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Multiple myeloma is a hematological neoplasm characterized by the accumulation of clonal plasma cells in the bone marrow. Its frequent relapse following achievement of clinical remissions implicates the existence of therapy-resistant myeloma-initiating cells. To date, results on the identity of myeloma-initiating cells have differed. Here, we prospectively identified a myeloma-initiating population by fractionating and transplanting patient bone marrow cells into human bone-bearing immunocompromised mice. Xenotransplantation of fractionated CD138(+)/CD38(high) cells from 40% of patients (8/20) led to a repopulation of CD19(+)CD38(low) or CD138(+)CD38(+) B-lineage cells in human bone grafts; and these grafts were clonally derived from patient myeloma cells. Meanwhile, CD19(+)CD38(low) xenografts were detected in human bone-bearing mice transplanted with CD19(+)CD38(low/-) B cells from 8 of 22 samples but were not clonally related to patient myeloma cells. Further fractionation and xenotransplantation of CD138(+)CD38(high) cells demonstrated that (CD45(low/-) or CD19(-)) CD38(high)/CD138(+) plasma cells, but not (CD45(high) or CD19(+)) CD38(high)/CD138(+) plasmablasts enrich for myeloma-initiating cells. Quantitative reverse transcription-PCR of two serially transplantable xenografts, which were CD19(-)CD138(+), revealed that they were Pax5 (a B-cell-specific transactivator)-negative. These results suggest that CD19(-)CD45(low/-) fully differentiated plasma cells enrich for long-lived and tumor-initiating cells whereas B cells or plasmablasts do not. [ABSTRACT FROM AUTHOR]

In healthy adolescents, cross-sectional studies show either no or negative relationships between serum 25-hydroxyvitamin D [25(OH)D] and calcium (Ca) absorption. Using a 2-period metabolic balance study, the effect of vitamin D supplementation on Ca absorption and retention in adolescent girls was investigated. Eleven girls aged 12-14 y with a mean entry serum 25(OH)D of 35.1 nmol/L consumed a controlled intake (providing 5 μg vitamin D and 1117 mg Ca/d) for two 3-wk metabolic balance periods separated by a 1-wk washout period. Sunlight exposure was minimized by sunscreen with a sun protection factor ≥ 15. After the first metabolic balance period, participants received 25 μg/d cholecalciferol supplementation for 4 wk. Fractional Ca absorption was measured in each metabolic balance period using a stable Ca isotope method. All urine and fecal samples were collected and analyzed to measure net Ca absorption and Ca retention. Paired t tests and correlations were used to analyze the data. Daily supplementation with 25 μg vitamin D resulted in a mean increase in serum 25(OH)D of 13.3 nmol/L (P < 0.01) but a decrease in fractional Ca absorption of 8.3% (P < 0.05) and no significant change in fasting serum 1,25-dihydroxyvitamin D, parathyroid hormone, net Ca absorption, or Ca skeletal retention. In pubertal girls with vitamin D status considered insufficient in adults, vitamin D supplementation of 25 μg/d for 4 wk did not improve fractional Ca absorption, net Ca absorption, or Ca retention. [ABSTRACT FROM AUTHOR]

Researchers have long studied malignant tumors using experimental techniques that assume that cancers are composed of identical cells; however, growing evidence indicates that cancers are composed of functionally heterogeneous cells maintained by a stem cell-like population. Identification of tumor-initiating, or cancer stem cells, has been largely guided by principles established for normal stem cells. Cancer stem cells must be capable of initiating tumors when transplanted into immunodeficient mice, and the resulting tumors must replicate the heterogeneity of the original tumor. Demonstration of the ability to self-renew, a key feature of stem cells, is achieved through serial passage of tumors in xenohosts. Given their potential roles in tumor initiation, maintenance, and metastasis, the impact of cancer stem cells on the practice of medicine is likely to be profound. [ABSTRACT FROM AUTHOR]

CYR61 over-expression promotes cell proliferation by inhibiting carboplatin-induced apoptosis, decreasing Bax expression, and increasing Bcl-xL, Mcl-1, and Bcl-2. At the same time, down-regulating p53 expression, while up-regulated NF-κB expression. Additionally, p21 and p53 promoter activities were reduced, while NF-κB and Bcl-2 activities increased. In parallel, CYR61-expressing cells, during carboplatin-induced apoptosis, resulted in an increase of Akt phosphorylation, while rapamycin-treated cells were not affected. Carboplatin effectively inhibited the activation of mTOR signaling cascade, which includes mTOR, 4E-BP1, p70S6K, HIF-1α, and VEGF. These results provide evidence that CYR61 promotes cell proliferation and inhibits apoptosis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether there is a difference in the association between nonalcoholic fatty liver disease (NAFLD) and incident diabetes based on the presence of impaired fasting glucose.Research Design and Methods: A total of 7,849 individuals (5,409 men and 2,440 women) without diabetes, who underwent comprehensive health check-ups annually for 5 years, were categorized into four groups by the presence of impaired fasting glucose and NAFLD at baseline. The association between NAFLD and incident diabetes was evaluated separately in groups with normal and impaired fasting glucose.Results: For 4 years, the incidence of diabetes in the NAFLD group was 9.9% compared with 3.7% in the non-NAFLD group, with multivariable-adjusted hazard ratio of 1.33 (95% CI 1.07-1.66). However, this higher risk for diabetes only existed in the impaired fasting glucose group.Conclusions: Our study suggests that NAFLD has an independent and additive effect on the development of diabetes under conditions of impaired insulin secretion. [ABSTRACT FROM AUTHOR]

Recently, the glucose-stimulated insulin release of isolated human islets has been shown to deteriorate progressively with advancing donor age. This decline in beta cell function with aging may contribute to the increasing development of IGT and type 2 diabetes and also to the progressive nature of the disease. This study was to see whether there is any change in expression of beta cell function-related genes in islets with aging. Islets were isolated from young (2-month old) and old (22-24-month old) LETO rats and C57BL/6N mice. The in vitro GSIR index was significantly lower in islets from old mice compared with young mice. In real-time RT-PCR, PDX-1, insulin, GLUT2 and prohormone convertase 1/3 gene expression in islets was markedly lower in old rats (33%, 13%, 20% and 34%, respectively) and old mice (56%, 42%, 28% and 22%, respectively) compared with young animals. On the other hand, genes not specifically related to beta cell-specific function, such as caspase 3, superoxide dismutase 2 and glycerol kinase were not significantly different in expression in islets according to age. In conclusion, with increasing age, insulin secretory function of islets deteriorates accompanied with a decrease in expression of beta cell-specific genes including PDX-1. [ABSTRACT FROM AUTHOR]