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American Journal of Surgery Jun 2024Pervasive symptoms from chronic pancreatitis despite noninvasive management is an indication for surgical intervention. Frey and Whipple procedures are appropriate...
BACKGROUND
Pervasive symptoms from chronic pancreatitis despite noninvasive management is an indication for surgical intervention. Frey and Whipple procedures are appropriate options for proximal pancreas disease; however, data are limited on symptomatic outcomes.
METHODS
We conducted a retrospective analysis of patients who underwent surgical intervention for chronic pancreatitis of the proximal pancreas from 2005 to 2019. Preoperative patient characteristics and postoperative outcomes were evaluated.
RESULTS
One hundred forty patients underwent surgical intervention for chronic pancreatitis, 91 Whipple and 49 Frey procedures. Mean age was 53 years (SD 12), and mean BMI 24 (SD 5.6). At post-operative follow-up, 74 % were asymptomatic, and 84 % at average follow-up of 2 years. Groove pancreatitis, lack of post-operative delayed gastric emptying, and decreased length of stay were predictive of symptom resolution.
CONCLUSIONS
Whipple and Frey procedures are appropriate surgical options for chronic pancreatitis affecting the proximal pancreas. Both lead to sustained symptom resolution for most patients.
PubMed: 38955621
DOI: 10.1016/j.amjsurg.2024.115810 -
The Journal of Pharmacology and... Jul 2024Oxidative stress, fibrosis, and inflammasome activation from AGE-RAGE interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study...
Oxidative stress, fibrosis, and inflammasome activation from AGE-RAGE interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating CB2 receptors against diabetes complications and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dosage of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance, insulin resistance, and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and SERCA2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NOX4 and activating PI3K/AKT/Nrf2 signaling. BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition (EndMT) in DCM mice by inhibiting TGF-β/Smad signaling. Further, BCP treatment suppressed NLRP3 inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate CB2 receptor dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2 receptor antagonist AM630 and AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP showed the potential to protect the myocardium and pancreas of DCM mice mediating CB2 receptor dependent mechanisms. 1. β-caryophyllene (BCP), a cannabinoid type 2 receptor (CB2R) agonist. 2. BCP attenuates diabetic cardiomyopathy via activating CB2R in mice 3. CB2R activation by BCP shows strong protection against fibrosis and inflammasome activation 4. It regulates AGE/RAGE and PI3K/Nrf2/Akt signaling in mice.
PubMed: 38955492
DOI: 10.1124/jpet.123.002037 -
Gut Jul 2024Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear.
DESIGN
We performed studies with ; (KC) mice or LSL-Kras; ; (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice.
RESULTS
The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1β and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation.
CONCLUSION
Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability.
PubMed: 38955401
DOI: 10.1136/gutjnl-2024-332225 -
BMJ Open Jul 2024Endoscopic retrograde cholangiopancreatography (ERCP) plays an indispensable role in treating pancreato-biliary diseases but carries a risk of post-ERCP pancreatitis...
Aggressive hydration with lactated Ringer's solution versus plasma solution for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (ALPS study): protocol for a multicentre, double-blind, randomised controlled trial.
INTRODUCTION
Endoscopic retrograde cholangiopancreatography (ERCP) plays an indispensable role in treating pancreato-biliary diseases but carries a risk of post-ERCP pancreatitis (PEP). Despite advances in the prevention strategies, prevention of PEP remains imperfect, necessitating more refined hydration methods. This study investigates the effectiveness of lactated Ringer's solution versus plasma solution in preventing PEP.
METHOD AND ANALYSIS
This multicentre, double-blind, randomised controlled trial, will be initiated by the investigator-sponsor, and conducted in three tertiary centres in South Korea. The aim of this study is to assess the effectiveness of hydration in preventing PEP in patients with naïve papillae. It will target patients with naïve papillae, focusing on those at medium to high risk of PEP. Patients aged ≤18 years and those with serious comorbidities, acute/chronic pancreatitis and various other medical conditions will be excluded. Eligible participants will be randomly assigned into two arms in equal numbers: (1) PEP prevention using lactated Ringer's solution and (2) PEP prevention using plasma solution. The primary outcome of this study will be the occurrence of PEP, and secondary outcomes will be additional risk factors and potential adverse events related to ERCP. With a total enrolment of 844 patients, the study will be able to detect significant differences between the intervention arms.
ETHICS AND DISSEMINATION
Ethical approval is obtained from each institution (Asan Medical Centre, 2023-0382; Seoul National University Hospital, H-2302-05-1404; Samsung Medical Centre, SMC 2023-02-001-009). All participants provided informed consent following clear explanation of the study procedures. The results of the study will be disseminated in peer-reviewed journals and research conferences.
TRIAL REGISTRATION NUMBER
NCT05832047.
PROTOCOL VERSION
Ver 4.1 (2023).
Topics: Humans; Cholangiopancreatography, Endoscopic Retrograde; Pancreatitis; Double-Blind Method; Ringer's Lactate; Republic of Korea; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Fluid Therapy; Male; Female
PubMed: 38955368
DOI: 10.1136/bmjopen-2024-084052 -
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