An IRF2-Expressing Oncolytic Virus Changes the Susceptibility of Tumor Cells to Antitumor T cells and Promotes Tumor Clearance.

Interferon regulatory factor 1 (IRF1) can promote antitumor immunity. However, we have shown previously that in the tumor cell, IRF1 can promote tumor growth, and IRF1-deficient tumor cells exhibit severely restricted tumor growth in several syngeneic mouse tumor models. Here, we investigate the potential of functionally modulating IRF1 to reduce tumor progression and prolong survival. Using inducible IRF1 expression, we established that it is possible to regulate IRF1 expression to modulate tumor progression in established B16-F10 tumors. Expression of IRF2, which is a functional antagonist of IRF1, down-regulated IFN-induced expression of inhibitory ligands, up-regulated MHC-related molecules, and slowed tumor growth and extended survival. We characterized the functional domain(s) of IRF2 needed for this antitumor activity, showing that a full-length IRF2 was required for its antitumor functions. Finally, using an oncolytic vaccinia virus as a delivery platform, we showed that IRF2-expressing vaccinia virus suppressed tumor progression and prolonged survival in multiple tumor models. These results suggest the potency of targeting IRF1 and using IRF2 to modulate immunotherapy.

Ashwagandha Diminishes Hippocampal Apoptosis Induced by Microwave Radiation by Acetylcholinesterase Dependent Neuro-Inflammatory Pathway in Male Coturnix coturnix Japonica.

Microwave radiation (MWR) has been linked to neurodegeneration by inducing oxidative stress in the hippocampus of brain responsible for learning and memory. Ashwagandha (ASW), a medicinal plant is known to prevent neurodegeneration and promote neuronal health. This study investigated the effects of MWR and ASW on oxidative stress and cholinergic imbalance in the hippocampus of adult male Japanese quail. One control group received no treatment, the second group quails were exposed to MWR at 2 h/day for 30 days, third was administered with ASW root extract orally 100 mg/day/kg body weight and the fourth was exposed to MWR and also treated with ASW. The results showed that MWR increased serum corticosterone levels, disrupted cholinergic balance and induced neuro-inflammation. This neuro-inflammation further led to oxidative stress, as evidenced by decreased activity of antioxidant enzymes SOD, CAT and GSH. MWR also caused a significant decline in the nissil substances in the hippocampus region of brain indicating neurodegeneration through oxidative stress mediated hippocampal apoptosis. ASW, on the other hand, was able to effectively enhance the cholinergic balance and subsequently lower inflammation in hippocampus neurons. This suggests that ASW can protect against the neurodegenerative effects of MWR. ASW also reduced excessive ROS production by increasing the activity of ROS-scavenging enzymes. Additionally, ASW prevented neurodegeneration through decreased expression of caspase-3 and caspase-7 in hippocampus, thus promoting neuronal health. In conclusion, this study showed that MWR induces apoptosis and oxidative stress in the brain, while ASW reduces excessive ROS production, prevents neurodegeneration and promotes neuronal health.

Oligoadenylate synthetase 1 displays dual antiviral mechanisms in driving translational shutdown and protecting interferon production.

In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.

Dietary restriction-induced alterations on estrogen receptor alpha expression in regulating fertility in male Coturnix coturnix japonica: Relevance of Withania somnifera in modulation of inflammation and oxidative stress in testis.

PROBLEM: Reproductive performance of animals gets affected by nutritional restrictions which act as potential stressors leading to hormonal imbalance and testicular inflammation, the major causes of infertility. Withania somnifera (WS), well-known traditional medicinal plant, has been used as antistress and infertility treatment. Therefore, the present study looks into the ameliorative effects of WS on the reproductive and immune system of male Coturnix coturnix japonica in stressed conditions like water and food restriction focussing on the modulation in estrogen receptor alpha (ERα). METHOD OF STUDY: Biochemical estimations for oxidative stress, histological alterations, immuno-fluorescent localization of ERα, interleukin (IL)-1ß, IL-4, and interferon gamma (IFN-γ) in testicular cells were performed. RESULTS: Nutritional restriction declines endogenous estradiol, ERα in testicular cells while it elevates corticosterone leading to oxidative stress in testis thereby reducing fertility by decrease in sperm. Results indicate significant reversal in all the parameters after the administration of WS by improving testicular cell morphology, increased superoxide and catalase activity thus reducing oxidative stress. WS increases spermatogenesis and enhances expression of ERα in testicular cells in quail. Further, WS increases IL-4, decreases IL-1ß and IFN-γ expression in testis, thereby improving immune profile contrary to stressed conditions. CONCLUSION: WS stimulates HPG-axis even after stress resulting in increased endogenous estradiol which stimulates the expression of ERα in testis; increases sperm count and immunity thereby improving the reproductive performance. WS may be the best therapy against nutritional-restriction stress induced reproductive toxicity by reducing oxidative stress mediated inflammatory response via increased testicular expression of ERα in quail.

Impact of Dietary Probiotics on the Immune and Reproductive Physiology of Pubertal Male Japanese Quail (Coturnix coturnix japonica) Administered at the Onset of Pre-Puberty.

Fertility in males is dependent on the proper production of sperms involving the synchronization of numerous factors like oxidative stress, inflammatory processes, and hormonal regulation. Inflammation associated with oxidative stress is also known to impair sperm function. Nutritional factors like probiotics and prebiotics have the potential benefits to modulate these factors which may enhance male fertility. In the present study, immature male Japanese quail at the beginning of 3rd week were administered with Lactobacillus rhamnosus (L), Bifidobacterium longum (B), and mannan-oligosaccharides (M) through dietary supplementation in individual groups as well as in combinations like LB and MLB. Markers of oxidative stress including SOD and catalase were examined by native PAGE; inflammatory biomarkers (IL-1ß, IL-10, and NFκB), apoptotic markers (caspase 3 and caspase 7), steroidal hormones, and their receptors estrogen receptor alpha (ERα) and beta (ERß) were assessed in testis. The study reveals that dietary supplementation of 1% L, B, and M in combination significantly and positively increases the overall growth of immature male quail specifically testicular weight and gonadosomatic index (GSI). Furthermore, significant improvement in testicular cell size; increased steroidal hormones like testosterone, FSH, and LH levels; increase in SOD, catalase enzymes; decrease in apoptotic factors Caspase 3, Caspase 7 and immune system strength observed indicated by a decrease in expression of IL-1ß, NFκB; and increase of IL-10 in testis when LBM was used in combination. These variations are attributed to the increase in testicular estrogen receptors alpha and beta, facilitated by the neuroendocrine gonadal axis, ultimately leading to improved male fertility. It can be concluded that the dietary supplementation in combination with L, B, and M enhances male fertility in immature quail by increased expression of estrogen receptors via gut microbiota modulation. It also sheds light on the potential use of these nutritional factors in avian species as therapeutic interventions to overcome low fertility problems in quail thereby benefitting the poultry industry.

Development of a human glioblastoma model using humanized DRAG mice for immunotherapy.

Glioblastoma (GBM) is the most common and lethal primary brain tumor. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. We successfully generated humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model by transplantation of human DR4+ hematopoietic stem cells (hHSCs), and effectively grafted GBM patient-derived tumorsphere cells to form xenografted tumors intracranially. The engrafted tumors recapitulated the pathological features and the immune cell composition of human GBM. Administration of anti-human PD-1 antibodies in these tumor-bearing humanized DRAG mice decreased the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR-CD15- and CD11b+CD14-CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mice as a useful model to test the efficacy of GBM immunotherapy. Taken together, these results suggest that the humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.

Bacterial worth in genotoxicity assessment studies.

Bacterial-based genotoxicity test systems play a significant role in the detection and evaluation of genotoxicity in vitro and have gained importance due to attributes like wide applicability, speed, high sensitivity, good reproducibility, and simplicity. The Salmonella microsomal mutagenicity assay was created by Ames and colleagues at the beginning of the 1970s, and it was based on the fundamental notion that in auxotrophic bacterial strains with inhibited growth, a mutant gene would revert to its original state on exposure to genotoxicants. This is the most successful and widely used in vitro genotoxicity test. Later, a number of additional test systems that incorporated DNA repair mechanisms including the bacterial SOS response were created. Genetic engineering has further provided significant advancement in these test systems with the development of highly sophisticated bacterial tester strains with significantly increased sensitivity to evaluate the chemical nature of hazardous substances and pollutants. These bacterial bioassays render an opportunity to detect the defined effects of compounds at the molecular level. In this review, all the aspects related to the bacterial system in genotoxicity assessment have been summarized and their role is elaborated concerning real-time requirements and future perspectives.

A Global Health Reciprocal Innovation grant programme: 5-year review with lessons learnt.

Unilateral approaches to global health innovations can be transformed into cocreative, uniquely collaborative relationships between low-income and middle-income countries (LMICs) and high-income countries (HIC), constituted as 'reciprocal innovation' (RI). Since 2018, the Indiana Clinical and Translational Sciences Institute (CTSI) and Indiana University (IU) Center for Global Health Equity have led a grants programme sculpted from the core elements of RI, a concept informed by a 30-year partnership started between IU (Indiana) and Moi University (Kenya), which leverages knowledge sharing, transformational learning and translational innovations to address shared health challenges. In this paper, we describe the evolution and implementation of an RI grants programme, as well as the challenges faced. We aim to share the successes of our RI engagement and encourage further funding opportunities to promote innovations grounded in the RI core elements. From the complex series of challenges encountered, three major lessons have been learnt: dedicating extensive time and resources to bring different settings together; establishing local linkages across investigators; and addressing longstanding inequities in global health research. We describe our efforts to address these challenges through educational materials and an online library of resources for RI projects. Using perspectives from RI investigators funded by this programme, we offer future directions resulting from our 5-year experience in applying this RI-focused approach. As the understanding and implementation of RI grow, global health investigators can share resources, knowledge and innovations that have the potential to significantly change the face of collaborative international research and address long-standing health inequities across diverse settings.

Withaferin-A attenuates diabetes mellitus induced male reproductive dysfunction mediated by ERα in brain and testes of Swiss albino mice.

Diabetes mellitus (DM) is a chronic metabolic disease, characterized by persistent hyperglycemia resulting from diminished insulin secretion or insulin resistance. The present study evaluated the ameliorative effects of Withaferin-A (WA) on DM-induced reproductive dysfunction in mice. For the same, mice were intraperitoneally injected with Streptozotocin (STZ), (40 mg/kg/day) for 5 consecutive days to induce DM. Mice were then treated with WA (8 mg/kg/day) in normal and diabetic conditions (STZ + WA). Next, blood glucose levels, oral glucose tolerance, intraperitoneal insulin tolerance, oxidative stress and reproductive parameters were estimated. For reproductive performance, immunofluorescent localization of gonadotropin-releasing hormone (GnRH-I) and estrogen receptor alpha (ERα) in the preoptic area and paraventricular nucleus region of hypothalamus and ERα in testes was performed. STZ-induced diabetes triggered reproductive dysfunctions as mediated by low GnRH-I and ERα in the brain and ERα in the testes along with declined testosterone and estradiol levels. Treatment with WA significantly reduced the blood glucose levels and enhanced glucose clearance accompanied by reduced oxidative stress in the brain, pancreas and testes as indicated by the low levels of H2O2 and MDA in diabetic mice treated with WA (STZ + WA). This study reports, for the first time, that WA can efficiently ameliorate DM-induced reproductive dysfunctions by enhancing endogenous testosterone, estrogen and increased GnRH-I and ERα in the brain and ERα in the testes of DM-induced male mice.

Withania somnifera inhibits photorefractoriness which triggers neuronal apoptosis in both pre-optic and paraventricular hypothalamic area of Coturnix coturnix japonica: involvement of oxidative stress induced p53 dependent Caspase-3 mediated low immunoreactivity of estrogen receptor alpha.

Light has a very important function in the regulation of the normal physiology including the neuroendocrine system, biological rhythms, cognitive behavior, etc. The variation in photoperiod acts as a stressor due to imbalance in endogenous hormones. Estrogen and its receptors ER alpha and beta play a vital role in the control of stress response in birds. The study investigates the estrogenic effects of a well-known medicinal plant Withania somnifera (WS), mediated by estrogen receptor alpha (ERα) in the hypothalamic pre-optic area (POA) and paraventricular nuclei (PVN). Further the study elucidates its anti-oxidants and anti-apoptotic activities in the brain of Japanese quail. To validate this hypothesis, mature male quails were exposed to long day length for 3 months and then transferred to intermediate day length to become photorefractory (PR) while controls were still continued under long daylength. Supplementation of WS root extract in PR quail increases plasma estrogen and lowers corticosterone. Further, in PR quail the variation in light downregulates immunoreactivity of ERα, oxidative stress and antioxidant enzyme activities i.e. superoxide dismutase and catalase in the brain. Neuronal apoptosis was observed in the POA and PVN of PR quail as indicated by the abundant expression of Caspase-3 and p53 which reduces after the administration of WS root extract. The neuronal population also found to decrease in PR although it increased in WS administered quails. Further, the study concluded that change in photoperiod from 3 months exposure of 16L: 8D to 13.5L: 10.5D directly activates neuronal apoptosis via expression of Caspase3 and p53 expression in the brain and increases neuronal and gonadal oxidative stress while WS root extract reverses them via enhanced estrogen and its receptor ERα expression in the hypothalamic pre-optic and PVN area of Japanese quail.

Tumor Niches: Perspectives for Targeted Therapies in Glioblastoma.

Significance: Glioblastoma (GBM), the most common and lethal primary brain tumor with a median survival rate of only 15 months and a 5-year survival rate of only 6.8%, remains largely incurable despite the intensive multimodal treatment of surgical resection and radiochemotherapy. Developing effective new therapies is an unmet need for patients with GBM. Recent Advances: Targeted therapies, such as antiangiogenesis therapy and immunotherapy, show great promise in treating GBM based upon increasing knowledge about brain tumor biology. Single-cell transcriptomics reveals the plasticity, heterogeneity, and dynamics of tumor cells during GBM development and progression. Critical Issues: While antiangiogenesis therapy and immunotherapy have been highly effective in some types of cancer, the disappointing results from clinical trials represent continued challenges in applying these treatments to GBM. Molecular and cellular heterogeneity of GBM is developed temporally and spatially, which profoundly contributes to therapeutic resistance and tumor recurrence. Future Directions: Deciphering mechanisms of tumor heterogeneity and mapping tumor niche trajectories and functions will provide a foundation for the development of more effective therapies for GBM patients. In this review, we discuss five different tumor niches and the intercellular and intracellular communications among these niches, including the perivascular, hypoxic, invasive, immunosuppressive, and glioma-stem cell niches. We also highlight the cellular and molecular biology of these niches and discuss potential strategies to target these tumor niches for GBM therapy. Antioxid. Redox Signal. 39, 904-922.

Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression.

Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.

DEIA is essential to advance the goals of translational science: Perspectives from NCATS.

The National Center for Advancing Translational Science (NCATS) seeks to improve upon the translational process to advance research and treatment across all diseases and conditions and bring these interventions to all who need them. Addressing the racial/ethnic health disparities and health inequities that persist in screening, diagnosis, treatment, and health outcomes (e.g., morbidity, mortality) is central to NCATS' mission to deliver more interventions to all people more quickly. Working toward this goal will require enhancing diversity, equity, inclusion, and accessibility (DEIA) in the translational workforce and in research conducted across the translational continuum, to support health equity. This paper discusses how aspects of DEIA are integral to the mission of translational science (TS). It describes recent NIH and NCATS efforts to advance DEIA in the TS workforce and in the research we support. Additionally, NCATS is developing approaches to apply a lens of DEIA in its activities and research - with relevance to the activities of the TS community - and will elucidate these approaches through related examples of NCATS-led, partnered, and supported activities, working toward the Center's goal of bringing more treatments to all people more quickly.

Development of a human glioblastoma model using humanized DRAG mice for immunotherapy.

Glioblastoma (GBM) is the most common and lethal primary brain tumor with high mortality rates and a short median survival rate of about 15 months despite intensive multimodal treatment of maximal surgical resection, radiotherapy, and chemotherapy. Although immunotherapies have been successful in the treatment of various cancers, disappointing results from clinical trials for GBM immunotherapy represent our incomplete understanding. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. In this study, we developed a humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model, in which the human hematopoietic stem cells (HSCs) were well-engrafted and subsequently differentiated into a full lineage of immune cells. Using this humanized DRAG mouse model, GBM patient-derived tumorsphere lines were successfully engrafted to form xenografted tumors, which can recapitulate the pathological features and the immune cell composition of human GBM. Importantly, the administration of anti-human PD-1 antibodies in these DRAG mice bearing a GBM patient-derived tumorsphere line resulted in decreasing the major tumor-infiltrating immunosuppressive cell populations, including CD4 + PD-1 + and CD8 + PD-1 + T cells, CD11b + CD14 + HLA-DR + macrophages, CD11b + CD14 + HLA-DR - CD15 - and CD11b + CD14 - CD15 + myeloid-derived suppressor cells, indicating the humanized DRAG mouse model as a useful model to test the efficacy of immune checkpoint inhibitors in GBM immunotherapy. Together, these results suggest that humanized DRAG mouse models are a reliable preclinical platform for brain cancer immunotherapy and beyond.

2.45 GHz microwave radiation induced oxidative stress: Role of inflammatory cytokines in regulating male fertility through estrogen receptor alpha in Gallus gallus domesticus.

Due to the growing number of gadgets emitting electromagnetic radiation (EMR), particularly microwave (MW) radiation, in our daily lives, it is believed that EMR have both long-term and short-term biological impacts that are quite concerning for avian as well as human health. Due to the negative impact of MW emitting equipment on the biological system this study looks into the mechanistic approach by which low-level of 2.45 GHz MW radiation causes an oxidative stress and inflammatory response in the testes micro-environment which further gets regulated by estrogen receptor alpha (ERα) expression in immature Gallus gallus domesticus leading to male infertility. Two weeks old immature male chickens were exposed to non-thermal low-level 2.45-GHz MW radiation for 2 h/day for 30 days (power density = 0.1264 mw/cm2 and SAR = 0.9978 W/kg). In the exposed group, morphometric examination of the testes revealed decreased testicular weight, volume and gonado-somatic index. Further, histological staining demonstrated a substantial reduction in the diameter of seminiferous tubules in the exposed group as compared to the control. The degree of oxidative stress was also determined showing an increase in oxidative stress parameters after exposure. The radiation exposed testes showed a significant increase in IL-1ß immunoreactivity and decline in IL-10 immunoreactivity, indicating a sense of MW radiation-induced oxidative stress-regulated inflammatory response. A substantial reduction in ERα expression was also observed in exposed testes by Western blotting. Our investigations conclude that testes being vulnerable to free radical damage become an easy target organ for MW exposure induced oxidative and inflammatory stress. Therefore it becomes evident that it may cause male infertility in chicks via downregulation of ER-α in testis.

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma.

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A-FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow-derived macrophages through activation of the FOSL2-ANXA1-FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. SIGNIFICANCE: GBM progression could be induced by hypoxia via the HIF1A-FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow-derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711.

Ethanol exposure of human pancreatic normal ductal epithelial cells induces EMT phenotype and enhances pancreatic cancer development in KC (Pdx1-Cre and LSL-KrasG12D ) mice.

Alcohol is a risk factor for pancreatic cancer. However, the molecular mechanism by which chronic alcohol consumption influences pancreatic cancer development is not well understood. We have recently demonstrated that chronic ethanol exposure of pancreatic normal ductal epithelial cells (HPNE) induces cellular transformation by generating cancer stem cells (CSCs). Here, we examined whether chronic ethanol treatment induces epithelial-mesenchymal transition in HPNE cells and promotes pancreatic cancer development in KC (Pdx1-Cre, and LSL-KrasG12D ) mice. Our data demonstrate that chronic ethanol exposure of HPNE cells induces SATB2 gene and those cells became highly motile. Ethanol treatment of HPNE cells results in downregulation of E-Cadherin and upregulation of N-Cadherin, Snail, Slug, Zeb1, Nanog and BMI-1. Suppression of SATB2 expression in ethanol-transformed HPNE cells inhibits EMT phenotypes. KC mice fed with an ethanol-containing diet show enhanced pancreatic cancer growth and development than those fed with a control diet. Pancreas isolated from KC mice fed with an ethanol-containing diet show higher expression of stem cell markers (CD133, CD44, CD24), pluripotency-maintaining factors (cMyc, KLF4, SOX-2, and Oct-4), N-Cadherin, EMT-transcription factors (Snail, Slug, and Zeb1), and lower expression of E-cadherin than those isolated from mice fed with a control diet. Furthermore, pancreas isolated from KC mice fed with an ethanol-containing diet show higher expression of inflammatory cytokines (TNF-α, IL-6, and IL-8) and PTGS-2 (COX-2) gene than those isolated from mice fed with a control diet. These data suggest that chronic alcohol consumption may contribute to pancreatic cancer development by generating inflammatory signals and CSCs.

Association of Diabetes Mellitus and Alcohol Abuse with Cancer: Molecular Mechanisms and Clinical Significance.

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.

Venous thromboembolism is linked to severity of disease in COVID-19 patients: A systematic literature review and exploratory meta-analysis.

PURPOSE: Coronavirus disease-2019 (COVID-19) may predispose to venous thromboembolism (VTE) and arterial thromboembolism because of excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. The understanding of the association might be helpful in early vigilant monitoring and better management of COVID-19 patients at high risk. Thus, in this meta-analysis, we aim to assess the association of VTE with the severity of COVID-19 disease. METHODS: A literature search was conducted on PubMed and Cochrane Central Register of Controlled Trials using the keywords "COVID-19 and thromboembolism" and "COVID-19 and embolism," till 20 February 2021. Thirteen studies including 6648 COVID-19 patients were incorporated in this systematic review and exploratory meta-analysis. RESULTS: The analysis revealed nearly three times more risk than intensive care unit (ICU) care in patients with VTE compared to non-VTE patients (RR: 2.78; 95% CI: 1.75-4.39; P < .001; I2 : 65.1%). Patients with pulmonary embolism and deep vein thrombosis are at increased risk of being admitted to ICU (RR: 2.21; 95% CI: 1.86-2.61; P < .001; I2 : 41.2%) and (RR: 2.69; 95% CI: 2.37-3.06; P < .001; I2 : 0.0%), respectively. The quality assessment indicated that the included studies were of fair quality. CONCLUSIONS: Our findings suggest that VTE either deep vein thrombosis or pulmonary embolism may have a negative effect on the health status of COVID-19 patients. This study highlights the need to consider measures for reducing thromboembolism risk amongst COVID-19 patients.

Stress and steroid interaction modulates expression of estrogen receptor alpha in the brain, pituitary, and testes of immature Gallus gallus domesticus.

In nature, food availability stimulates hypothalamo-pituitary-gonadal (HPG) axis while its scarcity induces stress, which further stimulates hypothalamo-pituitary-adrenal (HPA) axis producing a detrimental effect on the avian reproductive physiology. The present experiment was designed to examine the interaction of stress like food restriction and estradiol on male reproductive physiology with special emphasis on estrogen receptor alpha (ERα) as these play crucial role in reproduction. To achieve this, 60 day old White Leghorn immature cockrels were taken and divided into four groups (n = 8 per group). One group was provided with food and water ad libitum. Second group was food restricted (FR) for 9 h/day after 5 days, third and fourth were administered with estradiol benzoate (EB 0.5 mg/100g/day) for 12 days. Fourth group was FR for 9 h/day after 5 days of EB treatment till last day of experiment (EB + FR). Immunofluorescent localization of ERα was principally in the pre-optic area and paraventricular nuclei of hypothalamus and in anterior pituitary gland. ERα expression was highly reduced (from 40 AU to 20 AU) after FR in testis but it increased (50 AU) after EB administration, EB + FR reflects a diminishing pattern in the increment after EB. FR decreased plasma estradiol while EB increased it. Increased plasma corticosterone, hydrogen peroxide, malondialdehyde, and decreased anti-oxidant enzymes in brain and testis of all groups indicate oxidative stress in the HPG axis. The increased ERα after EB and a decrease with FR and EB + FR support their reproductive function. Estrogen and its receptor alpha are responsible for maintaining epithelial morphology but FR along with EB administration modulates the testicular development by significantly decreasing its size (p<.0001) and seminiferous tubules (p<.0001) and no sperm formation via highly reduced expression of ir-ERα in HPG axis. Our findings led us to conclude that stress like FR and estradiol induces testicular regression immature male chickens by modulating ir-ERα expression in the HPG axis thereby resulting in reduction in reproductive physiology.