Auto-adaptive Alpha Allocation: A Strategy to Mitigate Risk on Study Assumptions

In some clinical development programs, there are potential biomarkers with promising but uncertain predictive effect, while the probability of success in the overall population cannot be readily dismissed. It is risky to focus only on the overall population, or just the biomarker subpopulation. In 2009, Chen and Beckman proposed a Bayesian decision framework to optimize the type I error rate (alpha) allocation in a Phase III clinical study with possible predictive subset effect. The utilization of internal data in this framework is of particular interest because it provides an opportunity to mitigate the potential risk of misspecified study assumptions using an auto-adaptive strategy. In this paper, we examine this auto-adaptive strategy in detail through extensive numerical case studies and provide guidance on the appropriate use of partial current trial (internal) data in this data-driven optimization framework. We show that internal data can be used to inform the alpha allocation to hypothesis testing in the overall population and the subgroup. The resulting adaptive testing strategy is robust with respect to the uncertainty in the predictive subgroup effect and biomarker prevalence.     

Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart

Glycogen synthase kinase (GSK) 3beta is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3beta plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3beta in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca2+] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3beta, acting at the level of the SERCA2 promoter. These studies identify GSK-3beta as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. De-regulation of GSK-3beta leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.     

Metabolic alterations in yeast lacking copper-zinc superoxide dismutase

Yeast lacking copper-zinc superoxide dismutase (sod1?) have a number of oxygen-dependent defects, including auxotrophies for lysine and methionine and sensitivity to oxygen. Here we report additional defects in metabolic regulation. Under standard growth conditions with glucose as the carbon source, yeast undergo glucose repression in which mitochondrial respiration is deemphasized, energy is mainly derived from glycolysis, and ethanol is produced. When glucose is depleted, the diauxic shift is activated, in which mitochondrial respiration is reemphasized and stress resistance increases. We find that both of these programs are adversely affected by the lack of Sod1p. Key events in the diauxic shift do not occur and sod1? cells do not utilize ethanol and stop growing. The ability to shift to growth on ethanol is gradually lost as time in culture increases. In early stages of culture, sod1? cells consume more oxygen and have more mitochondrial mass than wild-type cells, indicating that glucose repression is not fully activated. These changes are at least partially dependent on the activity of the Hap2,3,4,5 complex, as indicated by CYC1-lacZ reporter assays. These changes may indicate a role for superoxide in metabolic signaling and regulation and/or a role for glucose derepression in defense against oxidative stress.     

Long noncoding RNA LINC01234 promoted cell proliferation and invasion via miR-1284/TRAF6 axis in colorectal cancer

Colorectal cancer is one of the most common and leading malignancies globally. Long noncoding RNAs (lncRNAs) function as potentially critical regulator in colorectal cancer. LINC01234, a novel lncRNA in tumor biology, regulates the progression of various tumors. However, the tumorigenic mechanism of LINC01234 in colorectal cancer is still unclear. This study was performed with the aim to prospectively investigate clinical significance, effect, and mechanism of lncRNA LINC01234 in colorectal cancer. First, we found that LINC01234, localized in the cytoplasm, was increased in both colorectal cancer cell lines and tissues. Subsequent functional assays suggested LINC01234 knockdown suppressed cell proliferation, migration, and invasion of colorectal cancer cells, while blocked cell cycle and induced cell apoptosis. Moreover, we identified that miR-1284 was target of LINC01234, we further demonstrated a negative correlation with LINC01234 in colorectal cancer tissues and cells. Furthermore, miR-1284 targeted and suppressed tumor necrosis factor receptor–associated factor 6 (TRAF6). Loss-of-function assay revealed that LINC01234 silencing suppressed colorectal cancer progression through inhibition of miR-1284. In vivo subcutaneous xenotransplanted tumor model indicated LINC01234 knockdown inhibited in vivo tumorigenic ability of colorectal cancer via downregulation of TRAF6. Collectively, this study clarified the biological significance of LINC01234/miR-1284/TRAF6 axis in colorectal cancer progression, providing insights into LINC01234 as novel potential therapeutic target for colorectal cancer therapeutic from bench to clinic.     

SPARC在子宫内膜癌组织中的表达及意义

目的：探讨富含半胱氨酸的酸性分泌型蛋白（secreted protien,acidic and rich in cysteine,SPARC）在子宫内膜癌组织中的表达及其临床意义。方法：应用组织芯片技术研究SPARC在正常子宫内膜、增生的子宫内膜和子宫内膜癌组织中的表达情况。结果：SPARC在正常子宫内膜、增生的子宫内膜和子宫内膜癌组织中的阳性表达率分别为96.55%、76.79%、59.50%,差异具有统计学意义（P〈0.05）。在子宫内膜癌中,SPARC的表达强度与手术-病理分期、组织学分级、肌层浸润深度和淋巴结转移相关,差异具有统计学意义（P〈0.05）。结论：SPARC表达的缺失与子宫内膜癌的发生、发展密切相关,检测SPARC可为子宫内膜癌的早期诊断、进一步治疗及预后判断提供一定的理论依据。     

Soluble expression, purification and functional identification of a disulfide-rich conotoxin derived from Conus litteratus

Conotoxins are a diverse array of small peptides mostly with multiple disulfide bridges. These peptides become an increasing significant source of neuro-pharmacological probes and drugs as a result of the high selectivity for ion channels and receptors. Usually, the analogue of natural conotoxins is produced by means of chemical synthesis. Here, we present a simple and fast strategy of producing disulfide-rich conotoxins via recombinant expression. By fused with thioredoxin and His tag, a novel O-superfamily conotoxin lt7a was successfully expressed in Escherichia coli and purified, resulting in a high yield of recombinant lt7a about 6 mg/l. The purity of target protein is up to 95% as identified by HPLC results. Whole cell patch-clamp recording revealed that the new conotoxin blocked voltage-sensitive sodium channels in rat dorsal root ganglion neurons, indicating it might be a novel microO-conotoxin.     

慢性非细菌性前列腺炎/慢性骨盆疼痛综合征患者的尿动力学检查

目的:探讨尿动力学检查在了解慢性非细菌性前列腺炎/慢性骨盆疼痛综合征(Chronicabacterialprostatitis/chronicpelvicpain syndrome,CPPS)患者中下尿路症状(LUTS)产生原因的作用。方法:对36例难治性慢性前列腺炎/盆腔疼痛综合征患者行尿流动力学压力-流率测定,同步测定膀胱压、逼尿肌压、同步肌电图测定,了解其症状产生的原因。结果:36例患者中,尿动力学证实膀胱出口梗阻14例(39%);逼尿肌过度活动者8例,其中有7例与BOO同时存在;假性逼尿肌尿道外括约肌协同失调6例(16.7%);逼尿肌收缩力低下者5例(13.9%)。结论:对难治性CPPS患者进行尿动力学检查有助于对此类患者LUTS产生的原因进行鉴别,从而可以采取有针对性的治疗。