Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras

Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, the contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1Cre and Pdx1Cre;LSL- KrasG12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. In addition, mice were treated with cerulein, for induction of pancreatitis, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the Pdx1Cre;LSL- KrasG12D mice but not in the control Pdx1Cre mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in Pdx1Cre;LSL- KrasG12D mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the Pdx1Cre;LSL- KrasG12D mice, but its origin remained elusive due to leakiness of Pdx1Cre in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors ( Epcam, Krt19, Prom1, Wt1, and Wwtr1), stroma ( Dcn, Fn1, and Tnc), and cytokines ( Tgfb1 and Tnf) and decreases expression of Fgf21 and Il6 in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of nephronectin, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC. NEW & NOTEWORTHY Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in Pdx1Cre;LSL- KrasG12D mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC.

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Age- and sex-specific modifiable risk factor profiles of dementia: evidence from the UK Biobank

10.21203/rs.3.rs-1057766/v1 ◽

2021 ◽

Author(s):

Hui Chen ◽

Yaying Cao ◽

Yuan Ma ◽

Geng Zong ◽

Changzheng Yuan

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Alcohol Intake ◽

Health Condition ◽

Modifiable Risk Factors ◽

Uk Biobank ◽

Younger Adults ◽

Moderate Alcohol Intake ◽

The Uk ◽

Age And Sex

Abstract Background: To inform targeted preventive strategies of dementia, systematic investigation in its age- and sex-specific modifiable risk factor profiles in the general adult population is warranted.Methods: We used data of 372,867 adults free from dementia at baseline (2006-2010) in the UK Biobank, and followed them up until March 2021. We assigned participants into five groups according to their age and into two groups according to their sex. We estimated the age- and sex-specific hazard ratios (HRs) using Cox proportional hazard models and calculated the corresponding population attributable fractions (PAFs) for dementia attributable to three major categories of modifiable risk factors, including socioeconomic (low education level, high Townsend deprivation index), lifestyle (non-moderate alcohol intake, current smoking, suboptimal diet, non-regular physical exercise, and sleep duration <=6 or >=8 hrs/d), and health condition (hypertension, diabetes, cardiovascular diseases, and depressive symptom) risk factors.Findings: During 4,338,030 person-years of follow-up, 113, 146, 360, 1,087, and 2,002 of participants across five increasing age groups (40-<50, 50-<55, 55-<60, 60-<65, or >=65 y), respectively, were newly diagnosed with dementia. Five out of eleven modifiable risk factors showed significantly stronger associations with dementia among younger adults than in relatively older adults (P-interactions < 0.05), including non-moderate alcohol intake (HR [95% confidence interval, CI]=1.90 [1.35, 2.68] for participants 50-<55 y vs. 1.22 [1.11, 1.35] for participants > 65 y), suboptimal diet (1.86 [1.26, 2.74] for participants 40-< 50 y vs. 0.96 [0.86, 1.06] for participants > 65 y), hypertension (1.52 [0.96, 2.42] vs. 1.08 [0.99, 1.19]), CVD (4.20 [2.15, 8.22] vs. 1.64 [1.45, 1.85]), and diabetes (3.09 [1.60, 6.00] vs. 1.73 [1.51, 2.00]). We observed no significant difference in dementia risk factor profiles between women and men. Dementia cases attributable to three categories of risk factors all decreased with age, with the PAFs (95% CI) for sociodemographic, lifestyle, and health condition risk factors being 52.56% (22.98%, 82.15%), 46.57% (8.08%, 85.06%), and 35.42% (24.09%, 46.75%) for participants aged 40-<50 y, and 12.29% (3.82%, 20.75%), 13.01% (2.53%, 23.49%), and 15.85% (11.81%, 19.90%) for those over 65 y.Interpretation: This study identified stronger association and greater attributable risk of several modifiable risk factors for dementia among younger adults, underscoring the importance of preventive strategies from an earlier age across adult life course to reduce the risk of dementia.

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Future Burden of Cancer Attributable to Current Modifiable Behaviours: A Pooled Study of Seven Australian Cohorts

Journal of Global Oncology ◽

10.1200/jgo.18.18500 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 5s-5s

Author(s):

M.A. Laaksonen ◽

M.E. Arriaga ◽

K. Canfell ◽

R.J. MacInnis ◽

P. Hull ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Risk Factor ◽

Alcohol Intake ◽

Breast Cancers ◽

Premenopausal Breast Cancer ◽

Current Smoking ◽

Cancer Burden ◽

The Future ◽

Future Burden

Background: The Population Attributable Fraction (PAF) quantifies the fraction of cancer cases attributable to specific exposures. PAF estimates for the future burden of cancer preventable through modifications to current exposure distributions are lacking. Previous PAF studies have also not compared population subgroup differences. Aim: To apply a novel PAF method and i) assess the future burden of cancer in Australia preventable through modifications to current behaviors, and ii) compare the distribution of the preventable cancer burden between population subgroups. Methods: We harmonized and pooled data from seven Australian cohort studies (N=367058) and linked them to national registries to identify cancers and deaths. We estimated the strength of the associations between behaviors and cancer incidence and death using a proportional hazards model, adjusting for age, sex, study and other risk factors. Exposure prevalence was estimated from contemporary national health surveys. We then combined these estimates to calculate PAFs and their 95% confidence intervals for both individual and joint behavior modifications using a novel method accounting for competing risk of death and risk factor interdependence. We also compared PAFs between population subgroups by calculating the 95% confidence interval of the difference in PAF estimates. Results: During the first 10 years of follow-up, there were 22078 deaths and 27483 incident cancers, including 2025 lung, 3471 colorectal, 640 premenopausal and 2632 postmenopausal breast cancers. The leading preventable cause for lung cancer is current smoking (PAF = 53.7%), for colorectal and postmenopausal breast cancer body fatness or BMI ≥ 25 kg/m2 (PAF = 11.1% and 10.9% respectively), and for premenopausal breast cancer regular alcohol intake (PAF = 12.3%). Three in five lung cancers, but only one in five colorectal and breast cancers, are jointly attributable to potentially modifiable exposures, which also included physical inactivity and inadequate fruit intake for lung, excessive alcohol intake and current smoking for colorectal, regular alcohol intake and current menopausal hormone therapy for 1 year or more for postmenopausal breast and current oral contraceptive use for 5 years or more for premenopausal breast cancer. The cancer burden attributable to modifiable factors is markedly higher in certain population subgroups, including men (lung, colorectal), people with risk factor clustering (lung, colorectal, breast), and individuals with low educational attainment (lung, breast). Conclusion: We provided up-to-date estimates of the future Australian cancer burden attributable to modifiable risk factors, and identified population subgroups that experience the highest preventable burden. Application of the novel PAF method can inform timely public health action to improve health and health equity, by identifying those with the most to gain from programs that support behavior change and early detection.

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Pancreatic ductal adenocarcinoma from a surgical perspective

International Journal of Cancer Research & Therapy ◽

10.33140/ijcrt.06.02.13 ◽

2021 ◽

Vol 6 (2) ◽

Keyword(s):

Risk Factors ◽

Pancreatic Ductal Adenocarcinoma ◽

Adjuvant Treatment ◽

Locally Advanced ◽

Historical Background ◽

Ductal Adenocarcinoma ◽

Curative Intent ◽

Pancreatic Cancers ◽

Operative Care ◽

Histological Staging

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancers. Whilst most patients present with locally advanced or metastatic disease, a minority are candidates for curative-intent resection. This review covers the aspects of PDAC which are relevant to the surgeon. Firstly, an up-to-date overview of epidemiology, risk factors and pathogenesis are provided. Secondly, presentation, diagnosis and staging are covered, including a summary of the most recent staging guidelines. The review will then focus on the historical background of the pancreatico-duodenectomy (PD), the modern procedure and post-operative care. Finally, short sections provide the reader with an update on histological staging and adjuvant treatment.

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Liver Metastases in Newly Diagnosed Pancreatic Ductal Adenocarcinoma: A Population Based Analysis

10.21203/rs.2.20788/v1 ◽

2020 ◽

Author(s):

Guoyi Wu ◽

Xiaoben Pan ◽

Baohua Wang ◽

Xiaolei Zhu ◽

Jing Wu ◽

...

Keyword(s):

Risk Factors ◽

Liver Metastases ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Size ◽

Cox Regression ◽

Population Based ◽

The Body ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Factors Associated

Abstract Background Estimates of the incidence and prognosis of developing liver metastases at the pancreatic ductal adenocarcinoma (PDAC) diagnosis are lacking.Methods In this study, we analyzed the association of liver metastases and the PDAC patients outcome. The risk factors associated with liver metastases in PDAC patients were analyzed using multivariable logistic regression analysis. The overall survival (OS) was estimated using Kaplan-Meier curves and log-rank test. Cox regression was performed to identify factors associated with OS.Results Patients with primary PDAC in the tail of the pancreas had a higher incidence of liver metastases (62.2%) than those with PDAC in the head (28.6%). Female gender, younger age, primary PDAC in the body or tail of the pancreas, and larger primary PDAC tumor size were positively associated with the occurrence of liver metastases. The median survival of patients with liver metastases was significantly shorter than that of patients without liver metastases. Older age, unmarried status, primary PDAC in the tail of the pancreas, and tumor size ≥4 cm were risk factors for OS in the liver metastases cohort.Conclusions Population-based estimates of the incidence and prognosis of PDAC with liver metastases may help decide whether diffusion-weighted magnetic resonance imaging should be performed in patients with primary PDAC in the tail or body of the pancreas. The location of primary PDAC should be considered during the diagnosis and treatment of primary PDAC.

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