Obg-like ATPase 1 exacerbated gemcitabine drug resistance of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

MicroRNA-34a Alleviates Gemcitabine Resistance in Pancreatic Cancer by Repression of Cancer Stem Cell Renewal.

OBJECTIVES: This study aimed to enhance the sensitivity of pancreatic ductal adenocarcinoma cells by microRNA-34a (miR-34a)-mediated targeting of Notch 1. METHODS: Cell viability was determined by using an MTT (3-(4,5)-dimethylthiahiazo(-2)-3,5-diphenytetrazoliumromide) assay. The expression levels of miR-34a and relevant mRNAs were determined using quantitative polymerase chain reaction. Protein levels were measured by Western blotting. Cellular stemness was assessed by cell invasiveness and sphere formation assays. A transplanted tumor model was established for in vivo experiments. RESULTS: MicroRNA-34a enhanced gemcitabine sensitivity both in vivo and in vitro. MicroRNA-34a suppressed the stemness and proliferation of pancreatic cancer stem cells. MicroRNA-34a directly associated with Notch 1, which lies upstream of epithelial-mesenchymal transition signaling pathways. CONCLUSIONS: MicroRNA-34a sensitized pancreatic cancer cells to gemcitabine treatment by inhibiting Notch 1 signaling in pancreatic cancer stem cells, indicating that miR-34a has the potential to be developed as a novel therapeutic agent for the treatment of gemcitabine-resistant pancreatic ductal adenocarcinoma cells.

Early Detection of Pancreatic Cancer: Applying Artificial Intelligence to Electronic Health Records.

ABSTRACT: The potential of artificial intelligence (AI) applied to clinical data from electronic health records (EHRs) to improve early detection for pancreatic and other cancers remains underexplored. The Kenner Family Research Fund, in collaboration with the Cancer Biomarker Research Group at the National Cancer Institute, organized the workshop entitled: "Early Detection of Pancreatic Cancer: Opportunities and Challenges in Utilizing Electronic Health Records (EHR)" in March 2021. The workshop included a select group of panelists with expertise in pancreatic cancer, EHR data mining, and AI-based modeling. This review article reflects the findings from the workshop and assesses the feasibility of AI-based data extraction and modeling applied to EHRs. It highlights the increasing role of data sharing networks and common data models in improving the secondary use of EHR data. Current efforts using EHR data for AI-based modeling to enhance early detection of pancreatic cancer show promise. Specific challenges (biology, limited data, standards, compatibility, legal, quality, AI chasm, incentives) are identified, with mitigation strategies summarized and next steps identified.

Progress on the role of reactive oxygen species-mediated tumor microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a devastating malignant tumor with high incidence and mortality rate worldwide. Meanwhile, the surgical approaches and drugs of this disease remain challenging. In recent years, reactive oxygen species (ROSs) study has become a hotspot in the field of PC research. ROSs may regulate tumor mic roenvironment (TME), cancer stem cells (CSCs) renewal and epithelial-mesenchymal transition (EMT), which result in drug-resistance and recurrence of the PC. Currently, TME that includes immune infiltrates, fibroblasts, vascular vessels and extracellular matrix has become a hotspot in the cancer research. Meanwhile, numerous researches have shown that ROSs-mediated TME plays a central role in the occurrence and development of PC. Targeting ROSs may be promising therapeutic treatments for the PC patients. Therefore, the purposes of the review were manifold: (1) to summarize the regulations of ROSs in tumorigenesis and drug-resistance of PC; (2) to investigate the modulation of ROSs in signaling cascades in PC; (3) to study the effects of ROSs in stromal cells in PC; (4) to generalize the potent therapies targeting ROSs in PC. Overall, this review summarized the current status of ROSs in PC research and suggested some potential anti-PC drugs that may target ROSs.

Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review.

ABSTRACT: Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.

Proceedings of the 3rd International Conference for Cancer Metabolism and Therapy, October 12-14, 2018, Shanghai, China.

The 3 International Conference for Cancer Metabolism and Therapy was successfully held at the South Hospital Conference Center of Shanghai First People's Hospital, nearly 200 international experts from the field of cancer metabolism and therapy and about two thousand local scientists attended the conference. The conference was sponsored by the Yangtze River Delta City Group Hospital Synergistic Development Strategic Alliance, the China Anti-Cancer Association Cancer Metabolism Professional Committee, the Chinese Association for Cancer Metabolism and Therapy under Chinese Medical Doctoral Association-Clinical Precision Medicine, and co-organized by the First People's Hospital Affiliated to Shanghai Jiaotong University, and Shanghai Jiao Tong University School of Basic Medicine Undertake, Translational Medicine Network, Shanghai Anti-Cancer Association Youth Council, Fudan University Affiliated Tumor Hospital, University of California, Los Angeles, Agi Hirshberg Center for Pancreatic Diseases and Hirshberg Foundation for Pancreatic Cancer Research, Dalian University of Technology, New York-Presbyterian, American Cancer Research Association (AACR). The theme of the conference was 'Inheritance, Innovation, Excellence, Leading' and its aim is to create a high-end academic exchange platform to discuss new technologies, new methods, and new products in tumor metabolism, tumor immunity, tumor markers and other fields. The conference involves cancer metabolism reprogramming, metabolism and tumor microenvironment, lipid metabolism, non-metabolic function of metabolic enzymes, metabolism and epigenetics, clinical transformation, new technologies for tumor immunotherapy, clinical application of tumor immunotherapy, emerging targeted therapy, PD-1/PD-L1 technology, CAR-T technology, novel tumor protein markers, novel tumor methylation markers, ctDNA, CTC, etc. The meeting ended in a lively discussion among scientists from different levels who truly benefit from the sessions about cancer metabolism and treatment. The next meeting is planned to be held October 2 through October 6, 2019 in Los Angeles, Calif. The meeting venue will be announced accordingly in the meeting web site (www.cmt.org).

Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis.

The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.

MicroRNAs as effective surrogate biomarkers for early diagnosis of oral cancer.

BACKGROUND: Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns. OBJECTIVE: Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer. METHODS: A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer. RESULTS: In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, Notch signaling, and TGF-ß/SMAD signaling pathway. CONCLUSIONS: A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility. CLINICAL RELEVANCE: These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.

Assessment of Lipid and Metabolite Changes in Obese Calf Muscle Using Multi-Echo Echo-planar Correlated Spectroscopic Imaging.

Obesity-related conditions including heart disease, stroke, and type 2 diabetes are leading causes of preventable death. Recent evidence suggests that altered myocellular lipid metabolism in obesity may lead to increased insulin resistance (IR) that predisposes to these disorders. To test the hypothesis that muscles rich in type I vs. type II muscle fibers would exhibit similar changes in intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) content in obesity, we utilized a new four-dimensional multi echo echo-planar correlated spectroscopic imaging technique that allows separate determination of IMCL and EMCL content in individual calf muscles in obese vs. normal healthy human subjects. Calf muscles were scanned in 32 obese and 11 healthy subjects using a 3T MRI/MRS scanner, and IR in the obese subjects was documented by glucose tolerance testing. In obese subjects, elevation of both IMCL and EMCL content was observed in the gastrocnemius and tibialis anterior muscles (with mixed type I and II fiber content), while a significant increase in only IMCL content (+48%, p < 0.001) was observed in the soleus muscle (predominantly type I fibers). These observations indicate unexpected differences in changes in myolipid metabolism in type I vs. type II rich muscle regions in obesity, perhaps related to IR, and warrant further investigation.

Metabolic Regulation in Mitochondria and Drug Resistance.

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.

Early Detection of Pancreatic Cancer: The Role of Industry in the Development of Biomarkers.

A diagnosis of pancreatic cancer is devastating owing to its poor prognosis, with a 5-year survival rate of only 9%. Currently, most individuals are diagnosed at a late stage when treatment options are limited. Early detection of pancreatic cancer provides the greatest hope for making substantial improvements in survival. The Kenner Family Research Fund in partnership with the American Pancreatic Association has sponsored a series of fora to stimulate discussion and collaboration on early detection of pancreatic cancer. At the first forum in 2014, "Early Detection of Sporadic Pancreatic Cancer Summit Conference," a strategic plan was set forth by an international group of interdisciplinary scientific representatives and subsequently The Strategic Map for Innovation was generated. The current conference report is the third forum in the series, "Early Detection of Pancreatic Cancer: The Role of Industry in the Development of Biomarkers," which was held in Boston, Massachusetts, on October 27, 2016. This report provides an overview of examples of innovative initiatives by industry and confirms the critical need for collaboration among industry, government, research institutions, and advocacy groups in order to make pancreatic cancer more easily detectable in its earlier stages, when it is more treatable.