Implicating the cholecystokinin B receptor in liver stem cell oncogenesis.

Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related deaths worldwide. Chronic inflammation and fibrosis are the greatest risk factors for the development of HCC. Although the cell of origin for HCC is uncertain, many theories believe this cancer may arise from liver progenitor cells or stem cells. Here, we describe the activation of hepatic stem cells that overexpress the cholecystokinin-B receptor (CCK-BR) after liver injury with either a DDC diet (0.1% 3, 5-diethoxy-carbonyl 1,4-dihydrocollidine) or a NASH-inducing CDE diet (choline-deficient ethionine) in murine models. Pharmacologic blockade of the CCK-BR with a receptor antagonist proglumide or knockout of the CCK-BR in genetically engineered mice during the injury diet reduces the expression of hepatic stem cells and prevents the formation of three-dimensional tumorspheres in culture. RNA sequencing of livers from DDC-fed mice treated with proglumide or DDC-fed CCK-BR knockout mice showed downregulation of differentially expressed genes involved in cell proliferation and oncogenesis and upregulation of tumor suppressor genes compared with controls. Inhibition of the CCK-BR decreases hepatic transaminases, fibrosis, cytokine expression, and alters the hepatic immune cell signature rendering the liver microenvironment less oncogenic. Furthermore, proglumide hastened recovery after liver injury by reversing fibrosis and improving markers of synthetic function. Proglumide is an older drug that is orally bioavailable and being repurposed for liver conditions. These findings support a promising therapeutic intervention applicable to patients to prevent the development of HCC and decrease hepatic fibrosis.NEW & NOTEWORTHY This investigation identified a novel pathway involving the activation of hepatic stem cells and liver oncogenesis. Receptor blockade or genetic disruption of the cholecystokinin-B receptor (CCK-BR) signaling pathway decreased the activation and proliferation of hepatic stem cells after liver injury without eliminating the regenerative capacity of healthy hepatocytes.

Household Water Is the Main Source of Iodine Consumption among Women in Hargeisa, Somaliland: A Cross-Sectional Study.

BACKGROUND: Iodine status surveys of women in Somaliland present widely conflicting results. Previous research indicates elevated concentrations of iodine (IQR 18-72 µg/L) in groundwater used for drinking and cooking, but the relation with iodine intake is not well characterized. OBJECTIVES: We aimed to investigate the contributions of household water iodine concentration (WIC), breastfeeding, total fluid intake, hydration levels, and urine volume on urinary iodine concentration (UIC) and excretion (UIE) over a 24-h period and to define iodine status from iodine intake estimates and median UIC, normalized to a mean urine volume of 1.38 L/d (hydration adjusted). METHODS: The study sample comprised 118 nonpregnant, healthy women aged 15-69 y. All participants resided in Hargeisa, and 27 were breastfeeding. Data collection consisted of a 24-h urine collection, a 24-h fluid intake diary, a beverage frequency questionnaire, and a structured recall interview. We measured UIC and WIC in all urine and in 49 household water samples using the Sandell-Kolthoff reaction. RESULTS: WIC ranged between 3 and 188 µg/L, with significant median differences across the water sources and city districts (P < 0.003). Nonbreastfeeding women were borderline iodine sufficient [hydration-adjusted median urinary iodine concentration (mUIC) 109 µg/L; 95% CI: 97, 121 µg/L], whereas breastfeeding women showed a mild iodine deficiency (73 µg/L; 95% CI: 54, 90 µg/L). There were strong correlations (ρ: 0.50-0.69, P = 0.001) between WIC and UIC, with iodine from household water contributing more than one-half of the total iodine intake. Multivariate regression showed hydration and breastfeeding status to be the main predictors of UIC. CONCLUSIONS: Iodine from household water is the main contributor to total iodine intake among women in Hargeisa, Somaliland. Variation in female hydration and spatial and temporal WIC may explain diverging mUIC between studies. Water sources at the extremes of low and high iodine concentrations increase the risk of subpopulations with insufficient or more than adequate iodine intake.

Estimates of fluid intake, urine output and hydration-levels in women from Somaliland: a cross-sectional study.

The study objective was to measure fluid intake and associations with background characteristics and hydration biomarkers in healthy, free-living, non-pregnant women aged 15-69 years from Hargeisa city. We also wanted to estimate the proportion of euhydrated participants and corresponding biomarker cut-off values. Data from 136 women, collected through diaries and questionnaires, 24h urine samples and anthropometric measurements, were obtained with a cross-sectional, purposeful sampling from fifty-two school and health clusters, representing approximately 2250 women. The mean (95 % CI) 24 h total fluid intake (TFI) for all women was 2⋅04 (1⋅88, 2⋅20) litres. In multivariate regression with weight, age, parity and a chronic health problem, only weight remained a predictor (P 0.034, B 0.0156 (l/kg)). Pure water, Somali tea and juice from powder and syrup represented 49⋅3, 24⋅6 and 11⋅7 % of TFI throughout the year, respectively. Mean (95 % CI) 24 h urine volume (Uvol) was 1⋅28 (1⋅17, 1⋅39) litres. TFI correlated strongly with 24 h urine units (r 0.67) and Uvol (r 0.59). Approximately 40 % of the women showed inadequate hydration, using a threshold of urine specific gravity (Usg) of 1⋅013 and urine colour (Ucol) of 4. Five percent had Usg > 1⋅020 and concomitant Ucol > 6, indicating dehydration. TFI lower cut-offs for euhydrated, non-breast-feeding women were 1⋅77 litres and for breast-feeding, 2⋅13 litres. Euhydration cut-off for Uvol was 0⋅95 litre, equalling 9⋅2 urine units. With the knowledge of adverse health effects of habitual hypohydration, Somaliland women should be encouraged to a higher fluid intake.