Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs.

BACKGROUND: Pancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic cancer often accompany with dismal prognosis, highlighting the need to investigate mechanisms of drug resistance and develop therapies to overcome chemoresistance. METHODS: This research was filed with the Chinese Clinical Trial Registry (ChiCTR2200061320). In order to isolate primary normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) samples of pancreatic ductal adenocarcinoma (PDAC) and paracancerous pancreatic tissue from individuals diagnosed with PDAC were obtained. The exosomes were obtained using ultracentrifugation, and their characteristics were determined by Western blotting, nanoparticle tracking analysis, and transmission electron microscopy. CAF-derived miRNAs were analyzed by RT-qPCR and high-throughput sequencing. Gemcitabine (GEM) was employed to promote ferroptosis, and ferroptosis levels were determined by monitoring lipid reactive oxygen species (ROS), cell survival, and intracellular Fe2+ concentrations. To assess in vivo tumor response to GEM therapy, a xenograft tumor mouse model was utilized. RESULTS: Exosomes derived from CAFs in PDAC did not exhibit innate GEM resistance. CAFs promoted chemoresistance in PDAC cells following GEM treatment by secreting exosomes, and maintaining signaling communication with cancer cells. Mechanistically, miR-3173-5p derived from CAF exosomes sponged ACSL4 and inhibited ferroptosis after uptake by cancer cells. CONCLUSION: This work demonstrates a novel mode of acquired chemoresistance in PDAC and identifies the miR-3173-5p/ACSL4 pathway as a promising treatment target for GEM-resistant pancreatic cancer.

Rupture and hemorrhage of a seminoma mixed with yolk sac tumors in 46XY partial gonadal dysgenesis: a case report and literature review.

BACKGROUND: 46XY partial gonadal dysgenesis (PGD) is a rare subtype of disorder of sex development (DSD). 46YY PGD is a congenital disease with atypical chromosomal, gonadal, or anatomical sex development. The patient in this case report had male and female genitalia simultaneously. We created a flowchart of the differential diagnosis for clinicians. CASE PRESENTATION: A 41-year-old male was admitted to the hospital complaining of lower quadrant abdominal pain for 1 day. Physical examination revealed that his penis size was normal, but a urethral orifice was located in the perineum area between the scrotum and anus. One small testicle was in the left scrotum, but no testicle was present on the right. The patient's abdomen was bulging, and he had lower abdominal pain. According to the emergency CT scan, a lesion (74*65 mm) was found in the right pelvis between the bladder and rectum. The lesion showed an unclear boundary and hematocele appearance. The lesion was removed by emergency surgery, and the pathology report indicated a mixed germ cell tumor with a seminoma and yolk sac tumors. CONCLUSION: This article is a case report of germ cell tumors in 46XY PGD patients. The literature review summarizes the clinical diagnosis, and a flowchart is provided for physicians in future practice. The importance of this report is that it will help acquaint physicians with this rare disease and make the right initial clinical decision quickly through the use of this flowchart. However, the variants of special subtypes of 46XY DSD are myriad, and all the diagnoses could not be covered in one flowchart.

Synchronous hepatocellular carcinoma and gallbladder adenocarcinoma with neuroendocrine differentiation: a case report and literature review.

BACKGROUND: Double primary cancers have a low incidence rate, and synchronous hepatocellular carcinoma and gallbladder adenocarcinoma are rarely reported. Here, we report such a case- the 12th case of synchronous double primary cancers featuring HCC and GC, but the first case of neuroendocrine differentiation in the gallbladder. CASE PRESENTATION: A 77-year-old female was admitted to the hospital complaining of weakness and inappetence for six months. Contrast-enhanced computed tomography (CT) of the abdomen indicated an 11 cm space-occupying lesion in the right lobe of the liver. Later, magnetic resonance imaging showed a high possibility of a massive hepatoma, and multiple gallstones were also seen. After transhepatic arterial chemoembolization, a repeat abdominal CT showed obvious local nodular thickening in the gallbladder wall. Finally, resection of the right lobe of the liver and cholecystectomy were performed. During an approximately 2-year follow-up, the patient recovered uneventfully without recurrence or metastasis. CONCLUSION: The disease in this case is rare and lacked typical radiological features. More precise and advanced diagnostic techniques are needed to obtain a clear diagnosis and refine treatment strategies. The management strategy should always be curative, even in the presence of multiple malignancies.

LACTB suppresses liver cancer progression through regulation of ferroptosis.

Ferroptosis, driven by iron-dependent phospholipid peroxidation, is emerging as an intrinsic cancer defense mechanism. However, the regulatory networks involved in ferroptosis remain largely unknown. Here, we found that serine beta-lactamase-like protein (LACTB) inhibits liver cancer progression by regulating ferroptosis. LACTB is downregulated in liver cancer, and the ectopic expression of LACTB markedly inhibits cell viability, colony formation, and tumour growth. LACTB knockout exerts the opposite effects. Further investigation revealed that LACTB blocks HSPA8 transcription in a p53-dependent manner, resulting in the elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signalling, thereby triggering ferroptosis and suppressing liver cancer progression. Liver cancer cells with an endogenous mutation of p53 binding site in the HSPA8 promoter exhibited increased resistance to ferroptosis inducers, and the ferroptosis-promoting effect of LACTB was significantly weakened in these mutant cells. Importantly, LACTB is identified as a downstream target of lenvatinib, and adeno-associated virus-mediated overexpression and knockdown of LACTB notably enhance and attenuate the anti-tumour efficacy of lenvatinib in vivo, respectively. Taken together, our study reveals a novel action of LACTB and provides potential therapeutic strategies for enhancing the efficacy of lenvatinib in liver cancer.

Acute diffuse peritonitis secondary to a seminal vesicle abscess: A case report.

BACKGROUND: Seminal vesicle abscess (SVA) is the manifestation of a relatively rare urinary system infection. In response to urinary system inflammation, an abscess forms in special locations. However, acute diffuse peritonitis (ADP) induced by SVA is unusual. CASE SUMMARY: We report a case of a left SVA in a male patient complicated with pelvic abscess, ADP, multiple organ dysfunction syndrome, infectious shock, bacteremia, and acute appendiceal extraserous suppurative inflammation as a result of a long-term indwelling urinary catheter. The patient received a course of morinidazole + cefminol antibiotics but showed no obvious relief, so the perineal SVA underwent puncture drainage and abdominal abscess drainage + appendectomy was performed. The operations were successful. After the operation, anti-infection, anti-shock, and nutritional support treatments were continued and various laboratory indicators were regularly reviewed. The patient was discharged from the hospital after recovery. This disease is a challenge for the clinician because of the unusual spreading path of the abscess. Moreover, appropriate intervention and adequate drainage of abdominal and pelvic lesions are necessary, especially when the primary focus cannot be determined. CONCLUSION: The etiology of ADP varies, but acute peritonitis secondary to SVA is very rare. In this patient, the left SVA not only affected the adjacent prostate and bladder but also spread retrogradely through the vas deferens, forming a pelvic abscess in the loose tissues of the extraperitoneal fascia layer. Inflammation involving the peritoneal layer led to ascites and pus accumulation in the abdominal cavity, and appendix involvement led to extraserous suppurative inflammation. In clinical practice, surgeons need to consider the results of various laboratory tests and imaging examinations to make comprehensive judgments involving the diagnosis and treatment plan.

Relationship between postoperative biliary stricture and clinical characteristics of patients with benign and malignant biliary diseases.

Introduction: Postoperative biliary stricture (POBS) is one of the common complications of biliary surgery. Previous literature on risk factors of POBS was scarce, and the classification of POBS in benign and malignant biliary diseases was incomplete. Aim: To analyze clinicopathological factors of POBS in usual biliary diseases, and to facilitate preoperative diagnosis of biliary stricture. Material and methods: A retrospective analysis was made on the clinical data of 2228 patients who underwent biliary surgery in our hospital from July 2010 to June 2022. With the inclusion and exclusion criteria, the clinicopathological factors for POBS were classified, and data analysis was conducted. Results: Benign diseases with age ≥ 60 years (p = 0.034), diabetes (p = 0.001), common bile duct diameter < 0.8 cm (p = 0.034), Mirizzi syndrome (p = 0.001), seniority of surgeons < 25 years (p = 0.001), and operation time for the first 6 years (p = 0.015) are more likely to evolve into POBS; malignant diseases with conjugated bilirubin ≥ 6.8 µmol/l (p = 0.042), alkaline phosphatase ≥ 125 U/l (p = 0.042), γ-glutamyl transferase ≥ 50 U/l (p = 0.047), diabetes (p = 0.038), and seniority of surgeons < 25 years (p = 0.008) are prone to POBS. Different surgical approaches affect the incidence of POBS (χ2 = 9.717, p = 0.034). The choice of surgical site is important for the incidence of POBS in malignant diseases (χ2 = 7.935, p = 0.041). Conclusions: Surgeons need to identify risk factors, conduct patient visits and assessments preoperatively, standardize the operation in order to avoid structural damage, and reduce the occurrence of POBS.

DHX37 Is a Promising Prognostic Biomarker and a Therapeutic Target for Immunotherapy and Chemotherapy in HCC.

DHX37, a member of the DEAD/H-box RNA helicase family, has been implicated in various diseases, including tumors. However, the biological characteristics and prognostic significance of DHX37 in HCC remain unclear. In this study, we use R software 3.6.3 and multiple bioinformatics analysis tools, such as GDSC, HPA, STRING, TISCH, and TIMER2, to analyze the characterization and function of DHX37 in HCC. In addition, Western blot (WB) and immunohistochemistry (IHC) based on clinical samples validated some of the findings. DHX37 was more highly expressed in HCC samples compared to adjacent non-tumor tissues. Higher DHX37 expression is correlated with various clinicopathological characteristics in HCC, including AFP, adjacent hepatic tissue inflammation, histologic grade, T stage, and pathologic stage. Survival analysis revealed that the high DHX37 group had significantly shorter overall survival (OS), progress-free interval (PFI), and disease-specific survival (DSS) compared to the low DHX37 group. By analyzing the correlation between DHX37 and the IC50 of chemotherapeutic drugs, the results showed that DHX37 expression level was negatively correlated with the IC50 of 11 chemotherapeutic drugs. Further analysis indicated that DHX37 and its co-expressed genes may play important roles in activating the cell cycle, DNA repair, chemokine signaling pathways, and regulating the immune response, which leads to a poor prognosis in HCC. High expression of DHX37 is an independent risk factor for poor prognosis in HCC, and DHX37 is expected to be a potential target to inhibit tumor progression. Targeting DHX37 may enhance chemotherapeutic drug sensitivity and immunotherapeutic efficacy in HCC.

The role of non-coding RNAs in ferroptosis regulation.

Ferroptosis is a newly recognized form of cell death that is distinct from apoptosis, necrosis, autophagy in morphology, biochemistry, and heredity. The basic process of ferroptosis involves disordered permeability of plasma membrane, which is caused by abnormal accumulation of lipids and reactive oxygen species (ROS). The regulatory mechanism of ferroptosis is important due to its involvement in tumor progression, neurotoxicity, neurodegenerative diseases, acute renal failure, and ischemia-reperfusion injury. Recent studies have shown that in ferroptosis metabolism, non-coding RNAs (ncRNAs) can interfere with multiple signaling pathways at both the pre-transcriptional and post-transcriptional levels. Despite great progress, current research on the mechanism of ncRNAs and ferroptosis remains insufficient. This review provides an overview of the main mechanisms and targets of ferroptosis and focuses on the mechanisms of non-coding RNA regulation. Analyzing the deficiencies in current research may provide ideas for future studies to investigate.

Asymptomatic gastric adenomyoma and heterotopic pancreas in a patient with pancreatic cancer: A case report and review of the literature.

BACKGROUND: Gastric adenomyoma (GA) is a rare submucosal benign neoplasm that occurs mostly in the gastric antrum and is often misdiagnosed. No standard treatment has been established for this disease in cases of malignancy. CASE SUMMARY: A 75-year-old woman with a 10-year history of hypertension was admitted to the Emergency Department of our hospital complaining of paroxysmal exacerbation of acute abdominal pain for 1 d with no apparent cause. Enhanced computed tomography and magnetic resonance imaging indicated a mass in the caudal pancreas, cholecystitis, and cholecystic polypus. Gastrointestinal endoscopy showed a mass arising from the gastric antrum. Due to the imaging findings, pancreatic cancer (PC), gastric lesion, cholecystitis, and cholecystic polypus were our primary consideration. Radical pancreatectomy, splenectomy, and cholecystectomy were performed successfully, and the gastric tumor was locally resected. Postoperative paraffin specimens confirmed the diagnosis of caudal PC, GA, and heterotopic pancreas (HP). Unfortunately, the patient died 13 mo later due to PC metastases to the liver, lung, and adrenal glands. CONCLUSION: GA is a rare benign disease, especially when occurring with HP. It may stem from the same origin as HP. This is the first case report to date of a patient suffering from the simultaneous occurrence of GA, HP, and PC. GA is a lesion that can mimic other benign or malignant gastrointestinal diseases; thus, a definitive diagnosis depends on postoperative pathological biopsy. Although GA and HP are both benign lesions, they should be resected because there is a chance of malignancy. Additional research should be conducted to better understand these submucosal lesions.

A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model.

Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/ß-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.

Human Mesenchymal Stem Cell-Derived Exosomal microRNA-143 Promotes Apoptosis and Suppresses Cell Growth in Pancreatic Cancer via Target Gene Regulation.

BACKGROUND: This study aimed to explore the regulatory mechanism of hsa-miR-143-3p and lncRNA RP11-363N22.3-functioning upstream of KRAS-in exosomes derived from human mesenchymal stem cells (hMSCs) in pancreatic cancer. METHODS: Western blotting and quantitative PCR were used to determine gene expression. In vitro, cell proliferation, apoptosis, and cell cycle and invasion were evaluated using CCK-8 assay, flow cytometry, and transwell assays, respectively. In vivo, the effect of hsa-miR143-3p was investigated using a tumorigenesis test in nude mice. The association between hsa-miR-143-3p and lncRNA RP11-363N22.3 was investigated using the dual-luciferase assay. RESULTS: hsa-miR-143-3p expression significantly increased in hMSC exosomes than in those in human pancreatic cancer cell line (CFPAC-1) exosomes. In vitro, compared to the MOCK (CFPAC-1 only) group, cell proliferation and invasion were inhibited and apoptosis was induced in the inhibitor NC (CFPAC-1 + MSC-hsa-miR-3p inhibitor NC) group, while these changes were reversed in the inhibitor (CFPAC-1 + MSC-hsa-miR-3p inhibitor) group. The expression of lncRNA RP11-363N22.3 and genes related to miR-143 significantly decreased in the inhibitor NC group compared to the MOCK group, and increased in the inhibitor group compared to inhibitor NC group. A targeted combinatorial effect was observed between lncRNA RP11-363N22.3 and hsa-miR-143-3p. In vivo, the tumor volume of the mimics (CFPAC-1 + MSC-hsa-miR-143-3p mimics) group was smaller than that of the mimics NC (CFPAC-1 + MSC-hsa-miR-143-3p mimics NC) and MOCK groups. H&E staining showed that there were no obvious pathological changes in MOCK and mimic NC groups, while cell necrosis was seen in some regions in mimic groups. CONCLUSION: hsa-miR-143-3p may promote apoptosis and suppress cell growth and invasion in pancreatic cancer.

Anticancer effects of miR-124 delivered by BM-MSC derived exosomes on cell proliferation, epithelial mesenchymal transition, and chemotherapy sensitivity of pancreatic cancer cells.

OBJECTIVE: This study aims to explore the roles of miR-124 in pancreatic tumor and potential vehicles. RESULTS: The miR-124 expression levels decreased in pancreatic adenocarcinoma tissues and cancer cell lines AsPC-1, PANC1, BxPC-3 and SW1990. Furthermore, the elevated expression of miR-124 in AsPC-1 and PANC1 via miR-124 mimic transfection-induced apoptosis, metastasis and epithelial mesenchymal transition was suppressed, and the EZH2 overexpression partly reversed the protective effects of miR-124 against pancreatic tumors. In addition, the expression of miR-124 was detected in exosomes extracted from miR-124-transfected BM-MSCs, and these exosomes delivered miR-124 into pancreatic cancer cells, and presented the anti-tumor effects in vitro and in vivo. CONCLUSION: MiR-124-carried BM-MSC-derived exosomes have potential applications for the treatment of pancreatic tumors. METHODS: The expression of miR-124 and EZH2 was determined in both pancreatic cancer tissues and cell lines. miR-124 or EZH2 was overexpressed in AsPC-1 and PANC1 cells. Then, the effects on cell viability. apoptosis, invasion, migration and epithelial mesenchymal transition were evaluated. Afterwards, the roles of miR-124 on the expression and function of EZH2 in pancreatic tumors were determined by dual luciferase reporter assay. Subsequently, miR-124 was transfected to bone marrow mesenchymal stromal cells (BM-MSCs), and the BM-MSCs derived exosomes were isolated and co-cultured with AsPC-1 and PANC1 cells, or injected into pancreatic cancer tumor-bearing mice.