-
Scandinavian Journal of Gastroenterology Jul 2024: International guidelines currently recommend the use of molecular testing in patients with advanced pancreatic cancer. The rate of actionable molecular alterations is...
Molecular testing for personalized therapy is underutilized in patients with borderline resectable and locally advanced pancreatic cancer - real world data from the NORPACT-2 study.
: International guidelines currently recommend the use of molecular testing in patients with advanced pancreatic cancer. The rate of actionable molecular alterations is low. The utility of molecular testing in patients with borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer in real world clinical practice is unclear. 188 consecutive patients included in a prospective, population-based study (NORPACT-2) in patients with BRPC and LAPC (2018-2020) were reviewed. Molecular testing was performed at the discretion of the treating oncologist and was not recommended as a routine investigation by the national guidelines. All patients were considered fit to undergo primary chemotherapy and potential surgical resection. The frequency and the results of molecular testing (microsatellite instability (MSI) and/or KRAS status) were assessed. Thirty patients (16%) underwent molecular testing. MSI tumour was detected in one (3.6%) of 28 tested patients. The patient received immunotherapy and subsequently underwent surgical resection. Histological assessment of the resected specimen revealed a complete response. KRAS wild type was detected in one (14.3%) of seven tested patient. Patients who initiated FOLFIRINOX as the primary chemotherapy regimen ( = 0.022), or were being treated at one of the eight hospital trusts ( = 0.001) were more likely to undergo molecular testing. Molecular testing was rarely performed in patients with BRPC or LAPC. Routine molecular testing for all patients with BRPC and LAPC should be considered to increase identification of targetable mutations and improve outcomes.
PubMed: 38957079
DOI: 10.1080/00365521.2024.2373115 -
Endocrine, Metabolic & Immune Disorders... Jul 2024Diabetes mellitus is a common chronic metabolic disease characterized by a high incidence and disability rate. Intestinal flora refers to the microbial community that...
Diabetes mellitus is a common chronic metabolic disease characterized by a high incidence and disability rate. Intestinal flora refers to the microbial community that lives in the intestines and plays a crucial role in maintaining intestinal health and the human immune system. In recent years, an increasing body of research has revealed a close relationship between intestinal flora and diabetes. The pathophysiological mechanisms between them have also been constantly uncovered, and the regulation of intestinal flora has shown promising efficacy in the adjuvant treatment of diabetes. This study mainly summarized the characteristics and mechanisms of intestinal flora in patients with diabetes in recent years, as well as the methods of regulating intestinal flora to prevent and treat diabetes, and prospected the future research direction. This will offer a theoretical basis for the clinical adjuvant treatment of diabetes with intestinal flora and the development of new drugs.
PubMed: 38956918
DOI: 10.2174/0118715303308965240624054156 -
Current Diabetes Reviews Jul 2024Diabetes mellitus (DM), arising from pancreatic β-cell dysfunction and disrupted alpha-amylase secretion, manifests as hyperglycemia. Synthetic inhibitors of...
BACKGROUND
Diabetes mellitus (DM), arising from pancreatic β-cell dysfunction and disrupted alpha-amylase secretion, manifests as hyperglycemia. Synthetic inhibitors of alphaamylase like acarbose manage glucose but pose adverse effects, prompting interest in plantderived alternatives rich in antioxidants and anti-inflammatory properties.
OBJECTIVE
The current review investigates plant-based alpha-amylase inhibitors, exploring their potential therapeutic roles in managing DM. Focusing on their ability to modulate postprandial hyperglycemia by regulating alpha-amylase secretion, it assesses their efficacy, health benefits, and implications for diabetes treatment.
METHOD
This review examines plant-derived alpha-amylase inhibitors as prospective diabetic mellitus treatments using PubMed, Google Scholar, and Scopus data.
RESULTS
Plant-derived inhibitors, including A. deliciosa, B. egyptiaca, and N. nucifera, exhibit anti-inflammatory and antioxidant properties, effectively reducing alpha-amylase levels in diabetic conditions. Such alpha-amylase inhibitors showed promising alternative treatment in managing diabetes with reduced adverse effects.
CONCLUSION
The current literature concludes that plant-derived alpha-amylase inhibitors present viable therapeutic avenues for diabetes management by modulating alpha-amylase secretion by regulating inflammatory, oxidative stress, and apoptotic mechanisms involved in the pathogenesis of diabetes. Further investigation into their formulations and clinical efficacy may reveal their more comprehensive diabetes therapeutic significance, emphasizing their potential impact on glucose regulation and overall health.
.PubMed: 38956911
DOI: 10.2174/0115733998304373240611110224 -
Molecular Therapy : the Journal of the... Jul 2024Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSC), accompanied by the destruction of pancreatic...
Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSC), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few researches explored the mechanism by which damaged ACs (DACs) contribute to PSC activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP or limiting the progression of pancreatic fibrosis. In this research, co-culture with intact acinar cells (IACs) suppressed PSC activation, while co-culture with DACs did the opposite. Krüppel-like factor 4 (KLF4) was significantly upregulated in DACs and was established as the key molecule that switches ACs from PSC-suppressor to PSC-activator. We revealed the exosomes of IACs contributed to the anti-activated function of IACs-CS on PSC. MiRNome profiling showed that let-7 family is significantly enriched in IACs-derived exosomes (>30% miRNome), which partially mediates IACs' suppressive impacts on PSC. Furthermore, it has been observed that the enrichment of let-7 in exosomes was influenced by the expression level of KLF4. Mechanistic studies demonstrated that KLF4 in ACs upregulated Lin28A, thereby decreasing let-7s levels in ACs-derived exosomes, and thus promoting PSC activation. We utilized an adeno-associated virus specifically targeting KLF4 in ACs (shKLF4-pAAV) to suppress PSC activation in CP, resulting in reduced pancreatic fibrosis. IACs-derived exosomes hold potential as potent weapons against PSC activation via let-7s, while activated KLF4/Lin28A signaling in DACs diminished such functions. ShKLF4-pAAV holds promise as a novel therapeutic approach for CP.
PubMed: 38956871
DOI: 10.1016/j.ymthe.2024.06.030 -
International Journal of Cancer Jul 2024There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess...
There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess real-world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab-paclitaxel (GEMNAB; n = 938) as palliative first-line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health-related quality of life (HRQoL) between three common first- to second-line treatment sequences, adjusting for time-varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5-fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX→GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB→FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB→NALIRI+5-fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor-risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB→NALIRI+5-fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%-confidence intervals. The estimated real-world effectiveness of the three treatment sequences evaluated were largely comparable. Poor-risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient-reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.
PubMed: 38956837
DOI: 10.1002/ijc.35071 -
Journal of Anesthesia, Analgesia and... Jul 2024Pancreatic surgery is associated with a significant risk for acute kidney injury (AKI) and clinically relevant postoperative pancreatic fistula (CR-POPF). This...
BACKGROUND
Pancreatic surgery is associated with a significant risk for acute kidney injury (AKI) and clinically relevant postoperative pancreatic fistula (CR-POPF). This investigation evaluated the impact of intraoperative volume administration, vasopressor therapy, and blood pressure management on the primary outcome of AKI and the secondary outcome of a CR-POPF after pancreatic surgery.
METHODS
This retrospective single-center cohort investigated 200 consecutive pancreatic surgeries (January 2018-December 2021). Patients were categorized for the presence/absence of AKI (Kidney Disease Improving Global Outcomes) and CR-POPF. After univariate analysis, multivariable models were constructed to control for the univariate cofactor differences in the primary and secondary outcomes.
RESULTS
AKI was identified in 20 patients (10%) with significant univariate differences in demographics (body mass index and gender), comorbidities, indices of chronic renal insufficiency, and an increased AKI Risk score. Surgical characteristics, intraoperative fluid, vasopressor, and blood pressure management were similar in patients with and without AKI. Patients with AKI had increased blood loss, lower urine output, and packed red blood cell administration. After multivariate analysis, male gender (OR = 7.9, 95% C.I. 1.8-35.1) and the AKI Risk score (OR = 6.3, 95% C.I. 2.4-16.4) were associated with the development of AKI (p < 0.001). Intraoperative and postoperative volume, vasopressor administration, and intraoperative hypotension had no significant impact in the multivariate analysis. CR-POPF occurred in 23 patients (11.9%) with no significant contributing factors in the multivariate analysis. Patients who developed AKI or a CR-POPF had an increase in surgical complications, length of stay, discharge to a skilled nursing facility, and mortality.
CONCLUSION
In this analysis, intraoperative volume administration, vasopressor therapy, and a blood pressure < 55 mmHg for more than 10 min were not associated with an increased risk of AKI. After multivariate analysis, male gender and an elevated AKI Risk score were associated with an increased likelihood of AKI.
PubMed: 38956707
DOI: 10.1186/s44158-024-00176-0 -
BMC Microbiology Jul 2024Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals....
BACKGROUND
Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited.
METHODS
Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16 S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm.
RESULTS
PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification.
CONCLUSION
PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Bile; Male; Female; Pancreatic Neoplasms; Microbiota; Middle Aged; Aged; Dysbiosis; Progression-Free Survival; Bacteria; Prospective Studies; RNA, Ribosomal, 16S
PubMed: 38956452
DOI: 10.1186/s12866-024-03371-9 -
Scientific Reports Jul 2024The aims of this study were to determine whether human umbilical cord mesenchymal stem cells (hucMSCs) modified by miRNA-25-3p (miR-25-3p) overexpression could promote...
The aims of this study were to determine whether human umbilical cord mesenchymal stem cells (hucMSCs) modified by miRNA-25-3p (miR-25-3p) overexpression could promote venous endothelial cell proliferation and attenuate portal endothelial cell injury. HucMSCs and human umbilical vein endothelial cells (HUVEC) were isolated and cultured from human umbilical cord and characterized. Lentiviral vectors expressing miRNA-25-3p were transfected into hucMSCs and confirmed by PCR. We verified the effect of miR-25-3p-modified hucMSCs on HUVEC by cell co-culture and cell supernatant experiments. Subsequently, exosomes of miR-25-3p-modified hucMSCs were isolated from cell culture supernatants and characterized by WB, NTA and TEM. We verified the effects of miR-25-3p-modified exosomes derived from hucMSCs on HUVEC proliferation, migration, and angiogenesis by in vitro cellular function experiments. Meanwhile, we further examined the downstream target genes and signaling pathways potentially affected by miR-25-3p-modified hucMSC-derived exosomes in HUVEC. Finally, we established a rat portal vein venous thrombosis model by injecting CM-DiR-labeled hucMSCs intravenously into rats and examining the homing of cells in the portal vein by fluorescence microscopy. Histological and immunohistochemical experiments were used to examine the effects of miRNA-25-3p-modified hucMSCs on the proliferation and damage of portal vein endothelial cells. Primary hucMSCs and HUVECs were successfully isolated, cultured and characterized. Primary hucMSCs were modified with a lentiviral vector carrying miR-25-3p at MOI 80. Co-culture and cell supernatant intervention experiments showed that overexpression of miRNA-25-3p in hucMSCs enhanced HUVEC proliferation, migration and tube formation in vitro. We successfully isolated and characterized exosomes of miR-25-3p-modified hucMSCs, and exosome intervention experiments demonstrated that miR-25-3p-modified exosomes derived from hucMSCs similarly enhanced the proliferation, migration, and angiogenesis of HUVECs. Subsequent PCR and WB analyses indicated PTEN/KLF4/AKT/ERK1/2 as potential pathways of action. Analysis in a rat portal vein thrombosis model showed that miR-25-3p-modified hucMSCs could homing to damaged portal veins. Subsequent histological and immunohistochemical examinations demonstrated that intervention with miR-25-3p overexpression-modified hucMSCs significantly reduced damage and attenuated thrombosis in rat portal veins. The above findings indicate suggest that hucMSCs based on miR-25-3p modification may be a promising therapeutic approach for use in venous thrombotic diseases.
Topics: MicroRNAs; Humans; Human Umbilical Vein Endothelial Cells; Animals; Mesenchymal Stem Cells; Rats; Cell Proliferation; Exosomes; Portal Vein; Cell Movement; Rats, Sprague-Dawley; Male; Venous Thrombosis; Cells, Cultured; Coculture Techniques; Signal Transduction; Umbilical Cord
PubMed: 38956421
DOI: 10.1038/s41598-024-64263-6 -
Scientific Reports Jul 2024Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation...
Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expression data were obtained from the Genotype-Tissue Expression (GTEx) project. The R package was used to construct anoikis-related PC prognostic models, which were later validated with the ICGC-PACA database. Survival analyses demonstrated a poorer prognosis for patients in the high-risk group, consistent across both TCGA-PAAD and ICGC-PACA datasets. A nomogram was designed as a predictive tool to estimate patient mortality. The study also analyzed tumor mutations and immune infiltration across various risk groups, uncovering notable differences in tumor mutation patterns and immune landscapes between high- and low-risk groups. In conclusion, this research successfully developed a prognostic model centered on anoikis-related genes, offering a novel tool for predicting the clinical trajectory of PC patients.
Topics: Anoikis; Humans; Pancreatic Neoplasms; Prognosis; Gene Expression Regulation, Neoplastic; Carcinoma, Pancreatic Ductal; Nomograms; Biomarkers, Tumor; Mutation; Female; Male; Survival Analysis; Gene Expression Profiling
PubMed: 38956290
DOI: 10.1038/s41598-024-65981-7 -
Nature Genetics Jul 2024
PubMed: 38956209
DOI: 10.1038/s41588-024-01797-5