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Gene Jun 2024Pancreatic adenocarcinoma (PAAD) is a life-threatening cancer. Exploring new diagnosis and treatment targets helps improve its prognosis. tRNA-derived small non-coding...
Pancreatic adenocarcinoma (PAAD) is a life-threatening cancer. Exploring new diagnosis and treatment targets helps improve its prognosis. tRNA-derived small non-coding RNAs (tsRNAs) are a novel type of gene expression regulators and their dysregulation is closely related to many human cancers. Yet the expression and functions of tsRNAs in PAAD are not well understood. Our study used RNA sequencing to identify tsRNA expression profiles in PAAD cells cultured in no or high glucose media and found tRF-18-8R6546D2 was an uncharacterized tsRNA, which has significantly high expression in PAAD cells and tissues. Clinically, tRF-18-8R6546D2 is linked to poor prognosis in PAAD patients and can be used to distinguish them from healthy populations. Functionally, in vitro and vivo, tRF-18-8R6546D2 over-expression promoted PAAD cell proliferation, migration and invasion, inhibited apoptosis, whereas tRF-18-8R6546D2 knock-down showed opposite effects. Mechanistically, tRF-18-8R6546D2 promoted PAAD malignancy partly by directly silencing ASCL2 and further regulating its downstream genes such as MYC and CASP3. These findings show that tRF-18-8R6546D2 is a novel oncogenic factor and can be a promising diagnostic or prognostic biomarker and therapeutic target for PAAD.
PubMed: 38955307
DOI: 10.1016/j.gene.2024.148739 -
Open Biology Jul 2024mosquitoes have an exclusively phytophagous feeding habit as adults, which leads to significant differences in their morphophysiology compared with haematophagous...
mosquitoes have an exclusively phytophagous feeding habit as adults, which leads to significant differences in their morphophysiology compared with haematophagous mosquitoes. However, the molecular mechanisms of digestion in this mosquito are not well understood. In this study, RNA sequencing of the posterior midgut (PMG) of the mosquito was undertaken, highlighting its significance in mosquito digestion. Subsequently, a comparison was made between the differential gene expression of the PMG and that of the anterior midgut. It was found that the most abundant proteases in the PMG were trypsin and chymotrypsin, and the level of gene expression for enzymes essential for digestion (such as serine protease, α-amylase and pancreatic triacylglycerol lipase) and innate immune response (including catalase, cecropin-A2 and superoxide dismutase) was like that of haematophagous mosquitoes. Peritrophin-1 was detected in the entire midgut, with an elevated expression level in the PMG. Based on our findings, it is hypothesized that a non-haematophagic habit might have been exhibited by the ancestor of , and this trait may have been retained. This study represents a pioneering investigation at the molecular level of midgut contents in a non-haematophagous mosquito. The findings offer valuable insights into the evolutionary aspects of feeding habits in culicids.
Topics: Animals; Culicidae; Insect Proteins; Transcriptome; Gene Expression Profiling; Digestive System; Digestion; Gastrointestinal Tract; Phylogeny; Feeding Behavior
PubMed: 38955221
DOI: 10.1098/rsob.230437 -
European Journal of Surgical Oncology :... Jun 2024The concept of textbook outcomes (TOs) has gained increased attention as a critical metric to assess the quality and success of outcomes following complex surgery. A...
BACKGROUND AND AIMS
The concept of textbook outcomes (TOs) has gained increased attention as a critical metric to assess the quality and success of outcomes following complex surgery. A simple yet effective scoring system was developed and validated to predict risk of not achieving textbook outcomes (non-TOs) following hepatectomy for hepatocellular carcinoma (HCC).
METHODS
Using a multicenter prospectively collected database, risk factors associated with non-TO among patients who underwent hepatectomy for HCC were identified. A predictive scoring system based on factors identified from multivariate regression analysis was used to risk stratify patients relative to non-TO. The score was developed using 70 % of the overall cohort and validated in the remaining 30 %.
RESULTS
Among 3681 patients, 1458 (39.6 %) failied to experience a TO. Based on the derivation cohort, obesity, American Society of Anaesthesiologists score(ASA score), Child-Pugh grade, tumor size, and extent of hepatectomy were identified as independent predictors of non-TO. The scoring system ranged from 0 to 10 points. Patients were categorized into low (0-3 points), intermediate (4-6 points), and high risk (7-10 points) of non-TO. In the validation cohort, the predicted risk of developing non-TOs was 39.0 %, which closely matched the observed risk of 39.9 %. There were no differences among the predicted and observed risks within the different risk categories.
CONCLUSIONS
A novel scoring system was able to predict risk of non-TO accurately following hepatectomy for HCC. The score may enable early identification of individuals at risk of adverse outcomes and inform surgical decision-making, and quality improvement initiatives.
PubMed: 38954879
DOI: 10.1016/j.ejso.2024.108477 -
Chemistry & Biodiversity Jul 2024α-Amylase inhibition is vital in controlling diabetic complications. Herein, we have synthesized a hybrid scaffold based on thiazole-chalcone to access α-amylase...
α-Amylase inhibition is vital in controlling diabetic complications. Herein, we have synthesized a hybrid scaffold based on thiazole-chalcone to access α-amylase inhbition. The proposed structures were verified with spectroscopic techniques (UV-vis, FT-IR, 1H-, 13C-NMR, and elemental analysis). The synthesized compounds were evaluated for their α-amylase and antioxidant potential. In vitro hemolytic assay was performed to test biocompatibility of all compounds. Among tested compounds, 4c (IC50= 3.8 µM), 4g (IC50= 14.5 µM), and 4f (IC50= 17.1 µM) were found excellent α-amylase inhibitors. However, none of the tested compounds exhibited significant antioxidant activity. All compounds showed less lysis than Triton X-100, but compounds 4f and 4h had the least lysis at all tested concentrations and were found to be safe for human erythrocytes. Molecular docking study was performed to evaluate the binding interactions of ligands with human pancreatic α-amylase (HPA). The binding score -8.09 to -8.507 kcal/mol revealed strong binding interactions in the ligand-protein complex. The docking results supplemented the observed α-amylase inhibition and hence augment the scaffold to serve as leads for the antidiabetic drug development.
PubMed: 38954767
DOI: 10.1002/cbdv.202401021 -
PloS One 2024Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized...
INTRODUCTION
Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics.
METHODS
Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma.
RESULTS
CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated.
CONCLUSIONS
PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.
Topics: Humans; Pancreatic Neoplasms; Male; Female; Adenocarcinoma; Middle Aged; Aged; Tumor Microenvironment; B7-H1 Antigen; HLA-G Antigens; Programmed Cell Death 1 Ligand 2 Protein; Prognosis; CD8-Positive T-Lymphocytes; Adult; T-Lymphocytes, Regulatory; Aged, 80 and over; Macrophages
PubMed: 38954689
DOI: 10.1371/journal.pone.0305648 -
International Journal of Surgery... Jul 2024Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) is a widely adopted surgical approach for benign and low-grade malignant neoplasms of the distal pancreas....
Interim analysis of short-term outcomes after laparoscopic spleen-preserving distal pancreatectomy with or without preservation of splenic vessels: a randomised controlled trial.
BACKGROUND
Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) is a widely adopted surgical approach for benign and low-grade malignant neoplasms of the distal pancreas. The Kimura and Warshaw techniques represent two principal strategies, yet it still needs to be determined which one is superior. Our investigation aimed to evaluate the clinical outcomes associated with each technique.
MATERIALS AND METHODS
This single-center, parallel-group, patient-blinded randomized controlled trial (RCT) was conducted at the XXXXX University. Stratified block randomization was utilized to enroll 114 patients starting in March 2022, with an interim analysis of short-term outcomes scheduled after 45%-50% of participant enrollment. Patients were randomized to receive LSPDP via either the Kimura or Warshaw technique. The primary endpoint was intraoperative blood loss, while secondary endpoints included a range of outcomes from composite outcome to quality of life, as quantified by the EQ-5D-5L.
RESULTS
From March 2022 to November 2023, 53 patients were randomly allocated to the Kimura (n=25) or Warshaw (n=28) groups for LSPDP. Baseline characteristics and postoperative outcomes were similar between the groups, such as pancreatic fistula incidence, EQ-5D-5L index scores, and delayed gastric emptying rates. Per-protocol (PP) analysis revealed that the Kimura group experienced significantly less blood loss (52.5±51.6 mL vs. 91.7±113.5 mL, P=0.007) and a reduced rate of composite outcome (23.8% vs. 56.7%, P=0.019), but incurred higher costs in the Warshaw group (¥56,227.4±¥7,027.0 vs. ¥63,513.8±¥12,944.5, P=0.013). Splenic infarction rates were higher in the Warshaw group, though not statistically significant (ITT: 39.3% vs. 12.5%, P=0.058; PP: 36.7% vs. 14.3%, P=0.113), without necessitating intervention. Neither group experienced postpancreatectomy haemorrhage, 90-day mortality, or ICU admissions, and all postoperative complications were mild (Clavien-Dindo Grade
CONCLUSIONS
The 90-day interim analysis postoperatively indicates that both Kimura and Warshaw techniques for LSPDP are safe and viable. The Kimura technique, however, confers superior in terms of reduced intraoperative blood loss and fewer complications, alongside lower costs.
PubMed: 38954668
DOI: 10.1097/JS9.0000000000001874 -
International Journal of Surgery... Jul 2024Tibial cortex transverse transport (TTT) surgery has become an ideal treatment for patients with type 2 severe diabetic foot ulcerations (DFUs) while conventional...
BACKGROUND
Tibial cortex transverse transport (TTT) surgery has become an ideal treatment for patients with type 2 severe diabetic foot ulcerations (DFUs) while conventional treatments are ineffective. Based on our clinical practice experience, the protective immune response from TTT surgery may play a role against infections to promote wound healing in patients with DFUs. Therefore, this research aimed to systematically study the specific clinical efficacy and the mechanism of TTT surgery.
MATERIALS AND METHODS
Between June 2022 and September 2023, 68 patients with type 2 severe DFUs were enrolled and therapized by TTT surgery in this cross-sectional and experimental study. Major clinical outcomes including limb salvage rate and antibiotics usage rate were investigated. Ten clinical characteristics and laboratory features of glucose metabolism and kidney function were statistically analyzed. Blood samples from 6 key time points of TTT surgery were collected for label-free proteomics and clinical immune biomarker analysis. Besides, tissue samples from 3 key time points were for spatially resolved metabolomics and transcriptomics analysis, as well as applied to validate the key TTT-regulated molecules by RT-qPCR.
RESULTS
Notably, 64.7% of patients did not use antibiotics during the entire TTT surgery. TTT surgery can achieve a high limb salvage rate of 92.6% in patients with unilateral or bilateral DFUs. Pathway analysis of a total of 252 differentially expressed proteins (DEPs) from the proteomic revealed that the immune response induced by TTT surgery at different stages was first comprehensively verified through multi-omics combined with immune biomarker analysis. The function of upward transport was activating the systemic immune response, and wound healing occurs with downward transport. The spatial metabolic characteristics of skin tissue from patients with DFUs indicated downregulated levels of stearoylcarnitine and the glycerophospholipid metabolism pathway in skin tissue from patients with severe DFUs. Finally, the expressions of PRNP (prion protein) to activate the immune response, PLCB3 (PLCB3, phospholipase C beta 3) and VE-cadherin to play roles in neovascularization, and PPDPF (pancreatic progenitor cell differentiation and proliferation factor), LAMC2 (laminin subunit gamma 2) and SPRR2G (small proline rich protein 2G) to facilitate the developmental process mainly keratinocyte differentiation were statistically significant in skin tissues through transcriptomic and RT-qPCR analysis.
CONCLUSION
Tibial cortex transverse transport (TTT) surgery demonstrates favorable outcomes for patients with severe type 2 DFUs by activating a systemic immune response, contributing to anti-infection, ulcer recurrence, and the limb salvage rate for unilateral or bilateral DFUs. The specific clinical immune responses, candidate proteins, genes, and metabolic characteristics provide directions for in-depth mechanistic research on TTT surgery. Further research and public awareness are needed to optimize TTT surgery in patients with severe type 2 DFUs.
PubMed: 38954658
DOI: 10.1097/JS9.0000000000001897 -
Endocrinology Jul 2024Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are...
BACKGROUND
Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are implicated in diabetes. Nephrin signaling is mediated in part through its three cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and β cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate β cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined.
METHODS
To further explore the role of nephrin YDxV phosphorylation in β cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests.
RESULTS
Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between WT and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls.
CONCLUSION
Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve β cell function.
PubMed: 38954536
DOI: 10.1210/endocr/bqae078 -
JCI Insight Jul 2024Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated...
Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knock-out neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.
PubMed: 38954474
DOI: 10.1172/jci.insight.167967 -
Cell Biochemistry and Biophysics Jul 2024Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million... (Review)
Review
Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.
PubMed: 38954353
DOI: 10.1007/s12013-024-01387-6