Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest

BACKGROUND: Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro. RESULTS: Apigenin caused both time- and concentration-dependent inhibition of DNA synthesis and cell proliferation in four pancreatic cancer cell lines. Apigenin induced G2/M phase cell cycle arrest. Apigenin reduced levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25, which are all proteins required for G2/M transition. CONCLUSION: Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer

Survival Among Patients With High-Risk Gastrointestinal Cancers During the COVID-19 Pandemic

Importance: Prior reports demonstrated that patients with cancer experienced worse outcomes from pandemic-related stressors and COVID-19 infection. Patients with certain malignant neoplasms, such as high-risk gastrointestinal (HRGI) cancers, may have been particularly affected. Objective: To evaluate disruptions in care and outcomes among patients with HRGI cancers during the COVID-19 pandemic, assessing for signs of long-term changes in populations and survival. Design, Setting, and Participants: This retrospective cohort study used data from the National Cancer Database to identify patients with HRGI cancer (esophageal, gastric, primary liver, or pancreatic) diagnosed between January 1, 2018, and December 31, 2020. Data were analyzed between August 23 and September 4, 2023. Main Outcome and Measures: Trends in monthly new cases and proportions by stage in 2020 were compared with the prior 2 years. Kaplan-Meier curves and Cox regression were used to assess 1-year mortality in 2020 compared with 2018 to 2019. Proportional monthly trends and multivariable logistic regression were used to evaluate 30-day and 90-day mortality in 2020 compared with prior years. Results: Of the 156 937 patients included in this study, 54 994 (35.0%) were aged 60 to 69 years and 100 050 (63.8%) were men. There was a substantial decrease in newly diagnosed HRGI cancers in March to May 2020, which returned to prepandemic levels by July 2020. For stage, there was a proportional decrease in the diagnosis of stage I (−3.9%) and stage II (−2.3%) disease, with an increase in stage IV disease (7.1%) during the early months of the pandemic. Despite a slight decrease in 1-year survival rates in 2020 (50.7% in 2018 and 2019 vs 47.4% in 2020), survival curves remained unchanged between years (all P > .05). After adjusting for confounders, diagnosis in 2020 was not associated with increased 1-year mortality compared with 2018 to 2019 (hazard ratio, 0.99; 95% CI, 0.97-1.01). The rates of 30-day (2.1% in 2018, 2.0% in 2019, and 2.1% in 2020) and 90-day (4.3% in 2018, 4.4% in 2019, and 4.6% in 2020) operative mortality also remained similar. Conclusions and Relevance: In this retrospective cohort study, a period of underdiagnosis and increase in stage IV disease was observed for HRGI cancers during the pandemic; however, there was no change in 1-year survival or operative mortality. These results demonstrate the risks associated with gaps in care and the tremendous efforts of the cancer community to ensure quality care delivery during the pandemic. Future research should investigate long-term survival changes among all cancer types as additional follow-up data are accrued.</p

Perception Is Reality: quality metrics in pancreas surgery – a Central Pancreas Consortium (CPC) analysis of 1399 patients

Several groups have defined pancreatic surgery quality metrics that identify centers delivering quality care. Although these metrics are perceived to be associated with good outcomes, their relationship with actual outcomes has not been established

The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation

Purpose: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. Patients and methods: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. Results: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70–0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63–0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. Conclusion: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.</p

Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study

Pancreatic mucinous cystic neoplasms (MCNs) harbor malignant potential, and current guidelines recommend resection. However, data are limited on preoperative risk factors for malignancy (adenocarcinoma or high-grade dysplasia) occurring in the setting of an MCN

The diagnosis of pancreatic mucinous cystic neoplasm and associated adenocarcinoma in males: An eight‐institution study of 349 patients over 15 years

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137278/1/jso24582_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137278/2/jso24582.pd

A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma

Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions

Iron drives anabolic metabolism through active histone demethylation and mTORC1

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.Metal analysis was performed at the Northwestern University Quantitative Bio-element Imaging Center generously supported by the National Research Resource for Quantitative Mapping in the Life Sciences (QE-Map) award number P41GM135018. Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Proteomics services were performed by Y. Ah Goo, in conjunction with N. L. Kelleher at the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. We thank M. J. Schipma, and B. Wray at the Northwestern University Sequencing Core and P. A. Ozark for their contribution to the ChIP–seq analyses. This work was supported through core services and support from the Northwestern University George M. O’Brien Kidney Research Core Center (NU GoKidney), an NIH/NIDDK-funded programme (P30 DK114857). This work was supported by the Northwestern University–Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system and BD FACSymphony S6 SORP system, purchased through the support of NIH 1S10OD011996-01 and 1S10OD026814-01. Additional funding for this work was provided through NRSA 5F30DK109608-02, and T32-DK007169 awarded to J.S.S., NHLBI HL127646, HL140973 and HL138982 awarded to H.A., U54CA193419 and R01GM038784 awarded to T.V.O., and the Spanish Ministry of Science, Innovation and Universities (MICINN) grant BIO2017-87828-C2-1-P and FEDER funds to S.P. Z.S.W. was supported in part by the National Institutes of Health Training Grant T32GM008449 through Northwestern University’s Biotechnology Training Program.Peer reviewe

Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection

The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival