The Role of CDK4 in the Pathogenesis of Pancreatic Cancer.

Pancreatic cancer (PC) continues to have the lowest overall survival and the lack of effective early diagnosis. Cyclin-dependent kinase 4 (CDK4) plays a fundamental role in the orderly progression of the cell cycle, binding to cyclin D to promote the progression through the G1/2 transition. The inhibition of CDK4/6 has therefore gained substantial interest in the hope of new and effective therapeutics in multiple cancers, such as advanced metastatic breast cancer. While the use of these agents is encouraging, their potential is yet to be fully explored. In this study we used the GLOBOCAN database to understand the most recent epidemiology of PC, Human Protein Atlas and KEGG to highlight the role, prevalence, and significance on patient survival of CDK4 in PC. We found that CDK4 cannot be used as prognostic in PC and no significant differences were observed between CDK4 expression and the patient's clinical status, though larger studies, especially concerning CDK4 protein expressions, are required for a more thorough understanding. The use of CDK4/6 inhibitors in PC is still in clinical trials. However, due to only modest improvements observed in the use of single-agent therapies, efforts have focused on combinatorial approaches

Inhibiting CDK4/6 in pancreatic ductal adenocarcinoma via microRNA-21

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a 5-year survival rate of 5–10 %. The high mortality rate is due to the asymptomatic progression of clinical features in metastatic stages of the disease, which renders standard therapeutic options futile. PDAC is characterised by alterations in several genes that drive carcinogenesis and limit therapeutic response. The two most common genetic aberrations in PDAC are the mutational activation of KRAS and loss of the tumour suppressor CDK inhibitor 2A (CDKN2A), which culminate the activation of the cyclin-dependent kinase 4 and 6 (CDK4/6), that promote G1 cell cycle progression. Therapeutic strategies focusing on the CDK4/6 inhibitors such as palbociclib (PD-0332991) may potentially improve outcomes in this malignancy. MicroRNAs (miRs/miRNAs) are small endogenous non-coding RNA molecules associated with cellular proliferation, invasion, apoptosis, and cell cycle. Primarily, miR-21 promotes cell proliferation and a higher proportion of PDAC cells in the S phase, while knockdown of miR-21 has been linked to cell cycle arrest at the G2/M phase and inhibition of cell proliferation. In this study, using a CRISPR/Cas9 loss-of-function screen, we individually silenced the expression of miR-21 in two PDAC cell lines and in combination with PD-0332991 treatment, we examined the synergetic mechanisms of CDK4/6 inhibitors and miR-21 knockouts (KOs) on cell survival and death. This combination reduced cell proliferation, cell viability, increased apoptosis and G1 arrest in vitro. We further analysed the mitochondrial respiration and glycolysis of PDAC cells; then assessed the protein content of these cells and revealed numerous Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PD-0332991 treatment and miR-21 knocking out. Our results demonstrate that combined targeting of CDK4/6 and silencing of miR-21 represents a novel therapeutic strategy in PDAC

Efficient Time and Space Representation of Uncertain Event Data

Process mining is a discipline which concerns the analysis of execution data of operational processes, the extraction of models from event data, the measurement of the conformance between event data and normative models, and the enhancement of all aspects of processes. Most approaches assume that event data is accurately capture behavior. However, this is not realistic in many applications: data can contain uncertainty, generated from errors in recording, imprecise measurements, and other factors. Recently, new methods have been developed to analyze event data containing uncertainty; these techniques prominently rely on representing uncertain event data by means of graph-based models explicitly capturing uncertainty. In this paper, we introduce a new approach to efficiently calculate a graph representation of the behavior contained in an uncertain process trace. We present our novel algorithm, prove its asymptotic time complexity, and show experimental results that highlight order-of-magnitude performance improvements for the behavior graph construction.Comment: 34 pages, 16 figures, 5 table

MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC

AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines

The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells

miR-34a-FOXP1 Loop in Ovarian Cancer

Ovarian cancer (OC) is the main cause of gynecological cancer mortality in most developed countries. microRNA (miR) expression dysregulation has been highlighted in human cancers, and miR-34a is found to be downregulated and associated with inhibition of tumor growth and invasion in several malignancies, including OC. The winged helix transcription factor forkhead box P1 (FOXP1) is reported as either an oncogene or tumor suppressor in various cancers. This study aimed to elucidate potential clinical and biological associations of miR-34a and transcription factor FOXP1 in OC. We investigated nine OC patients’ blood samples and two OC cell lines (SKOV-3 and OVCAR-3) using quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) to determine both miR-34a and FOXP1 expressions. We have found that miR-34a and FOXP1 are reversely correlated in both in vitro and in vivo. Inhibition of miR-34a transiently led to upregulation of FOXP1 mRNA expression and increased cellular invasion in vitro. Our data indicate that miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC, and miR-34a overexpression may reduce OC pathogenesis by targeting FOXP1