Takshan/R1 huggingface dataset:
Multi-omics integration for neuroblastoma clinical endpoint prediction.

BACKGROUND: High-throughput methodologies such as microarrays and next-generation sequencing are routinely used in cancer research, generating complex data at different omics layers. The effective integration of omics data could provide a broader insight into the mechanisms of cancer biology, helping researchers and clinicians to develop personalized therapies. RESULTS: In the context of CAMDA 2017 Neuroblastoma Data Integration challenge, we explore the use of Integrative Network Fusion (INF), a bioinformatics framework combining a similarity network fusion with machine learning for the integration of multiple omics data. We apply the INF framework for the prediction of neuroblastoma patient outcome, integrating RNA-Seq, microarray and array comparative genomic hybridization data. We additionally explore the use of autoencoders as a method to integrate microarray expression and copy number data. CONCLUSIONS: The INF method is effective for the integration of multiple data sources providing compact feature signatures for patient classification with performances comparable to other methods. Latent space representation of the integrated data provided by the autoencoder approach gives promising results, both by improving classification on survival endpoints and by providing means to discover two groups of patients characterized by distinct overall survival (OS) curves. REVIEWERS: This article was reviewed by Djork-Arné Clevert and Tieliu Shi.
Increase in fertility following coal and oil power plant retirements in California.

BACKGROUND: Few studies have explored the relationship between air pollution and fertility. We used a natural experiment in California when coal and oil power plants retired to estimate associations with nearby fertility rates. METHODS: We used a difference-in-differences negative binomial model on the incident rate ratio scale to analyze the change in annual fertility rates among California mothers living within 0-5 km and 5-10 km of 8 retired power plants between 2001 and 2011. The difference-in-differences method isolates the portion of the pre- versus post-retirement contrast in the 0-5 km and 5-10 km bins, respectively, that is due to retirement rather than secular trends. We controlled for secular trends with mothers living 10-20 km away. Adjusted models included fixed effects for power plant, proportion Hispanic, Black, high school educated, and aged > 30 years mothers, and neighborhood poverty and educational attainment. RESULTS: Analyses included 58,909 live births. In adjusted models, we estimated that after power plant retirement annual fertility rates per 1000 women aged 15-44 years increased by 8 births within 5 km and 2 births within 5-10 km of power plants, corresponding to incident rate ratios of 1.2 (95% CI: 1.1-1.4) and 1.1 (95% CI: 1.0-1.2), respectively. We implemented a negative exposure control by randomly selecting power plants that did not retire and repeating our analysis with those locations using the retirement dates from original 8 power plants. There was no association, suggesting that statewide temporal trends may not account for results. CONCLUSIONS: Fertility rates among nearby populations appeared to increase after coal and oil power plant retirements. Our study design limited the possibility that our findings resulted from temporal trends or changes in population composition. These results require confirmation in other populations, given known methodological limitations of ecologic study designs.
Oncological and functional efficacy of nephron-sparing surgery versus radical nephrectomy in renal cell carcinoma stages ≥cT1b: a single institution, matched analysis.

Introduction: The purpose of this paper is to compare oncological outcomes of partial nephrectomy (PN) versus radical nephrectomy (RN) in renal cell carcinoma (RCC) clinical stages ≥T1b, in a retrospective propensity-score matched cohort of a high-volume, tertiary referral center. This paper also aims to compare renal function and complication rates between groups. Material and methods: Our single-institution RCC database was queried to select patients with clinical stages defined by tumor size (T), lymph nodes(N), and metastasis (M) scores of T1b-4 N0 M0, that underwent PN or RN between 2000 and 2014. All images of patients that underwent RN were reviewed, and only patients deemed eligible for PN were included. Medical records were reviewed to obtain data on tumor characteristics, comorbidities, renal function, and complications. After propensity score matching, 152 patients (76 per group) were included in the final analysis. Primary outcomes were cancer specific survival (CSS), overall survival (OS), and clinical progression-free survival (CPFS). Secondary outcomes were renal function preservation and post-operative complication rates. Results: Groups were propensity-score matched. The only parameters that were significantly different between groups were the median follow-up time (RN: 79 months, range 24.1-100.5 vs. PN: 38.5 months, range 20.5-72.1) and a better performance status in the RN group (p = 0.002). The five-year CPFS, CSS, and OS rates were 77.2%, 90.5%, and 86.4%, respectively, in the RN group, and 83.6%, 91.1%, and 82.0%, respectively, in the PN group (p = 0.33, p = 0.55, and p = 0.33, respectively). In the multivariate Cox model, the surgical method was not an independent predictor of CPFS, CSS, or OS. The RN group showed a significantly greater reduction in estimated glomerular filtration rate (RN: 14.1 vs. PN: 5.4 ml/min per 1.73 m²; p <0.03). There was no significant difference in complication rates between the two groups (p = 0.3). The main limitations of this study were its retrospective design and the medium-term follow-up. Conclusions: Our results demonstrated the efficacy and safety of PN in patients with RCC in clinical stages ≥T1b. We observed no significant difference in oncological outcomes between the PN and RN groups at medium-term follow ups. The surgical method did not influence these outcomes. Renal function was preserved significantly more frequently in the PN than in the RN group, but the groups had similar complication rates. These findings suggested that PN could be considered an oncologically safe procedure for treating large RCC tumors; thus, PN should always be considered, when technically feasible, regardless of tumor stage.
Efficacy and safety of Ding-Kun-Dan for female infertility patients with predicted poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection: study protocol for a randomized controlled trial.

BACKGROUND: Women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) who have a predicted poor ovarian response (POR) present a challenge for reproductive medicine specialists. Traditional Chinese medicine (TCM) is commonly used in China for such patients, in the belief that it will improve the ovarian response and ultimately increase pregnancy rates. However, there is a lack of high-quality evidence about the effect of TCM on improving ovarian response in such patients. The purpose of this study is to evaluate ongoing viable pregnancy rate at 12 weeks' gestation and related indicators of ovarian response in fertile women who have a predicted poor ovarian response having immediate versus delayed IVF/ICSI after 3 months of Ding-Kun-Dan (DKD) pre-treatment. METHODS/DESIGN: This study is a multicenter, randomized controlled, parallel-group, phase III, superiority clinical trial. Two hundred and seventy-eight eligible female infertility patients with POR will be included in the study and randomly allocated into an immediate treatment group and a DKD group in a 1:1 ratio. Both groups will receive IVF or ICSI as a standard treatment while in the DKD group, a commercially available Chinese medicine, DKD, will be administrated for 3 months before the IVF/ICSI cycle starts. The primary outcome of the study is the ongoing pregnancy rate at 12 weeks' gestation. The secondary outcomes include total gonadotropin dosage, duration of stimulation, estradiol (E2) and progesterone (P) levels on human chorionic gonadotropin (hCG) trigger day, cycle cancellation rate, number of oocytes retrieved, high-quality embryo rate, biochemical pregnancy rate, the change of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and E2 levels and all side effects, safety outcomes, and any adverse events. The protocol was approved by the Ethics Committee of the First Teaching Hospital of Tianjin university of TCM (approval no. TYLL2017[K] 004). DISCUSSION: IVF/ICSI is increasingly used to treat couples desiring a baby. Many of these women will have poor ovarian function. In China, DKD is commonly used for these patients prior to undergoing IVF/ICSI. There is no effective treatment for poor ovarian response in Western medicine currently. It is important, therefore, to undertake this randomized control trial to determine whether DKD is effective or not. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-17011697 . Registered on 19 June 2017.
Bacterial genome engineering and synthetic biology: combating pathogens.

BACKGROUND: The emergence and prevalence of multidrug resistant (MDR) pathogenic bacteria poses a serious threat to human and animal health globally. Nosocomial infections and common ailments such as pneumonia, wound, urinary tract, and bloodstream infections are becoming more challenging to treat due to the rapid spread of MDR pathogenic bacteria. According to recent reports by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), there is an unprecedented increase in the occurrence of MDR infections worldwide. The rise in these infections has generated an economic strain worldwide, prompting the WHO to endorse a global action plan to improve awareness and understanding of antimicrobial resistance. This health crisis necessitates an immediate action to target the underlying mechanisms of drug resistance in bacteria. RESEARCH: The advent of new bacterial genome engineering and synthetic biology (SB) tools is providing promising diagnostic and treatment plans to monitor and treat widespread recalcitrant bacterial infections. Key advances in genetic engineering approaches can successfully aid in targeting and editing pathogenic bacterial genomes for understanding and mitigating drug resistance mechanisms. In this review, we discuss the application of specific genome engineering and SB methods such as recombineering, clustered regularly interspaced short palindromic repeats (CRISPR), and bacterial cell-cell signaling mechanisms for pathogen targeting. The utility of these tools in developing antibacterial strategies such as novel antibiotic production, phage therapy, diagnostics and vaccine production to name a few, are also highlighted. CONCLUSIONS: The prevalent use of antibiotics and the spread of MDR bacteria raise the prospect of a post-antibiotic era, which underscores the need for developing novel therapeutics to target MDR pathogens. The development of enabling SB technologies offers promising solutions to deliver safe and effective antibacterial therapies.
Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.

BACKGROUND: Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014. METHODS: A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting. RESULTS: We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours. CONCLUSION: This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.
Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models.

PURPOSE: Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single-agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor, OSI-906, in combination with a mitogen-activated protein (MAP)-ERK kinase (MEK) 1/2 inhibitor based on evidence that the MAP kinase pathway was upregulated in colorectal cancer cell lines that were resistant to OSI-906. EXPERIMENTAL DESIGN: The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126 were analyzed both as single agents and in combination in 13 colorectal cancer cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. In addition, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) was evaluated in vivo using human colorectal cancer xenograft models. RESULTS: The combination of OSI-906 and U0126 resulted in synergistic effects in 11 of 13 colorectal cancer cell lines tested. This synergy was variably associated with apoptosis or cell-cycle arrest in addition to molecular effects on prosurvival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib. CONCLUSIONS: Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with an MEK 1/2 inhibitor in colorectal cancer cell line models both in vitro and in vivo, which supports the rational combination of OSI-906 with an MEK inhibitor in patients with colorectal cancer. Clin Cancer Res; 19(22); 6219-29. ©2013 AACR.
DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma.

BACKGROUND: Hypermethylation in promoter regions of genes might lead to altered gene functions and result in malignant cellular transformation. Thus, biomarker identification for hypermethylated genes would be very useful for early diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). The objectives of this study were to screen and validate differentially hypermethylated genes in OSCC and correlate the hypermethylation-induced genes with demographic, clinocopathological characteristics and survival rate of OSCC. METHODS: DNA methylation profiling was utilized to screen the differentially hypermethylated genes in OSCC. Three selected differentially-hypermethylated genes of p16, DDAH2 and DUSP1 were further validated for methylation status and protein expression. The correlation between demographic, clinicopathological characteristics, and survival rate of OSCC patients with hypermethylation of p16, DDAH2 and DUSP1 genes were analysed in the study. RESULTS: Methylation profiling demonstrated 33 promoter hypermethylated genes in OSCC. The differentially-hypermethylated genes of p16, DDAH2 and DUSP1 revealed positivity of 78%, 80% and 88% in methylation-specific polymerase chain reaction and 24% and 22% of immunoreactivity in DDAH2 and DUSP1 genes, respectively. Promoter hypermethylation of p16 gene was found significantly associated with tumour site of buccal, gum, tongue and lip (P=0.001). In addition, DDAH2 methylation level was correlated significantly with patients' age (P=0.050). In this study, overall five-year survival rate was 38.1% for OSCC patients and was influenced by sex difference. CONCLUSIONS: The study has identified 33 promoter hypermethylated genes that were significantly silenced in OSCC, which might be involved in an important mechanism in oral carcinogenesis. Our approaches revealed signature candidates of differentially hypermethylated genes of DDAH2 and DUSP1 which can be further developed as potential biomarkers for OSCC as diagnostic, prognostic and therapeutic targets in the future.
Should de Winter T-Wave Electrocardiography Pattern Be Treated as ST-Segment Elevation Myocardial Infarction Equivalent with Consequent Reperfusion? A Dilemmatic Experience in Rural Area of Indonesia.

Background: Although de Winter T-wave electrocardiography pattern is rare, it signifies proximal left anterior descending artery occlusion and is often unrecognized by physicians. The aim of this case report was to highlight the dilemma in the management of a patient with de Winter T-wave pattern in the hospital without interventional cardiology facility. Case Presentation: A 65-year-old male presented with typical chest pain since 2 hours before admission, and ECG showed sinus rhythm of 57 bpm and >1 mm upsloping ST depression with symmetric tall T in lead V2-3 characteristic of de Winter T-wave ECG pattern. He was given dual antiplatelet therapy, nitrate, statin, and anticoagulant. He refused referral to interventional cardiology available hospital. 3 hours after admission, the electrocardiography transformed into Q-waves consistent with final stages of acute STEMI and ST-segment elevation that barely meets the threshold in the guideline, and thrombolytic was administered and successful. There is a suggestion that de Winter T-wave electrocardiography should be treated as ST-segment myocardial infarction equivalent and should undergo coronary angiography; however, not every hospital has the luxury of interventional cardiology facility. The other modality for reperfusion is thrombolysis; however, without a clear guideline and scarcity of study, we prefer to resort to conservative treatment. " Fortunately," transformation into ST-segment elevation helps us to determine the course of action which is reperfusion using thrombolytic. Conclusions: de Winter T-wave ECG pattern is not mentioned in any guidelines regarding acute coronary syndromes, and there are no clear recommendations. Physicians in rural area without interventional cardiology facility face a dilemma with the lack of evidence-based guideline. Fibrinolytic may be appropriate in those without contraindications with strong chest pain consistent with acute coronary occlusion, less than 3 hours of symptoms, and convincing de Winter T-wave ECG pattern for a rural non-PCI hospital far away from PCI capable hospital.
Heritability of glaucoma and glaucoma-related endophenotypes: systematic review and meta-analysis protocol.

INTRODUCTION: Glaucoma is the second leading cause of age-related vision loss worldwide; it is an umbrella term that is used to describe a set of complex ocular disorders with a multifactorial aetiology. Both genetic and lifestyle risk factors for glaucoma are well established. Thus far, however, systematic reviews on the heritability of glaucoma have focused on the heritability of primary open-angle glaucoma only. No systematic review has comprehensively reviewed or meta-analysed the heritability of other types of glaucoma, including glaucoma-related endophenotypes. The aim of this study will be to identify relevant scientific literature regarding the heritability of both glaucoma and related endophenotypes and summarise the evidence by performing a systematic review and meta-analysis. METHODS AND ANALYSIS: This systematic review will follow the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols 2015 checklist, which provides a standardised approach for carrying out systematic reviews. To capture as much literature as possible, a comprehensive step-by-step systematic search will be undertaken in MEDLINE (PubMed), EMBASE, Web of Science and ScienceDirect, and studies published until 31 December 2017 will be included. Two reviewers will independently search the articles for eligibility according to predefined selection criteria. A database will be used for screening of eligible articles. The quality of the included studies will be rated independently by two reviewers, using the National Health Institute Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. A random-effects model will be used for the meta-analysis. This systematic review is registered with the International Prospective Register of Systematic Reviews with a registration number: CRD42017064504. ETHICS AND DISSEMINATION: We will use secondary data from peer-reviewed published articles, and hence there is no requirement for ethics approval. The results of this systematic review will be disseminated through publication in a peer-reviewed scientific journal.
Ahmed glaucoma valve in uveitic patients with fluocinolone acetonide implant-induced glaucoma: 3-year follow-up.

Purpose: To evaluate the efficacy and safety of Ahmed glaucoma valve (AGV) in eyes with noninfectious uveitis that had fluocinolone acetonide intravitreal implant (Retisert™)-induced glaucoma. Methods: This retrospective study reviewed the safety and efficacy of AGV implantation in patients with persistently elevated intraocular pressure (IOP) after implantation of a fluocinolone acetonide intravitreal implant at the Massachusetts Eye Research and Surgery Institution between August 2006 and November 2015. Results: Nine patients with 10 uveitic eyes were included in this study, none of which had preexisting glaucoma in the study eye. Mean patient age was 42 years; 6 patients were female and 3 were male. Baseline mean IOP was 30.6 mmHg prior to AGV placement while mean IOP-lowering medications were 2.9. In the treatment groups, there was a statistically significant reduction in post-AGV IOP. IOP was lowest at 1-week after AGV implantation (9.0 mmHg). Nine out of 10 eyes achieved an IOP below target value of 22 mmHg and/or a 20% reduction in IOP from baseline 1 month and 1 year following AGV placement. All other postoperative time points showed all 10 eyes reaching this goal. A statistically significant decrease in IOP-lowering medication was seen at the 1-week, 1-month, and 3-year time points compared to baseline, while a statistically significant increase was seen at the 3-month, 6-month, and 2-year post-AGV time points. No significant change in retinal nerve thickness or visual field analysis was found. Conclusion: AGV is an effective and safe method of treatment in fluocinolone acetonide intravitreal implant-induced glaucoma. High survival rate is expected for at least 3 years.
K-Map: connecting kinases with therapeutics for drug repurposing and development.

UNLABELLED: Protein kinases play important roles in regulating signal transduction in eukaryotic cells. Due to evolutionary conserved binding sites in the catalytic domain of the kinases, most inhibitors that target these sites promiscuously inhibit multiple kinases. Quantitative analysis can reveal complex and unexpected interactions between protein kinases and kinase inhibitors, providing opportunities for identifying multi-targeted inhibitors of specific diverse kinases for drug repurposing and development. We have developed K-Map-a novel and user-friendly web-based program that systematically connects a set of query kinases to kinase inhibitors based on quantitative profiles of the kinase inhibitor activities. Users can use K-Map to find kinase inhibitors for a set of query kinases (obtained from high-throughput 'omics' experiments) or to reveal new interactions between kinases and kinase inhibitors for rational drug combination studies. AVAILABILITY AND IMPLEMENTATION: K-Map has been implemented in python scripting language and the website is freely available at: http://tanlab.ucdenver.edu/kMap.