Systematic identification of pharmacogenomics information from clinical trials

AbstractRecent progress in high-throughput genomic technologies has shifted pharmacogenomic research from candidate gene pharmacogenetics to clinical pharmacogenomics (PGx). Many clinical related questions may be asked such as ‘what drug should be prescribed for a patient with mutant alleles?’ Typically, answers to such questions can be found in publications mentioning the relationships of the gene–drug–disease of interest. In this work, we hypothesize that ClinicalTrials.gov is a comparable source rich in PGx related information. In this regard, we developed a systematic approach to automatically identify PGx relationships between genes, drugs and diseases from trial records in ClinicalTrials.gov. In our evaluation, we found that our extracted relationships overlap significantly with the curated factual knowledge through the literature in a PGx database and that most relationships appear on average 5years earlier in clinical trials than in their corresponding publications, suggesting that clinical trials may be valuable for both validating known and capturing new PGx related information in a more timely manner. Furthermore, two human reviewers judged a portion of computer-generated relationships and found an overall accuracy of 74% for our text-mining approach. This work has practical implications in enriching our existing knowledge on PGx gene–drug–disease relationships as well as suggesting crosslinks between ClinicalTrials.gov and other PGx knowledge bases

miR-96/HBP1/Wnt/β-catenin regulatory circuitry promotes glioma growth

AbstractWe found that miR-96 is overexpressed in glioma, and its level inversely correlates with the survival of patients. The reduction in miR-96 abundance suppresses the proliferation and colony formation of glioma cells. The tumorigenicity of U-87 MG cells is reduced by miR-96 silencing. miR-96 contributes to the activation of Wnt/β-catenin pathway in glioma cells. HMG-box transcription factor 1 (HBP-1), a Wnt/β-catenin pathway inhibitor, is suppressed by miR-96. The reactivation of Wnt/β-catenin signaling causes an increase in the proliferation of glioma cells, and a decrease in miR-96 expression. On the other hand, HBP1 silencing promotes miR-96 expression. Collectively, miR-96 contributes to the progression of glioma by enhancing the activation of the Wnt/β-catenin pathway, and the miR-96/HBP1/Wnt/β-catenin regulatory circuitry promotes the proliferation of glioma cells

Optimization of Protein-Protein Interaction Measurements for Drug Discovery Using AFM Force Spectroscopy

Increasingly targeted in drug discovery, protein-protein interactions challenge current high throughput screening technologies in the pharmaceutical industry. Developing an effective and efficient method for screening small molecules or compounds is critical to accelerate the discovery of ligands for enzymes, receptors and other pharmaceutical targets. Here, we report developments of methods to increase the signal-to-noise ratio (SNR) for screening protein-protein interactions using atomic force microscopy (AFM) force spectroscopy. We have demonstrated the effectiveness of these developments on detecting the binding process between focal adhesion kinases (FAK) with protein kinase B (Akt1), which is a target for potential cancer drugs. These developments include optimized probe and substrate functionalization processes and redesigned probe-substrate contact regimes. Furthermore, a statistical-based data processing method was developed to enhance the contrast of the experimental data. Collectively, these results demonstrate the potential of the AFM force spectroscopy in automating drug screening with high throughput

dRecQ4 Is Required for DNA Synthesis and Essential for Cell Proliferation in Drosophila

Background: The family of RecQ DNA helicases plays an important role in the maintenance of genomic integrity. Mutations in three of the five known RecQ family members in humans, BLM, WRN and RecQ4, lead to disorders that are characterized by predisposition to cancer and premature aging. Methodology/Principal Findings: To address the in vivo functions of Drosophila RecQ4 (dRecQ4), we generated mutant alleles of dRecQ4 using the targeted gene knock-out technique. Our data show that dRecQ4 mutants are homozygous lethal with defects in DNA replication, cell cycle progression and cell proliferation. Two sets of experiments suggest that dRecQ4 also plays a role in DNA double strand break repair. First, mutant animals exhibit sensitivity to gamma irradiation. Second, the efficiency of DsRed reconstitution via single strand annealing repair is significantly reduced in the dRecQ4 mutant animals. Rescue experiments further show that both the N-terminal domain and the helicase domain are essential to dRecQ4 function in vivo. The N-terminal domain is sufficient for the DNA repair function of dRecQ4. Conclusions/Significance: Together, our results show that dRecQ4 is an essential gene that plays an important role in no

Effects of Fibrin Clot Inhibitors and Statins on the Intravesical Bacille Calmette–Guérin Therapy for Bladder Cancer: A Systematic Review and Meta-Analysis

ObjectiveTo assess the effect of fibrin clot inhibitors (aspirin, clopidogrel, and warfarin) and statins on intravesical BCG therapy.MethodA systematic literature search was carried out through PubMed, Embase, and the Cochrane Central Search Library in March 2020. Accumulative analyses of odds ratios (ORs), hazard ratio (HR), and corresponding 95% confidence intervals (CIs) were performed. All analyses were performed by using Review Manager software version 5.3 and Stata 15.1.ResultsFour cohort studies and nine case–control studies containing 3,451 patients were included. The pooled analysis indicated that statins (HR = 1.00; 95%CI, 0.82 to 1.22; p = 1.00) and fibrin clot inhibitors (HR = 1.01; 95%CI, 0.64 to 1.59; p = 0.98) did not affect the efficacy of BCG on recurrence-free survival. The cumulative analysis showed that statins (HR = 0.79; 95%CI, 0.41 to 1.49; p = 0.46) and fibrin clot inhibitors (HR = 1.62; 95%CI, 0.90 to 2.91; p = 0.11) did not affect the efficacy of BCG on progression-free survival. There were no differences on cancer-specific survival (HR = 1.68; 95%CI, 0.64 to 4.40; p = 0.29) and overall survival (HR = 1.13; 95%CI, 0.73 to 1.78; p = 0.58) after taking statins.ConclusionThe present study shows that the application of fibrin clot inhibitors and statins do not influence the efficacy of BCG on oncological prognosis. Consequently, we do not need to stop using them or change to other drugs during intravesical BCG treatment. However, large-scale multi-center prospective research is still needed to confirm the above conclusions

The temporal trend of disease burden attributable to metabolic risk factors in China, 1990–2019 : An analysis of the Global Burden of Disease study

Background and aims: The disease burden attributable to metabolic risk factors is rapidly increasing in China, especially in older people. The objective of this study was to (i) estimate the pattern and trend of six metabolic risk factors and attributable causes in China from 1990 to 2019, (ii) ascertain its association with societal development, and (iii) compare the disease burden among the Group of 20 (G20) countries. Methods: The main outcome measures were disability-adjusted life-years (DALYs) and mortality (deaths) attributable to high fasting plasma glucose (HFPG), high systolic blood pressure (HSBP), high low-density lipoprotein (HLDL) cholesterol, high body-mass index (HBMI), kidney dysfunction (KDF), and low bone mineral density (LBMD). The average annual percent change (AAPC) between 1990 and 2019 was analyzed using Joinpoint regression. Results: For all six metabolic risk factors, the rate of DALYs and death increased with age, accelerating for individuals older than 60 and 70 for DALYs and death, respectively. The AAPC value in rate of DALYs and death were higher in male patients than in female patients across 20 age groups. A double-peak pattern was observed for AAPC in the rate of DALYs and death, peaking at age 20–49 and at age 70–95 plus. The age-standardized rate of DALYs increased for HBMI and LBMD, decreased for HFPG, HSBP, KDF, and remained stable for HLDL from 1990 to 2019. In terms of age-standardized rate of DALYs, there was an increasing trend of neoplasms and neurological disorders attributable to HFPG; diabetes and kidney diseases, neurological disorders, sense organ diseases, musculoskeletal disorders, neoplasms, cardiovascular diseases, digestive diseases to HBMI; unintentional injuries to LBMD; and musculoskeletal disorders to KDF. Among 19 countries of Group 20, in 2019, the age-standardized rate of DALYs and death were ranked fourth to sixth for HFPG, HSBP, and HLDL, but ranked 10th to 15th for LBMD, KDF, and HBMI, despite the number of DALYs and death ranked first to second for six metabolic risk factors. Conclusions: Population aging continuously accelerates the metabolic risk factor driven disease burden in China. Comprehensive and tight control of metabolic risk factors before 20 and 70 may help to mitigate the increasing disease burden and achieve healthy aging, respectively

The First Case of Ischemia-Free Kidney Transplantation in Humans

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation

More sustainable electricity generation in hot and dry fuel cells with a novel hybrid membrane of Nafion/nano-silica/hydroxyl ionic liquid

A new hybrid proton exchange membrane (PEM) has been prepared from hydroxyl functionalized imidazolium ionic liquid (IL-OH), Nafion and nano-SiO2. The IL-OH, with a hydroxyl group that acts as both a proton acceptor and donor, forms strong hydrogen bonds with both Nafion and nano-SiO2, resulting in an effective hydrogen bond network in the ternary membrane. Such an anhydrous hydrogen-bond network, which is unknown previously, endows the PEMs with higher proton conductivity, greater thermal stability and surprisingly a more robust mechanical performance than PEMs consisting of conventional ionic liquids. The resulting PEMs have a tensile strength that is more than twice as strong as recast Nafion and an anhydrous ionic conductivity of ∼55 mS cm−1 at temperatures above 160 °C, with a proton transfer number of ∼0.9. A laboratory assembled H2–O2 fuel cell employing this new PEM delivered a power density of 340 and 420 mW cm−2 at 160 and 180 °C, respectively