Meta-analysis of gene-based genome-wide association studies of bone mineral density in Chinese and European subjects

Summary Gene-based association approach could be regarded as a complementary analysis to the single SNP association analysis. We meta-analyzed the findings from the gene-based association approach using the genome-wide association studies (GWAS) data from Chinese and European subjects, confirmed several well established bone mineral density (BMD) genes, and suggested several novel BMD genes. Introduction The introduction of GWAS has greatly increased the number of genes that are known to be associated with common diseases. Nonetheless, such a single SNP GWAS has a lower power to detect genes with multiple causal variants. We aimed to assess the association of each gene with BMD variation at the spine and hip using gene-based GWAS approach. Methods We studied 778 Hong Kong Southern Chinese (HKSC) women and 5,858 Northern Europeans (dCG); age, sex, and weight were adjusted in the model. The main outcome measure was BMD at the spine and hip. Results Nine genes showed suggestive p value in HKSC, while 4 and 17 genes showed significant and suggestive p values respectively in dCG. Meta-analysis using weighted Z-transformed test confirmed several known BMD genes and suggested some novel ones at 1q21.3, 9q22, 9q33.2, 20p13, and 20q12. Top BMD genes were significantly associated with connective tissue, skeletal, and muscular system development and function (p<0.05). Gene network inference revealed that a large number of these genes were significantly connected with each other to form a functional gene network, and several signaling pathways were strongly connected with these gene networks. Conclusion Our gene-based GWAS confirmed several BMD genes and suggested several novel BMD genes. Genetic contribution to BMD variation may operate through multiple genes identified in this study in functional gene networks. This finding may be useful in identifying and prioritizing candidate genes/loci for further study. © International Osteoporosis Foundation and National Osteoporosis Foundation 2011.published_or_final_versionSpringer Open Choice, 21 Feb 201

R+R2R + R^2 Gravity as R+R + Backreaction

Quadratic theory of gravity is a complicated constraint system. We investigate some consequences of treating quadratic terms perturbatively (higher derivative version of backreaction effects). This approach is shown to overcome some well known problems associated with higher derivative theories, i.e., the physical gravitational degree of freedom remains unchanged from those of Einstein gravity. Using such an interpretation of $R + \beta R^2$ gravity, we investigate a classical and Wheeler DeWitt evolution of $R + \beta R^2$ gravity for a particular sign of $\beta$, corresponding to non- tachyon case. Matter is described by a phenomenological $\rho \propto a(t)^{-n}$. It is concluded that both the Friedmann potential $U(a)$ (${\dot a}^2 + 2U(a) = 0$) and the Wheeler DeWitt potential $W(a)$ ($\left[-{\partial^2\over \partial a^2} + 2W(a)\right]\psi (a) =0$) develop repulsive barriers near $a\approx 0$ for $n>4$ (i.e., $p > {1\over 3}\rho$). The interpretations is clear. Repulsive barrier in $U(a)$ implies that a contracting FRW universe ($k>0, k=0, k<0$) will bounce to an expansion phase without a total gravitational collapse. Repulsive barrier in $W(a)$ means that $a \approx 0$ is a classically forbidden region. Therefore, probability of finding a universe with the big bang singularity ($a=0$ ) is exponentially suppressed.Comment: Accepted for publication in Phy. Rev. D.,18 pages, 6 figures, Latex fil

Liver Development, Regeneration, and Carcinogenesis

The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor.

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a 'wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model

Bone mineral density enhances use of clinical risk factors in predicting ten-year risk of osteoporotic fractures in Chinese men: the Hong Kong Osteoporosis Study

This prospective study aimed to determine the risk factors and the 10-year probability of osteoporotic fracture in Southern Chinese men. The findings show substantial population differences in fracture incidence and risk prediction compared to the FRAX TM model, and the addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men. Introduction: Clinical risk factors with or without bone mineral density (BMD) measurements are increasingly recognized as reliable predictors of fracture risk. Prospective data on fracture incidence in Asian men remain sparse. This prospective study aimed to determine the risk factors and the 10-year absolute fracture risk in Southern Chinese men. Methods: This is a part of the Hong Kong Osteoporosis Study. One thousand eight hundred ten (1,810) community-dwelling, treatment-naive men aged 50 years or above were evaluated. Baseline demographic characteristics, clinical risk factors and BMD were recorded. Ten-year risk of osteoporotic fracture was calculated using Cox proportional hazards models. Results: The mean age of subjects was 68.0 ± 10.3 years. After a mean follow-up period of 3.5±2.9 years (range 1 to 14 years), 37 incident low-trauma fractures were recorded. The incidence for all osteoporotic fractures and hip fractures was 635/100,000 and 123/100,000 person-years, respectively. The most significant predictors of osteoporotic fracture were history of fall (RR 14.5), femoral neck BMD T-score < -2.5 (RR 13.8) and history of fracture (RR 4.4). Each SD reduction in BMD was associated with a 1.8 to 2.6-fold increase in fracture risk. Subjects with seven clinical risk factors and BMD T-score of -1 had an absolute 10-year risk of osteoporotic fracture of 8.9%, but this increased to 22.7% if they also had a femoral neck BMD T-score of -2.5. Conclusions: These findings show substantial population differences in fracture incidence and risk prediction. The addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Direct Photon Scattering by Plasmons in BiTeI

We use polarization resolved Raman spectroscopy to show that for 3D giant Rashba system the bulk plasmon collective mode directly couples to the Raman response even in the long wavelength $\mathbf q \rightarrow 0$ limit although the standard theory predicts that the plasmon spectral weight should scale as the square of its quasi-momentum and hence be negligibly weak in the Raman spectra. Such plasmon coupling to the Raman response at $\mathbf q \rightarrow 0$ arises for a polar system with spin-orbit coupling when the incoming photon excitation is turned to a resonance with Rashba-split intermediates states involved in the resonant Raman process. As an example, we identify special features of BiTeI's chiral band structure that enable the appearance of plasmon mode in the Raman spectrum