bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computer-aided molecular modeling studies of some 2, 3-dihydro-[1, 4] dioxino [2, 3-f] quinazoline derivatives as EGFRWT inhibitors
Authors: Ibrahim Muhammad Tukur , Uzairu Adamu , Shallangwa Gideon Adamu , Uba Sani 
Published: April 2020

Abstract
Background
Quinazoline are known to possess different biological activities which among is anti-cancer most especially NSCLC. Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinases (RTKs) family, which is known to be one of the most important therapeutic targets for the treatment of cancer most especially NSCLC.

Results
QSAR modeling was performed to develop a model with high predictive power on some non-small cell lung cancer agents (NSCLC) (EGFRWT inhibitors). The EGFRWT inhibitors were optimized using density functional theory (DFT) method utilizing B3LYP/6-31G* level of theory. Genetic function algorithm (GFA) was used to build five models. Out of these five models, the studied one was selected and reported because of its fitness statistically with the following validation parameters: R2trng = 0.9459, R2adj = 0.9311, Q2cv = 0.8947, R2test = 0.7008, and LOF = 0.1195. The selected model was further subjected to other validation test such as VIF and Y-scrambling test applicability domain and found to be statistically significant. The kind of interactions between five most active EGFRWT inhibitors and EGFRWT enzyme were explored via molecular docking. Molecule 4 was ranked top in comparison to other ligands because it has the highest docking score of − 8.3 kcal/mol. The pharmacokinetics studies indicated that these molecules have good absorption, low toxicity level, and permeability properties because none of them violate the Lipinski’s rule of five.

Conclusion
A model with a very high predictive power on some EGFRWT inhibitors was developed using QSAR model. The model was validated and found to have good internal and external assessment parameters: R2 of 0.9459, R2adj of 0.9311, Qcv2 of 0.8947, R2test of 0.7008, and LOF of 0.1195. The nature of interaction of these molecules with their target protein was explored via molecular docking and found molecule 4 to have the highest docking score of − 8.3 kcal/mol among co-ligands. Pharmacokinetics studies revealed that these molecules have good absorption, low toxicity level, and permeability properties. These findings proposed a way for designing potent EGFRWT inhibitors against their target enzyme.
Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study
Authors: Zamarin Dmitriy , Burger Robert A. , Sill Michael W. , Powell Daniel J. , Lankes Heather A. , Feldman Michael D. , Zivanovic Oliver , Gunderson Camille , Ko Emily , Mathews Cara , Sharma Sudarshan , Hagemann Andrea R. , Khleif Samir , Aghajanian Carol 
Published: April 2020

PURPOSESingle-agent PD-1 blockade exhibits limited efficacy in epithelial ovarian cancer (EOC). We evaluated ipilimumab plus nivolumab compared with nivolumab alone in women with persistent or recurrent EOC.METHODSEligibility criteria included measurable disease, 1-3 prior regimens, and platinum-free interval (PFI) < 12 months. Participants were randomly allocated to intravenous nivolumab (every 2 weeks) or induction with nivolumab plus ipilimumab for 4 doses (every 3 weeks), followed by every-2-week maintenance nivolumab for a maximum of 42 doses. The primary null hypothesis was equal probability of objective response within 6 months of random allocation in each arm.RESULTSOne hundred patients were allocated to receive either nivolumab (n = 49), or nivolumab plus ipilimumab (n = 51), with PFI of < 6 months in 62%. Six (12.2%) responses occurred within 6 months in the nivolumab group and 16 (31.4%) in the nivolumab plus ipilimumab group (odds ratio, 3.28; 85% CI, 1.54 to infinity; P = .034). The median progression-free survival (PFS) was 2 and 3.9 months in the nivolumab and nivolumab plus ipilimumab groups, respectively, with a PFI-stratified hazard ratio of 0.53 (95% CI, 0.34 to 0.82); the respective hazard ratio for death was 0.79 (95% CI, 0.44 to 1.42). Grade ≥ 3 related adverse events occurred in 33% of patients in the nivolumab group and 49% in the combination group, with no treatment-related deaths. PD-L1 expression was not significantly associated with response in either treatment group.CONCLUSIONCompared with nivolumab alone, the combination of nivolumab and ipilimumab in EOC resulted in superior response rate and longer, albeit limited, PFS, with toxicity of the combination regimen comparable to prior reports. Additional combination studies to enhance durability of the dual regimen are warranted.
Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism
Authors: Saiki Aya , Otsuki Michio , Tamada Daisuke , Kitamura Tetsuhiro , Shimomura Iichiro , Kurihara Isao , Ichijo Takamasa , Takeda Yoshiyu , Katabami Takuyuki , Tsuiki Mika , Wada Norio , Yanase Toshihiko , Ogawa Yoshihiro , Kawashima Junji , Sone Masakatsu , Inagaki Nobuya , Yoshimoto Takanobu , Okamoto Ryuji , Takahashi Katsutoshi , Kobayashi Hiroki , Tamura Kouichi , Kamemura Kohei , Yamamoto Koichi , Izawa Shoichiro , Kakutani Miki , Yamada Masanobu , Tanabe Akiyo , Naruse Mitsuhide 
Published: April 2020

Abstract

Context
The prevalence of diabetes mellitus (DM) in patients with primary aldosteronism (PA) is higher than in those with essential hypertension and the general population. Although DM is a common major risk factor for cardio-cerebrovascular (CCV) diseases and renal complications, details of its effects in PA have not been demonstrated.

Objective
The aim of this study was to determine the effects of coexistent DM on the risk of CCV events and progression of renal complications in PA patients.

Design
A multi-institutional, cross-sectional study was conducted.

Patients and Methods
PA patients experienced between January 2006 and October 2016 and with available data of CCV events and DM were enrolled from the Japan PA registry of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Diseases Study (n = 2524). CCV events and renal complications were compared between a DM group and a non-DM group by logistic and liner-regression analysis.

Results
DM significantly increased the odds ratio (OR) of CCV events (OR 1.59, 95% CI: 1.05-2.41) and that of proteinuria (OR 2.25, 95% CI: 1.59-3.16). DM correlated significantly with declines in estimated glomerular filtration rate (β = .05, P = .02).

Conclusions
This the first report to demonstrate the presence of DM as an independent risk factor for CCV events and renal complications, even in PA patients. Management of DM should be considered in addition to the specific treatment of PA.
Optimizing for Distributional Goals in School Choice Problems
Authors: Bodoh-Creed Aaron L. 
Published: April 2020

I investigate three goals of school choice: welfare, encouraging neighborhood schools, and diversity. I use optimization problems to find the best stable and incentive compatible match for any combination of these objectives. These problems assume there is a continuum of students and school seats, which allows me to describe the incentive compatibility conditions in a tractable form. I prove that the set of stable matchings is generically continuous in the distribution of students and the school capacities, which implies that the characterization of the possible stable matches in the continuum model approximates the set of stable matches in a matching market with a large, but finite, number of students. I then apply my framework to data from Boston Public Schools. If the mechanism conditions on demographics, the improvement (relative to the status quo) in student welfare is equivalent to moving 291 students (out of 3,479) to schools one rank higher in their preference lists. In contrast, if the mechanism does not condition on demographics, the welfare improvement is equivalent to moving only 25.1 students to schools one rank higher. Improvements in the distributional goals can be made (e.g., increasing enrollment in neighborhood schools by 50%) without reducing welfare or diversity. This paper was accepted by Gabriel Weintraub, revenue management and market analytics.
M-Current Inhibition in Hippocampal Excitatory Neurons Triggers Intrinsic and Synaptic Homeostatic Responses at Different Temporal Scales
Authors: Lezmy Jonathan , Gelman Hana , Katsenelson Maxim , Styr Boaz , Tikochinsky Eliav , Lipinsky Maya , Peretz Asher , Slutsky Inna , Attali Bernard 
Published: April 2020

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Nav1.6 and Kv7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (∼2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.SIGNIFICANCE STATEMENTPersistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.
Aspek Estetis dalam Cerita Pendek “Inu to Hito to Hana” Karya Ogawa Mimei
Authors: Priventa Hendrike 
Published: April 2020

The short story "Inu to Hito to Hana" by Ogawa Mimei is a simple story that is full of elements of ethics and aesthetics. The purpose of this study is to describe the aesthetic aspects of the short story "Inu to Hito to Hana". The method used is literature study using an aesthetic identity approach. The results of this study can be seen from aesthetic aspects, namely 1) language style, 2) symbols, 3) imagination process, and 4) philosophical values.
Keywords : Aesthetic aspects, aesthetic identity, ethics, Japanese short story
Bayes Theorem and Forward Chaining Method On Expert System for Determine Hypercholesterolemia Drugs
Authors: Perbawawati Anna Adi , Sugiharti Endang , Muslim Much Aziz 
Published: April 2020

The development of technology capable to imitating the process of human thinking and led to a new branch of computer science named the expert system. One of the problem that can be solved by an expert system is selecting hypercholesterolemia drugs. Drug selection starts from find the symptoms and then determine the best drug for the patient. This is consist with the mechanism of forward chaining which starts from searching for information about the symptoms, and then try to illustrate the conclusions. To accommodate the missing fact, expert systems can be complemented with the Bayes theorem that provides a simple rule for calculating the conditional probability so the accuracy of the method approaches the accuracy of the experts. This reseacrh uses 30 training data and 76 testing data of medical record that use hypercholesterolemia drugs from Tugurejo Hospital of Semarang. The variable are common symptoms and some hypercholesterolemia drugs. This research obtained a selection of hypercholesterolemia drugs system with 96.05% accuracy
Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer
Authors: Yin Ming , Grivas Petros , Wang Qi-En , Mortazavi Amir , Emamekhoo Hamid , Holder Sheldon L. , Drabick Joseph J. , Woo Michele Sue-Ann , Pal Sumanta , Vasekar Monali , Folefac Edmund , Clinton Steven K. , Monk Paul , Joshi Monika 
Published: April 2020

AbstractBackgroundDNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear.Materials and MethodsWe retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI.ResultsDDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003).ConclusionsGenomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression.Implications for PracticeSomatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.
The utility of red cell distribution width to predict mortality of septic patients in a tertiary hospital of Nepal
Authors: Ghimire Rajan , Shakya Yogendra Man , Shrestha Tirtha Man , Neupane Ram Prasad 
Published: April 2020

Abstract
Background: Sepsis is a common problem encountered in the emergency room which needs to be intervened early. Predicting prognosis is always a difficult task in busy emergency rooms using present scores, which has several variables to calculate. Red cell distribution width (RDW) is an easy, cheap, and efficacious score to predict the severity and mortality of patients with sepsis.Methods: This prospective analytical study was conducted in the emergency room of Tribhuvan University Teaching Hospital among the patients age ≥16 years and with a clinical diagnosis of sepsis using qSOFA score. 148 patients were analyzed in the study by using a non-probability purposive sampling method. Results: RDW has fair efficacy to predict the mortality in sepsis (Area under the Curve of 0.734; 95% C. I= 0.649-0.818; p-value=0.000) as APACHE II (AUC of 0.728; 95% C. I= 0.637 to 0.819; p-value=0.000) or SOFA (AUC of 0.680, 95% C.I =0.591-0.770; p-value=0.001). Youden Index was maximum (37%) at RDW value 14.75, which has a sensitivity of 83% (positive likelihood ratio=1.81) and specificity of 54% (negative likelihood ratio=0.32). Out of 44 patients with septic shock 16 died (36.4 %) and among 104 patients without septic shock, 24 died (22.9%) which had the odds ratio of 0.713 (p=0.555, 95% C. I= 0.231-2.194). Overall mortality was 27.02% (n=40). RDW group analysis showed no mortality in RDW <13.1 group, 3.6% mortality in 13.1 to 14 RDW group, 22.0% mortality in 14 to >15.6 RDW group and 45.9% mortality in >15.6 RDW group. Significant mortality difference was seen in 14 to >15.6 and >15.6 RDW subgroups with a p-value of 0.003 and 0.008 respectively.Conclusion: Area under the curve value for RDW is fair enough to predict the mortality of patients with sepsis in the emergency room. It can be integrated with other severity scores (APACHE II or SOFA score) for better prediction of prognosis of septic patients.
PS4DR: A multimodal workflow for identification and prioritization of drugs based on pathway signatures
Authors: Emon Mhammad Asif , Domingo-Fernández Daniel , Hoyt Charles Tapley , Hofmann-Apitius Martin 
Published: April 2020

Abstract
Background: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning.Results: Here, we present a customizable workflow (PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. Conclusion: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr.
Live-attenuated Salmonella enterica serotype Choleraesuis vaccine with regulated delayed fur mutation confer protection against Streptococcus suis in mice
Authors: Li Yu-an , New Yunyun Chen , Du Yuan zhao , Guo Weiwei , Chu Dianfeng , Fan Juan , Wang Xiaobo , Bellefleur Matthew , Wang Shifeng , Shi Huoying 
Published: April 2020

Abstract
Background: Recombinant Salmonella enterica serotype Choleraesuis (S. Choleraesuis) vaccine vector could be used to deliver heterologous antigens to prevent and control pig diseases. We have previously shown that a live-attenuated S. Choleraesuis vaccine candidate strain rSC0011 (ΔPcrp527::TT araC PBAD crp Δpmi-2426 ΔrelA199::araC PBAD lacI TT ΔasdA33, Δ, deletion, TT, terminator) delivering SaoA, a conserved surface protein in most of S. suis serotypes, provided excellent protection against S. suis challenge, but occasionally lead to morbidity (enteritidis) in vaccinated mice (approximately 1 in every 10 mice). Thus, alternated attenuation method was sought to reduce the reactogenicity of strain rSC0011. Herein, we described another recombinant attenuated S. Choleraesuis vector, rSC0012 (ΔPfur88:: TT araC PBAD fur Δpmi-2426 ΔrelA199:: araC PBAD lacI TT ΔasdA33) with regulated delayed fur mutation to avoid inducing disease symptoms while exhibiting a high degree of immunogenicity. Results: The strain rSC0012 strain with the ΔPfur88::TT araC PBAD fur mutation induced less production of inflammatory cytokines than strain rSC0011 with the ΔPcrp527::TT araC PBAD crp mutation in mice. When delivering the same pS-SaoA plasmid, the intraperitoneal LD50 of rSC0012 was 18.2 times higher than that of rSC0011 in 3-week-old BALB/C mice. rSC0012 with either pS-SaoA or pYA3493 was cleared from spleen and liver tissues 7 days earlier than rSC0011 with same vectors after oral inoculation. The strain rSC0012 synthesizing SaoA induced high titers of anti-SaoA antibodies in both systemic (IgG in serum) and mucosal (IgA in vaginal washes) sites, as well as increased level of IL-4, the facilitator of Th2-type T cell immune response in mice. The recombinant vaccine rSC0012(pS-SaoA) conferred high percentage of protection against S. suis or S. Choleraesuis challenge in BALB/C mice.Conclusions: The live-attenuated Salmonella enterica serotype Choleraesuis vaccine rSC0012(pS-SaoA) with regulated delayed fur mutation provides a foundation for the development of a safe and effective vaccine against S. Choleraesuis and S. suis.