A Small Molecule Compound Targeting STAT3 DNA-Binding Domain Inhibits Cancer Cell Proliferation, Migration, and Invasion

Signal transducer and activator of transcription 3 (STAT3) plays important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. STAT3 is constitutively activated in many malignant tumors and its activation is associated with high histological grade and advanced cancer stages. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced and metastatic cancers. Herein, we identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding domain of STAT3 using an improved virtual screening strategy. InS3-54 preferentially suppresses proliferation of cancer over non-cancer cells and inhibits migration and invasion of malignant cells. Biochemical analyses show that inS3-54 selectively inhibits STAT3 binding to DNA without affecting the activation and dimerization of STAT3. Furthermore, inS3-54 inhibits expression of STAT3 downstream target genes and STAT3 binding to chromatin in situ. Thus, inS3-54 represents a novel probe for development of specific inhibitors targeting the DNA-binding domain of STAT3 and a potential therapeutic for cancer treatments

Attenuating effect of pretreatment with Yiqifumai on lipopolysaccharide-induced intestine injury and survival rate in rat

<p>Abstract</p> <p>Background</p> <p>Yiqifumai is a traditional Chinese medicine compound preparation used for treatment of microcirculatory disturbance-related diseases in China. We have previous reported that pretreatment with Yiqifumai could improve the lipopolysaccharide (LPS) -induced microcirculatory disturbance in rat mesentery. The present study intended to investigate the effect of pretreatment with Yiqifumai on intestine injury and survival rate of the rats subjected to LPS challenge.</p> <p>Methods</p> <p>Male Wistar rats were continuously infused with LPS (5 mg kg^-1body weight h^-1) via the left jugular vein for 90 min. In some rats, Yiqifumai 80 (mg/kg) was administrated through the left jugular vein 10 min before LPS infusion. The mean arterial pressure (MAP), heart rate (HR), rectal temperature (RT), respiratory rate (RR) and survival rate were measured at 24 h, 48 h and 72 h after LPS infusion. At 72 h after exposure to LPS, the intestine morphology was observed under a stereomicroscope and the immunohistochemistry staining of intestine was conducted to evaluate the expression of intercellular adhesion molecule 1 (ICAM-1) and the number of myeloperoxidase (MPO) positive cells in tissue. After observation of intestine microcirculation, blood was collected from the abdominal aorta of each animal to analyze the level of inflammatory markers in plasma, including TNF-α and MCP-1.</p> <p>Results</p> <p>Compared to the control, LPS infusion significantly decreased MAP and the survival rate and increased the HR, RT and RR, as well as elicited leukocyte infiltration, intestine hemorrhage, enhanced expression of ICAM-1 and raised level of inflammatory markers. All of indicators, except for the RT, were significantly attenuated by Yiqifumai, in contrast to the LPS group.</p> <p>Conclusions</p> <p>The results demonstrated the potential of pretreatment with Yiqifumai to ameliorate rat intestine injury, inflammatory response to LPS and the decrease in survival rate caused by LPS challenge.</p

Methodological reporting of randomized controlled trials in major hepato-gastroenterology journals in 2008 and 1998: a comparative study

<p>Abstract</p> <p>Background</p> <p>It was still unclear whether the methodological reporting quality of randomized controlled trials (RCTs) in major hepato-gastroenterology journals improved after the Consolidated Standards of Reporting Trials (CONSORT) Statement was revised in 2001.</p> <p>Methods</p> <p>RCTs in five major hepato-gastroenterology journals published in 1998 or 2008 were retrieved from MEDLINE using a high sensitivity search method and their reporting quality of methodological details were evaluated based on the CONSORT Statement and Cochrane Handbook for Systematic Reviews of interventions. Changes of the methodological reporting quality between 2008 and 1998 were calculated by risk ratios with 95% confidence intervals.</p> <p>Results</p> <p>A total of 107 RCTs published in 2008 and 99 RCTs published in 1998 were found. Compared to those in 1998, the proportion of RCTs that reported sequence generation (RR, 5.70; 95%CI 3.11-10.42), allocation concealment (RR, 4.08; 95%CI 2.25-7.39), sample size calculation (RR, 3.83; 95%CI 2.10-6.98), incomplete outecome data addressed (RR, 1.81; 95%CI, 1.03-3.17), intention-to-treat analyses (RR, 3.04; 95%CI 1.72-5.39) increased in 2008. Blinding and intent-to-treat analysis were reported better in multi-center trials than in single-center trials. The reporting of allocation concealment and blinding were better in industry-sponsored trials than in public-funded trials. Compared with historical studies, the methodological reporting quality improved with time.</p> <p>Conclusion</p> <p>Although the reporting of several important methodological aspects improved in 2008 compared with those published in 1998, which may indicate the researchers had increased awareness of and compliance with the revised CONSORT statement, some items were still reported badly. There is much room for future improvement.</p

Event and strategy analytics

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Assessing economic, social and environmental impacts on housing prices in Hong Kong: a time-series study of 2006, 2011 and 2016

Given Hong Kong's unique high-density urban environment and limited land resources, more and more general public has been concerned about the living quality. Based on three waves of census data (2006, 2011 and 2016), combined with our spatial-temporal urban environmental database consisting of three local datasets of urban climate and air quality, this paper assesses the impacts of social, economic and environmental factors on the logarithm of housing prices in Hong Kong through linear regression analysis. Specifically, both supply- and demand-side economic factors have significant impacts on housing prices. Demographic factors are not as significant as expected in affecting housing prices. Transportation factors have more significant effects in the short run than in the long run. Environmental factors, including the number of hot night hours, Annual Air Quality Index (AAQI) of nitrogen dioxide (NO2) and particulates with particle sizes less than 10 microns (PM10), significantly affect housing prices over time. The results have important implications: current policy instruments to prevent housing price escalation are focused on increasing property tax or land supply (economic factors), while little attention is paid to social or environmental factors, which are geographically heterogeneous. Our findings suggest that housing provision in the New Territories may be a feasible solution to alleviate the housing crisis as its demographic pattern, transportation connectivity and air quality are significantly different from Hong Kong Island or Kowloon Peninsula. In regard to urban environmental problems brought by the high-density development in Hong Kong despite land-use saving, intensified urban infrastructure and promotion of public transportation, our study contributes to the understanding of its housing price dynamics from a more holistic perspective by comparing the impacts of economic, social and environmental factors

Relationship between Subclinical Thyroid Dysfunction and the Risk of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Cohort Studies

Background. Evidence on the association between subclinical thyroid dysfunction and the risk of cardiovascular outcomes are conflicting. Methods and Results. PubMed, EMbase, Web of Science, Cochrane Library, and China Biology Medicine (CBM) databases were searched from inception to July 10, 2016. A total of 16 studies were included for meta-analysis. We found that subclinical hypothyroidism was not correlated with coronary heart disease (CHD) (RR = 1.17; 95% CI, 0.91–1.52), total mortality (RR = 1.02; 95% CI, 0.93–1.13), cardiovascular mortality (RR = 1.06; 95% CI, 0.77–1.45), heart failure (RR = 1.17; 95% CI, 0.87–1.57), and atrial fibrillation (RR = 1.05; 95% CI, 0.91–1.21), except CHD mortality (RR = 1.37; 95% CI, 1.03–1.84). Subgroup analysis indicated a higher estimation risk in CHD (RR = 1.54; 95% CI, 1.00–2.39), cardiovascular mortality (RR = 2.14; 95% CI, 1.43–3.22), and CHD mortality (RR = 1.54; 95% CI, 1.11–2.15) among participants < 65 years. Furthermore, subclinical hyperthyroidism was found to be associated with CHD (RR = 1.20; 95% CI, 1.02–1.42), total mortality (RR = 1.27; 95% CI, 1.07–1.51), and CHD mortality (RR = 1.45; 95% CI, 1.12–1.86). Conclusions. Subclinical hypothyroidism is likely associated with an increased risk of CHD mortality, and subclinical hyperthyroidism is likely associated with increased risk of CHD, CHD mortality, and total mortality