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SummaryInactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.

SummaryThe natural product englerin A (EA) binds to and activates protein kinase C-θ (PKCθ). EA-dependent activation of PKCθ induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCθ-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors.

Background Liver cancer is one of most commonly diagnosed cancers among Koreans. Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cancer. HBV infection can be prevented by effective screening and vaccination programs. The purpose of this study is to examine the status of HBV infection and the predictors associated with HBV vaccination. Methods The study population was derived from the 2005 Korea National Cancer Screening Survey (KNCSS). The KNCSS is an annual cross-sectional survey that uses a nationally-representative random sampling to investigate cancer screening rates. A total of 1,786 Koreans over 40 years of age participated in this study. Results Of all the participants, 5.9% reported HBV positive (HBsAg+, HBsAb-), 41.8% were HBV negative but protected (HBsAg-, HBsAb+), and 52.3% were unprotected (HBsAg-, HBsAb-). Among unprotected individuals (n = 934), 23.1% reported to have received the vaccination. About half of those who had vaccinations completed the 3-shot vaccine series. In multiple analyses, education, having private cancer insurance, alcohol use, having regular check-up, and doing regular exercise were associated with completed HBV vaccination. Conclusion This study result suggests that we need a liver cancer education program to increase HBV awareness and to increase the liver cancer prevention message among low educated populations.

Figure S1. Contingency plot of HPV subtype and development of a partial response to avelumab. Assessed for statistical significance with the Fisher’s exact test. Figure S2. Contingency plot of HPV subtype and the presence of pulmonary disease. Assessed for statistical significance with the Fisher’s exact test. Figure S3. Contingency plot of patients who received polyvalent HPV vaccine prior to enrollment and patients who experienced a partial response to avelumab. Assessed for statistical significance with the Fisher’s exact test. Figure S4. Expression of individual HPV 6 or 11 genes. Expression of individual HPV 6 (patients 5, 7, and 8) or HPV 11 (patient 9) genes in papilloma and normal mucosa was measured by droplet digital polymerase chain reaction. Figure S5. Baseline representative immunohistochemistry photomicrographs and quantification of percentage of papilloma infiltrating CD8+ cells and total PD-L1+ cells. Percentage of positive cells inset within photomicrographs. Quantification of staining in eleven of twelve patients with evaluable biopsies represent percentage of total cells in the entire section. Assessed for statistical significance with the Mann-Whitney test. Figure S6. Gene expression profiling of papillomas and normal tissue. A heatmap demonstrating unsupervised hierarchical clustering of expression of individual genes or gene signatures is shown. Gene expression was measured by NanoString IO 360 analysis in pre-treatment (pre), on-treatment (2wk) and post-treatment (off) papilloma and normal mucosa biopsies. Each horizontal row represents a separate biopsy. Each unit increase of expression on the heatmap scale is a doubling of the biologic process it represents. The red box highlights differences in TGFβ gene expression between papilloma and normal mucosa biopsies. (DOCX 3090 kb)

Figure S1. Contingency plot of HPV subtype and development of a partial response to avelumab. Assessed for statistical significance with the Fisher’s exact test. Figure S2. Contingency plot of HPV subtype and the presence of pulmonary disease. Assessed for statistical significance with the Fisher’s exact test. Figure S3. Contingency plot of patients who received polyvalent HPV vaccine prior to enrollment and patients who experienced a partial response to avelumab. Assessed for statistical significance with the Fisher’s exact test. Figure S4. Expression of individual HPV 6 or 11 genes. Expression of individual HPV 6 (patients 5, 7, and 8) or HPV 11 (patient 9) genes in papilloma and normal mucosa was measured by droplet digital polymerase chain reaction. Figure S5. Baseline representative immunohistochemistry photomicrographs and quantification of percentage of papilloma infiltrating CD8+ cells and total PD-L1+ cells. Percentage of positive cells inset within photomicrographs. Quantification of staining in eleven of twelve patients with evaluable biopsies represent percentage of total cells in the entire section. Assessed for statistical significance with the Mann-Whitney test. Figure S6. Gene expression profiling of papillomas and normal tissue. A heatmap demonstrating unsupervised hierarchical clustering of expression of individual genes or gene signatures is shown. Gene expression was measured by NanoString IO 360 analysis in pre-treatment (pre), on-treatment (2wk) and post-treatment (off) papilloma and normal mucosa biopsies. Each horizontal row represents a separate biopsy. Each unit increase of expression on the heatmap scale is a doubling of the biologic process it represents. The red box highlights differences in TGFβ gene expression between papilloma and normal mucosa biopsies. (DOCX 3090 kb)

Objectives. We examined the relationship between burden of providing care to non-ill children and grandchildren and incidence of coronary heart disease (CHD) among women. Methods. A prospective cohort study was conducted as part of the Nurses’ Health Study among 54 412 women aged 46 to 71 years who were registered nurses. Women answered questions about their child care responsibilities. Results. We documented 321 incident cases of CHD during 4 years of follow-up. Multivariate analyses showed that caring for non-ill children 21 hours or more per week and caring for non-ill grandchildren 9 hours or more per week (vs no caregiving) were associated with an increased risk of CHD (relative risks were 1.59 and 1.55, respectively). Conclusions. High levels of care provision to grandchildren (and possibly children) may increase the risk of CHD among women.

Background Africa is facing a nutritional transition where underweight and overweight coexist. Although the majority of programs for orphan and vulnerable children (OVC) focus on undernourishment, the association between OVC primary caregiving and the caregivers’ overweight status remains unclear. We investigated the association between OVC primary caregiving status with women’s overweight status in Namibia, Swaziland and Zambia. Methods Demographic Health Survey (DHS) cross-sectional data collected during 2006–2007 were analyzed using weighted marginal means and logistic regressions. We analyzed data from 20–49 year old women in Namibia (N 6638), Swaziland (N 2875), and Zambia (N 4497.) Results The overweight prevalence of the primary caregivers of OVC ranged from 27.0 % (Namibia) to 61.3 % (Swaziland). In Namibia, OVC primary caregivers were just as likely or even less likely to be overweight than other primary caregivers. In Swaziland and Zambia, OVC primary caregivers were just as likely or more likely to be overweight than other primary caregivers. In Swaziland and Zambia, OVC primary caregivers were more likely to be overweight than non-primary caregivers living with OVC (Swaziland AOR = 1.56, Zambia AOR = 2.62) and non-primary caregivers not living with OVC (Swaziland AOR = 1.92, Zambia AOR = 1.94). Namibian OVC caregivers were less likely to be overweight than non-caregivers not living with an OVC only in certain age groups (21–29 and 41–49 years old). Conclusions African public health systems/OVC programs may face an overweight epidemic alongside existing HIV/AIDS, tuberculosis and malaria epidemics. Future studies/interventions to curb overweight should consider OVC caregiving status and address country-level differences.

Dexamethasone-suppressible hyperaldosteronism(DSH),a form of low renin hypertension,is a familial disorder of aldosterone secretion which is transmitted by an autosomal dominant gene. With dexamethasone(DEX) administration there is a prompt suppression of aldosterone excretion to unmeasurable levels and return to normal blood pressure in young subjects. With prolonged ACTH administration, unlike normal subjects in whom aldosterone excretion decreases after an initial rise, the DSH patient demonstrates a sustained and continuous increase of aldosterone excretion.This unusual aldosterone response mimics that of cortisol(F). These findings suggest that in DSH, aldosterone may be a product of the adrenal fasciculata or that ACTH regulates aldosterone secretion by the adrenal glomerulosa. We studied adrenal glomerulosa function in ten patients with DSH treated continuously with DEX 2mg/d and studied on a regular Na+diet(87meq/m2)and on a 10meq Na+ diet. With DEX treatment all patients showed a prompt suppression of adrenal fasciculata function as evidenced by suppression of serum F,corticosterone,desoxycorticosterone and urinary 18-OH-desoxy-corticosterone. The complete suppression of urinary pH 1 aldosterone by DEX was paralleled by a prompt suppression of urinary 18-OH-corticosterone. With continued DEX administration plasma renin levels rose to the normal range. Dietary sodium restriction resulted in a further rise in plasma renin activity and a rise in urinary pH 1 aldosterone and 180Hcorticosterone. Thus, in DSH the adrenal glomerulosa is responsive to the stimulation of reninangiotensin II.

Meeting abstracts Levels of circulating tumor cells (CTCs) have been associated with overall survival (OS) in metastatic breast [[1][1]] and prostate cancer [[2][2]]. Here we report the preliminary associations between CTCs and OS in subjects receiving an autologous adenoviral transduced dendritic