KLK10/LIPH/PARD6B/SLC52A3 are promising molecular biomarkers for the prognosis of pancreatic cancer through a ceRNA network.

Pancreatic adenocarcinoma (PAAD) remains challenging to diagnose and treat clinically due to its difficult early diagnosis, low surgical resection rate, and high risk of postoperative recurrence and metastasis. SMAD4 is a classical mutated gene in pancreatic cancer and is lost in up to 60%-90 % of PAAD patients, and its mutation often predicts a poor prognosis and treatment resistance. In this study, based on the expression profile data in The Cancer Genome Atlas database, we identified a ceRNA network composed of 2 lncRNAs, 1 miRNA, and 4 mRNAs through differential expression analysis and survival prognosis analysis. Among them, high expression of KLK10/LIPH/PARD6B/SLC52A3 influenced the prognosis and overall survival of PAAD patients. We confirmed the high expression of these target genes in pancreatic tissue of pancreatic-specific SMAD4-deficient mice. In addition, immune infiltration analysis showed that the high expression of these target genes affects the tumor immune environment and contributes to the progression of PAAD. Abnormal overexpression of these target genes may be caused by hypermethylation. In conclusion, we found that KLK10/LIPH/PARD6B/SLC52A3 is a potential prognostic marker for PAAD based on a competing endogenous RNA-mediated mechanism and revealed the potential pathogenic mechanism by which deficient expression of SMAD4 promotes pancreatic cancer progression, which provides a new pathway and theoretical basis for targeted therapy or improved prognosis of pancreatic cancer. These data will help reveal potential therapeutic targets for pancreatic cancer and improve the prognosis of pancreatic cancer patients.

The power and the promise of CAR-mediated cell immunotherapy for clinical application in pancreatic cancer.

BACKGROUND: Pancreatic cancer, referred to as the "monarch of malignancies," is a neoplastic growth mostly arising from the epithelial cells of the pancreatic duct and acinar cells. This particular neoplasm has a highly unfavorable prognosis due to its marked malignancy, inconspicuous initial manifestation, challenging early detection, rapid advancement, and limited survival duration. Cellular immunotherapy is the ex vivo culture and expansion of immune effector cells, granting them the capacity to selectively target malignant cells using specialized techniques. Subsequently, these modified cells are reintroduced into the patient's organism with the purpose of eradicating tumor cells and providing therapeutic intervention for cancer. PRESENT SITUATION: Presently, the primary cellular therapeutic modalities employed in the treatment of pancreatic cancer encompass CAR T-cell therapy, TCR T-cell therapy, NK-cell therapy, and CAR NK-cell therapy. AIM OF REVIEW: This review provides a concise overview of the mechanisms and primary targets associated with various cell therapies. Additionally, we will explore the prospective outlook of cell therapy in the context of treating pancreatic cancer.

Role of immune dysfunction in pathogenesis of type 1 diabetes mellitus in children.

OBJECTIVES: To investigate the function of cytokines, chemokines, and regulatory T cells (Tregs) in the pathogenesis of type 1 diabetes mellitus (T1DM) in children. METHODS: A total of 35 children with T1DM and 30 healthy controls were enrolled in this study. Levels of serum cytokines (IL-1α, IL-6, IL-10, IL-12, and TNF-α) and chemokines (MIP-1α, MIP-1α and MCP-1) were detected by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) were isolated and culture supernatant of phytohaemagglutinin (PHA)-stimulated PBMCs was subjected to ELISA for levels of cytokines (IL-1α, IL-6, IL-10, IL-12 and TNF-α) in T1DM and control group. Furthermore, flow cytometry was used to determine the percentage of Tregs in PBMCs of two groups. RESULTS: Levels of serum cytokines including IL-1α, IL-6, IL-10 and TNF-α as well as chemokines, such as MIP-1α and MIP-1α in children with T1DM children were significantly higher than those in healthy controls (P<0.05, respectively). PBMCs with PHA stimulation in T1DM group secreted more IL-1α and TNF-α (P<0.05, respectively), but less IL-10 (P<0.05), as compared with control group. Furthermore, the proportion of CD4(+), CD25(+), Foxp3(+), Tregs in PBMCs isolated from children with T1DM was obviously lower than those in healthy controls (P<0.05). CONCLUSIONS: Immune dysfunction, with upregulation of inflammatory factors such as IL-1α, IL-6, TNF-α and MIP-1α, downregulation of IL-10 and Tregs, plays an important role in the pathogenesis of T1DM in children.

Molecular analysis in combination with iodine staining may contribute to the risk prediction of esophageal squamous cell carcinoma.

PURPOSE: Mucosal iodine staining has improved the detection of precancerous lesions of the esophagus. However, this method is unable to exactly evaluate the risk status of the lesions. In the present study, we conducted a molecular analysis combining the iodine staining in esophageal squamous cell carcinomas (ESCC) and different premalignant lesions of the esophagus in order to improve the early diagnosis of ESCC. METHODS: Tumorous and precancerous lesions were procured as iodine-unstained areas in the resected specimens of ESCC patients by means of Lugol's iodine staining. Loss of heterozygosity (LOH) was detected with 35 microsatellite markers frequently reported to be deleted in ESCC. The markers with high frequency of LOH in tumorous and precancerous lesions of the same patient were subjected to further detection in iodine-unstained biopsy samples from the population screening in ESCC high-incidence region. RESULTS: Common alterations were observed at D3S3644, D3S1768, D3S3040, D3S4542, RPL14, D9S169, D13S171 and D13S263 in both cancer tissues and precancerous lesions around tumors. Interestingly, D3S3644, D3S1768, D3S3040, D3S4542, RPL14 and D13S263 were also found with high frequency of LOH in iodine-staining abnormal lesions from the population screening. Most importantly, LOH frequency increased with histological severity. CONCLUSION: Our data suggest that detection of these six markers in combination with iodine staining might contribute to the prediction for the risk of ESCC development and for the diagnosis of patients in preclinical and preneoplastic phase of the disease.

Alteration of RPL14 in squamous cell carcinomas and preneoplastic lesions of the esophagus.

Allelic loss on chromosome 3p occurs frequently in esophageal cancer. The human ribosomal protein L14 gene (RPL14) is located on chromosome 3p21.3. In the present study, we investigated alteration of RPL14 at both the genomic DNA and RNA levels in 129 Chinese esophageal squamous cell carcinomas (ESCC) and 17 dysplasia adjacent to tumor tissues by a combination of tissue microdissection, microsatellite analysis of the intragenic marker, reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequencing. In the tested informative cases, loss of heterozygosity (LOH) of RPL14 was observed in 29 out of 68 (43%) tumors. Decreased expression of the gene was detected in 31 out of 49 (63%) carcinomas. No mutation was found in the remaining RPL14 allele of the tumors with LOH. We examined subsequently the allelic status of RPL14 in the dysplasia (preneoplastic lesions) between malignant tissues and histologically normal epithelia. Of 17 tested dysplasia in which the tumors showed LOH, eight (47%) displayed the same allelic loss as their corresponding tumors, seven (41%) exhibited microsatellite instability (MSI), and only two retained both the RPL14 alleles. The data suggest that alteration of RPL14 occurred frequently in ESCC and might be an earlier event in the tumorigenesis of the esophagus. Analysis to RPL14 gene may contribute to the early detection of ESCC as a potential molecular marker.

Alterations of MLH1 and microsatellite instability in esophageal squamous cell carcinomas.

Human MLH1 is one of the DNA mismatch repair genes and located in chromosome 3p21.3. Alterations of the MLH1 were associated with various kinds of human tumors. The present study was to investigate allelic loss of MLH1 and microsatellite instability (MSI) in esophageal squamous cell carcinomas (ESCC), and to estimate the correlation between MSI status and allelic loss of the MLH1 gene. The MSI of 14 microsatellite markers and mRNA expression of MLH1 were assessed in a large cohort of patients with ESCC by using denaturing polyacrylamide gel electrophoresis (PAGE) and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. Thirty-five percent of tumors displayed MSI in at least one tested marker. MSI in D3S1611, an intragenic marker of the MLH1, was observed in 66.7% of tumors. No down-expression of MLH1 was found at the transcriptional level. The presence of MSI did not correlate with tumor stage, degree of differentiation, lymphonode-metastasis, age and sex of the patients, neither with allelic loss of the MLH1 gene. The data suggested that LOH of MLH1 is common in ESCC, but not lead to the alteration of MLH1 at the level of RNA expression. MSI in tested microsatellite markers occurs frequently in ESCC but is not associated with allelic loss of the MLH1 gene.

[Allelic loss and down-regulation of FHIT gene expression in esophageal squamous cell carcinoma].

BACKGROUND & OBJECTIVE: Deletions and translocations involving the short arm of chromosome 3 (3p14) have been observed frequently in esophageal cancer. Fragile histidine triad (FHIT) gene is located in 3p14.2, and its deletion or abnormal expression was found in many kinds of cancers. The study was to investigate the alterations of FHIT gene, and its significance in esophageal squamous cell carcinoma (ESCC). METHODS: The deletion of FHIT gene in 80 cases of ESCC was evaluated by microsatellite analysis, and the mRNA expression of FHIT gene in 20 cases of ESCC was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Intragenic markers of FHIT gene, D3S3356, D3S3378, and D3S3361, showed homozygous in all samples. D3S1234 and D3S1540, located near FHIT, presented high heterozygosity. In the tested informative cases, loss of heterozygosity (LOH) of D3S1234 was detected in 30 out of 52 tumors (57.69%), and that of D3S1540 was observed in 38 out of 56 carcinomas (67.86%). Reduced expression of FHIT mRNA occurred in 15 of 20 (75.00%) cases, and was often accompanied with LOH. However, the FHIT down-regulation was not always coincident with LOH. CONCLUSIONS: The abnormal expression of FHIT gene occurred frequently in ESCC. LOH was the main factor leading to down-regulation of FHIT expression. Epigenetic mechanism might be associated with reduced expression of FHIT in a part of ESCC cases.