A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo.

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

-765G>C and 8473T>C polymorphisms of COX-2 and cancer risk: a meta-analysis based on 33 case-control studies.

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in cancer etiology. The -765G>C and 8473T>C polymorphisms have been implicated in cancer risk. However, the results on the association between the two COX-2 polymorphisms and cancer risk are conflicting. To derive a more precise estimation of the association between them, we performed a meta-analysis of 8,090 cancer cases and 11,010 controls concerning -765G>C polymorphism and 14,283 cancer cases and 15,489 controls concerning 8473T>C polymorphism from 33 case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the -765GC or GC/CC genotypes were associated with higher cancer risk than those with the -765GG genotype and in the stratified analysis this effect maintained in colorectal carcinoma or esophageal cancer of Asian descents. Overall, no significant cancer risk of 8473T>C polymorphism was found. Stratified by cancer types, the variant 8473CC was associated with a decreased risk in breast cancer, compared with the TT or TC/TT genotypes and in lung cancer subgroup after sensitive analysis, there was a decreased risk in CC versus TT, TC versus TT and the dominant models. Moreover, a decreased risk of lung cancer was observed among smokers in the dominant model. In summary, this meta-analysis suggesting that -765G>C may cause an increased risk of colorectal carcinoma and esophageal cancer in Asian descents while 8473T>C polymorphism may cause a decreased risk of breast and lung cancer.

Note: Inter-satellite laser range-rate measurement by using digital phase locked loop.

This note presents an improved high-resolution frequency measurement system dedicated for the inter-satellite range-rate monitoring that could be used in the future's gravity recovery mission. We set up a simplified common signal test instead of the three frequencies test. The experimental results show that the dominant noises are the sampling time jitter and the thermal drift of electronic components, which can be reduced by using the pilot-tone correction and passive thermal control. The improved noise level is about 10(-8) Hz/Hz(1/2)@0.01Hz, limited by the signal-to-noise ratio of the sampling circuit.

TGFbeta1 T29C polymorphism and cancer risk: a meta-analysis based on 40 case-control studies.

Transforming growth factor-beta1 (TGFbeta1) plays a significant role in regulating cellular proliferation and apoptosis. The TGFbeta1 T29C polymorphism reportedly affects cancer risk, but pertinent studies offer conflicting results. We therefore performed a meta-analysis based on 40 studies from 32 publications, assessing the strength of the association using odds ratios with 95% confidence intervals. Overall, no evidence has indicated that individuals carrying CC or CT genotypes had significantly increased cancer risks, compared with TT genotype carriers [CC vs. TT: odds ratio (OR)=1.10, 95% confidence interval (95% CI)=1.00-1.21, P=0.06; CT vs. TT: OR=1.07, 95% CI=0.99-1.16, P=0.09). However, stratified analysis by cancer type and ethnicity indicated a significantly increased risk of prostate cancer (CT vs. TT: OR=1.28, 95% CI=1.01-1.61, P=0.04) and cancer in those of Asian descent (CC vs. TT: OR=1.26, 95% CI=1.03-1.53, P=0.02; CT vs. TT: OR=1.20, 95% CI=1.01-1.43, P=0.04). This association was also observed in the dominant model for prostate cancer. Although not all bias could be eliminated, this meta-analysis suggested that TGFbeta1 29C was a low-penetrant risk factor for prostate cancer and cancer in Asians. A larger single study is still required to evaluate any association with other types of cancer or in other populations.