Breast Cancer in Younger and Older Women: A Comparison of Clinicopathological Traits.

Breast cancer stands as the prevailing invasive cancer globally, bearing high mortality rates among women. Existing evidence indicates diminished survival rates in younger patients. Consequently, this study endeavors to assess and contrast the pathological features of breast cancer in women under 40 years of age with their older counterparts. Conducted as a cross-sectional analysis, this study encompasses 560 patients diagnosed with breast cancer, seeking treatment at Mymensingh Medical College Hospital (MMCH), Community Based Medical College Bangladesh (CBMCB) and several private hospitals in Mymensingh. The gathered data incorporates information such as age, residential area, occupation, tumor histopathology, TNM classification, staging and status of hormone receptor. The patients' mean age (standard deviation) was 49.7±11.9 years, with 20.5% below 40, most were from rural areas and were housewives. Ductal carcinoma prevailed as the most common histopathologic type (87.67%). However, younger patients exhibited a higher prevalence of lobular and other rare carcinomas compared to their older counterparts (p=0.04). Additionally, the younger group demonstrated larger tumor sizes (p=0.01), lymphatic node involvement (p=0.04) and advanced staging (p=0.004). Notably, younger age showed more negativity for estrogen and/or progesterone receptors. The results suggested that women under 40 years old exhibit more aggressive tumor characteristics and a more severe form of breast cancer compared to their older counterparts.

Early Outcome of On-pump Versus Off-pump Elective Surgical Revascularization in Patients with Prior ST-Segment Elevation Myocardial Infarction.

Coronary artery bypass graft surgery (CABG) is a proven treatment for coronary artery disease. History of a ST-elevation myocardial infarction (STEMI) is considered an independent risk factor for CABG irrespective of timing for an emergency or elective surgery. Patients with STEMI are candidates for both On-pump and Off-pump CABG procedures. This paper discusses the possible best option for elective surgical revascularization in patients with prior STEMI. This prospective clinical trial of 60 eligible patients with prior STEMI was conducted in a Tertiary Care Hospital from April 2018 to March 2019. Among them, 30 patients underwent off-pump (Group A) and 30 patients underwent on-pump (Group B) CABG procedures. Outcomes between both groups were observed from surgery to 1 month postoperatively. Data was analysed by the software statistical program for social science (SPSS 25.0 Inc). The surgery was successful in both groups of patients. Differences were observed by mean number of grafts per patient (2.77±0.43 vs. 3.10±0.71) and duration of operation (4.41±0.35 hours vs. 5.71±0.48 hours). An improvement in Left Ventricular Ejection Fraction (LVEF %) was observed in both groups postoperatively (17.98% vs. 10.98%) and the postoperative LVEF% at different time points were found statistically significant (p<0.05) over preoperative LVEF%. Multivariable stepwise logistic regression analysis correlated on-pump CABG with prolonged need for ionotropic support, need for blood transfusion, longer hospital stay and less improvement in LVEF%. The study supports the Off-pump CABG as a better surgical option over on-pump CABG in patients with prior STEMI.

Primary Tuberculosis of Cervix Which Simulated Endocervical Polyp: A Case Study.

Tuberculosis has been described as the second great "Imitator" as it can imitate various other disease processes. The manifestations of genitourinary tuberculosis are protean in nature; still tuberculosis is a health concern in South-East Asia region. Tuberculosis of the cervix is rarely found and accounts for 5-10% among all types of genital tuberculosis. Despite meticulous history and clinical examination does not always lead to suspect this disease, the definitive diagnosis is based on the demonstration of the characteristic lesion on histopathology or on bacterial isolation. We are reporting a case of a 26-years-old woman who presented with secondary amenorrhea and a benign looking endocervical polyp. Diagnosis of cervical tuberculosis could be clinched after tissue biopsy which revealed caseous granuloma on histopathological examination along with other supportive laboratory investigation reports. Patient was subsequently started on antitubercular therapy (ATT) according to directly observed treatment schedule- category I, resulting in resumption of her menses after four months of starting of ATT. An awareness of the atypical clinical manifestations of tuberculosis is important, especially in regions where tuberculosis continues to be a major public health problem, such as Bangladesh. One should have high index of suspicion in order to diagnose tuberculosis of cervix in such cases, especially in high prevalence areas, so that patients can be managed appropriately with antitubercular therapy and complications can be prevented.

The evaluation of rosemary (Rosmarinus officinalis) leaf extract inclusion in freezing medium on quality parameters of buffalo bull spermatozoa.

BACKGROUND: The discrepancy between the endogenous antioxidants concentrations and free radicals results in oxidative stress and cellular injury. OBJECTIVE: To appraise the usefulness of Rosemarinus officinalis (RO) aqueous extract in protecting buffalo spermatozoa during freezing / thawing process. MATERIALS AND METHODS: Qualifying ejaculates from four well-restrained bulls were evaluated initially and then diluted in a freezing medium supplemented with RO-0.0, RO-0.5 %, RO-1.0%, RO-2.0 %, and RO-4.0 %, cooled to 4 degree C in 2 h, equilibrated for 4 h at 4 degree C, packed in straws, and cryopreserved, and thawed at 37 degree C for 30 s followed by evaluation. RESULTS: We found that freezing medium supplemented with RO-2.0 % improves progressive motility (%) compared to the control. Similarly, a lower rate of apoptosis-like changes (%) was recorded with RO-4.0 % than the control, RO-0.5 % and RO-1.0 %. This response was accompanied by an increment in viable spermatozoa. Semen samples supplemented with RO-2.0 % and RO-4.0 % displayed higher TAC (total antioxidant capacity, uM per L) and ATP (nmol/million) content than the control. In addition, semen samples supplemented with RO-2.0 % displayed lower concentrations of ROS (reactive oxygen species, 104 RLU/20 min/25 million) than the control and RO-0.05 %. Also LPO (lipid peroxidation, uM per L) with RO-2.0 % and RO-4.0 % was lower than the control. CONCLUSION: The inclusion of rosemary aqueous extract ameliorates motility features, structural and functional parameters, viability, TAC and ATP content of bull sperm. Conversely, the inclusion of rosemary aqueous extract alleviates apoptosis-like changes, ROS and LPO in comparison to the control. Further studies are required to determine the mechanism of action of rosemary aqueous extract in ameliorating semen quality and fertility of buffalo spermatozoa. doi.org/10.54680/fr22210110712.

Ameliorative effects of morel mushroom (Morchella esculenta) against Cadmium-induced reproductive toxicity in adult male rats / Efeitos benéficos do cogumelo morel (Morchella esculenta) contra a toxicidade reprodutiva induzida por cádmio em ratos machos adultos

Cadmium (Cd) is one of the major toxicants, which affects human health through occupational and environmental exposure. In the current study, we evaluated the protective effects of morel mushrooms against Cd-induced reproductive damages in rats. For this purpose, 30 male rats were divided into 6 groups (n=5/group), the first group served as the control group, second group was treated with an intraperitoneal (i.p) injection of 1 mg/kg/day of Cd. Third and fourth groups were co-treated with 1 mg/kg/day of Cd (i.p) and 10 and 20 mg/kg/day of morel mushroom extract (orally) respectively. The final 2 groups received oral gavage of 10 and 20 mg/kg/day of morel mushroom extract alone. After treatment for 17 days, the animals were euthanized, and testes and epididymis were dissected out. One testis and epididymis of each animal were processed for histology, while the other testis and epididymis were used for daily sperm production (DSP) and comet assay. Our results showed that Cd and morel mushrooms have no effect on animal weight, but Cd significantly decreases the DSP count and damages the heritable DNA which is reversed in co-treatment groups. Similarly, the histopathological results of testes and epididymis show that morel mushrooms control the damage to these tissues. Whereas the morel mushroom extract alone could enhance the production of testosterone. These results conclude that morel mushrooms not only control the damage done by Cd, but it could also be used as a protection mechanism for heritable DNA damage.

O cádmio (Cd) é um dos principais tóxicos, que afeta a saúde humana por meio da exposição ocupacional e ambiental. No presente estudo, avaliamos os efeitos protetores dos cogumelos morel contra os danos reprodutivos induzidos pelo Cd em ratos. Para tanto, 30 ratos machos foram divididos em 6 grupos (n = 5 / grupo); o primeiro grupo serviu de controle, o segundo grupo foi tratado com injeção intraperitoneal (i.p) de 1 mg / kg / dia de Cd. O terceiro e o quarto grupos foram cotratados com 1 mg / kg / dia de Cd (i.p) e 10 e 20 mg / kg / dia de extrato de cogumelo morel (por via oral), respectivamente. Os dois grupos finais receberam gavagem oral de 10 e 20 mg / kg / dia de extrato de cogumelo morel sozinho. Após o tratamento por 17 dias, os animais foram sacrificados e os testículos e o epidídimo foram dissecados. Um testículo e epidídimo de cada animal foram processados para histologia, enquanto o outro testículo e epidídimo foram usados para produção diária de esperma (DSP) e ensaio cometa. Nossos resultados mostraram que os cogumelos Cd e morel não têm efeito sobre o peso do animal, mas o Cd diminui significativamente a contagem de DSP e danifica o DNA hereditário, que é revertido em grupos de cotratamento. Da mesma forma, os resultados histopatológicos dos testículos e do epidídimo mostram que os cogumelos morel controlam os danos a esses tecidos. Considerando que o extrato de cogumelo morel sozinho pode aumentar a produção de testosterona. Esses resultados concluem que os cogumelos morel não apenas controlam os danos causados pelo Cd, mas também podem ser usados como um mecanismo de proteção para danos hereditários ao DNA.

Ameliorative effects of morel mushroom (Morchella esculenta) against Cadmium-induced reproductive toxicity in adult male rats

Abstract Cadmium (Cd) is one of the major toxicants, which affects human health through occupational and environmental exposure. In the current study, we evaluated the protective effects of morel mushrooms against Cd-induced reproductive damages in rats. For this purpose, 30 male rats were divided into 6 groups (n=5/group), the first group served as the control group, second group was treated with an intraperitoneal (i.p) injection of 1 mg/kg/day of Cd. Third and fourth groups were co-treated with 1 mg/kg/day of Cd (i.p) and 10 and 20 mg/kg/day of morel mushroom extract (orally) respectively. The final 2 groups received oral gavage of 10 and 20 mg/kg/day of morel mushroom extract alone. After treatment for 17 days, the animals were euthanized, and testes and epididymis were dissected out. One testis and epididymis of each animal were processed for histology, while the other testis and epididymis were used for daily sperm production (DSP) and comet assay. Our results showed that Cd and morel mushrooms have no effect on animal weight, but Cd significantly decreases the DSP count and damages the heritable DNA which is reversed in co-treatment groups. Similarly, the histopathological results of testes and epididymis show that morel mushrooms control the damage to these tissues. Whereas the morel mushroom extract alone could enhance the production of testosterone. These results conclude that morel mushrooms not only control the damage done by Cd, but it could also be used as a protection mechanism for heritable DNA damage.

Resumo O cádmio (Cd) é um dos principais tóxicos, que afeta a saúde humana por meio da exposição ocupacional e ambiental. No presente estudo, avaliamos os efeitos protetores dos cogumelos morel contra os danos reprodutivos induzidos pelo Cd em ratos. Para tanto, 30 ratos machos foram divididos em 6 grupos (n = 5 / grupo); o primeiro grupo serviu de controle, o segundo grupo foi tratado com injeção intraperitoneal (i.p) de 1 mg / kg / dia de Cd. O terceiro e o quarto grupos foram cotratados com 1 mg / kg / dia de Cd (i.p) e 10 e 20 mg / kg / dia de extrato de cogumelo morel (por via oral), respectivamente. Os dois grupos finais receberam gavagem oral de 10 e 20 mg / kg / dia de extrato de cogumelo morel sozinho. Após o tratamento por 17 dias, os animais foram sacrificados e os testículos e o epidídimo foram dissecados. Um testículo e epidídimo de cada animal foram processados para histologia, enquanto o outro testículo e epidídimo foram usados para produção diária de esperma (DSP) e ensaio cometa. Nossos resultados mostraram que os cogumelos Cd e morel não têm efeito sobre o peso do animal, mas o Cd diminui significativamente a contagem de DSP e danifica o DNA hereditário, que é revertido em grupos de cotratamento. Da mesma forma, os resultados histopatológicos dos testículos e do epidídimo mostram que os cogumelos morel controlam os danos a esses tecidos. Considerando que o extrato de cogumelo morel sozinho pode aumentar a produção de testosterona. Esses resultados concluem que os cogumelos morel não apenas controlam os danos causados pelo Cd, mas também podem ser usados como um mecanismo de proteção para danos hereditários ao DNA.

Ameliorative effects of morel mushroom (Morchella esculenta) against Cadmium-induced reproductive toxicity in adult male rats / Efeitos benéficos do cogumelo morel (Morchella esculenta) contra a toxicidade reprodutiva induzida por cádmio em ratos machos adultos

Cadmium (Cd) is one of the major toxicants, which affects human health through occupational and environmental exposure. In the current study, we evaluated the protective effects of morel mushrooms against Cd-induced reproductive damages in rats. For this purpose, 30 male rats were divided into 6 groups (n=5/group), the first group served as the control group, second group was treated with an intraperitoneal (i.p) injection of 1 mg/kg/day of Cd. Third and fourth groups were co-treated with 1 mg/kg/day of Cd (i.p) and 10 and 20 mg/kg/day of morel mushroom extract (orally) respectively. The final 2 groups received oral gavage of 10 and 20 mg/kg/day of morel mushroom extract alone. After treatment for 17 days, the animals were euthanized, and testes and epididymis were dissected out. One testis and epididymis of each animal were processed for histology, while the other testis and epididymis were used for daily sperm production (DSP) and comet assay. Our results showed that Cd and morel mushrooms have no effect on animal weight, but Cd significantly decreases the DSP count and damages the heritable DNA which is reversed in co-treatment groups. Similarly, the histopathological results of tests and epididymis show that morel mushrooms control the damage to these tissues. Whereas the morel mushroom extract alone could enhance the production of testosterone. These results conclude that morel mushrooms not only control the damage done by Cd, but it could also be used as a protection mechanism for heritable DNA damage.

O cádmio (Cd) é um dos principais tóxicos, que afeta a saúde humana por meio da exposição ocupacional e ambiental. No presente estudo, avaliamos os efeitos protetores dos cogumelos morel contra os danos reprodutivos induzidos pelo Cd em ratos. Para tanto, 30 ratos machos foram divididos em 6 grupos (n = 5 / grupo); o primeiro grupo serviu de controle, o segundo grupo foi tratado com injeção intraperitoneal (i.p) de 1 mg / kg / dia de Cd. O terceiro e o quarto grupos foram cotratados com 1 mg / kg / dia de Cd (i.p) e 10 e 20 mg / kg / dia de extrato de cogumelo morel (por via oral), respectivamente. Os dois grupos finais receberam gavagem oral de 10 e 20 mg / kg / dia de extrato de cogumelo morel sozinho. Após o tratamento por 17 dias, os animais foram sacrificados e os testículos e o epidídimo foram dissecados. Um testículo e epidídimo de cada animal foram processados para histologia, enquanto o outro testículo e epidídimo foram usados para produção diária de esperma (DSP) e ensaio cometa. Nossos resultados mostraram que os cogumelos Cd e morel não têm efeito sobre o peso do animal, mas o Cd diminui significativamente a contagem de DSP e danifica o DNA hereditário, que é revertido em grupos de cotratamento. Da mesma forma, os resultados histopatológicos dos testículos e do epidídimo mostram que os cogumelos morel controlam os danos a esses tecidos. Considerando que o extrato de cogumelo morel sozinho pode aumentar a produção de testosterona. Esses resultados concluem que os cogumelos morel não apenas controlam os danos causados pelo Cd, mas também podem ser usados como um mecanismo de proteção para danos hereditários ao DNA.

Ameliorative effects of morel mushroom (Morchella esculenta) against Cadmium-induced reproductive toxicity in adult male rats.

Cadmium (Cd) is one of the major toxicants, which affects human health through occupational and environmental exposure. In the current study, we evaluated the protective effects of morel mushrooms against Cd-induced reproductive damages in rats. For this purpose, 30 male rats were divided into 6 groups (n=5/group), the first group served as the control group, second group was treated with an intraperitoneal (i.p) injection of 1 mg/kg/day of Cd. Third and fourth groups were co-treated with 1 mg/kg/day of Cd (i.p) and 10 and 20 mg/kg/day of morel mushroom extract (orally) respectively. The final 2 groups received oral gavage of 10 and 20 mg/kg/day of morel mushroom extract alone. After treatment for 17 days, the animals were euthanized, and testes and epididymis were dissected out. One testis and epididymis of each animal were processed for histology, while the other testis and epididymis were used for daily sperm production (DSP) and comet assay. Our results showed that Cd and morel mushrooms have no effect on animal weight, but Cd significantly decreases the DSP count and damages the heritable DNA which is reversed in co-treatment groups. Similarly, the histopathological results of testes and epididymis show that morel mushrooms control the damage to these tissues. Whereas the morel mushroom extract alone could enhance the production of testosterone. These results conclude that morel mushrooms not only control the damage done by Cd, but it could also be used as a protection mechanism for heritable DNA damage.

Results of Laparoscopic Cholecystectomy in Acute Cholecystitis in Diabetic Patients: A Study with 50 Cases.

Acute cholecystitis (AC) is a common surgical condition requiring emergency hospitalization. Diabetic patient with gall stones disease is more prone to develop acute cholecystitis and its complications e.g. mucocele, empyema, gangrene and perforation. Early laparoscopic cholecystectomy (ELC) has proved to be an effective and safe day case surgical procedure for AC and their complications. This cross sectional study of diabetic patients admitted with acute cholecystitis, at the Department of Surgery of Bangladesh Institute of Researcher of Rehabilitation in Diabetes, Endocrine and Metabolic Disorder (BIRDEM) General Hospital, Dhaka, Bangladesh from March 2016 to January 2017. A total number of 50 patients of known diabetes of acute cholecystitis were recruited irrespective of their age and sex and by excluding pregnant woman, obstructed jaundice and severe cardiopulmonary disease. More than half (52.0%) of the cholecystitis patients belonged to 31-40 years with mean age was 52.5±12.1 years. Females were predominant in this study (68.0%) with male: female ratio was 1:2.1. All (100%) patents had pain in right hypochondrium but relatively lower than non-diabetic patient due to diabetic neuropathy followed by majority 74.0% had nausea/vomiting, 70.0% had history of flatulence and dyspepsia, 62.0% had Murphy's sign positive. Thirty (60.0%) patients had glycaemic control and 20(40.0%) had uncontrolled DM. Insulin received patients were 35(70.0%) and 15 took oral hypoglycemic drug. Regarding postoperative complication, 8.0% had severe vomiting, right hypochondriac pain, 4.0% had wound sepsis and 2.0% had decreased pulmonary function and mild chest infection. In this study among laparoscopic finding during operation age and sex were not statistically significant. There was no mortality; laparoscopic cholecystectomy is the safe, accepted and preferred method of treatment for acute cholecystitis.

Human forebrain endothelial cell therapy for psychiatric disorders.

Abnormalities of or reductions in GABAergic interneurons are implicated in the pathology of severe neuropsychiatric disorders, for which effective treatments are still elusive. Transplantation of human stem cell-derived interneurons is a promising cell-based therapy for treatment of these disorders. In mouse xenograft studies, human stem cell-derived-interneuron precursors could differentiate in vivo, but required a prolonged time of four to seven months to migrate from the graft site and integrate with the host tissue. This poses a serious roadblock for clinical translation of this approach. For transplantation to be effective, grafted neurons should migrate to affected areas at a faster rate. We have previously shown that endothelial cells of the periventricular vascular network are the natural substrates for GABAergic interneurons in the developing mouse forebrain, and provide valuable guidance cues for their long-distance migration. In addition, periventricular endothelial cells house a GABA signaling pathway with direct implications for psychiatric disease origin. In this study we translated this discovery into human, with significant therapeutic implications. We generated human periventricular endothelial cells, using human pluripotent stem cell technology, and extensively characterized its molecular, cellular, and functional properties. Co-culture of human periventricular endothelial cells with human interneurons significantly accelerated interneuron migration in vitro and led to faster migration and wider distribution of grafted interneurons in vivo, compared to neuron-only transplants. Furthermore, the co-transplantation strategy was able to rescue abnormal behavioral symptoms in a pre-clinical model of psychiatric disorder, within 1 month after transplantation. We anticipate this strategy to open new doors and facilitate exciting advances in angiogenesis-mediated treatment of psychiatric disorders.

Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.

Effects of endocrine disruptor furan on reproductive physiology of Sprague Dawley rats: An F1 Extended One-Generation Reproductive Toxicity Study (EOGRTS).

The present study investigated the reproductive toxicity of furan in an Extended One-Generation Reproductive Toxicity Study in rats. Sprague Dawley F0 weaning rats (30 per sex per group) were exposed to furan orally at 0, 1, 2.5, 5, and 10 mg kg-1 for 10 weeks (males) and 2 weeks (females) and then mated. Results of F0 indicated that in the furan-treated groups (5 mg kg-1 and 10 mg kg-1), body weight (bw) gain decreased during prebreed and gestational period while increased during lactation periods. F0 animals prebreeding exposure resulted in head tilt and foot splay at 10 mg kg-1. Number of live pups at birth were decreased (p < 0.001) at 10 mg kg-1. At postnatal day (PND) 70, a significant (p = 0.03) decrease in testosterone levels of male rats and estrogen levels of female rats (p = 0.05) was observed in 10 mg kg-1 furan-treated group in F1 generation. Luteinizing hormone, follicle-stimulating hormone, and progesterone levels were also reduced, but their reduction was not statistically significant in all groups. In higher dose furan group (10 mg kg-1), testicular and ovarian weights were reduced in F1 generation at PND 70, with decreased daily sperm production (p = 0.01) and disturbed estrous cyclicity (p < 0.01). Some histopathological changes were also observed in testis and ovaries in groups whose parents were previously exposed to 10 mg kg-1 bw of furan group. Based on the above results, it is suggested that exposure to food-based contaminant furan induced remarkable changes in the F0 (parental stage) and F1 (offspring, pubertal, and adult stage) generations of Sprague Dawley rats.

Detection of Retinopathy of Prematurity (ROP) in very Low Birth Weight Babies and Outcome of Management.

The purpose of the present study was to early detection and management of retinopathy of prematurity (ROP). This observational descriptive/ interventional study was carried out to evaluate 96 babies brought by their parents to BIRDEM General Hospital during the period of January 2016 to June 2016 who fulfilled the inclusion and exclusion criteria. Screening of ROP was performed in all 96 babies after taking informed written consent. After screening of ROP, the babies who had ROP, staging was done and treatment was given as per requirement. Descriptive data in the study were shown by cross table and compared by student paired 't' test and Chi-square test. The study included total 96 babies of preterm low birth weight. Among them 64(66.66%) babies had no ROP, where 32(33.33%) babies had different stages of ROP. In these 32 babies, 18 babies didn't need any treatment, only 14 babies needed treatment according to their requirement (14 babies had 28 eyes, where 16 eyes needed Inj. Anti VEGF and laser and 11 eyes needed only laser and one eye had Stage V ROP, so observed that eye). Early detection of ROP and proper management not only restore the anatomical and functional outcome of the retina, but also restore the vision, prevent childhood blindness and decrease morbidity.

Resveratrol Prevents the Cellular Damages Induced by Monocrotophos via PI3K Signaling Pathway in Human Cord Blood Mesenchymal Stem Cells.

The role of resveratrol (RV) as a neuroprotectant is well recognized, and cellular molecules involved in imparting the physiological effect have been well illustrated. However, some ambiguity still prevails as the specific receptor, and downstream signaling molecules are not yet clearly stated. So, we investigated the signaling pathway(s) involved in its cellular protection in the human umbilical cord blood mesenchymal stem cell (hUCB-MSC) derived neuronal cells. The mesenchymal stem cells were exposed to various concentrations (10, 100, 1000 µM) of monocrotophos (MCP), a known developmental neurotoxic organophosphate pesticide, for a period of 24 h. The MAPK signaling pathways (JNK, p38, and ERK) known to be associated with MCP-induced damages were also taken into consideration to identify the potential connection. The biological safe dose of RV (10 µM) shows a significant restoration in the MCP-induced alterations. Under the specific growth conditions, RV exposure was found to promote neuronal differentiation in the hUCB-MSCs. The exposure of cells to a specific pharmacological inhibitor (LY294002) of PI3K confirms the significant involvement of PI3K-mediated pathway in the ameliorative responses of RV against MCP exposure. Our data identifies the substantial role of RV in the restoration of MCP-induced cellular damages, thus proving to have a therapeutic potential against organophosphate pesticide-induced neurodegeneration.

PKA-GSK3ß and ß-Catenin Signaling Play a Critical Role in Trans-Resveratrol Mediated Neuronal Differentiation in Human Cord Blood Stem Cells.

The role of resveratrol (RV), a natural polyphenol, is well documented, although its role on neurogenesis is still controversial and poorly understood. Therefore, to decipher the cellular insights of RV on neurogenesis, we investigated the potential effects of the compound on the survival, proliferation, and neuronal differentiation of human cord blood-derived mesenchymal stem cells (hCBMSCs). For neuronal differentiation, purified and characterized hCBMSCs were exposed to biological safe doses of RV (10 µM) alone and in combination with nerve growth factor (NGF-50 ng). The cells exposed only to NGF (50 ng/mL) served as positive control for neuronal differentiation. The genes showing significant involvement in the process of neuronal differentiation were further funneled down at transcriptional and translational level. It was observed that RV promotes PKA-mediated neuronal differentiation in hCBMSCs by inducing canonical pathway. The studies with pharmacological inhibitors also confirmed that PKA significantly induces ß-catenin expression via GSK3ß induction and stimulates CREB phosphorylation and pERK1/2 induction. Besides that, the studies also revealed that RV additionally possesses the binding sites for molecules other than PKA and GSK3ß, with which it interacts. The present study therefore highlights the positive impact of RV over the survival, proliferation, and neuronal differentiation in hCBMSCs via PKA-mediated induction of GSK3ß, ß catenin, CREB, and ERK1/2.

SLC45A2: A Melanoma Antigen with High Tumor Selectivity and Reduced Potential for Autoimmune Toxicity.

Cytotoxic T lymphocyte (CTL)-based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopeptidomes of 55 melanoma patient-derived cell lines, we identified a number of shared HLA class I-bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402-restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity. Cancer Immunol Res; 5(8); 618-29. ©2017 AACR.

Adoptive Autophagy Activation: a Much-Needed Remedy Against Chemical Induced Neurotoxicity/Developmental Neurotoxicity.

The profound significance of autophagy as a cell survival mechanism under conditions of metabolic stress is a well-proven fact. Nearly a decade-long research in this area has led scientists to unearth various roles played by autophagy other than just being an auto cell death mechanism. It is implicated as a vital cell survival pathway for clearance of all the aberrant cellular materials in case of cellular injury, metastasis, disease states, cellular stress, neurodegeneration and so on. In this review, we emphasise the critical role of autophagy in the environmental stressors-induced neurotoxicity and its therapeutic implications for the same. We also attempt to shed some light on the possible protective role of autophagy in developmental neurotoxicity (DNT) which is a rapidly growing health issue of the human population at large and hence a point of rising concern amongst researchers. The intimate association between DNT and neurodegenerative disorders strongly indicates towards adopting autophagy activation as a much-needed remedy for DNT.

Obestatin modulates ghrelin's effects on the basal and stimulated testosterone secretion by the testis of rat: an in vitro study.

The functional antagonism between obestatin and ghrelin in the testis is under investigation. We investigated the ability of obestatin to counteract the inhibitory effect of ghrelin on basal and stimulated testosterone (T) secretion in vitro. Testicular strips from adult rats were incubated with 10 ng/ml and 100 ng/ml of obestatin alone, ghrelin alone and obestatin + ghrelin. Obestatin modulation of stimulated T secretion was evaluated by incubation of testicular samples with 10 ng/ml and 100 ng/ml obestatin, ghrelin and obestatin + ghrelin in the absence and presence of 10 IU of human chorionic gonadotrophin (hCG). T concentrations in the hCG treated groups were significantly (P<0.0001) higher than those in the control groups. Obestatin caused a significant increase in basal T secretion in a dose-dependent manner; however, obestatin at the both 10 ng/ml and 100 ng/ml significantly (P<0.0001) increased hCG-stimulated T secretion. In contrast, ghrelin in a dose-dependent manner significantly (P<0.001) decreased both basal and hCG-induced T secretion by testicular slices. Obestatin opposed the inhibitory effect of ghrelin on T secretion under both basal and hCG-stimulated conditions at all doses tested. In conclusions, administration of obestatin was able to antagonize the inhibitory effect of ghrelin on testosterone secretion in vitro.

BRAFV600E Co-opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8+ T-cell Recognition of Melanoma.

Oncogene activation in tumor cells induces broad and complex cellular changes that contribute significantly to disease initiation and progression. In melanoma, oncogenic BRAF(V600E) has been shown to drive the transcription of a specific gene signature that can promote multiple mechanisms of immune suppression within the tumor microenvironment. We show here that BRAF(V600E) also induces rapid internalization of MHC class I (MHC-I) from the melanoma cell surface and its intracellular sequestration within endolysosomal compartments. Importantly, MAPK inhibitor treatment quickly restored MHC-I surface expression in tumor cells, thereby enhancing melanoma antigen-specific T-cell recognition and effector function. MAPK pathway-driven relocalization of HLA-A*0201 required a highly conserved cytoplasmic serine phosphorylation site previously implicated in rapid MHC-I internalization and recycling by activated immune cells. Collectively, these data suggest that oncogenic activation of BRAF allows tumor cells to co-opt an evolutionarily conserved MHC-I trafficking pathway as a strategy to facilitate immune evasion. This link between MAPK pathway activation and the MHC-I cytoplasmic tail has direct implications for immunologic recognition of tumor cells and provides further evidence to support testing therapeutic strategies combining MAPK pathway inhibition with immunotherapies in the clinical setting.

Lead Intoxication Synergies of the Ethanol-Induced Toxic Responses in Neuronal Cells--PC12.

Lead (Pb)-induced neurodegeneration and its link with widespread neurobehavioral changes are well documented. Experimental evidences suggest that ethanol could enhance the absorption of metals in the body, and alcohol consumption may increase the susceptibility to metal intoxication in the brain. However, the underlying mechanism of ethanol action in affecting metal toxicity in brain cells is poorly understood. Thus, an attempt was made to investigate the modulatory effect of ethanol on Pb intoxication in PC12 cells, a rat pheochromocytoma. Cells were co-exposed to biological safe doses of Pb (10 µM) and ethanol (200 mM), and data were compared to the response of cells which received independent exposure to these chemicals at similar doses. Ethanol (200 mM) exposure significantly aggravated the Pb-induced alterations in the end points associated with oxidative stress and apoptosis. The finding confirms the involvement of reactive oxygen species (ROS)-mediated oxidative stress, and impairment of mitochondrial membrane potential, which subsequently facilitate the translocation of triggering proteins between cytoplasm and mitochondria. We further confirmed the apoptotic changes due to induction of mitochondria-mediated caspase cascade. These cellular changes were found to recover significantly, if the cells are exposed to N-acetyl cysteine (NAC), a known antioxidant. Our data suggest that ethanol may potentiate Pb-induced cellular damage in brain cells, but such damaging effects could be recovered by inhibition of ROS generation. These results open up further possibilities for the design of new therapeutics based on antioxidants to prevent neurodegeneration and associated health problems.