bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the validity of strong cosmic censorship conjecture in presence of Dirac fields
Authors: Rahman Mostafizur 
Published: May 2020

AbstractAn well posed theory of nature is expected to determine the future of an observer uniquely from a given set of appropriate initial data. In the context of general relativity, this is ensured by Penrose’s strong cosmic censorship conjecture. But in recent years, several examples are found which suggest breakdown of the deterministic nature of the theory in Reissner–Nordström–de Sitter black holes under the influence of different fundamental fields. Nevertheless, the situation has been reassuring for the case of astrophysically meaningful Kerr–de Sitter black hole solutions which seems to respect the conjecture. However, the previous analyses were done considering only the effect of scalar fields. In this paper, we extend the study by considering Dirac fields in Kerr–de Sitter background and show that there exist a parameter space which does not respect the conjecture.
Same Trade Openness Yet Different Environmental Quality — But Why?
Authors: Chang Shu-Chen , Chang Hsiao-Fen 
Published: May 2020

This paper re-studies the relationship between trade openness and environmental pollution. Through the theoretical framework, there is a non-uniform effect of trade openness on environmental pollution. Utilizing four alternative measures of trade openness as threshold variables, this paper examines the effect of trade openness on environmental pollution. We adopt a regression with nonlinearity, in which our nonlinear model includes two regressions — a threshold model and an interaction-term model. Utilizing four alternative measures of trade openness, our threshold test shows a single-threshold effect on pollutant emissions, implying that there are two regimes: low- and high-corruption. Our empirical results show that for countries with high-corruption, increases in trade openness significantly reduce pollutants emissions whatever CO2 emissions or SO2 emissions, and the larger effects of trade openness on environmental quality. However, the impact of trade openness on pollution was not found in countries with low-corruption. This study suggests that further trade openness and reduced environmental degradation (i.e., decline in CO2 and SO2 emissions) are compatible rather than competing objectives, especially in high-corruption countries. Furthermore, our results also show that in low-corruption countries, the negative effects of income on CO2 emissions are statistically significant, but in high-corruption countries it is not so.
Security and Privacy Requirements for Cloud Computing in Healthcare
Authors: Ermakova Tatiana , Fabian Benjamin , Kornacka Marta , Thiebes Scott , Sunyaev Ali 
Published: May 2020

Cloud computing promises essential improvements in healthcare delivery performance. However, its wide adoption in healthcare is yet to be seen, one main reason being patients’ concerns for security and privacy of their sensitive medical records. These concerns can be addressed through corresponding security and privacy requirements within the system engineering process. Despite a plethora of related research, security and privacy requirements for cloud systems and services have seldomly been investigated methodically so far, whereas their individual priorities to increase the system success probability have been neglected. Against this background, this study applies a systematic requirements engineering process: First, based on a systematic literature review, an extensive initial set of security and privacy requirements is elicited. Second, an online survey based on the best-worst scaling method is designed, conducted, and evaluated to determine priorities of security and privacy requirements.
Our results show that confidentiality and integrity of medical data are ranked at the top of the hierarchy of prioritized requirements, followed by control of data use and modification, patients’ anonymity, and patients’ control of access rights. Availability, fine-grained access control, revocation of access rights, flexible access, clinicians’ anonymity, as well as usability, scalability, and efficiency of the system complete the ranking. The level of agreement among patients is rather small, but statistically significant at the 0.01 level.
The main contribution of the present research comprises the study method and results highlighting the role of strong security and privacy and excluding any trade-offs with system usability. Enabling a richer understanding of patients’ security and privacy requirements for adopting cloud computing in healthcare, these are of particular importance to researchers and practitioners interested in supporting the process of security and privacy engineering for health-cloud solutions. It further represents a supplement that can support time-intensive negotiation meetings between the requirements engineers and patients.
Changes in Colorectal Cancer 5-Year Survival Disparities in California, 1997–2014
Authors: Oh Debora L. , Santiago-Rodríguez Eduardo J. , Canchola Alison J. , Ellis Libby , Tao Li , Gomez Scarlett L. 
Published: May 2020

Abstract

Background:
Colorectal cancer incidence and mortality have declined with increased screening and scientific advances in treatment. However, improvement in colorectal cancer outcomes has not been equal for all groups and disparities have persisted over time.

Methods:
Data from the California Cancer Registry were used to estimate changes in 5-year colorectal cancer–specific survival over three diagnostic time periods: 1997–2002, 2003–2008, and 2009–2014. Analyses included all patients in California with colorectal cancer as a first primary malignancy. Multivariable Cox proportional hazard regression models were used to evaluate the effect of race/ethnicity, insurance status, and neighborhood socioeconomic status (nSES) on 5-year colorectal cancer–specific survival.

Results:
On the basis of a population-based sample of 197,060 colorectal cancer cases, racial/ethnic survival disparities decreased over time among non-Hispanic Blacks (NHB) compared with non-Hispanic Whites (NHW), after adjusting for demographic, clinical, and treatment characteristics. For cases diagnosed 1997–2002, colorectal cancer–specific hazard rates were higher for NHB [HR, 1.12; 95% confidence interval (CI), 1.06–1.19] and lower for Asians/Pacific Islanders (HR, 0.92; 95% CI, 0.87–0.96) and Hispanics (HR, 0.94; 95% CI, 0.90–0.99) compared with NHW. In 2009–2014, colorectal cancer–specific HR for NHB was not significantly different to the rate observed for NHW (HR, 1.03; 95% CI, 0.97–1.10). There were no changes in disparities in nSES, but increasing disparities by health insurance status.

Conclusions:
We found a decrease in survival disparities over time by race/ethnicity, but a persistence of disparities by neighborhood socioeconomic status and health insurance status.

Impact:
Further investigation into the drivers for these disparities can help direct policy and practice toward health equity for all groups.
The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action
Authors: Chan Andrew T. , Drew David A. , Nguyen Long H. , Joshi Amit D. , Ma Wenjie , Guo Chuan-Guo , Lo Chun-Han , Mehta Raaj S. , Kwon Sohee , Sikavi Daniel R. , Magicheva-Gupta Marina V. , Fatehi Zahra S. , Flynn Jacqueline J. , Leonardo Brianna M. , Albert Christine M. , Andreotti Gabriella , Beane-Freeman Laura E. , Balasubramanian Bijal A. , Brownstein John S. , Bruinsma Fiona , Cowan Annie N. , Deka Anusila , Ernst Michael E. , Figueiredo Jane C. , Franks Paul W. , Gardner Christopher D. , Ghobrial Irene M. , Haiman Christopher A. , Hall Janet E. , Deming-Halverson Sandra L. , Kirpach Brenda , Lacey James V. , Marchand Loïc Le , Marinac Catherine R. , Martinez Maria Elena , Milne Roger L. , Murray Anne M. , Nash Denis , Palmer Julie R. , Patel Alpa V. , Rosenberg Lynn , Sandler Dale P. , Sharma Shreela V. , Schurman Shepherd H. , Wilkens Lynne R. , Chavarro Jorge E. , Eliassen A. Heather , Hart Jaime E. , Kang Jae Hee , Koenen Karestan C. , Kubzansky Laura D. , Mucci Lorelei A. , Ourselin Sebastien , Rich-Edwards Janet W. , Song Mingyang , Stampfer Meir J. , Steves Claire J. , Willett Walter C. , Wolf Jonathan , Spector Tim 
Published: May 2020

Abstract
The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.
Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials
Authors: Shi Donghua , Shi Yaoping , Kaseb Ahmed O. , Qi Xingxing , Zhang Yuan , Chi Jiachang , Lu Qing , Gao Huiping , Jiang Hua , Wang Huamao , Yuan Daijing , Ma Hong , Wang Hongyang , Li Zonghai , Zhai Bo 
Published: May 2020

Abstract

Purpose:
Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC.

Patients and Methods:
In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1).

Results:
A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan–Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response.

Conclusions:
This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.
NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response
Authors: Swain Sandra M. , Tang Gong , Brauer Heather Ann , Goerlitz David S. , Lucas Peter C. , Robidoux André , Harris Brent T. , Bandos Hanna , Ren Yuqi , Geyer Charles E. , Rastogi Priya , Mamounas Eleftherios P. , Wolmark Norman 
Published: May 2020

AbstractPurpose:In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41.Patients and Methods:Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization.Results:Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial–mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73.Conclusions:The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.
Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication
Authors: Weiss Jared , Sheth Siddharth , Deal Allison M. , Grilley Olson Juneko E. , Patel Samip , Hackman Trevor G. , Blumberg Jeffrey M. , Galloway Thomas J. , Patel Shetal , Zanation Adam M. , Shen Colette J. , Hayes D. Neil , Hilliard Christopher , Mehra Ranee , McKinnon Karen P. , Wang Hsing-Hui , Weissler Mark Christian , Bauman Jessica R. , Chera Bhishamjit S. , Vincent Benjamin G. 
Published: May 2020

AbstractPurpose:Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC.Patients and Methods:This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling.Results:Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells.Conclusions:Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.
Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids
Authors: Vernon Mégane , Lambert Bernard , Meryet-Figuière Matthieu , Brotin Emilie , Weiswald Louis-Bastien , Paysant Hippolyte , Vigneron Nicolas , Wambecke Anaïs , Abeilard Edwige , Giffard Florence , Louis Marie-Hélène , Blanc-Fournier Cécile , Gauduchon Pascal , Poulain Laurent , Denoyelle Christophe 
Published: May 2020

AbstractNovel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecologic malignancies. miRNAs hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain-of-function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs with robust cytotoxic effects in chemoresistant ovarian cancer cells. Focusing on miR-3622b-5p, we show that it induces apoptosis in several ovarian cancer cell lines by both directly targeting Bcl-xL and EGFR-mediating BIM upregulation. miR-3622b-5p also sensitizes cells to cisplatin by inhibiting Bcl-xL in ovarian cancer cell lines escaping BIM induction. miR-3622b-5p also exerts antimigratory capacities by targeting both LIMK1 and NOTCH1. These wide-ranging antitumor properties of miR-3622b-5p in ovarian cancer cells are mimicked by the associations of pharmacologic inhibitors targeting these proteins. The combination of an EGFR inhibitor together with a BH3-mimetic molecule induced a large decrease in cell viability in a panel of ovarian cancer cell lines and several ovarian patient-derived tumor organoids, suggesting the value of pursuing such a combination therapy in ovarian carcinoma. Altogether, our work highlights the potential of phenotype-based miRNA screening approaches to identify lethal interactions which might lead to new drug combinations and clinically applicable strategies.
Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma Cell Death Requires EGFR Overexpression, but not EGFRY1068 Phosphorylation
Authors: von Achenbach Caroline , Silginer Manuela , Blot Vincent , Weiss William A. , Weller Michael 
Published: May 2020

Abstract
Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification; half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2–7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed.
Depatuxizumab mafodotin (ABT-414) is an EGFR-targeting antibody–drug conjugate consisting of the mAb 806 and a toxic payload, monomethyl auristatin F. Because glioma cell lines and patient-derived glioma-initiating cell models expressed too little EGFR in vitro to be ABT-414–sensitive, we generated glioma sublines overexpressing EGFR or EGFRvIII to explore determinants of ABT-414–induced cell death.
Overexpression of EGFRvIII induces sensitization to ABT-414 more readily than overexpression of EGFR in vitro and in vivo. Exposure to ABT-414 in vivo eliminated EGFRvIII-expressing tumor cells, and recurrent tumors were devoid of EGFRvIII expression. There is no bystander killing of cells devoid of EGFR expression. Surprisingly, either exposure to EGF or to EGFR tyrosin kinase inhibitors reduce EGFR protein levels and are thus not strategies to promote ABT-414–induced cell killing. Furthermore, glioma cells overexpressing kinase-dead EGFR or EGFRvIII retain binding of mAb 806 and sensitivity to ABT-414, allowing to dissociate EGFR phosphorylation from the emergence of the “active” EGFR conformation required for ABT-414 binding.
The combination of EGFR-targeting antibody–drug conjugates with EGFR tyrosine kinase inhibitors carries a high risk of failure. Promoting EGFR expression rather than phosphorylation should result in glioblastoma cell sensitization to ABT-414.
Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma
Authors: Reddy Gireesh B. , Kerr David L. , Spasojevic Ivan , Tovmasyan Artak , Hsu David S. , Brigman Brian E. , Somarelli Jason A. , Needham David , Eward William C. 
Published: May 2020

Abstract
Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2–2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.