Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

The Impact of the Comprehensive Unit-Based Safety Program on the Perioperative Efficiency and Patient Safety of Adult Hip and Knee Arthroplasty Procedures: Retrospective Comparative Study.

BACKGROUND: The complexity of health care delivery systems presents a unique challenge for the perioperative space. In the area of arthroplasty procedures, the shift of complex patients into ambulatory surgery centers and reimbursement that is no longer commensurate with the inflated costs of performing these procedures have created difficulties for hospitals and physicians alike. Thus, there is a critical need to optimize perioperative workflows while maintaining high-quality care provision. METHODS: Our institution implemented the Comprehensive Unit-based Safety Program (CUSP) to improve the quality and efficiency of total knee and hip arthroplasties (TKAs and THAs). This initiative involved extensive collaboration with clinical and administrative teams, as well as 5 intervention-driven workgroups. First-case on-time start rates and duration of first-case delays, case length, anesthesia preparation, in-room patient preparation, operation, patient exit, and room turnover after CUSP implementation were analyzed using independent samples median testing, Mann-Whitney U testing, and a percentage-point difference calculation. RESULTS: After CUSP arthroplasty implementation, first-case on-time start rates increased from 43 to 81%. Statistically significant decreases were observed in median times for first-case delays, case length, in-room patient preparation, operation, patient exit, and room turnover for TKAs and THAs, but not anesthesia preparation. CONCLUSIONS: The implementation of CUSP arthroplasty for TKAs and THAs resulted in significant improvements in nearly all efficiency metrics, as well as preventions of patient safety missteps. These results exemplify the versatility of CUSP as a quality improvement method that can maintain patient safety and perioperative efficiency in the arthroplasty service of a large-scale medical center. LEVEL OF EVIDENCE: III.

An individualized causal framework for learning intercellular communication networks that define microenvironments of individual tumors.

Cells within a tumor microenvironment (TME) dynamically communicate and influence each other's cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an individualized causal analysis framework for discovering tumor specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied individualized causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating individual ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.

Temporal trends of de novo urological malignancy in renal transplant recipients without a cancer history: A longitudinal cohort study.

BACKGROUND: The incidence of malignancies after successful kidney transplantation has historically been higher than in the general population, with adverse impact on clinical outcomes. However, uncertainty remains as to which cancers occur at what time points after kidney transplantation. METHODS: We conducted a longitudinal cohort study to investigate the temporal trends and topographic patterns of de novo malignancies to optimize surveillance protocols and improve transplant outcome in renal transplant recipients. Measurement of death and cancer events was performed to calculate the cumulative risk of events of interest. RESULTS: Between 2000 and 2013, 3169 renal transplant recipients were retrospectively screened; 3035 (96%) of them met eligibility criteria and were evaluated with a follow-up of 27612 person-years. There was suboptimal overall survival and malignancy-free survival in renal transplant recipients compared to reference groups (HR: 1.65; 95% CI: 1.50-1.82; p < .001; HR: 2.33; 95% CI: 2.04-2.66; p < .001, respectively). Among renal transplant recipients, urological malignancies were predominant (57.5%), followed by digestive tract malignancies (21.4%). The cancer risks of the urinary bladder and upper urinary tract were lower in male subjects (HR: .48; 95% CI: .33-.72; p < .001; HR: .34; 95% CI: .20-.59; p < .001, respectively). The temporal trends of urological malignancies among renal transplant recipients were expressed in a bimodal pattern, with M-shaped peaks at 3 and 9 years, with gender disparity. CONCLUSIONS: In renal transplant recipients, cancer occurrences are shown as M-shaped twin peaks. Our study highlights that specific customized 'targeted' strategies for cancer surveillance programs are required to optimize posttransplant care.

Management of infection among Medicare beneficiaries with HIV/AIDS: risk of diabetes with protease inhibitors and associated racial disparities using big data approach.

Association between protease inhibitors (PI) and Type II diabetes mellitus (T2DM) in human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients is largely debated. This study examined the odds of developing T2DM among HIV/AIDS Medicare beneficiaries treated with PI and possible racial disparities in the odds. We performed a nested casecontrol study of Medicare database 2013-2017. We included HIV/AIDS positive beneficiaries who were enrolled continuously in Medicare Part A/B with no previous history of T2DM. PI-users were matched to non-PI users and non-anti-retroviral therapies (ART) users using a1:1 greedy propensity score (PS) matching . Multivariablee logistic regressions were performed to assess the odds of developing T2DM. The analysis included 2,353 HIV/AIDS beneficiaries. Matched samples were generated for PI vs. non-PI groups (n = 484) and PI vs. non-ART groups (n = 490). Compared to the non-PI group, the odds of developing T2DM were higher in PI-users (AOR: 1.76; 95% CI: 1.17-2.64), in Caucasian PI-users (AOR: 1.81; 95% CI: 1.02-3.22) and in African-American PI-users (AOR: 1.86; 95% CI: 1.03-3.36). Compared to the non-ART group, the odds of developing T2DM were higher in PI-users (AOR: 1.87; 95% CI: 1.25-2.81), in Caucasian PI-users (AOR: 1.96; 95% CI: 1.14-3.39) and in African-American PI-users (AOR: 2.05; 95% CI: 1.03-4.09). The use of PI is associated with higher odds of T2DM; odds were higher among African-Americans than Caucasians.

Economic impact of comorbid diabetes and associated racial disparities in managing Medicare beneficiaries with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).

Clinical management of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is progressing to include chronic/metabolic complications, which may impose a significant economic burden on beneficiaries and Medicare. We assessed the national economic impact of comorbid Type-II Diabetes Mellitus (T2DM) on HIV/AIDS patients and potential raical disparities. This study was a cross-sectional study of Medicare database 2013-2017. Analytical sample included HIV/AIDS positive beneficiaries continuously enrolled in Part A/B. Total medical costs, prescription costs, inpatient costs, outpatient costs, out-of-pocket (OOP) costs, and Medicare costs were assessed from Medicare claims. Generalized linear models with log-link and gamma distribution were used to examine the impact of T2DM on different costs. A total of 2,509 eligible HIV/AIDS positive beneficiaries were identified of which 19.9% (n=498) had T2DM. After adjusting for covariates, T2DM beneficiaries had higher inpatient costs: 63.34% (95% CI: 42.73%-86.94%), outpatient costs: 50.26% (95% CI: 30.70%-72.75%), Medicare costs: 27.95% (95% CI: 13.81%-43.84%), OOP costs: 59.15% (95% CI: 40.02%-80.92%), and total medical costs: 27.83% (95% CI: 14.27%-43.00%) than non-T2DM beneficiaries. Incremental costs were higher among African Americans than Caucasians. Comorbid T2DM mposes a significant economic burden on HIV/AIDS patients and Medicare, which is higheramong African Americans.

Genomics4RD: An integrated platform to share Canadian deep-phenotype and multiomic data for international rare disease gene discovery.

Despite recent progress in the understanding of the genetic etiologies of rare diseases (RDs), a significant number remain intractable to diagnostic and discovery efforts. Broad data collection and sharing of information among RD researchers is therefore critical. In 2018, the Care4Rare Canada Consortium launched the project C4R-SOLVE, a subaim of which was to collect, harmonize, and share both retrospective and prospective Canadian clinical and multiomic data. Here, we introduce Genomics4RD, an integrated web-accessible platform to share Canadian phenotypic and multiomic data between researchers, both within Canada and internationally, for the purpose of discovering the mechanisms that cause RDs. Genomics4RD has been designed to standardize data collection and processing, and to help users systematically collect, prioritize, and visualize participant information. Data storage, authorization, and access procedures have been developed in collaboration with policy experts and stakeholders to ensure the trusted and secure access of data by external researchers. The breadth and standardization of data offered by Genomics4RD allows researchers to compare candidate disease genes and variants between participants (i.e., matchmaking) for discovery purposes, while facilitating the development of computational approaches for multiomic data analyses and enabling clinical translation efforts for new genetic technologies in the future.

Immunotherapy in Genitourinary Malignancy: Evolution in Revolution or Revolution in Evolution.

Immunotherapy, the 5th pillar of cancer care after surgery, radiotherapy, cytotoxic chemotherapy, and precision therapy (molecular targeted therapy), is revolutionizing the standard of care in certain patients with genitourinary malignancies. As modest clinical benefits of IL-2 for metastatic renal cell carcinoma and Bacillus Calmette-Guerin therapy for early-stage bladder cancers in the past years, immune checkpoint inhibitors therapies demonstrate meaningful survival benefit and durable clinical response in renal cell carcinoma, urothelial carcinoma, and some prostate cancer. Despite best efforts, the benefits are limited to a minority of unselected patients due to the complexities of biomarker development. Now come the next hurdles: figuring out which patients best respond to immune checkpoint inhibitors and which patients won't respond to immune checkpoint inhibitors? How best to approach immune checkpoint inhibitors therapies to extend/maximize the treatment response as long as possible? How to overcome therapeutic resistance by specific concurrent immunomodulators or targeted therapy or chemotherapy? The role of immune checkpoint inhibitors in combination or sequencing with chemotherapy or other targeted therapies or other immunomodulating therapeutics in the early disease, neoadjuvant, adjuvant, and metastatic setting is actively under exploration. Ideal strategy for cancer care is to provide not just more time, but more quality time: there remain unmet needs for novel therapies that exploit molecular or genetic pathways to extend survival without compromising health-related quality of life for patients with advanced genitourinary malignancies. Further research is needed to discover new therapeutic strategies, and validate efficacy and effectiveness in real-world settings.

Cui Bono? Identifying Patient Groups That May Benefit From Granulocyte Transfusions in Pediatric Hematology and Oncology.

INTRODUCTION: Granulocyte transfusions have long been used to bridge the time to neutrophil recovery in patients with neutropenia and severe infection. Recent randomized controlled trials did not prove a beneficial effect of granulocyte transfusions, but were likely underpowered and suffered from very heterogeneous study populations. METHODS: We retrospectively reviewed data of all patients treated with granulocyte transfusions at our pediatric center from 2004 to 2019. To identify parameters that predict the success of granulocyte transfusions, we stratified patients in 3 groups. Patients in group 1 cleared their infection, whereas patients in group 2 succumbed to an infection in neutropenia despite granulocyte transfusions. A third group included all patients who died of causes that were not related to infection. RESULTS: We demonstrate that patients without respiratory or cardiocirculatory insufficiency are enriched in group 1 and more likely to benefit from granulocyte transfusions than patients who already require these intensive care measures. The effect of granulocyte transfusions correlates with the cell dose per body weight applied per time. With our standard twice weekly dosing, patients with a body weight below 40 kg are more likely to achieve a sufficient leukocyte increment and clear their infection in comparison to patients with a higher body weight. DISCUSSION/CONCLUSIONS: We suggest that future studies on the benefits of granulocyte transfusions stratify patients according to clinical risk factors that include the need for respiratory or cardiocirculatory support and strive for a sufficient dose density of granulocyte transfusions.

CReSCENT: CanceR Single Cell ExpressioN Toolkit.

CReSCENT: CanceR Single Cell ExpressioN Toolkit (https://crescent.cloud), is an intuitive and scalable web portal incorporating a containerized pipeline execution engine for standardized analysis of single-cell RNA sequencing (scRNA-seq) data. While scRNA-seq data for tumour specimens are readily generated, subsequent analysis requires high-performance computing infrastructure and user expertise to build analysis pipelines and tailor interpretation for cancer biology. CReSCENT uses public data sets and preconfigured pipelines that are accessible to computational biology non-experts and are user-editable to allow optimization, comparison, and reanalysis for specific experiments. Users can also upload their own scRNA-seq data for analysis and results can be kept private or shared with other users.

Effect of cognitive impairment on risk of death in Hispanic/Latino adults over the age of 50 residing in the United States with and without diabetes: Data from the Health and Retirement Study 1995-2014.

OBJECTIVE: To understand the relationship between mortality and cognitive function among older US Hispanic adults with and without diabetes. METHODS: Data from the Health and Retirement Study (1995-2014) were analyzed. Cox proportional hazard models were used to estimate the association between mortality and cognitive function. Models were stratified by diabetes. RESULTS: Four thousand thirteen older US Hispanic adults were included. Fully adjusted models for individuals with diabetes showed those with mild cognitive impairment (MCI; hazard ratio [HR]: 1.61; 95% confidence interval [CI]: 1.06, 2.45; P = .025) and dementia (HR: 2.14; 95% CI: 1.25, 3.67; P = .006) had increased mortality compared to normal cognition. Fully adjusted models for individuals without diabetes showed those with MCI (HR: 1.87; 95% CI: 1.28, 2.74; P = .001) and dementia (HR: 3.25; 95% CI: 1.91, 5.55; P < .001) had increased mortality compared to normal cognition. CONCLUSIONS: Cognitive impairment is associated with increased mortality in older US Hispanic adults with and without diabetes. Clinicians should regularly assess cognitive function in this group to quickly identify declines and make appropriate referrals for support to optimize health and reduce mortality.

Using a Diabetes Risk Score to Identify Patients Without Diabetes at Risk for New Hyperglycemia in the Hospital.

OBJECTIVE: To assess the value of a validated diabetes risk test, the Cambridge Risk Score (CRS), to identify patients admitted to hospital without diabetes at risk for new hyperglycemia (NH). METHODS: This retrospective cross-sectional study included adults admitted to a hospital over a 4-year period. Patients with no diabetes diagnosis and not on antidiabetics were included. The CRS was calculated for each patient, and those with available glycated hemoglobin (HbA1C) results were investigated in a second analysis. Multivariate regression analyses were performed to assess the association among CRS, HbA1C, and the risk for NH. RESULTS: A total of 19,830 subjects comprised the sample, of which 38% were found to have developed NH, defined as a blood glucose level ≥140 mg/dL. After accounting for covariates, the CRS was significantly associated with NH (odds ratio [OR], 1.19 [1.16, 1.22]; P < .001). Only 17% of patients had their HbA1C values checked within 6 months of admission. Compared with patients without diabetes, patients with prediabetes based on their HbA1C level (OR, 1.59 [1.37, 1.86]; P < .001) and patients with undiagnosed diabetes (OR, 5.95 [3.50, 10.65]; P < .001) were also significantly more likely to have NH. CONCLUSION: Results of this study show that the CRS and HbA1C levels were significantly associated with the risk of developing NH in inpatient adults without diabetes. Given that an HbA1C level was missing in most medical records of hospitalized patients without diabetes, the CRS could be a useful tool for early identification and management of NH, possibly leading to better outcomes.

EpigenCentral: Portal for DNA methylation data analysis and classification in rare diseases.

Epigenetic processes play a key role in regulating gene expression. Genetic variants that disrupt chromatin-modifying proteins are associated with a broad range of diseases, some of which have specific epigenetic patterns, such as aberrant DNA methylation (DNAm), which may be used as disease biomarkers. While much of the epigenetic research has focused on cancer, there is a paucity of resources devoted to neurodevelopmental disorders (NDDs), which include autism spectrum disorder and many rare, clinically overlapping syndromes. To address this challenge, we created EpigenCentral, a free web resource for biomedical researchers, molecular diagnostic laboratories, and clinical practitioners to perform the interactive classification and analysis of DNAm data related to NDDs. It allows users to search for known disease-associated patterns in their DNAm data, classify genetic variants as pathogenic or benign to assist in molecular diagnostics, or analyze patterns of differential methylation in their data through a simple web form. EpigenCentral is freely available at http://epigen.ccm.sickkids.ca/.

Stay Connected: A Germ Cell Strategy.

Germ cells develop as a cyst of interconnected sibling cells in a broad range of organisms in both sexes. A well-established function of intercellular connectivity is to transport cytoplasmic materials from 'nurse' cells to oocytes, a critical process for developing functional oocytes in ovaries of many species. However, there are situations where connectivity exists without a nursing mechanism, and the biological meaning of such connectivity remains obscure. In this review, we summarize current knowledge on the formation of intercellular connectivity, and discuss its meaning by visiting multiple examples of germ cell connectivity observed in evolutionarily distant species.

Systematic discovery of the functional impact of somatic genome alterations in individual tumors through tumor-specific causal inference.

Cancer is mainly caused by somatic genome alterations (SGAs). Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. We developed a novel tumor-specific computational framework that finds the likely causative SGAs in an individual tumor and estimates their impact on oncogenic processes, which suggests the disease mechanisms that are acting in that tumor. This information can be used to guide precision oncology. We report a tumor-specific causal inference (TCI) framework, which estimates causative SGAs by modeling causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and estimated for each tumor the SGAs that causally regulate the differentially expressed genes (DEGs) in that tumor. Overall, TCI identified 634 SGAs that are predicted to cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both the well-known and the novel candidate drivers that are predicted by TCI. TCI provides a unified framework that integrates multiple types of SGAs and molecular phenotypes to estimate which genome perturbations are causally influencing one or more molecular/cellular phenotypes in an individual tumor. By identifying major candidate drivers and revealing their functional impact in an individual tumor, TCI sheds light on the disease mechanisms of that tumor, which can serve to advance our basic knowledge of cancer biology and to support precision oncology that provides tailored treatment of individual tumors.

Economic and clinical burdens and associated health disparities in HIV/AIDS management using big data: potentially inappropriate use and deprescribing of benzodiazepines.

This study aimed to examine factors, healthcare utilization, and medical costs associated with potentially inappropriate use of benzodiazepines in persons living with HIV (PLWH). We used big data from Medicare claims in 2017. Potentially inappropriate use of benzodiazepines was defined as having any benzodiazepine claims in individuals 65+ years or having benzodiazepine claims for more than four weeks in individuals 18-64 years. Logistic regressions, zero-inflated negative binomial regressions, and generalized linear models were used. This study included 1,211 PLWH and 235 (19.41%) had potentially inappropriate use of benzodiazepines. PLWH who were 65+ years (OR: 0.56; 95% CI: 0.33, 0.96), non-Hispanic blacks (OR: 0.29; 95% CI: 0.20, 0.41), or Hispanics (OR: 0.55; 95% CI: 0.35, 0.88) were less likely to use benzodiazepines inappropriately. PLWH who had potentially inappropriate use of benzodiazepines had more inpatient (IRR: 1.46; 95% CI: 1.10, 1.94), outpatient (IRR: 1.14; 95% CI 1.02, 1.28), and emergency room (IRR: 1.32; 95% CI: 1.03, 1.68) visits. Potentially inappropriate use of benzodiazepines was associated with higher total (ß: 0.16; 95% CI: 0.07, 0.25), Medicare (ß: 0.18; 95% CI: 0.07, 0.28), and out-of-pocket (ß: 0.21; 95% CI: 0.05, 0.36) costs. This study provides real-world evidence to support deprescribing benzodiazepines in PLWH.

Synthesis of FeP nanotube arrays as negative electrode for solid-state asymmetric supercapacitor.

Recently, metal phosphides have attracted considerable attention as promising electrode materials for supercapacitors. In this work, FeP nanotube arrays have been successfully synthesized on carbon cloth using ZnO nanorod arrays as the sacrificial templets, via a phosphidation process. The dimensions of the FeP nanotubes are characterized using SEM and TEM showing the diameter to be approximately 200 nm and with a wall thickness of 50-100 nm. The tubular structure of FeP nanotubes provides a facile ion pathway and reduced inner inactive material, thus they are favorable for supercapacitor applications. As a result, the as-synthesized FeP nanotube arrays deliver an improved specific capacitance of 149.11 F g-1 and a high areal capacitance of 300.1 mF cm-2 at a current density of 1 mA cm-2. Furthermore, an MnO2//FeP solid-state asymmetric supercapacitor was fabricated with a high areal capacitance of 142 mF cm-2, which indicates the great potential of FeP nanotube arrays to be a high-performing negative electrode material for supercapacitors.

Effect of time of day and specialty on polyp detection rates in Australia.

BACKGROUND AND AIM: Adenoma detection rate (ADR) is an important quality metric in colonoscopy. However, there is conflicting evidence around factors that influence ADR. This study aims to investigate the effect of time of day and endoscopist background on ADR and sessile serrated adenoma/polyp detection rate (SSA/P-DR) for screening colonoscopies. METHODS: Consecutive patients undergoing colonoscopy in 2016 were retrospectively evaluated. Primary outcome was the effect of time of day and endoscopist specialty on screening ADR. Secondary outcomes included evaluation of the same factors on SSA/P-DR and other metrics and collinearity of ADR and SSA/P-DR. Linear regression models were used for association between ADR, time of day, and endoscopist background. Bowel preparation, endoscopist, session, patient age, and gender were adjusted for. Linear regression model was also used for comparing ADR and SSA/P-DR. Chi-square was used for difference of proportions. RESULTS: Two thousand six hundred fifty-seven colonoscopies, of which 558 were screening colonoscopies, were performed. The adjusted mean ADR (screening) was 36.8% in the morning compared with 30.5% in the afternoon (P < 0.0001) and was 36.8% for gastroenterologists compared with 30.4% for surgeons (P < 0.0001). For every 1-h delay in commencing the procedure, there was a reduction in mean ADR by 3.4%. Using a linear regression model, a statistically significant positive association was found between ADR and SSA/P-DR (P < 0.0001). CONCLUSIONS: Morning and afternoon sessions and gastroenterologists and surgeons achieved the minimum standards recommended for ADR. Afternoon lists and surgeons were associated with a lower ADR compared with morning and gastroenterologists, respectively. Additionally, SSA/P-DR showed collinearity with ADR.

Identifying Driver Genomic Alterations in Cancers by Searching Minimum-Weight, Mutually Exclusive Sets.

An important goal of cancer genomic research is to identify the driving pathways underlying disease mechanisms and the heterogeneity of cancers. It is well known that somatic genome alterations (SGAs) affecting the genes that encode the proteins within a common signaling pathway exhibit mutual exclusivity, in which these SGAs usually do not co-occur in a tumor. With some success, this characteristic has been utilized as an objective function to guide the search for driver mutations within a pathway. However, mutual exclusivity alone is not sufficient to indicate that genes affected by such SGAs are in common pathways. Here, we propose a novel, signal-oriented framework for identifying driver SGAs. First, we identify the perturbed cellular signals by mining the gene expression data. Next, we search for a set of SGA events that carries strong information with respect to such perturbed signals while exhibiting mutual exclusivity. Finally, we design and implement an efficient exact algorithm to solve an NP-hard problem encountered in our approach. We apply this framework to the ovarian and glioblastoma tumor data available at the TCGA database, and perform systematic evaluations. Our results indicate that the signal-oriented approach enhances the ability to find informative sets of driver SGAs that likely constitute signaling pathways.

Estrogen represses gene expression through reconfiguring chromatin structures.

Estrogen regulates over a thousand genes, with an equal number of them being induced or repressed. The distinct mechanisms underlying these dual transcriptional effects remain largely unknown. We derived comprehensive views of the transcription machineries assembled at estrogen-responsive genes through integrating multiple types of genomic data. In the absence of estrogen, the majority of genes formed higher-order chromatin structures, including DNA loops tethered to protein complexes involving RNA polymerase II (Pol II), estrogen receptor alpha (ERα) and ERα-pioneer factors. Genes to be 'repressed' by estrogen showed active transcription at promoters and throughout the gene bodies; genes to be 'induced' exhibited active transcription initiation at promoters, but with transcription paused in gene bodies. In the presence of estrogen, the majority of estrogen-induced genes retained the original higher-order chromatin structures, whereas most estrogen-repressed genes underwent a chromatin reconfiguration. For estrogen-induced genes, estrogen enhances transcription elongation, potentially through recruitment of co-activators or release of co-repressors with unique roles in elongation. For estrogen-repressed genes, estrogen treatment leads to chromatin structure reconfiguration, thereby disrupting the originally transcription-efficient chromatin structures. Our in silico studies have shown that estrogen regulates gene expression, at least in part, through modifying previously assembled higher-order complexes, rather than by facilitating de novo assembly of machineries.