is a standard of care therapy for non-muscle invasive bladder cancer (NMIBC), which accounts for about 75% of newly diagnosed urothelial cancer. However, given the frequent recurrence and progression, identification of a pre-treatment biomarker capable of predicting responsiveness to BCG in NMIBC is of utmost importance. Herein, using multiparametric flow cytometry, we characterized CD8+ T cells from peripheral blood and tumor tissues collected from 27 pre-BCG patients bearing NMIBC to obtain immune correlates of bladder cancer prognosis and responsiveness to BCG therapy. We observed that intratumoral CD8+ T cell subsets were highly heterogenous in terms of their differentiation state and exist at different proportions in tumor tissues. Remarkably, among the different CD8+ T cell subsets present in the tumor tissues, the frequency of the terminally exhausted-like CD8+ T cell subset, marked as PD1+CD38+Tim3+ CD8+ T cells, was inversely correlated with a favorable outcome for patients and a responsiveness to BCG therapy. Moreover, we also noted that the intratumoral abundance of the progenitor exhausted-like PD1+CD8+ T cell subset in pre-BCG NMIBC tumor tissues was indicative of better recurrence-free survival after BCG. Collectively, our study led to the identification of biomarkers that can predict the therapeutic responsiveness of BCG in NMIBC.

The face behind the Covid-19 mask - A comprehensive review.

The threat of epidemic outbreaks like SARS-CoV-2 is growing owing to the exponential growth of the global population and the continual increase in human mobility. Personal protection against viral infections was enforced using ambient air filters, face masks, and other respiratory protective equipment. Available facemasks feature considerable variation in efficacy, materials usage and characteristic properties. Despite their widespread use and importance, face masks pose major potential threats due to the uncontrolled manufacture and disposal techniques. Improper solid waste management enables viral propagation and increases the volume of associated biomedical waste at an alarming rate. Polymers used in single-use face masks include a spectrum of chemical constituents: plasticisers and flame retardants leading to health-related issues over time. Despite ample research in this field, the efficacy of personal protective equipment and its impact post-disposal is yet to be explored satisfactorily. The following review assimilates information on the different forms of personal protective equipment currently in use. Proper waste management techniques pertaining to such special wastes have also been discussed. The study features a holistic overview of innovations made in face masks and their corresponding impact on human health and environment. Strategies with SDG3 and SDG12, outlining safe and proper disposal of solid waste, have also been discussed. Furthermore, employing the CFD paradigm, a 3D model of a face mask was created based on fluid flow during breathing techniques. Lastly, the review concludes with possible future advancements and promising research avenues in personal protective equipment.

Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8+ T Cells.

Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T-cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust antitumor immune response. Here, we report that IL12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumor-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL12-stimulated CD8+ T cells and displayed improved antitumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T-cell therapy. SIGNIFICANCE: IL12-mediated metabolic reprogramming increases intracellular acetyl CoA to promote the effector function of CD8+ T cells in nutrient-depleted tumor microenvironments, revealing strategies to potentiate the antitumor efficacy of T cells.

Individual behavioral profiling as a translational approach to assess treatment efficacy in an animal model of post-traumatic stress disorder.

A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large variability in responsiveness to pharmacotherapy. Only 20-30% of patients experience total remission to a specific treatment, while others demonstrate either partial remission or no response. However, this heterogeneity in response to pharmacotherapy has not been adequately addressed in animal models, since these analyze the averaged group effects, ignoring the individual variability to treatment response, which seriously compromises the translation power of such models. Here we examined the possibility of employing an "individual behavioral profiling" approach, originally developed to differentiate between "affected" and "exposed-unaffected" individuals in an animal model of PTSD, to also enable dissociating "responders" or "non-responders" after SSRI (fluoxetine) treatment. Importantly, this approach does not rely on a group averaged response to a single behavioral parameter, but considers a cluster of behavioral parameters, to individually characterize an animal as either "responder" or "non-responder" to the treatment. The main variable to assess drug efficacy thus being the proportion of "responders" following treatment. Alteration in excitatory/inhibitory (E/I) balance has been proposed as being associated with stress-related psychopathology. Toward a functional proof of concept for our behaviorally-based characterization approach, we examined the expression patterns of α1 and α2 subunits of GABAA receptor, and GluN1 and GluN2A subunits of the NMDAR receptor in the ventral hippocampus, as well as electrophysiologically local circuit activity in the dorsal dentate gyrus (DG). We demonstrate that with both parameters, treatment "responders" differed from treatment "non-responders," confirming the functional validity of the behavior-based categorization. The results suggest that the ability to respond to fluoxetine treatment may be linked to the ability to modulate excitation-inhibition balance in the hippocampus. We propose that employing the "individual behavioral profiling" approach, and the resultant novel variable of the proportion of "recovered" individuals following treatment, offers an effective translational tool to assess pharmacotherapy treatment efficacy in animal models of stress and trauma-related psychopathology.

A history of juvenile mild malaria exacerbates chronic stress-evoked anxiety-like behavior, neuroinflammation, and decline of adult hippocampal neurogenesis in mice.

Children residing in high malaria transmission regions are particularly susceptible to malaria. This early-life window is also a critical period for development and maturation of the nervous system, and inflammatory insults during this period may evoke a persistent increase in vulnerability for psychopathology. We employed a two-hit model of juvenile mild malaria and a two-week chronic unpredictable mild stress (CUMS) regime, commencing 60 days post-parasite clearance, to assess whether a history of juvenile infection predisposed the mice towards mood-related behavioral alterations and neurocognitive deficits. We showed that adult mice with a history of juvenile malaria (A-H/JMAL) exhibited heightened CUMS-associated anxiety-like behavior, with no observable change in cognitive behavior. In contrast, mice with a history of adult malaria did not exhibit such enhanced stress vulnerability. At baseline, A-H/JMAL mice showed increased activated microglia within the hippocampal dentate gyrus subfield. This was accompanied by a decrease in proliferating neuronal progenitors, with total number of immature hippocampal neurons unaltered. This neuroinflammatory and neurogenic decline was further exacerbated by CUMS. At day-14 post-CUMS, hippocampi of A-H/JMAL mice showed significantly higher microglial activation, and a concomitant decrease in progenitor proliferation and number of immature neurons. Taken together, these results suggest that a history of juvenile mild malaria leaves a neuroinflammatory mark within the hippocampal niche, and this may contribute to a heightened stress response in adulthood. Our findings lend credence to the idea that the burden of malaria in early-life results in sustained CNS changes that could contribute to increased vulnerability to adult-onset neuronal insults.

Screening antenatal anxiety: Predicting its effect on fetal growth.

CONTEXT: Maternal anxiety has an association with low birth weight. However, studies are scarce to determine any association between maternal anxiety and fetal growth. AIMS: This study aims to determine the effect of maternal anxiety on fetal growth, measured by gestational age-dependent increase in fetal abdominal circumference (AC). The secondary objective is to determine the effect of maternal anxiety on other fetal parameters (biparietal diameter [BPD], head circumference [HC], femur length [FL]). SETTINGS AND DESIGN: This cross-sectional study was conducted in a tertiary care hospital, Kolkata. MATERIALS AND METHODS: Four hundred and ten pregnant mothers, between 14 and 40 weeks of gestation, were interviewed with socioeconomic and obstetric profile questionnaire and examined for anthropometric profile and presence and severity of pallor. Anxiety was assessed using Generalized Anxiety Disorder-7 (GAD) questionnaire. HC, AC, BPD, and FL were measured by ultrasound biometry. ANALYSIS USED: A multivariable logistic regression analysis was done to determine the predictors of small-for-gestational-age (SGA). A robust mediation analysis was done to determine mediating effect of anxiety on gestational age-dependent increase in fetal AC. RESULTS: Mild (odds ratio [OR]Adjusted = 6.23, [2.41, 16.15]) and moderate (ORAdjusted = 22.42, [5.00, 100.57]) anxiety was significantly associated with SGA fetus. Anxiety increased with the progression of gestation (ßGAD: 0.011 [0.007-0.015]) and it had a negative effect on fetal growth (standardized indirect effect of gestational age-mediated by anxiety on AC: -0.037 [-0.059, -0.022]). Anxiety also attenuated gestational age-dependent increment of HC. CONCLUSION: Mother's anxiety has a gestational age-dependent temporally incremental negative effect on fetal growth and brain development.

Determinants of menstrual hygiene among school going adolescent girls in a rural area of West Bengal.

BACKGROUND: Menstrual hygiene is a neglected issue in rural India. Lack of menstrual hygiene in adolescent girls can make them susceptible to various morbidities, for example, reproductive tract infection and urinary tract infection and their long-term consequences, for example, cervical cancer, infertility, and ectopic pregnancy. This study aims to find out the determinants of menstrual hygiene among the school going adolescent girls in a rural area of West Bengal. OBJECTIVES: To elicit the menstrual hygiene practices among the study population and to find out the association of poor menstrual hygiene practices with sociodemographic factors, such as age, occupation and education of the parents, housing, and presence of sanitary toilet. MATERIALS AND METHODS: A descriptive, cross-sectional study was conducted among 307 school going adolescent girls of 12-17 years age group in a rural area of West Bengal. RESULTS: Majority of the students in both schools (62.9%) were Hindu, general caste (54.1%) and belonged to nuclear family (69.7%). Most of the parents in both schools had completed their education up to primary level. Bivariate analyses were done, and the significant factors predicting good menstrual hygiene were entered into the multivariable logistic regression model. It revealed that good menstrual hygiene was more among those whose mothers were educated (adjusted odds ratios [AOR] 2.3 [1.06-5.01]), and who were homemakers (AOR 2.3 [1.06-5.01]). CONCLUSIONS: Menstrual hygiene among the study population was found to be poor. The improving education level of the mothers can go a long way in improving menstrual hygiene practice.