bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors
Authors: Wang Rui , Gao Chan , Raymond Megan , Dito Gennaro , Kabbabe Dominic , Shao Xiao , Hilt Ed , Sun Yongliang , Pak Irene , Gutierrez Martin , Melero Ignacio , Spreafico Anna , Carvajal Richard D. , Ong Michael , Olszanski Anthony J. , Milburn Christina , Thudium Kent , Yang Zheng , Feng Yan , Fracasso Paula M. , Korman Alan J. , Aanur Praveen , Huang Shih-Min A. , Quigley Michael 
Published: October 2019

Abstract

Purpose:
The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study.

Experimental Design:
We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade.

Results:
Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4+ and CD8+ T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy &gt; 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing.

Conclusions:
Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.
Amplification of the Mutation-Carrying BRCA2 Allele Promotes RAD51 Loading and PARP Inhibitor Resistance in the Absence of Reversion Mutations
Authors: Park Pyoung Hwa , Yamamoto Tomomi M. , Li Hua , Alcivar Allen L. , Xia Bing , Wang Yifan , Bernhardy Andrea J. , Turner Kristen M. , Kossenkov Andrew V. , Watson Zachary L. , Behbakht Kian , Casadei Silvia , Swisher Elizabeth M. , Mischel Paul S. , Johnson Neil , Bitler Benjamin G. 
Published: October 2019

Abstract
Patients harboring germline breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutations are predisposed to developing breast, pancreatic, and ovarian cancers. BRCA2 plays a critical role in homologous recombination (HR) DNA repair and deleterious mutations in BRCA2 confer sensitivity to PARP inhibition. Recently, the PARP inhibitors olaparib and rucaparib were FDA approved for the treatment of metastatic breast cancer and patients with recurrent ovarian cancer with mutations in BRCA1/2. Despite their initial antitumor activity, the development of resistance limits the clinical utility of PARP inhibitor therapy. Multiple resistance mechanisms have been described, including reversion mutations that restore the reading frame of the BRCA2 gene. In this study, we generated olaparib- and rucaparib-resistant BRCA2-mutant Capan1 cell lines. We did not detect secondary reversion mutations in the olaparib- or rucaparib-resistant clones. Several of the resistant clones had gene duplication and amplification of the mutant BRCA2 allele, with a corresponding increase in expression of a truncated BRCA2 protein. In addition, HR-mediated DNA repair was rescued, as evidenced by the restoration of RAD51 foci formation. Using mass spectrometry, we identified Disruptor Of Telomeric silencing 1-Like (DOT1L), as an interacting partner of truncated BRCA2. RNAi-mediated knockdown of BRCA2 or DOT1L was sufficient to resensitize cells to olaparib. The results demonstrate that independent of a BRCA2 reversion, mutation amplification of a mutant-carrying BRCA2 contributes to PARP inhibitor resistance.
Pralatrexate in Combination with Oxaliplatin in Advanced Esophagogastric Cancer: A Phase II Trial with Predictive Molecular Correlates
Authors: Malhotra Usha , Mukherjee Sarbajit , Fountzilas Christos , Boland Patrick , Miller Austin , Patnaik Santosh , Attwood Kristopher , Yendamuri Sai , Adjei Araba , Kannisto Eric , Opyrchal Mateusz , Bushunow Peter , Loud Peter , Iyer Renuka , Khushalani Nikhil 
Published: October 2019

AbstractThe purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T&gt;C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G&gt;A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A&gt;T and SLC19A1 rs1051266 G&gt;A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T&gt;C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.
Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer
Authors: Song Heyu , Zeng Jiping , Roychoudhury Shrabasti , Biswas Pranjal , Mohapatra Bhopal , Ray Sutapa , Dowlatshahi Kayvon , Wang Jing , Band Vimla , Talmon Geoffrey , Bhakat Kishor K. 
Published: October 2019

Abstract
Fluorouracil (5-FU) remains a first-line chemotherapeutic agent for colorectal cancer. However, a subset of colorectal cancer patients who have defective mismatch-repair (dMMR) pathway show resistance to 5-FU. Here, we demonstrate that the efficacy of 5-FU in dMMR colorectal cancer cells is largely dependent on the DNA base excision repair (BER) pathway. Downregulation of APE1, a key enzyme in the BER pathway, decreases IC50 of 5-FU in dMMR colorectal cancer cells by 10-fold. Furthermore, we discover that the facilitates chromatin transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to damage sites in chromatin. Downregulation of FACT affects 5-FU damage repair in DNA and sensitizes dMMR colorectal cancer cells to 5-FU. Targeting the FACT complex with curaxins, a class of small molecules, significantly improves the 5-FU efficacy in dMMR colorectal cancer in vitro (∼50-fold decrease in IC50) and in vivo xenograft models. We show that primary tumor tissues of colorectal cancer patients have higher FACT and AcAPE1 levels compared with adjacent nontumor tissues. Additionally, there is a strong clinical correlation of FACT and AcAPE1 levels with colorectal cancer patients' response to chemotherapy. Together, our study demonstrates that targeting FACT with curaxins is a promising strategy to overcome 5-FU resistance in dMMR colorectal cancer patients.
Effects of OSA Surgery on Leptin and Metabolic Profiles
Authors: Chin Chien‐Hung , Lin Pei‐Wen , Lin Hsin‐Ching , Friedman Michael , Lin Meng‐Chih 
Published: October 2019

ObjectivesThis study is designed to investigate the effects of obstructive sleep apnea/hypopnea syndrome (OSA) surgery on serum leptin levels and metabolic disturbances, both of which contribute to the risk of cardiovascular diseases.Study DesignCase series with planned data collection.SettingTertiary referral medical center.Subjects and MethodsA retrospective chart review of 101 consecutive patients with OSA who refused or failed conservative therapy and who then underwent upper airway surgery for OSA treatment was conducted. The personal medical history, anthropometric measurements, subjective symptoms, and objective polysomnographic parameters and fasting morning blood samples for leptin and metabolic biomarkers measurements were collected preoperatively and at a minimum of 3 months postoperatively.ResultsEighty patients with OSA (69 men and 11 women; mean [SD] age of 42.2 [10.2] years) with complete data were included in the final analysis. At least 3 months after surgery, serum leptin, low‐density lipoprotein cholesterol (LDL‐C), and triglyceride levels and the mean systolic blood pressure (SBP) (night and morning) significantly decreased. According to the classical definition of surgical success, 40 subjects had successful surgery and were categorized as surgical responders, and the other 40 patients who failed surgery were categorized as surgical nonresponders. Significant reductions in serum leptin, total cholesterol, LDL‐C, and triglyceride levels and improvement of mean SBP (morning) occurred in surgical responders but not in nonresponders.ConclusionsEffective OSA surgery improves serum leptin, lipid profiles, and SBP. Further studies are needed to investigate the role of serial measurements of these biomarkers in monitoring surgical outcome of OSA treatment.
Surgical Explantation of Bone‐Anchored Hearing Devices: A 10‐year Single Institution Review
Authors: Fritz Christian G. , Bojrab Dennis I. , Lin Kenny F. , Schutt Christopher A. , Babu Seilesh C. , Hong Robert S. 
Published: October 2019

ObjectiveTo identify clinical variables associated with the decision to surgically discontinue bone‐anchored hearing device function.Study DesignRetrospective chart review.SettingTertiary neurotology referral center.Subjects and MethodsThis study examines surgical interventions performed on existing bone‐anchored hearing devices at a single institution from 2008 to 2018. Patient characteristics, indications for implantation, and complications prompting surgical intervention were assessed.ResultsSeventy‐seven cases were included in this study. Among patients in the younger cohort (<37 years old), 100% (13 of 13) of those discontinuing their device had a contralateral normal‐hearing ear. Conversely, 0% (0 of 14) of the younger patients with bilateral hearing loss surgically discontinued their devices. Within the older cohort (≥37 years old), female patients (P =. 002) and those with an increased body mass index (P =. 035) were more likely to surgically discontinue their devices. Multivariate analysis revealed that a contralateral normal‐hearing ear (P =. 001) and infection without soft tissue overgrowth of the abutment (P =. 026) were the strongest predictors of device discontinuation, after adjusting for potential confounders.ConclusionSurgical discontinuation is associated with several clinical variables. Targeted interventions that are viable alternatives to removal, such as device relocation, should be presented to younger patients with a contralateral normal‐hearing ear who experience persistent complications. Patients with persistent infection in the absence of soft tissue overgrowth would especially benefit from enhanced counseling on proper hygiene.
Tracking pregnant women displacements in Sao Paulo, Brazil: a complex systems approach to regionalization through the emergence of patterns
Authors: Rigoli Felix , Mascarenhas Sergio , Alves Domingos , Canelas Tiago , Duarte Geraldo 
Published: October 2019

AbstractBackgroundThe healthcare system can be understood as the dynamic result of the interaction of hospitals, patients, providers, and government configuring a complex network of reciprocal influences. In order to better understand such a complex system, the analysis must include characteristics that are feasible to be studied in order to redesign its functioning. The analysis of the emergent patterns of pregnant women flows crossing municipal borders for birth-related hospitalizations in a region of São Paulo, Brazil, allowed to examine the functionality of the regional division in the state using a complex systems approach and to propose answers to the dilemma of concentration vs. distribution of maternal care regional services in the context of the Brazilian Unified Health System (SUS).MethodsCross-sectional research of the areas of influence of hospitals using spatial interaction methods, recording the points of origin and destination of the patients and exploring the emergent patterns of displacement.ResultsThe resulting functional region is broader than the limits established in the legal provisions, verifying that 85% of patients move to hospitals with high technology to perform normal deliveries and cesarean sections. The region has high independence rates and behaves as a “service exporter.” Patients going to centrally located hospitals travel twice as long as patients who receive care in other municipalities even when the patients’ conditions do not demand technologically sophisticated services. The effects of regulation and the agents’ preferences reinforce the tendency to refer patients to centrally located hospitals.ConclusionsDisplacement of patients during delivery may affect indicators of maternal and perinatal health. The emergent pattern of movements allowed examining the contradiction between wider deployments of services versus concentration of highly specialized resources in a few places. The study shows the potential of this type of analysis applied to other type of patients’ flows, such as cancer or specialized surgery, as tools to guide the regionalization of the Brazilian Health System.
All-cause mortality in patients with treatment-resistant depression: a cohort study in the US population
Authors: Li Gang , Fife Daniel , Wang Grace , Sheehan John J. , Bodén Robert , Brandt Lena , Brenner Philip , Reutfors Johan , DiBernardo Allitia 
Published: October 2019

AbstractBackgroundTreatment-resistant depression (TRD) may represent a substantial proportion of major depressive disorder (MDD); however, the risk of mortality in TRD is still incompletely assessed.MethodsData were obtained from Optum Clinformatics™ Extended, a US claims database. Date of the first antidepressant (AD) dispensing was designated as the index date for study entry and 6 months prior to that was considered the baseline period. Patients with MDD aged ≥ 18 years, index date between January 1, 2008 and September 30, 2015, no AD claims during baseline, and continuous enrollment in the database during baseline were included. Patients who started a third AD regimen after two regimens of appropriate duration were included in the TRD cohort. All-cause mortality was compared between patients with TRD and non-TRD MDD using a proportional hazards model and Kaplan–Meier estimate with TRD status being treated as a time-varying covariate. The model was adjusted for study year, age, gender, depression diagnosis, substance use disorder, psychiatric comorbidities, and Charlson comorbidity index.ResultsOut of 355,942 patients with MDD, 34,176 (9.6%) met the criterion for TRD. TRD was associated with a significantly higher mortality compared with non-TRD MDD (adjusted HR: 1.29; 95% CI 1.22–1.38;p < 0.0001). Survival time was significantly shorter in the TRD cohort compared with the non-TRD MDD cohort (p < 0.0001).ConclusionsPatients with TRD had a higher all-cause mortality compared with non-TRD MDD patients.
Approximations and inequalities for the exponential beta function
Authors: Dragomir Silvestru Sever , Khosrowshahi Farzad 
Published: October 2019

AbstractIn this paper, motivated by interest in simulating the expenditure patterns of construction projects, we introduce the mathematical concept of Exponential-Beta function by$$ F ( \alpha ,\beta ) := \int _{0}^{1}\exp \bigl[ x^{\alpha } ( 1-x ) ^{\beta } \bigr]\,dx, $$F(α,β):=∫01exp[xα(1−x)β]dx,whereα,βare positive numbers. Taylor’s-type approximations, several analytic inequalities, and global convexity properties are established.
Applications of maximum modulus method and Phragmén–Lindelöf method for second-order boundary value problems with respect to the Schrödinger operator
Authors: Liu Zhen 
Published: October 2019

Abstract
In this paper, we present a reliable combination of the maximum modulus method with respect to the Schrödinger operator (Meng in J. Syst. Sci. Complex. 16:446–452, 2003) and Phragmén–Lindelöf method (Shehu in Matematiche 64:57–66, 2015) to investigate the solution of a second-order boundary value problem with respect to the Schrödinger operator. We establish the uniqueness of the solution for this problem. The results reveal that this method is effective and simple.
Serum vascular endothelial growth factor is a biomolecular biomarker of severity of diabetic retinopathy
Authors: Ahuja Sukriti , Saxena Sandeep , Akduman Levent , Meyer Carsten H. , Kruzliak Peter , Khanna Vinay K. 
Published: October 2019

AbstractBackgroundElevated serum vascular endothelial growth factor (VEGF) levels are associated with diabetic retinopathy (DR). Serum VEGF levels correlate with vitreous levels. Neuroretinal changes occur even before the appearance of vascular signs in DR. Role of VEGF as a biomarker for DR has not been assessed. Serum VEGF as a biomarker for severity of DR, was evaluated for the first time.MethodsConsecutive cases of type 2 diabetes mellitus [without DR, (no DR, n = 38); non-proliferative DR, (NPDR, n = 38); proliferative DR, (PDR, n = 40)] and healthy controls (n = 40) were included. Serum VEGF was measured using enzyme linked immunosorbent assay. Accuracy of VEGF as a biomarker for severity of retinopathy was measured using the area under the receiver operator characteristic (ROC) curve.ResultsSerum VEGF levels in controls, No DR, NPDR and PDR groups showed significant incremental trend from 138.96 ± 63.37 pg/ml (controls) to 457.18 ± 165.69 pg/ml (PDR) (F = 48.47;p < 0.001). Serum VEGF levels were observed to be significantly elevated even before DR had set in clinically. ROC for serum VEGF levels was significant in discriminating between the cases and the controls and had good accuracy in discerning between subjects with and without retinopathy. The area under curve (AUC ± SE) for discrimination was significant: (a) cases and controls (n = 156): AUC = 0.858 ± 0.029,p < 0.001; (b) DR (NPDR + PDR) and No DR (n = 116): AUC = 0.791 ± 0.044,p < 0.001; and (c) NPDR and PDR (n = 78): AUC = 0.761 ± 0.056,p < 0.001, with over 90% projected sensitivity and specificity at various cut off values.ConclusionSerum VEGF level is a simple, effective laboratory investigative test in predicting the onset of DR in eyes showing no evidence of DR and serves as a reliable biomolecular biomarker for severity of DR.
Psychiatry and the global drugs debate: what every psychiatrist needs to know
Authors: Bowden-Jones Owen , Sinclair Julia , Lingford-Hughes Anne 
Published: October 2019

SummaryThere are few topics that divide public opinion as sharply as the use of psychoactive substances and it is easy to see why. Substance use is complex and can be examined from numerous perspectives, including legal, health, economic, cultural and ethical. These varying approaches can lead to a range of different conclusions. Here we explore some of the common approaches adopted towards drug policy and suggest a number of principles, which may inform a psychiatrist's own view.
Fontes de Caixa e Restrições Financeiras: Evidências das Firmas Listadas na BM&FBOVESPA
Authors: Chalhoub Leonardo , Kirch Guilherme , Terra Paulo Renato Soares 
Published: October 2019

A literatura de Finanças oferece evidências de que, tanto no Brasil quanto nos E.U.A., as firmas de capital aberto retêm cada vez mais caixa ao longo das últimas décadas. Usando uma base de dados em painel com informações contábeis e de mercado de firmas listadas na BMF&BOVESPA de 1995 a 2013 e o modelo proposto por McLean (2011), estimado através do método dos mínimos quadrados, este estudo objetiva obter evidências sobre as fontes de caixa retido pelas firmas no mercado brasileiro. Os resultados encontrados sugerem que a emissão de ações, o endividamento e o fluxo de caixa operacional têm correlação positiva e significante com a variação em caixa e que o fluxo de caixa operacional é a principal fonte de caixa retido das firmas brasileiras. Sobre o papel dos motivos precaucionários sobre a
retenção, foram encontradas evidências de que o grupo de firmas restritas financeiramente retém mais a partir do fluxo de caixa operacional em tempos de crescimento nestes motivos.
Brazilian Review of Finance 2017 Editorial Report
Authors: Laurini Marcio Poletti 
Published: October 2019

RBFin is the main Brazilian publication outlet of academic papers about finance. Using the Open Journals System to manage the editorial process, publication of RBFin adheres to a strict publication schedule. The journal is indexed by EconLit, RedALyC, Proquest, Google Scholar, Gale and Ebsco and is listed in the JEL, DOAJ, Latindex, OpenJGate, and Cabell’s directories.
RBFin is rated B1 in the business and economics areas of the Brazilian classification system. The editorial board undergoes partial turnover every year and comprises 19 individuals from four countries, the Brazilian members being affiliated with universities in five different Brazilian states. The acceptance rate was 53% for the 2016 year. The average number of days between receipt and first decision for articles submitted in 2016 was 185.
The average number of days between receipt and final decision for articles submitted in 2016 was 192. The worst case was 459 days. Twenty-nine individuals served as reviewers in 2017.
Robotic technology in total knee arthroplasty: a systematic review
Authors: Kayani Babar , Konan Sujith , Ayuob Atif , Onochie Elliot , Al-Jabri Talal , Haddad Fares S. 
Published: October 2019

Robotic total knee arthroplasty (TKA) improves the accuracy of implant positioning and reduces outliers in achieving the planned limb alignment compared to conventional jig-based TKA. Robotic TKA does not have a learning curve effect for achieving the planned implant positioning. The learning curve for achieving operative times comparable to conventional jig-based TKA is 7–20 robotic TKA cases. Cadaveric studies have shown robotic TKA is associated with reduced iatrogenic injury to the periarticular soft tissue envelope compared to conventional jig-based TKA. Robotic TKA is associated with decreased postoperative pain, enhanced early functional rehabilitation, and decreased time to hospital discharge compared to conventional jig-based TKA. However, there are no differences in medium- to long-term functional outcomes between conventional jig-based TKA and robotic TKA. Limitations of robotic TKA include high installation costs, additional radiation exposure, learning curves for gaining surgical proficiency, and compatibility of the robotic technology with a limited number of implant designs. Further higher quality studies are required to compare differences in conventional TKA versus robotic TKA in relation to long-term functional outcomes, implant survivorship, time to revision surgery, and cost-effectiveness. Cite this article: EFORT Open Rev 2019;4:611-617. DOI: 10.1302/2058-5241.4.190022