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Abstract: Metformin is a widely used drug in patients with type 2 diabetes mellitus. Metformin in-hibits hepatic gluconeogenesis and increases glucose utilization in peripheral tissues. In recent years, several studies have shown that metformin is a potential therapeutic agent against cancer, alone or combined with other anticancer treatments. Metformin mainly activates the AMPK com-plex and regulates intracellular energy status, inhibiting the mitochondrial respiratory chain com-plex I and reducing the production of reactive oxygen species. Other anticancer targets of metfor-min are specific transcription factors inhibiting cell proliferation, promoting apoptosis and reducing drug resistance. In addition, metformin modulates tumor cells' response to anticancer treatments, favoring the activity of T cells. In diabetic patients, metformin reduces the occurrence of cancer and improves the prognosis and efficacy of anticancer treatments. In this review, we provided a com-prehensive perspective of metformin as an anticancer drug.

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.

This paper uses the 2003 severe acute respiratory syndrome (SARS) epidemic as a quasi-experiment to study the economic impact of epidemic shocks. It aims to answer the following two questions. 1) H...

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Sensitivity and specificity are key aspects in evaluating the performance of diagnostic tests. Accuracy and AUC are commonly used composite measures that incorporate sensitivity and specificity. Average Weighted Accuracy (AWA) is motivated by the need for a statistical measure of diagnostic yield that can be used to compare diagnostic tests from the medical costs and clinical impact point of view, while incorporating the relevant prevalence range of the disease as well as the relative importance of false positive versus false negative cases. We derive the variance/covariance estimators and testing procedures in four different scenarios comparing diagnostic tests: (i) one diagnostic test vs. the best random test, (ii) two diagnostic tests from two independent samples, (iii) two diagnostic tests from the same sample, and (iv) more than two diagnostic tests from different or the same samples. The impacts of sample size, prevalence, and relative importance on power and average medical costs/clinical loss are examined through simulation studies. Accuracy has the highest power while AWA provides a consistent criterion in selecting the optimal threshold and better diagnostic tests with direct clinical interpretations. The use of AWA is illustrated on a three-arm clinical trial evaluating three different assays in detecting Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) in the rectum and pharynx.

Gadolinium-enhanced magnetic resonance angiography (MRA) and computed tomography angiography (CTA) are commonly used for diagnosing renal arterial stenosis (RAS); however, the diagnostic value is yet controversial. The aim of the study was to evaluate the diagnostic values of both methods. Electronic databases, including PubMed, Embase, and the Cochrane Library, were searched for studies, since inception until October 2017. A total of four articles involving 486 subjects were included in the analysis. The summary of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic (ROC) (AUC) were 0.70, 0.82, 14.54, 0.29, 63.80, and 0.81 for MRA-based diagnosis of RAS, respectively. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for CTA detecting RAS were 0.73, 0.96, 13.04, 0.29, 71.99, and 0.93, respectively. Gadolinium-enhanced MRA and CTA provide a satisfactory diagnostic accuracy, thereby playing a critical role in the diagnosis of RAS.

Three rapid diagnostic test panels (Verigene BC-GN, BioFire BCID, and BCID 2 [RUO]) were compared using the Desirability of Outcome Ranking Management of Antimicrobial Therapy (DOOR-MAT) to evaluate potential downstream antimicrobial prescribing decisions resulting from the panels’ different organism and resistance detection. BioFire BCID 2 (RUO) had the best mean DOOR-MAT scores.

This paper explores a multiperiod portfolio optimization problem under uncertain measure involving background risk, liquidity constraints and V-shaped transaction costs. Unlike traditional studies, we establish multiperiod mean-variance portfolio optimization models with multiple criteria in which security returns, background asset returns and turnover rates are assumed to be uncertain variables that can be estimated by experienced experts. When the returns of the securities and background assets follow normal uncertainty distributions, we use the deterministic forms of the multiperiod portfolio optimization model. The uncertain multiperiod portfolio selection models are practical but complicated. Therefore, the models are solved by employing a genetic algorithm. The uncertain multiperiod model with multiple criteria is compared with an uncertain multiperiod model without background risk and an uncertain multiperiod model without liquidity constraint respectively, we discuss how background risk and liquidity affect optimal terminal wealth. Finally, we give two numerical examples to demonstrate the effectiveness of the proposed approach and models.

Exopolysaccharide (EPS)-producing lactic acid bacteria have been widely used in dairy products, but how calcium, the main metal ion component in milk, regulates the EPS biosynthesis in lactic acid bacteria is not clear. In this study, the effect of Ca2+ on the biosynthesis of EPS in the probiotic Lactobacillus plantarum K25 was studied. The results showed that addition of CaCl2 at 20 mg/L in a semi-defined medium did not affect the growth of strain K25, but it increased the EPS yield and changed the microstructure of the polymer. The presence of Ca2+ also changed the monosaccharide composition of the EPS with decreased high molecular weight components and more content of rhamnose, though the functional groups of the polymer were not altered as revealed by Fourier transform infrared spectral analysis. These were further confirmed by analysis of the mRNA expression of cps genes, 9 of which were upregulated by Ca2+, including cps4F and rfbD associated with EPS biosynthesis with rhamnose. Proteomics analysis showed that Ca2+ upregulated most of the proteins related to carbon transport and metabolism, fatty acid synthesis, amino acid synthesis, ion transport, UMP synthesis. Specially, the increased expression of MelB, PtlIIBC, EIIABC, PtlIIC, PtlIID, Bgl, GH1, MalFGK, DhaK, and FBPase provided substrates for the EPS synthesis. Meanwhile, metabolomics analysis revealed significant change of the small molecular metabolites in tricarboxylic acid cycle, glucose metabolism and propionic acid metabolism. Among them the content of active small molecules such as polygalitol, lyxose, and 5-phosphate ribose increased, facilitating the EPS biosynthesis. Furthermore, Ca2+ activated HipB signaling pathway to inhibit the expression of manipulator repressor such as ArsR, LytR/AlgR, IscR, and RafR, and activated the expression of GntR to regulate the EPS synthesis genes. This study provides a basis for understanding the overall change of metabolic pathways related to the EPS biosynthesis in L. plantarum K25 in response to Ca2+, facilitating exploitation of its EPS-producing potential for application in probiotic dairy products.

The complexities of antibiotic resistance mean that successful stewardship must consider both the effectiveness of a given antibiotic and the spectrum of that therapy to minimize imposing further selective pressure. To meet this challenge, we propose the Desirability of Outcome Ranking approach for the Management of Antimicrobial Therapy (DOOR MAT), a flexible quantitative framework that evaluates the desirability of antibiotic selection. Herein, we describe the steps required to implement DOOR MAT and present examples to illustrate how the desirability of treatment selection can be evaluated using resistance information. While treatments and the scoring of treatment selections must be adapted to specific clinical settings, the principle of DOOR MAT remains constant: The most desirable antibiotic choice effectively treats the patient while exerting minimal pressure on future resistance.

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus. National Institutes of Health Revisión por pares

The percentage of institutional ownership in China has increased gradually. Does this characteristic of Chinese institutional investors affect their participation in corporate governance, which in ...

From solar, geothermal and waste energy, ultra-low-grade heat of 45–60 °C is large in scale, and is still interesting challenges in converting into useful refrigeration of 7 °C. In this study, a novel cascade refrigeration system was developed to utilize 45–60 °C heat. It is composed of a novel two-stage vapor absorption refrigeration (VAR) subsystem with LiBr/H2O working pairs and a conventional vapor compression refrigeration (VCR) subsystem. The VCR subsystem employs potential R1234yf and R1234ze(E) refrigerants. The novel VAR subsystem operates by utilizing ultra-low-grade heat of renewable energy and recycling condensing heat of the VCR subsystem. Based on thermodynamic models of the novel system, its operating mechanism was theoretically investigated and discussed. The results indicate that the novel cascade system can effectively refrigerate by utilizing 45–60 °C ultra-low-grade heat. Its operation is mainly determined by the novel VAR subsystem. There are optimal Tm and Tg1 to maximize its performance. Tg2 has a greater impact on the optimal Tm and little effects on the optimal Tg1. Furthermore, it implies that an available temperature span could be obviously enlarged from 90 °C down to 45 °C. And, progress of utilizing ultra-low-grade heat of renewable energy could be promoted, beneficially.

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement., In 2018, the Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened to discuss strategies to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship.To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI.This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc.The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection.Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score0.73]) and compared with procalcitonin measurement.Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection.In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Metformin is one of the first-line and widely-used drugs in patients with T2DM due to its safety profile, clinical efficacy and cheap cost. It is clearly that metformin has benefits on lowering hyperglycemia and diabetes-related complications in clinical use. The classic effect of metformin is to reduce hepatic glucose production by inhibiting gluconeogenesis in liver and increase glucose utilization in peripheral tissues. Metformin targets mitochondrial respiratory chain complex I to specifically reduce reactive oxygen species generation to protect cells against oxidative stress-induced cell apoptosis. AMPK complex is a key factor in the action of metformin; however it is inconclusive that whether metformin activate AMPK directly or indirectly. In addition, more and more studies showed that metformin act on gut microbiota to exert anti-hyperglycemia effect. Emerging evidence showed that metformin has off-label function on antitumor therapy; however the underlying mechanism of this property of metformin still remains elusive. Taken together, in this review we provide a new perspective on metformin and repurpose its novel and promising application in antitumor therapy.

Summary Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.

Decisions regarding which rapid diagnostic test (RDT) for bloodstream infections to implement remain challenging given the diversity of organisms detected by different platforms. We used the desirability of outcome ranking management of antimicrobial therapy (DOOR-MAT) as a framework to compare two RDT platforms on potential desirability of antimicrobial therapy decisions. An observational study was performed at University of Maryland Medical System comparing Verigene blood culture (BC) to GenMark Dx ePlex blood culture ID (BCID) (research use only) panels on blood cultures from adult patients. Positive percent agreement (PPA) between each RDT platform and Vitek MS was calculated for comparison of on-panel targets. Theoretical antimicrobial decisions were made based on RDT results, taking into consideration patient parameters, antimicrobial stewardship practices, and local infectious diseases epidemiology. DOOR-MAT with a partial credit scoring system was applied to these decisions, and mean scores were compared across platforms using a paired t test. The study consisted of 160 unique patients. The Verigene BC PPA was 98.6% (95% confidence interval [CI], 95.1 to 99.8), and ePlex BCID PPA was 98% (95% CI, 94.3 to 99.6). Among the 31 organisms not on the Verigene BC panels, 61% were identified by the ePlex BCID panels. The mean (standard deviation [SD]) DOOR-MAT score for Verigene BC was 86.8 (28.5), while that for ePlex BCID was 91.9 (23.1) (P = 0.01). Both RDT platforms had high PPA for on-panel targets. The ePlex BCID was able to identify more organisms than Verigene, resulting in higher mean DOOR-MAT scores.

What can romantic comedies teach us about response adaptive randomization for clinical trials? The answer might be surprising.In the mid 1940s, the British epidemiologist and statistician A. Bradfo...

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

With the relatively fixed retirement age, the dramatic increase in life expectancy and the sharp decline in fertility have caused a serious aging problem and an unsustainable pension crisis. It is therefore necessary to design flexible retirement benefits rules that consider life expectancy. By introducing the lifetime utility optimization model, the closed-form solution for the flexible retirement age is obtained. Pension benefits incentive strategies are constructed to encourage contributors to choose a retirement age that is beneficial toward narrowing the pension gap. The empirical studies show that China will face a serious pension gap in the future if the current statutory retirement age is not adjusted. If the retirement age is delayed according to life expectancy, the future pension gap will be greatly reduced.

Interleukin-34 (IL-34) is a known cytokine that plays an important role in the survival, proliferation, and differentiation of macrophages. In previous studies, IL-34 can induce macrophage migration through syndecan-1 or focal adhesion kinase and extracellular signal-related kinase 1 and 2 pathway. These studies mainly focused on in vitro experiments, but the effect of IL-34 on macrophage migration in vivo is less understood. In our study, we artificially induced macrophage, but not neutrophil, enrichment in the skin or liver by overexpressing IL-34 in epidermal cells or hepatocytes in zebrafish. Live imaging showed that the enrichment of macrophages in the liver is due to the direct attraction of macrophages by IL-34. Our results demonstrated that ectopically expressed IL-34 can induce macrophage migration to liver in vivo.