A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction.

Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.

An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study.

AIMS/HYPOTHESIS: We aimed to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus decreases the risk of new-onset adverse cardiovascular events (CVEs) and mortality rate compared with other glucose-lowering drugs in a real setting at a population level. METHODS: We conducted a population-based propensity-matched retrospective cohort study using TriNetX. The cohort comprised patients over 20 years old who were newly treated with glucose-lowering drugs between 1 January 2013 and 31 December 2021, and followed until 30 September 2022. New users of GLP-1RAs were matched based on age, demographics, comorbidities and medication use by using 1:1 propensity matching with other glucose-lowering drugs. The primary outcome was the new onset of adverse CVEs, including heart failure, composite incidence of major adverse cardiovascular events (MACE; defined as unstable angina, myocardial infarction, or coronary artery procedures or surgeries) and composite cerebrovascular events (defined as the first occurrence of stroke, transient ischaemic attack, cerebral infarction, carotid intervention or surgery), and the secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate HRs. RESULTS: The study involved 2,835,398 patients with both NAFLD and type 2 diabetes. When compared with the sodium-glucose cotransporter 2 (SGLT2) inhibitors group, the GLP-1RAs group showed no evidence of a difference in terms of new-onset heart failure (HR 0.97; 95% CI 0.93, 1.01), MACE (HR 0.95; 95% CI 0.90, 1.01) and cerebrovascular events (HR 0.99; 95% CI 0.94, 1.03). Furthermore, the two groups had no evidence of a difference in mortality rate (HR 1.06; 95% CI 0.97, 1.15). Similar results were observed across sensitivity analyses. Compared with other second- or third-line glucose-lowering medications, the GLP-1RAs demonstrated a lower rate of adverse CVEs, including heart failure (HR 0.88; 95% CI 0.85, 0.92), MACE (HR 0.89; 95% CI 0.85, 0.94), cerebrovascular events (HR 0.93; 95% CI 0.89, 0.96) and all-cause mortality rate (HR 0.70; 95% CI 0.66, 0.75). CONCLUSIONS/INTERPRETATION: In individuals with NAFLD and type 2 diabetes, GLP-1RAs are associated with lower incidences of adverse CVEs and all-cause mortality compared with metformin or other second- and third-line glucose-lowering medications. However, there was no significant difference in adverse CVEs or all-cause mortality when compared with those taking SGLT2 inhibitors.

Racial Disparities in Candidates for Hepatocellular Carcinoma Liver Transplant After 6-Month Wait Policy Change.

Importance: Racial disparities in liver transplant (LT) for hepatocellular carcinoma (HCC) may be associated with unequal access to life-saving treatment. Objective: To quantify racial disparities in LT for HCC and mortality after LT, adjusting for demographic, clinical, and socioeconomic factors. Design, Setting, and Participants: This cohort study was a retrospective analysis of United Network Organ Sharing/Organ Procurement Transplant Network (OPTN) data from 2003 to 2021. Participants were adult patients with HCC on the LT waiting list and those who received LT. Data were analyzed from March 2022 to September 2023. Exposures: Race and time before and after the 2015 OPTN policy change. Main Outcomes and Measures: Proportion of LT from wait-listed candidates, the proportion of waiting list removals, and mortality after LT. Results: Among 12 031 patients wait-listed for LT with HCC (mean [SD] age, 60.8 [7.4] years; 9054 [75.3%] male; 7234 [60.1%] White, 2590 [21.5%] Latinx/o/a, and 1172 [9.7%] Black or African American), this study found that after the 2015 model of end-stage liver disease (MELD) exception policy changes for HCC (era 2), the overall proportion of LT for HCC across all races decreased while the proportion of dropouts on the LT waiting list remained steady compared with patients who did not have HCC. In Kaplan-Meier analysis, Asian patients demonstrated the lowest dropout rates in both era 1 and era 2 (1-year dropout, 16% and 17%, respectively; P < .001). In contrast, Black or African American patients had the highest dropout rates in era 1 (1-year dropout, 24%), but comparable dropout rates (23%) with White patients (23%) and Latinx/o/a patients in era 2 (23%). In both eras, Asian patients had the highest survival after LT (5-year survival, 82% for era 1 and 86% for era 2), while Black or African American patients had the worst survival after LT (5-year survival, 71% for era 1 and 79% for era 2). In the multivariable analysis for HCC LT recipients, Black or African American race was associated with increased risk of mortality in both eras, compared with White race (HR for era 1, 1.17; 95% CI, 1.05-1.35; and HR for era 2, 1.31; 95% CI, 1.10-1.56). Conclusions and Relevance: This cohort study of LT candidates in the US found that after the 2015 MELD exception policy change for HCC, the proportion of LT for HCC had decreased for all races. Black or African American patients had worse outcomes after LT than other races. Further research is needed to identify the underlying causes of this disparity and develop strategies to improve outcomes for HCC LT candidates.

Epigenetic control of pancreatic cancer metastasis.

Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.

Association of Statin Use With Risk of Liver Disease, Hepatocellular Carcinoma, and Liver-Related Mortality.

Importance: Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed. Objective: To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population. Design, Setting, and Participants: This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023. Exposure: Regular statin use. Main Outcomes and Measures: Primary outcomes were liver disease and HCC development as well as liver-associated death. Results: A total of 1 785 491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98 497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205 057) without previously diagnosed liver disease, statin users (n = 56 109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P < .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1 568 794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11 640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02). Conclusions and Relevance: This cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.

Association of Helicobacter pylori Positivity With Risk of Disease and Mortality.

INTRODUCTION: Helicobacter pylori colonizes the human stomach. Infection causes chronic gastritis and increases the risk of gastroduodenal ulcer and gastric cancer. Its chronic colonization in the stomach triggers aberrant epithelial and inflammatory signals that are also associated with systemic alterations. METHODS: Using a PheWAS analysis in more than 8,000 participants in the community-based UK Biobank, we explored the association of H. pylori positivity with gastric and extragastric disease and mortality in a European country. RESULTS: Along with well-established gastric diseases, we dominantly found overrepresented cardiovascular, respiratory, and metabolic disorders. Using multivariate analysis, the overall mortality of H. pylori -positive participants was not altered, while the respiratory and Coronovirus 2019-associated mortality increased. Lipidomic analysis for H. pylori -positive participants revealed a dyslipidemic profile with reduced high-density lipoprotein cholesterol and omega-3 fatty acids, which may represent a causative link between infection, systemic inflammation, and disease. DISCUSSION: Our study of H. pylori positivity demonstrates that it plays an organ- and disease entity-specific role in the development of human disease and highlights the importance of further research into the systemic effects of H. pylori infection.

A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids.

BACKGROUND: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis. AIM: To examine the effects of missense variants in MTTP on hepatic and circulating lipids. METHODS: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444). RESULTS: We analysed 24 missense variants in MTTP in PMBB for association with biopsy-proven hepatic steatosis and found that an isoleucine 128 to threonine variant (I128T: rs3816873-A, frequency 26%) was associated with reduced steatosis (p < 0.001). PMBB subjects with imaging-proven steatosis also revealed significantly fewer carriers of MTTP I128T compared to controls. Analysis in UKB also showed that MTTP I128T was associated with reduced risk of hepatic steatosis. Unexpectedly, MTTP I128T was found to be associated with reduced plasma levels of LDL-cholesterol and apoB (all p < 0.001). Functional studies indicated that MTTP I128T is neither a classic loss nor gain of function allele. CONCLUSIONS: MTTP I128T is associated with reduced hepatic steatosis as well as reduced plasma lipids and apoB. This paradoxical profile is not consistent with a simple gain or loss of function in MTP activity and suggests a more complex effect on MTP function. Further investigation of MTTP I128T will provide insight into the structure-function of MTP and potentially new approaches to modulate MTP activity that could both reduce hepatic and circulating lipids.

Comorbidities, biomarkers and cause specific mortality in patients with irritable bowel syndrome: A phenome-wide association study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional digestive disorders. Our understanding about its comorbidities, biomarkers, or long-term risks is still incomplete. OBJECTIVE: To characterize comorbidities and biomarkers for IBS and establish the effect of IBS on overall- and cause specific mortality. METHODS: We analyzed data from the population-based cohort of the UK Biobank (UKB) with 493,974 participants, including self-reported physician-diagnosed (n = 20,603) and ICD-10 diagnosed (n = 7656) IBS patients, with a mean follow-up of 11 years. We performed a phenome-wide association study (PheWAS) and competing risk analysis to characterize common clinical features in IBS patients. RESULTS: In PheWAS analyses, 260 PheCodes were significantly overrepresented in self-reported physician-diagnosed IBS patients, 633 in patients with ICD-10 diagnosed IBS (ICD-10-IBS), with 221 (40%) overlapping. In addition to gastrointestinal diseases, psychiatric, musculoskeletal, and endocrine/metabolic disorders represented the most strongly associated PheCodes in IBS patients. Self-reported physician-diagnosed IBS was not associated with increased overall mortality and the risk of death from cancer was decreased (hazard ratio [HR] = 0.78 [95% CI = 0.7-0.9]). Lastly, we evaluated changes in serum metabolites in IBS patients and identified glycoprotein acetyls (GlycA) as a potential biomarker in IBS. One standard deviation increase in GlycA raised the risk of self-reported IBS/ICD-10 coded by 9%-20% (odds ratio [OR] = 1.09 [95% CI = 1.1-1.1]/OR = 1.20 [95% CI = 1.1-1.3]) and the risk of overall mortality in ICD-10-IBS patients by 28% (HR = 1.28 [95% CI = 1.1-1.5]). CONCLUSION: Our large-scale association study determined IBS patients having an increased risk of several different comorbidities and that GlycA was increased in IBS patients.

AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer.

Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF-MEK-ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.

Phenome of coeliac disease vs. inflammatory bowel disease.

Coeliac disease (CeD) is characterized by gliadin-induced intestinal inflammation appearing in genetically susceptible individuals, such as HLA-DQ2.5 carriers. CeD, as well as other chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis, has been associated with increased morbidity and mortality, but the causes are unknown. We systematically analysed CeD-associated diagnoses and compared them to conditions enriched in subjects with CD/UC as well as in HLA-DQ2.5 carriers without CeD. We compared the overall and cause-specific mortality and morbidity of 3,001 patients with CeD, 2,020 with CD, 4,399 with UC and 492,200 controls in the community-based UK Biobank. Disease-specific phenotypes were assessed with the multivariable Phenome Wide Association Study (PheWAS) method. Associations were adjusted for age, sex and body mass index. All disease groups displayed higher overall mortality than controls (CD: aHR = 1.91[1.70-2.17]; UC: aHR = 1.32 [1.20-1.46]; CeD: aHR = 1.38 [1.22-1.55]). Cardiovascular and cancer-related deaths were responsible for the majority of fatalities. PheWAS analysis revealed 166 Phecodes overrepresented in all three disorders, whereas only ~ 20% of enriched Phecodes were disease specific. Seven of the 58 identified CeD-specific Phecodes were enriched in individuals homozygous for HLA-DQ2.5 without diagnosed CeD. Four out of these seven Phecodes and eight out of 19 HLA-DQ2.5 specific Phecodes were more common in homozygous HLA-DQ2.5 subjects with vs. without CeD, highlighting the interplay between genetics and diagnosis-related factors. Our study illustrates that the morbidity and mortality in CeD share similarities with CD/UC, while the CeD-restricted conditions might be driven by both inherited and acquired factors.

Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6-/- mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.

COVID-19: Challenges and solutions for the provision of care to seriously ill and dying people and their relatives during SARS-CoV-2 pandemic - perspectives of pandemic response team members: A qualitative study on the basis of expert interviews (part of PallPan).

BACKGROUND: During the SARS-CoV-2 pandemic's initial waves, bans on visiting and isolation measures placed limits on providing services for seriously ill and dying people and their relatives. Pandemic response teams at governmental level (macro), at federal state and municipal level (meso) and in healthcare facilities (micro) played their role in pandemic management procedures. AIM: To explore pandemic-related challenges and solutions of pandemic response teams regarding the provision of care to seriously ill and dying people and their relatives. Findings were to be integrated into a national strategy (PallPan). DESIGN: Semi-structured expert interviews (10/2020-2/2021) analysed via structured content analysis. SETTINGPARTICIPANTS: We interviewed 41 members, who discussed the work of 43 German pandemic response teams (micro n = 23; meso n = 20; no members were available at macro level) from 14 German federal states. RESULTS: Twenty-nine of 43 teams took account of the needs of seriously ill and dying. Their main challenges resulted from pandemic-related legal requirements in hospitals and long-term care facilities. The implementation of such was in the remits of the meso level. Dysfunctional or non-existent communication between the levels was reported to be challenging. To foster patient-related solutions the micro level pandemic response teams supported individual decisions to enable patient-relative contact for example, visiting and saying goodbye outside, meeting via digital solutions. CONCLUSIONS: Pandemic response teams evidently struggled to find appropriate solutions to ease pandemic-related impact on the care of seriously ill and dying patients and their relatives. We recommend bringing palliative care expertise on board.

Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype.

Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need for novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered an MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirmed the increased efficacy of PRMT5 inhibitors in MYC-deregulated PDACs. Although inhibition of PRMT5 was inducing DNA damage and arresting PDAC cells in the G2/M phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor-sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.

Association of Telomere Length With Risk of Disease and Mortality.

IMPORTANCE: Telomeres protect DNA from damage. Because they shorten with each mitotic cycle, leukocyte telomere length (LTL) serves as a mitotic clock. Reduced LTL has been associated with multiple human disorders. OBJECTIVE: To determine the association between LTL and overall as well as disease-specific mortality and morbidity. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, community-based cohort study conducted from March 2006 to December 2010 included longitudinal follow-up (mean [SD], 12 [2] years) for 472 432 English participants from the United Kingdom Biobank (UK Biobank) and analyzed morbidity and mortality. The data were analyzed in 2021. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) and odds ratios for mortality and morbidity associated with a standard deviation change in LTL, adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), and ethnicity. RESULTS: This study included a total of 472 432 English participants, of whom 54% were women (mean age, 57 years). Reduced LTL was associated with increased overall (HR, 1.08; 95% CI, 1.07-1.09), cardiovascular (HR, 1.09; 95% CI, 1.06-1.12), respiratory (HR, 1.40; 95% CI, 1.34-1.45), digestive (HR, 1.26; 95% CI, 1.19-1.33), musculoskeletal (HR, 1.51; 95% CI, 1.35-1.92), and COVID-19 (HR, 1.15; 95% CI, 1.07-1.23) mortality, but not cancer-related mortality. A total of 214 disorders were significantly overrepresented and 37 underrepresented in participants with shorter LTL. Respiratory (11%), digestive/liver-related (14%), circulatory (18%), and musculoskeletal conditions (6%), together with infections (5%), accounted for most positive associations, whereas (benign) neoplasms and endocrinologic/metabolic disorders were the most underrepresented entities. Malignant tumors, esophageal cancer, and lymphoid and myeloid leukemia were significantly more common in participants with shorter LTL, whereas brain cancer and melanoma were less prevalent. While smoking and alcohol consumption were associated with shorter LTL, additional adjustment for both factors, as well as cognitive function/major comorbid conditions, did not significantly alter the results. CONCLUSIONS AND RELEVANCE: This cohort study found that shorter LTL was associated with a small risk increase of overall mortality, but a higher risk of mortality was associated with specific organs and diseases.