Differential progression of unhealthy dietinduced hepatocellular carcinoma in obese and non-obese mice

Background Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. Methods In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/ fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. Results Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. Conclusions Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis

Disparities in Awareness of and Willingness to Participate in Cancer Clinical Trials Between African American and White Cancer Survivors

BACKGROUND: Cancer clinical trials (CCTs) are essential for cancer care, yet the evidence is scarce when it comes to racial disparities in CCT participation among cancer survivors in the Midwest. This study aimed to 1) assess disparities in the awareness of and willingness to participate in CCTs between African American and White cancer survivors; and 2) compare perceptions about CCTs between the two racial groups. METHODS: The study was based on cross-sectional data from the survey Minority Patient Participation in Cancer Clinical Trials that collected information from 147 Black and White cancer survivors from Nebraska between 2015 and 2016. Chi-square tests and logistic regressions were used to assess differences between Black and White cancer survivors regarding their awareness, willingness, and perceptions associated with CCT participation. RESULTS: After adjusting for the effects of socio-demographic, health status, and psychosocial variables, Black cancer survivors were much less likely than White cancer survivors to be aware of CCTs (AOR 0.26; CI 0.08-0.81), to express willingness to participate in CCTs (AOR 0.03; CI 0.01, 0.32) and to actually participate in CCTs (AOR 0.13; CI 0.04-0.38). Black cancer survivors reported a lower level of trust in physicians and were less likely than White cancer survivors to believe that CCTs make a significant contribution to science. CONCLUSIONS: Relative to White cancer survivors, Black cancer survivors had much lower awareness of and willingness to participate in CCTs. Part of these differences might be related to the differential perception of CCTs, psychosocial factors, and trust in physicians between the two groups

Differential Progression of Unhealthy Diet-Induced Hepatocellular Carcinoma in Obese and Non-Obese Mice

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25-30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. METHODS: In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. RESULTS: Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. CONCLUSIONS: Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis

Socioeconomic status and cigarette expenditure among US households: results from 2010 to 2015 Consumer Expenditure Survey

Objectives To examine (1) the association between household socioeconomic status (SES) and whether a household spends money on cigarettes and (2) socioeconomic variations in proportion of total household expenditure spent on cigarettes among smoking households. Methods We pooled data from six consecutive years, 2010–2015, of the Consumer Expenditure Interview Survey. The interviews involved a structured questionnaire about household income, demographics and expenditures including expenditure on cigarettes. Households that reported cigarette expenditure in the previous 3 months were distinguished as smoking households. SES indicators were household poverty status, education and occupation of the head of household. Logistic regression was used to assess the association of household smoking status with SES. Fractional logistic regression was used to assess the association of cigarette expenditure as a proportion of total household expenditure with SES. The analysis sample size was 39 218. Results The probability of spending money on cigarettes was higher among lower SES households. Households in poverty compared with those above 300% of poverty threshold had 1.86 (95% CI 1.61 to 2.16), households headed by a person with less than high school education compared with those headed by a person with at least a bachelor’s degree had 3.37 (95% CI 2.92 to 3.89) and households headed by a blue-collar work compared with those headed by a person in a managerial occupation had 1.45 (95% CI 1.26 to 1.66) higher odds of spending money on cigarettes. Similarly, the proportion of total household expenditure spent on cigarettes was higher among lower SES smoking households. Conclusion Lower SES households are more likely to spend money on cigarettes and spend a larger proportion of their total expenditure on cigarettes. We recommend strategies effective in reducing smoking among low SES smokers

Relationships of Serum CC16 Levels with Smoking Status and Lung Function in COPD

Background: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects, and low CC16 serum levels have been associated with both risk and progression of COPD, yet the interaction between smoking and CC16 on lung function outcomes remains unknown. Methods: Utilizing cross-sectional data on United States veterans, CC16 serum concentrations were measured by ELISA and log transformed for analyses. Spirometry was conducted and COPD status was defined by post-bronchodilator FEV1/FVC ratio \u3c 0.7. Smoking measures were self-reported on questionnaire. Multivariable logistic and linear regression were employed to examine associations between CC16 levels and COPD, and lung function with adjustment for covariates. Unadjusted Pearson correlations described relationships between CC16 level and lung function measures, pack-years smoked, and years since smoking cessation. Results: The study population (N = 351) was mostly male, white, with an average age over 60 years. An interaction between CC16 and smoking status on FEV1/FVC ratio was demonstrated among subjects with COPD (N = 245, p = 0.01). There was a positive correlation among former smokers and negative correlation among current or never smokers with COPD. Among former smokers with COPD, CC16 levels were also positively correlated with years since smoking cessation, and inversely related with pack-years smoked. Increasing CC16 levels were associated with lower odds of COPD (ORadj = 0.36, 95% CI 0.22-0.57, Padj \u3c 0.0001). Conclusions: Smoking status is an important effect modifier of CC16 relationships with lung function. Increasing serum CC16 corresponded to increases in FEV1/FVC ratio in former smokers with COPD versus opposite relationships in current or never smokers. Additional longitudinal studies may be warranted to assess relationship of CC16 with smoking cessation on lung function among subjects with COPD

Practice, Knowledge, and Barriers for Screening of Hepatocellular Carcinoma Among High-Risk Chinese Patients

Background: Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths in China. Considering its poor prognosis when diagnosed late, Chinese guidelines recommend biannual screening for HCC with abdominal ultrasound and serum α-fetoprotein (AFP) test for high-risk populations. Objectives: To investigate the practice, knowledge, and self-perceived barriers for HCC screening among high-risk hospital patients in China. Methods: An interview-based questionnaire was conducted among Chinese patients with chronic hepatitis B and/or chronic hepatitis C infection from outpatient clinics at 2 tertiary medical institutions in Shanghai and Wuhan, China. Findings: Among 352 participating patients, 50.0% had routine screening, 23.3% had irregular screening, and 26.7% had incomplete or no screening. Significant determinants for screening included higher level of education, underlying liver cirrhosis, a family history of HCC, and better knowledge concerning viral hepatitis, HCC, and HCC screening guidelines. Moreover, factors associated with better knowledge were younger age, female gender, urban residency, education level of college or above, annual household income of greater than 150,000 RMB, and longer duration of hepatitis infection. The 3 most common barriers reported for not receiving screening were not aware that screening for HCC exists (41.5%), no symptoms or discomfort (38.3%), and lack of recommendation from physicians (31.9%). Conlusions: Health care professionals and community leaders should actively inform patients regarding the benefits of HCC screening through design of educational programs. Such interventions are expected to increase knowledge about HCC and HCC screening, as well as improve screening adherence and earlier diagnosis

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug–cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug–cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug–cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.Pfizer Inc.Institute for Collaborative BiotechnologiesMIT Center for Cell Decision ProcessesNational Institute of Mental Health (U.S.) (grant P50-GM68762)National Institute of Mental Health (U.S.) (grant T32-GM008334)Massachusetts Institute of Technology. Biotechnology Process Engineering CenterMassachusetts Institute of Technology. Center for Environmental Health SciencesNational Institute of Mental Health (U.S.) (grant U19ES011399)Whitaker Foundatio

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)