Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target.

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.

New-onset diabetes in COVID-19: The molecular pathogenesis.

Diabetes mellitus (DM) is still a challenging metabolic disease worldwide. In the current situation, the world is facing a COVID-19 pandemic due to SARS-CoV-2 infection. DM is one of the comorbid conditions that can worsen the severity of the COVID-19 condition. Surprisingly, SARS-CoV-2 infection can induce new-onset diabetes, a condition in which acute hyperglycemia occurs and may develop into a complication in nondiabetic patients. Angiotensinconverting enzyme 2 (ACE2) is a crucial entry factor for SARS-CoV-2 infection. ACE2 will bind to the spike protein of SARS-CoV-2, potentially initiating a damaging process in many tissues in the human body, including metabolic tissues. This mechanism suggests a potential role of ACE2 in the pathogenesis of diabetes since ACE2 has been proven to localize in essential metabolic tissues, one of which is the acini and islets part of the pancreas. This interrelated ACE2 in COVID-19 and DM is thought of as the mechanism that induces new-onset diabetes in COVID-19 patients. This review will thoroughly describe the current findings and theories regarding the molecular mechanism of SARS-CoV-2-induced new-onset diabetes and the possible therapeutic intervention.

Analysis of PD-L1 Expression in Breast Cancer: A Systematic Review and Meta-Analysis in Asian Population.

OBJECTIVE: This study aimed to investigate the level of PD-L1 protein expression in patients with BCs who were of Asian descent. METHODS: Three databases were conducted on this article up to August 10th, 2022. The reference lists of the publications were examined for further studies, and in cases of duplicates, a study with a larger sample size was added. In survival analysis, the hazard ratio (HR) was applied to the circumstances characterized by the frequency of occurrences, and for the clinicopathological characteristic, the best-adjusted odds ratio (OR) with a 95% confidence interval (CI) was employed. The Newcastle-Ottawa Scale (NOS) was utilized to evaluate selection criteria, comparison, and exposure to establish the quality of the technique in the under-consideration studies. The Z test determined the association analysis of OS, DFS, and clinicopathological characteristics with PD-L1 expression. RESULT: All eight trials for OS and six for DFS were considered, with 4.111 and 3.071 participants, respectively. Overexpression of PD-L1 was linked to a reduced OS compared to individuals with undetectable expression (HR= 1.58, 95% CI 1.04-2.40; P=0.03). We analyzed clinicopathological features, and it elevated in individuals with histological grade III (OR=2.39, 95% CI 1.26-4.54; P=0.008) and positive node (OR=0.68, 95% CI 0.48-0.97; P<0.05). CONCLUSION: Overexpression of PD-L1 was associated with a shorter OS in BCs patients. High PDL1 was higher in persons with nodal positivity and histological grade III.

Clinicopathological and Prognostic Significance of Ubiquitin-Specific Protease 39 Overexpression in solid Cancers: A Meta-Analysis.

OBJECTIVES: This meta-analysis aimed to evaluate the association between USP39 expression, the prognosis of patients with solid cancer, and to identify the clinicopathological characteristics of these patients. MATERIAL AND METHOD: This study was carried out using PRISMA strategy. Pubmed, ScienceDirect, Google Scholar, Ebsco, Cochrane Library electronic databases were searched for relevant studies published up to April 2022. 14 studies was included in this study. Hazard ratio (HR) and 95% confidence interval (CI) data were collected, including number of samples, detection methods, number of sample with high USP39 expression, and cut-off value. HR and 95% CI was used to evaluate the prognostic value of USP39 expression. Odds ratio (OR) with 95% CI was used to assess the effect of USP39 expression on clinicopathological parameters. RESULTS: Qualitative analysis using 14 included studies and quantitative analysis using 7 included studies. We found that USP39 expression has significant risk for histological grade (OR 3.14, CI 95% 2.15-4.58, p<0.001), TNM stage (OR 2.23, CI 95% 1.66-3.00, p<0.001), tumor size (OR 2.17, CI 95% 1.56-3.03, p<0.001), lymph node metastasis (OR 2.31, CI 95% 1.23-4.33, p=0.009), vascular invasion (OR = 1.76, 95% CI = 1.13-2.73, p=0.01). Furthermore, high expression of USP39 protein was associated with worse OS (OR 1.17, CI 95% 1.13-1.21, p<0.001) and DFS (OR 1.39, CI 95% 1.23-1.57, p<0.001) in cancer patients. CONCLUSION: It can be concluded that USP39 has a significant prognostic value in patients with solid cancer and was found to have a significant relationship in the clinicopathology of solid cancer patients.

Pretreatment Leukocyte Count Ratios as Metastatic Predictive Factors in Luminal Type Breast Cancer.

OBJECTIVE: Molecular based predictive biomarkers have been developed but still unaffordable in developing countries. The leukocyte ratio is known as a promising, affordable and practical biomarker. However, the evidence to support their application is still lacking, especially from developing countries. Therefore, this study aimed to evaluate the association between leukocytes count ratios as predictive markers of metastasis in luminal type breast cancer. METHODS: A retrospective cross-sectional study was conducted using breast cancer patient data obtained at Sanglah General Hospital (2016-2020). Complete blood count (CBC) and histopathological records of the patients were collected and the basophil-to-lymphocyte ratio (BLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) were calculated. Tumor stadium was classified into early (I-II) and advance (III-IV) stage while distant metastasis was classified into M0 and M1. Data were then analyzed using ROC curve and then followed by chi square and logistic regression analysis to obtain OR value. RESULTS: Two hundred eighty-three  luminal breast cancer patient data were used in this study with mean age 49.27 ± 9.451. Most of the patient had advanced disease (177 patients; 62.5%) while metastatic disease accounted for 54 patients (19.1%) of all patients. Patients with metastatic disease had higher median of BLR, MLR, NLR and PLR (0.043 ± 0.025, p=0.034; 0.289 ± 0.285, p=0.008; 3.489 ± 5.027, p=0.044; 159.538 ± 127.79, p=0.008) than patients without metastasis. The AUC (sensitivity and specificity) of BLR, MLR, NLR and PLR in predicting metastasis were 0.593 (51%; 65%), 0.616 (35%; 89%), 0.588 (46%; 75%) and 0.615 (40%; 81%), respectively. In multivariate risk analysis model, patients with metastasis were found in high BLR (Adjusted OR: 2.045; 95%CI=1.123-3.723; p=0.019), MLR (Adjusted OR: 4.862; 95%CI=2.401-9.844; p<0.001), NLR (Adjusted OR: 2.727; 95%CI=1.475-5.044; p=0.001) and PLR (Adjusted OR: 3.061; 95%CI=1.618-5.792; p=0.001). CONCLUSION: Pretreatment leukocyte ratios are potential predictive markers for metastasis. However, these findings need to be validated in larger and prospective studies with more comprehensive design.

Clinicopathological and prognostic significance of CXCR4 expression in osteosarcoma: a meta-analysis.

Background: C-X-C Motif Chemokine Receptor (CXCR4) is an oncogene that widely studied and associated with worse clinicopathological features and prognosis outcome on many types of cancer. Beside that, significance of CXCR4 expression on clinicopathological features and prognostic on osteosarcoma (OS) require further validation. Aim: We conducted a meta-analysis to evaluate association between positive CXCR4 expression with clinicopathological features, and prognosis in OS. Methods: Literature searches on Pubmed, Cochrane Library and Web of Science was conducted systematically up to December 2021 to find relevant references. Effect of CXCR4 expression on clinicopathological characteristic and prognostic were analyzed using Review Manager 5.4 (Cochrane Collaboration, Oxford, UK). Significance value less than 0.05 was considered statistically significant. Results: By considering inclusion and exclusion criteria, 940 patients from 12 studies were suitable to included in qualitative analysis, and 10 studies were suitable for quantitative analysis. Association between CXCR4 expression and OS clinicopathological features was found significant on metastasis (OR = 4.01, 95%CI = 1.58-10.18; p = 0.003), stage (stage III & IV vs I & II, OR = 6.52, 95%CI = 1.05-40.62; p = 0.04), and tumor primary site (femur/tibia vs other, OR = 1.60, 95%CI = 1.04-2.45; p = 0.03), but not associated with histological type, gender, and age. Furthermore, CXCR4 expression is associated with poor overall survival in OS (HR = 2.13, 95%CI = 1.78-2.55; p < 0.001). Conclusion: In conclusion, the results of our meta-analysis suggest that CXCR4 expression may be valuable as a histopathological predictor of poor clinicopathological features and prognosis of OS.

Interrelationship between miRNA and splicing factors in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of diagnosis at late stage and inherent/acquired chemoresistance. Recent advances in genomic profiling and biology of this disease have not yet been translated to a relevant improvement in terms of disease management and patient's survival. However, new possibilities for treatment may emerge from studies on key epigenetic factors. Deregulation of microRNA (miRNA) dependent gene expression and mRNA splicing are epigenetic processes that modulate the protein repertoire at the transcriptional level. These processes affect all aspects of PDAC pathogenesis and have great potential to unravel new therapeutic targets and/or biomarkers. Remarkably, several studies showed that they actually interact with each other in influencing PDAC progression. Some splicing factors directly interact with specific miRNAs and either facilitate or inhibit their expression, such as Rbfox2, which cleaves the well-known oncogenic miRNA miR-21. Conversely, miR-15a-5p and miR-25-3p significantly downregulate the splicing factor hnRNPA1 which acts also as a tumour suppressor gene and is involved in processing of miR-18a, which in turn, is a negative regulator of KRAS expression. Therefore, this review describes the interaction between splicing and miRNA, as well as bioinformatic tools to explore the effect of splicing modulation towards miRNA profiles, in order to exploit this interplay for the development of innovative treatments. Targeting aberrant splicing and deregulated miRNA, alone or in combination, may hopefully provide novel therapeutic approaches to fight the complex biology and the common treatment recalcitrance of PDAC.

Organotypic-liver slide culture systems to explore the role of extracellular vesicles in pancreatic cancer metastatic behavior and guide new therapeutic approaches.

Introduction: Recent studies suggested that extracellular vesicles (EVs) play a role both in the metastatic niche formation and in the progression of several tumors, including pancreatic cancer. In particular, the effects of EVs on metastasis should be studied in model systems that take into account both the tumor cells and the metastatic site/tumor microenvironment. Studies with labeled EVs or EV-secreting cells in ex vivo models will reflect the physiological and pathological functions of EVs. The organotypic-tissue slide culture systems can fulfill such a role.Areas covered: This review provides an overview of available organotypic-culture slide systems. We specifically focus on the assay system of liver culture-slides in combination with pancreatic tumors, which can be modulated to test the efficacy of new therapeutic approaches.Expert opinion: The intercellular exchange of EVs has emerged as a biologically relevant phenomenon to drive cancer metastasis. However, further models need to be developed to better elucidate the functional roles of EVs. The use of novel organotypic slide culture systems provides the opportunity to explore the role of EVs in the metastatic behavior of pancreatic cancer, decreasing the use of costly and cumbersome organoid or animal models.

The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: Interplay with the complex tumor microenvironment and novel therapeutic strategies.

Cancer metastasis to distant organs is initiated by tumor cells that disseminate from primary heterogeneous tumors. The subsequent growth and survival of tumor metastases depend on different metabolic changes, which constitute one of the enigmatic properties of tumor cells. Aerobic glycolysis, 'the Warburg effect', contributes to tumor energy supply, by oxidizing glucose in a faster manner compared to oxidative phosphorylation, leading to an increased lactate production by lactate dehydrogenase A (LDH-A), which in turn affects the immune response. Surrounding stromal cells contribute to feedback mechanisms further prompting the acquisition of pro-invasive metabolic features. Hence, therapeutic strategies targeting the glycolytic pathway are intensively investigated, with a special interest on their anti-metastatic properties. Various small molecules, such as LDH-A inhibitors, have shown pre-clinical activity against different cancer types, and blocking LDH-A could also help in designing future complimentary therapies. Modulation of specific targets in cells with an altered glycolytic metabolism should indeed result in a milder and distinct toxicity profile, compared to conventional cytotoxic therapy, while a combination treatment with vitamin C leading to increasing reactive oxygen species levels, should further inhibit cancer cell survival and invasion. In this review we describe the impact of metabolic reprogramming in cancer metastasis, the contribution of lactate in this aberrant process and its effect on oncogenic processes. Furthermore, we discuss experimental compounds that target glycolytic metabolism, such as LDH-A inhibitors, and their potential to improve current and experimental therapeutics against metastatic tumors.