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Biomedicine & Pharmacotherapy =... Jun 2024Macropinocytosis is a cellular process that enables cells to engulf extracellular material, such as nutrients, growth factors, and even whole cells. It is involved in...
Macropinocytosis is a cellular process that enables cells to engulf extracellular material, such as nutrients, growth factors, and even whole cells. It is involved in several physiological functions as well as pathological conditions. In cancer cells, macropinocytosis plays a crucial role in promoting tumor growth and survival under nutrient-limited conditions. In particular KRAS mutations have been identified as main drivers of macropinocytosis in pancreatic, breast, and non-small cell lung cancers. We performed a high-content screening to identify inhibitors of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC)-derived cells, aiming to prevent nutrient scavenging of PDAC tumors. The screening campaign was conducted in a well-known pancreatic KRAS-mutated cell line (MIAPaCa-2) cultured under nutrient deprivation and using FITC-dextran to precisely quantify macropinocytosis. We assembled a collection of 3584 small molecules, including drugs approved by the Food and Drug Administration (FDA), drug-like molecules against molecular targets, kinase-targeted compounds, and molecules designed to hamper protein-protein interactions. We identified 28 molecules that inhibited macropinocytosis, with potency ranging from 0.4 to 29.9 μM (EC). A few of them interfered with other endocytic pathways, while 11 compounds did not and were therefore considered specific "bona fide" macropinocytosis inhibitors and further characterized. Four compounds (Ivermectin, Tyrphostin A9, LY2090314, and Pyrvinium Pamoate) selectively hampered nutrient scavenging in KRAS-mutated cancer cells. Their ability to impair albumin-dependent proliferation was replicated both in different 2D cell culture systems and 3D organotypic models. These findings provide a new set of compounds specifically targeting macropinocytosis, which could have therapeutic applications in cancer and infectious diseases.
PubMed: 38906021
DOI: 10.1016/j.biopha.2024.116991 -
Medicine Jun 2024To explore the relationships between gastrointestinal radiation injuries of pancreatic cancer patients treated with TOMO and dose-volume histogram parameters... (Observational Study)
Observational Study
To explore the relationships between gastrointestinal radiation injuries of pancreatic cancer patients treated with TOMO and dose-volume histogram parameters prospectively. Seventy patients with pancreatic cancer who underwent TOMO were enrolled in this prospective study from February 2015 to May 2020. The clinical and dose-volume histogram parameters of the patients were collected. The optimal dose parameters for gastrointestinal radiation ulcers were confirmed based on the receiver operating characteristic curve (ROC) and the area below the ROC curve. Acute gastrointestinal tract toxic and side effect and injury grading correlation analyzed by Kruskal-Wallis rank sum test. Gastrointestinal injury often occurs during radiotherapy for pancreatic cancer, as observed using gastroscopy. The main adverse reactions were radioactive gastrointestinal inflammation (58.5%), radioactive gastrointestinal ulcers (41.4%), active bleeding (10%), newly-developed gastric retention (8.6%), and gastric varices (5.7%). As for the stomach, Dmean and V10 were related to radiation ulcer injury. ROC curve indicated that for stomach a Dmean of 13.39 Gy (area under ROC curves = 0.74, P = .048) and a V10 of 72.21% (area = 0.74, P = .048) was the tolerated dose for the injury of stomach radiation ulcer. As for duodenum, aV20 and aV25 are related to radiation ulcer injury. ROC curve indicated that aV20 of 22.82 cm3 (area = 0.68, P = .025) and aV25 of 32.04 cm3 (area = 0.66, P < .047) was the tolerated dose for the injury of duodenum radiation ulcer. The acute gastrointestinal tract toxic and side effects have no significant correlation with injury grading under gastroscope. Dmean > 13.39 Gy and V10 > 72.21% were the key dosimetric indices for predicting radiation-induced gastric ulcer, and aV20 > 22.82 cm3 and aV25 > 32.04 cm3 were for duodenal. Gastrointestinal reactions cannot be used as an overall basis for the diagnosis of gastrointestinal injury, and gastroscopy is recommended as a review item after radiotherapy.
Topics: Humans; Male; Female; Pancreatic Neoplasms; Middle Aged; Prospective Studies; Aged; Radiation Injuries; Gastroscopy; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Adult; ROC Curve; Aged, 80 and over
PubMed: 38905414
DOI: 10.1097/MD.0000000000038469 -
Medicine Jun 2024walled-off pancreatic necrosis (WOPN) is one of the complications of acute pancreatitis (AP) with high mortality. A method to predict the development of WOPN in AP... (Observational Study)
Observational Study
The success of SII, MII-1, MII-2, MII-3, and QT dispersion in predicting the walled-off pancreatic necrosis development in acute pancreatitis in the emergency department: An observational study.
walled-off pancreatic necrosis (WOPN) is one of the complications of acute pancreatitis (AP) with high mortality. A method to predict the development of WOPN in AP patients admitted to the emergency department may guide life-saving practices such as early initiation of antibiotic therapy and, when necessary, referral of the patient to a center where necrosectomy can be performed. This study is a prospective observational study. One hundred eleven AP patients who applied to the emergency department were included in the study. The mean of QT interval (QT) dispersion, systemic immune-inflammation Index (SII), multi-inflammatory index-I (MII-1), multi-inflammatory index-II (MII-2), and multi-inflammatory index-III (MII-3) were compared between patients who developed WOPN and patients who did not develop WOPN during their hospitalization. In the study, the mean of QT dispersion, SII, MII-1, MII-2, and MII-3 were significantly lower in the patient group who developed WOPN compared to those who did not develop WOPN. In the receiver operating characteristic analysis, all methods except SII were found to be successful in predicting WOPN. QT dispersion, SII, MII-1, MII-2, and MII-3 are valuable tools that provide rapid results and successfully predict the development of WOPN in AP. However, MII-2 and QT dispersion appears to be slightly more successful than the others.
Topics: Humans; Male; Female; Middle Aged; Prospective Studies; Emergency Service, Hospital; Pancreatitis, Acute Necrotizing; Adult; Electrocardiography; Severity of Illness Index; Aged; Predictive Value of Tests; ROC Curve; Pancreatitis
PubMed: 38905406
DOI: 10.1097/MD.0000000000038599 -
Medicine Jun 2024This study aimed to evaluate the significance of serum salusin beta (SAL-β) levels in predicting the severity of acute pancreatitis (AP) in patients diagnosed with this... (Observational Study)
Observational Study
BACKGROUND
This study aimed to evaluate the significance of serum salusin beta (SAL-β) levels in predicting the severity of acute pancreatitis (AP) in patients diagnosed with this condition and to assess its relationship with disease and prognosis.
METHODS
Sixty-four patients between 18 and 100 years of age diagnosed with AP, were included in the study. Patients were categorized into 3 groups based on the Revised Atlanta Classification: mild, moderate, and severe AP. Eighteen healthy adults were included as the control group. Sex, age, height, weight, presence of additional diseases, laboratory results, imaging findings, levels of white blood cells, neutrophil-lymphocyte ratio, mean platelet volume, amylase, lipase, sensitive C-reactive protein, sedimentation, and serum SAL-β were measured and recorded. SAL-β levels were reevaluated on the third day of hospitalization.
RESULTS
The average age of the patients included in the study was 62.66 ± 17.67. Gallstones were present in 64.1% of the patients. The difference in the SAL-β averages on the 1st and 3rd days was statistically significant (P < .05). On the first day, the SAL-β averages of those with severe Atlanta scores were higher than those with mild and moderate Atlanta severity. Similarly, on the third day, the SAL-β averages of those with severe Atlanta scores were higher than those with mild and moderate Atlanta severity. According to receiver operating characteristic analysis using the Youden index, the cutoff value for SAL-β for severe pancreatitis was 178.8 pg/mL on the 1st day and 207.5 pg/mL on the 3rd day.
CONCLUSION
SAL-β can be used to detect and monitor severe pancreatitis. Further extensive clinical studies with larger case series are needed.
Topics: Humans; Male; Female; Middle Aged; Pancreatitis; Severity of Illness Index; Adult; Aged; Intercellular Signaling Peptides and Proteins; Aged, 80 and over; Young Adult; Biomarkers; Adolescent; Prognosis; Acute Disease; Case-Control Studies
PubMed: 38905397
DOI: 10.1097/MD.0000000000038685 -
PLoS Pathogens Jun 2024Histone demethylase JMJD2D (also known as KDM4D) can specifically demethylate H3K9me2/3 to activate its target gene expression. Our previous study has demonstrated that...
Histone demethylase JMJD2D (also known as KDM4D) can specifically demethylate H3K9me2/3 to activate its target gene expression. Our previous study has demonstrated that JMJD2D can protect intestine from dextran sulfate sodium (DSS)-induced colitis by activating Hedgehog signaling; however, its involvement in host defense against enteric attaching and effacing bacterial infection remains unclear. The present study was aimed to investigate the role of JMJD2D in host defense against enteric bacteria and its underlying mechanisms. The enteric pathogen Citrobacter rodentium (C. rodentium) model was used to mimic clinical colonic infection. The responses of wild-type and JMJD2D-/- mice to oral infection of C. rodentium were investigated. Bone marrow chimeric mice were infected with C. rodentium. JMJD2D expression was knocked down in CMT93 cells by using small hairpin RNAs, and Western blot and real-time PCR assays were performed in these cells. The relationship between JMJD2D and STAT3 was studied by co-immunoprecipitation and chromatin immunoprecipitation. JMJD2D was significantly up-regulated in colonic epithelial cells of mice in response to Citrobacter rodentium infection. JMJD2D-/- mice displayed an impaired clearance of C. rodentium, more body weight loss, and more severe colonic tissue pathology compared with wild-type mice. JMJD2D-/- mice exhibited an impaired expression of IL-17F in the colonic epithelial cells, which restricts C. rodentium infection by inducing the expression of antimicrobial peptides. Accordingly, JMJD2D-/- mice showed a decreased expression of β-defensin-1, β-defensin-3, and β-defensin-4 in the colonic epithelial cells. Mechanistically, JMJD2D activated STAT3 signaling by inducing STAT3 phosphorylation and cooperated with STAT3 to induce IL-17F expression by interacting with STAT3 and been recruited to the IL-17F promoter to demethylate H3K9me3. Our study demonstrates that JMJD2D contributes to host defense against enteric bacteria through up-regulating IL-17F to induce β-defensin expression.
PubMed: 38905308
DOI: 10.1371/journal.ppat.1012316 -
Therapeutic Advances in Respiratory... 2024Cystic fibrosis (CF) is an autosomal recessive disease caused by the inheritance of two mutant cystic fibrosis transmembrane conductance regulator (CFTR) alleles, one...
Identification and structural analysis for the first mutation in the cystic fibrosis transmembrane conductance regulator protein in Iran: case report and developmental insight using microsatellite markers.
Cystic fibrosis (CF) is an autosomal recessive disease caused by the inheritance of two mutant cystic fibrosis transmembrane conductance regulator (CFTR) alleles, one from each parent. Autosomal recessive disorders are rarely associated with germline mutations or mosaicism. Here, we propose a case of paternal germline mutation causing CF. The subject also had an identifiable maternal mutant allele. We identified the compound heterozygous variants in the proband through Sanger sequencing, and studies predicted functional effects on the protein. Also, short tandem repeat markers revealed the nature of the mutation. The maternal mutation in the CFTR gene was c.1000C > T. The mutation was c.178G > A, p.Glu60Lys. This mutation is located in the lasso motif of the CFTR protein and, according to structural analysis, disrupts the interaction of the lasso motif and R-domain, thus influencing protein function. This first reported case of mutation in Asia has notable implications for molecular diagnostics, genetic counseling, and understanding the genetic etiology of recessive disorders in the Iranian population.
Topics: Female; Humans; Male; Computer Simulation; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Genetic Predisposition to Disease; Germ-Line Mutation; Iran; Microsatellite Repeats; Phenotype; Child, Preschool; Infant
PubMed: 38904297
DOI: 10.1177/17534666241253990 -
Ugeskrift For Laeger Jun 2024This is a case report of a 70-year-old woman with possible cholestyramine-induced bowel perforation. She had a prior history of pancreaticoduodenectomy for pancreatic...
This is a case report of a 70-year-old woman with possible cholestyramine-induced bowel perforation. She had a prior history of pancreaticoduodenectomy for pancreatic cancer with a daily intake of cholestyramine. She underwent emergency laparotomy for small bowel perforation twice. Subsequent pathology reports showed crystal depositions in the small bowel wall. Leasions spread out on the small bowel and the omentum during the second surgery were thought to be carcinomatosis. However, the pathology report showed no malignant cells but plenty of crystal depositions as seen with cholestyramine intake.
Topics: Humans; Aged; Female; Intestinal Perforation; Cholestyramine Resin; Intestine, Small; Pancreaticoduodenectomy; Anticholesteremic Agents; Pancreatic Neoplasms
PubMed: 38904283
DOI: 10.61409/V02240109 -
International Journal of Biological... 2024Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new...
Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.
Topics: Humans; RNA Splicing Factors; Pancreatic Neoplasms; Animals; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Epoxy Compounds; Prognosis; Phosphoproteins; Macrolides; Apoptosis; RNA Splicing; Alternative Splicing; Female; Cell Movement
PubMed: 38904016
DOI: 10.7150/ijbs.92671 -
International Journal of Biological... 2024Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs)....
Hypoxic tumor-derived exosomal miR-4488 induces macrophage M2 polarization to promote liver metastasis of pancreatic neuroendocrine neoplasm through RTN3/FABP5 mediated fatty acid oxidation.
Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs). There is a growing body of evidence highlighting the critical role of exosomes in facilitating communication between tumor cells and TAMs, thereby contributing to the establishment of the premetastatic niche. Nonetheless, the specific mechanisms through which exosomes derived from tumor cells influence macrophage polarization under hypoxic conditions in pNENs, and the manner in which these interactions support cancer metastasis, remain largely unexplored. Recognizing the capacity of exosomes to transfer miRNAs that can modify cellular behaviors, our research identified a significant overexpression of miR-4488 in exosomes derived from hypoxic pNEN cells. Furthermore, we observed that macrophages that absorbed circulating exosomal miR-4488 underwent M2-like polarization. Our investigations revealed that miR-4488 promotes M2-like polarization by directly targeting and suppressing RTN3 in macrophages. This suppression of RTN3 enhances fatty acid oxidation and activates the PI3K/AKT/mTOR signaling pathway through the interaction and downregulation of FABP5. Additionally, M2 polarized macrophages contribute to the formation of the premetastatic niche and advance pNENs metastasis by releasing MMP2, thereby establishing a positive feedback loop involving miR-4488, RTN3, FABP5, and MMP2 in pNEN cells. Together, these findings shed light on the role of exosomal miRNAs from hypoxic pNEN cells in mediating interactions between pNEN cells and intrahepatic macrophages, suggesting that miR-4488 holds potential as a valuable biomarker and therapeutic target for pNENs.
Topics: MicroRNAs; Pancreatic Neoplasms; Exosomes; Humans; Animals; Mice; Neuroendocrine Tumors; Macrophages; Liver Neoplasms; Cell Line, Tumor; Fatty Acids; Oxidation-Reduction; Tumor Microenvironment; Fatty Acid-Binding Proteins; Nerve Tissue Proteins; Mice, Nude; Signal Transduction
PubMed: 38904015
DOI: 10.7150/ijbs.96831 -
International Journal of Biological... 2024Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that...
Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates NRF2 proteostasis and susceptibility to ferroptosis in pancreatic ductal adenocarcinoma (PDAC). We found that CPEB1 deficiency in cancer cells promotes the translation of p62/SQSTM1 by facilitating mRNA polyadenylation. Consequently, upregulated p62 enhances NRF2 stability by sequestering KEAP1, an E3 ligase for proteasomal degradation of NRF2, leading to the transcriptional activation of anti-ferroptosis genes. In support of the critical role of this signaling cascade in cancer therapy, CPEB1-deficient pancreatic cancer cells display higher resistance to ferroptosis-inducing agents than their CPEB1-normal counterparts and . Furthermore, based on the pathological evaluation of tissue specimens from 90 PDAC patients, we established that CPEB1 is an independent prognosticator whose expression level is closely associated with clinical therapeutic outcomes in PDAC. These findings identify the role of CPEB1 as a key ferroptosis regulator and a potential prognosticator in pancreatic cancer.
Topics: Humans; Ferroptosis; Pancreatic Neoplasms; NF-E2-Related Factor 2; Cell Line, Tumor; Animals; mRNA Cleavage and Polyadenylation Factors; Mice; Proteostasis; Transcription Factors; Carcinoma, Pancreatic Ductal; Kelch-Like ECH-Associated Protein 1; Mice, Nude
PubMed: 38904009
DOI: 10.7150/ijbs.95962