Heritability and Demographic Analyses in the Large Isolated Population of Val Borbera Suggest Advantages in Mapping Complex Traits Genes

Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South.The study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits.The data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations

The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and the current chemotherapeutic options for GBM are limited to temozolomide. Recently, inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity and our group has demonstrated that one of these inhibitors of kinesin Eg5, named K858, exerts important anti-proliferative and apoptotic effects on breast cancer cells. Since GBM cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human GBM cell lines (U-251 and U-87) and found that K858 could inhibit cell growth, induce apoptosis, revert epithelial-mesenchymal transition and inhibit migration in both cell lines. However, at the same time, K858 increased survivin expression, an anti-apoptotic molecule; so, down-regulating survivin with the specific inhibitor YM155, we obtained an important increase of K858-dependent apoptosis. This indicated that the anti-tumor activity of K858 on GBM was limited by the over-expression of survivin and that the negative regulation of this protein could sensitize tumor cells to K858-induced apoptosis. These data support the choice of kinesin Eg5 as target of new therapeutic approaches for GBM; in particular, K858 has been demonstrated to be a potent inhibitor of replication, inducer of apoptosis and negative regulator of the invasive phenotype for GBM cells

Breast cancer cells respond differently to docetaxel depending on their phenotype and on survivin upregulation

Breast cancer is characterized by molecular heterogeneity, and four major breast cancer subtypes have been identified, each characterized by significant differences in survival, prognosis, and response to therapy. We have studied the effects of docetaxel treatment on apoptosis and survivin expression in four breast cancer cell lines: MCF7 (luminal A: estrogen receptor-positive and progesterone receptor-positive, ErbB2-negative), BT474 (luminal B: estrogen receptor/progesterone receptor/ErbB2-positive), SKBR3 (HER2-like: estrogen receptor/progesterone receptor-negative, ErbB2-positive), and MDA-MB231 (basal-like: estrogen receptor/progesterone receptor/ErbB2-negative). We demonstrated that docetaxel-induced apoptosis and survivin upregulation (MCF7 p = 0.002, BT474 p = 0.001, SKBR3 p = 0.001) in luminal A/B and HER2-like cells, while it induced mainly necrosis and a lower rate of survivin upregulation (MDA-MB231 p = 0.035) in basal-like cells. Wortmannin, a p-Akt inhibitor, was able to revert surviving upregulation and, at the same time, induced an increase of docetaxel-dependent apoptosis, suggesting that reduced levels of survivin can sensitize tumor cells to apoptosis. These data show that the analyzed breast cancer cell lines respond differently to docetaxel, depending on their receptor expression profile and molecular phenotype. Yet, these data confirm that one of the pathways involved in taxane-related chemoresistance is the upregulation of survivin. Further studies on the molecular mechanisms of chemoresistance and on the different modalities of apoptosis induced by chemotherapeutic agents are requested to better understand how cancer cells evade cell death, in order to design new kind of anticancer agents and survivin could represent a future target for this kind of research

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone

A link between hypertension and long-term bone health has been suggested. The aim of this study was to investigate the effects of chronic angiotensin II administration on urinary calcium/phosphate excretion, bone mineral density, bone remodeling and osteoblast population in a well-established experimental model of hypertension, in the absence of possible confounding factors that could affect bone metabolism. Male Sprague–Dawley rats, divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis, n = 8); (b) Ang II+losartan (Los, 50 mg/kg/day, per os, n = 6); (c) control group (physiological saline, sub cutis, n = 9); and (d) control+losartan (n = 6) were treated for four weeks. During the experimental period, 24-hour diuresis, urinary calcium, phosphate and sodium excretion were measured prior to the treatment, at two weeks of treatment, and at the end of the treatment. Systolic blood pressure was measured by plethysmography technique (tail cuff method). At the end of the experimental protocol, the rats were euthanized and peripheral quantitative computed tomography at the proximal metaphysis and at the diaphysis of the tibiae and quantitative bone histomorphometry on distal femora were performed. Angiotensin II-dependent hypertension is associated with increased calcium and phosphate excretion. AT1 receptor blockade prevented the increase of blood pressure and phosphate excretion but did not affect the increase of calcium excretion. These changes took place without significantly affecting bone density, bone histology or osteoblast population. In conclusion, in our experimental conditions, angiotensin II-dependent hypertension gave rise to an increased urinary excretion of calcium and phosphate without affecting bone density