Targeting the dynamic transcriptional landscape of Treg subpopulations in pancreatic ductal adenocarcinoma: Insights from single-cell RNA sequencing analysis with a focus on CTLA4 and TIGIT.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that represents a significant challenge in cancer research and clinical management. In this study, we reanalyzed a published single-cell RNA sequencing (scRNA-seq) dataset from PDAC and adjacent tissues to investigate the heterogeneity of tumor and normal tissue, specifically focusing on the regulatory T cells (Tregs) and their interactions with other cells in the tumor microenvironment (TME). Treg cells were identified and clustered into natural Tregs (nTreg) and induced Tregs (iTreg) based on the expression of specific genes. It was found that the number of iTregs was higher in the tumor than in healthy tissues, while the number of n Tregs was higher in healthy tissues. Differential gene expression analysis was performed, and biological process analysis revealed that the Tregs in PDAC were mostly involved in protein targeting and translation pathways. In addition, ligand-receptor pairs between Tregs and other cell types were identified, and the critical communication pathways between Tregs and endothelial and ductal cells were revealed, which could potentially contribute to the immunosuppressive TME of PDAC. These findings provide insights into the role of Tregs in PDAC and their interactions with other cell types in the TME, highlighting potential targets for immunotherapy, such as the inhibitory immune checkpoint receptors CTLA4 and TIGIT, which are known to be expressed on Tregs and have been shown to play a role in suppressing anti-tumor immune responses.

Curcumin as a natural potential drug candidate against important zoonotic viruses and prions: A narrative review.

Zoonotic diseases are major public health concerns and undeniable threats to human health. Among Zoonotic diseases, zoonotic viruses and prions are much more difficult to eradicate, as they result in higher infections and mortality rates. Several investigations have shown curcumin, the active ingredient of turmeric, to have wide spectrum properties such as anti-microbial, anti-vascular, anti-inflammatory, anti-tumor, anti-neoplastic, anti-oxidant, and immune system modulator properties. In the present study, we performed a comprehensive review of existing in silico, in vitro, and in vivo evidence on the antiviral (54 important zoonotic viruses) and anti-prion properties of curcumin and curcuminoids in PubMed, Google Scholar, Science Direct, Scopus, and Web of Science databases. Database searches yielded 13,380 results, out of which 216 studies were eligible according to inclusion criteria. Of 216 studies, 135 (62.5%), 24 (11.1%), and 19 (8.8%) were conducted on the effect of curcumin and curcuminoids against SARS-CoV-2, Influenza A virus, and dengue virus, respectively. This review suggests curcumin and curcuminoids as promising therapeutic agents against a wide range of viral zoonoses by targeting different proteins and signaling pathways.

Deciphering the immune landscape of head and neck squamous cell carcinoma: A single-cell transcriptomic analysis of regulatory T cell responses to PD-1 blockade therapy.

Immunotherapy is changing the Head and Neck Squamous Cell Carcinoma (HNSCC) landscape and improving outcomes for patients with recurrent or metastatic HNSCC. A deeper understanding of the tumor microenvironment (TME) is required in light of the limitations of patients' responses to immunotherapy. Here, we aimed to examine how Nivolumab affects infiltrating Tregs in the HNSCC TME. We used single-cell RNA sequencing data from eight tissues isolated from four HNSCC donors before and after Nivolumab treatment. Interestingly, the study found that Treg counts and suppressive activity increased following Nivolumab therapy. We also discovered that changes in the CD44-SSP1 axis, NKG2C/D-HLA-E axis, and KRAS signaling may have contributed to the increase in Treg numbers. Furthermore, our study suggests that decreasing the activity of the KRAS and Notch signaling pathways, and increasing FOXP3, CTLA-4, LAG-3, and GZMA expression, may be mechanisms that enhance the killing and suppressive capacity of Tregs. Additionally, the result of pseudo-temporal analysis of the HNSCC TME indicated that after Nivolumab therapy, the expression of certain inhibitory immune checkpoints including TIGIT, ENTPD1, and CD276 and LY9, were decreased in Tregs, while LAG-3 showed an increased expression level. The study also found that Tregs had a dense communication network with cluster two, and that certain ligand-receptor pairs, including SPP1/CD44, HLA-E/KLRC2, HLA-E/KLRK1, ANXA1/FPR3, and CXCL9/FCGR2A, had notable changes after the therapy. These changes in gene expression and cell interactions may have implications for the role of Tregs in the TME and in response to Nivolumab therapy.

Early clinical exposure as a highly interesting educational program for undergraduate medical students: an interventional study.

BACKGROUND: Training professional medical experts is so much dependent on the efficacy of the medical curriculum. Bearing this in mind, we aimed to evaluate the attitude of the undergraduate medical students toward the Early clinical exposure (ECE) program as a facilitator transition to the clinical phase. METHODS: This quasi-experimental study was conducted on undergraduate medical students at the Mashhad University of Medical Sciences, Mashhad, Iran who were transferring from the pre-clinical course to the externship course from 2021 to 2022 by census method (i.e. all eligible students were included and no sampling was performed). An eight-session ECE intervention was performed on the participants by two professors of the Internal medicine department of Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. The participants' attitude toward the program and the program quality was assessed with the valid and reliable scale developed by Mirzazadeh et al. (Cronbach's alpha = 0.72). Statistical analyses were performed by SPSS software (version.16) with a statistically significant level of less than 0.05. RESULTS: A total of 118 undergraduate medical students were enrolled in the study. Our results revealed that this program could familiarize (n = 95,81.2%)the students with the role of basic sciences knowledge in clinical settings, and 104(88.9%) participants believed that this intervention could motivate them toward learning more. The data revealed that this program was highly interesting for international students. There was a significant differentiation between Iranian and international students in familiarity with doctoring skills in medicine(P < 0.001), familiarity with the roles and responsibilities of clinical students(P < 0.001), and utility of early clinical exposure and providing more experiences(P < 0.001). According to the students' reports, the major strengths of the program were familiarizing themselves with the clinical fields, having excellent instructors, and performing admirable training. On the other hand, the major weakness of the program was the short duration and the high population of participants in each group. CONCLUSIONS: The ECE program had a positive impact on the students' satisfaction with medical education, and it also enhanced their understanding of the role they will play as future physicians. Therefore, we recommend that this program be implemented as a part of the medical education curriculum in medical universities.

Probiotics for glycemic and lipid profile control of the pre-diabetic patients: a randomized, double-blinded, placebo-controlled clinical trial study.

BACKGROUND: Pre-diabetes is a condition in which blood glucose levels are high but not as high as in diabetic patients. However, it can lead to diabetes, making it a serious global health issue. Previous studies have shown that the gut microbiome can affect insulin sensitivity and improve glucose management, which can reduce or delay the progression of pre-diabetes to type 2 diabetes mellitus. This study was designed to investigate the effects of probiotics on glycemic and lipid profile control in pre-diabetic patients. METHODS: This randomized, double-blinded clinical trial was conducted on 70 pre-diabetic patients at the Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. Participants were divided into two groups, both of which received lifestyle modification training. One of the groups also received 500 mg/day probiotic capsules for three months, while the other group received a placebo. Before and after the three-month period, systolic and diastolic blood pressure, serum insulin level, hemoglobin A1c (HbA1c), fasting blood sugar (FBS), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were measured and compared using statistical tests to examine the effect of probiotics. RESULTS: A total of 70 individuals participated in the trial, including 50 women (71.4%) and 20 men (28.6%), with an average age of 43.53 ± 8.54 years. At the end of the trial, the mean weight (P < 0.001), FBS (P < 0.001), HbA1c (P = 0.035), TG (P = 0.004), and LDL (P = 0.016) were significantly reduced in the intervention group, while their insulin level (P = 0.041) and HDL (P = 0.001) were significantly increased. However, mean systolic (P = 0.459) and diastolic blood pressure (P = 0.961) and insulin resistance (P = 0.235) did not show any significant difference in the intervention group from the beginning of the study. CONCLUSION: Our study showed that probiotic administration is effective in improving the glucose and lipid profile of pre-diabetic patients. However, it was not significantly different from the placebo.