bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study
Authors: Shen Lin , Guo Jun , Zhang Qingyuan , Pan Hongming , Yuan Ying , Bai Yuxian , Liu Tianshu , Zhou Qing , Zhao Jun , Shu Yongqian , Huang Xiaoming , Wang Siyang , Wang Jie , Zhou Aiping , Ye Dingwei , Sun Ting , Gao Yujuan , Yang Silu , Wang Zoubai , Li Jian , Wu Yi-Long 
Published: June 2020

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.
Dying individuals and suffering populations: applying a population-level bioethics lens to palliative care in humanitarian contexts: before, during and after the COVID-19 pandemic
Authors: Wynne Keona Jeane , Petrova Mila , Coghlan Rachel 
Published: June 2020

BackgroundHumanitarian crises and emergencies, events often marked by high mortality, have until recently excluded palliative care—a specialty focusing on supporting people with serious or terminal illness or those nearing death. In the COVID-19 pandemic, palliative care has received unprecedented levels of societal attention. Unfortunately, this has not been enough to prevent patients dying alone, relatives not being able to say goodbye and palliative care being used instead of intensive care due to resource limitations. Yet global guidance was available. In 2018, the WHO released a guide on‘Integrating palliative care and symptom relief into the response to humanitarian emergencies and crises’—the first guidance on the topic by an international body.AimsThis paper argues that while a landmark document, the WHO guide took a narrowly clinical bioethics perspective and missed crucial moral dilemmas. We argue for adding a population-level bioethics lens, which draws forth complex moral dilemmas arising from the fact that groups having differential innate and acquired resources in the context of social and historical determinants of health. We discuss dilemmas concerning: limitations of material and human resources; patient prioritisation; euthanasia; and legacy inequalities, discrimination and power imbalances.ImplicationsIn parts of the world where opportunity for preparation still exists, and as countries emerge from COVID-19, planners must consider care for the dying. Immediate steps to support better resolutions to ethical dilemmas of the provision of palliative care in humanitarian and emergency contexts will require honest debate; concerted research effort; and international, national and local ethical guidance.
Factors associated with academic rank among chronic pain medicine faculty in the USA
Authors: Orhurhu Mariam Salisu , Orhurhu Vwaire , Salisu Bisola , Abimbola Adeniyi , Cohen Steven P 
Published: June 2020

BackgroundNumerous factors are considered in the academic promotion of pain medicine physicians. In this study, we investigated the importance of research productivity, career duration, leadership, and gender on attaining professorship in chronic pain medicine fellowship programs in the USA.MethodsWe identified 98 pain fellowship programs in the American Medical Association Fellowship and Residency Electronic Interactive Database. Faculty demographics and institutional characteristics were obtained from institutional websites, and h-index (number of publications (h) cited at least h times) and m-index (h-index divided by research career duration) were calculated from Scopus. A nested mixed effect hierarchical modeling was used to determine factors that were associated with attaining professorship.ResultsA total of 696 chronic pain medicine faculty members from 98 academic pain fellowship programs were identified, of whom 74.7% were males. For the 15.5% who were full professors, the median h-index was 16.5 (6.0 to 30.0), the median career duration was 20.5 (16.0 to 27.0) years, and the median m-index was 0.7 (0.3 to 1.3). In an adjusted analysis, the top quartile (compared with bottom) h-index (OR 6.27; 95% CI: 2.11 to 18.59), publication citations (OR 1.13; 95% CI: 1.10 to 1.21), division chief position (OR 3.72; 95% CI: 1.62 to 8.50), institutions located in the western region (OR 3.81; 95% CI: 1.52 to 9.57), and graduating from a foreign medical school (OR 1.98; 95% CI: 1.10 to 3.92) were independently associated with attaining professorship (p<0.05), but gender was not (p=0.71).ConclusionsOur study shows that, higher h-index, publication citations, division chief position, affiliation at a lower tier medical school, and location in the Western region were independently associated with full professorship, whereas gender was not. The identified variables for professorship may be considered as factors in faculty promotions.
Current versus revised anatomical targets for genicular nerve blockade and radiofrequency ablation: evidence from a cadaveric model
Authors: Fonkoue Loïc , Behets Catherine Wydemans , Steyaert Arnaud , Kouassi Jean-Eric Kouame , Detrembleur Christine , De Waroux Bernard LePolain , Cornu Olivier 
Published: June 2020

IntroductionRecent studies have proposed revised anatomical targets to improve accuracy of genicular nerve (GN) radiofrequency ablation (RFA). This study aims to compare the accuracy of classical and revised techniques for fluoroscopic-guided GN-RFA in cadaveric models.Materials and methodsFourteen knees from seven fresh frozen human cadavers were included in this study. For each cadaver, RF cannulas were placed to capture the GN according to the current targets in one knee, and the revised targets in the other knee, randomly. The stylet was removed from the cannula, plunged into non-diffusible black paint, and reintroduced entirely in the cannula, to create a limited black spot on the tissues at the top of the active tip. Anatomical dissection was performed, and the accuracy of both techniques was compared.ResultsThe mean distance from the top of the active tip to the nerve was significantly lower with revised than current targets for the superior-medial GN (0.7 mm vs 17.8 mm, p=0.01) and the descending branch of the superior-lateral GN (3.7 mm vs 24.4 mm, p=0.02). In both superior-medial GN and superior-lateral GN, the accuracy rate was higher with revised than current targets: 100% vs 0% and 64% vs 35%, respectively. In addition, the accuracy of revised targets for the recurrent fibular nerve and the infrapatellar branch of saphenous nerve was 100%.ConclusionThis study demonstrates that the revised targets are more accurate than the current targets for GN-RFA.
Spontaneously broken 3d Hietarinta/Maxwell Chern–Simons theory and minimal massive gravity
Authors: Chernyavsky Dmitry , Deger Nihat Sadik , Sorokin Dmitri 
Published: June 2020

AbstractWe show that minimal massive 3d gravity (MMG) of (Bergshoeff et al. in Class Quantum Grav 31:145008, 2014), as well as the topological massive gravity, are particular cases of a more general ‘minimal massive gravity’ theory (with a single massive propagating mode) arising upon spontaneous breaking of a local symmetry in a Chern–Simons gravity based on a Hietarinta or Maxwell algebra. Similar to the MMG case, the requirements that the propagating massive mode is neither tachyon nor ghost and that the central charges of an asymptotic algebra associated with a boundary CFT are positive, impose restrictions on the range of the parameters of the theory.
Curvature and thermal corrections in tree-level CPT-Violating Leptogenesis
Authors: Mavromatos Nick E. , Sarkar Sarben 
Published: June 2020

AbstractIn a model for leptogenesis based on spontaneous breaking of Lorentz and $$\mathcal {CPT}$$CPT symmetry [1–3], we examine the consistency of using the approximation of plane-wave solutions for a free spin-$$\frac{1}{2}$$12 Dirac (or Majorana) fermion field propagating in a Friedmann–Lema$$\hat{\mathrm{i}}$$i^tre–Robertson–Walker space time augmented with a cosmic time-dependent (or, equivalently, a temperature-dependent) Kalb–Ramond (KR) background. For the range of parameters relevant for leptogenesis, our analysis fully justifies the use of plane-wave solutions in our study of leptogenesis with Boltzmann equations; any corrections induced by space-time-curvature are negligible. We also elaborate further on how the lepton asymmetry is communicated to the Baryon sector. We demonstrate that the KR background (KRB) does not contribute to the anomaly equations that determine the baryon asymmetry (a) through an explicit evaluation of a triangle Feynman graph and (b) indirectly, on topological grounds, by identifying the KRB as torsion (in the effective string-inspired low energy gravitational field theory).
Efficacy and Safety Exposure–Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer
Authors: Perez-Ruixo Carlos , Ackaert Oliver , Ouellet Daniele , Chien Caly , Uemura Hiroji , Olmos David , Mainwaring Paul , Lee Ji Youl , Yu Margaret K. , Perez-Ruixo Juan Jose , Smith Matthew R. , Small Eric J. 
Published: June 2020

Abstract

Purpose:
To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer.

Patients and Methods:
An exploratory exposure–response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration–time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia.

Results:
A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure.

Conclusions:
The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure–safety analysis supports dose reductions in patients experiencing adverse events.
Proteasome Subunits Differentially Control Myeloma Cell Viability and Proteasome Inhibitor Sensitivity
Authors: Shi Chang-Xin , Zhu Yuan Xiao , Bruins Laura A. , Bonolo de Campos Cecilia , Stewart William , Braggio Esteban , Stewart A. Keith 
Published: June 2020

Abstract

We generated eight multiple myeloma cell lines resistant to bortezomib; five acquired PSMB5 mutations. In 1,500 patients such mutations were rare clinically. To better understand disruption of proteasomes on multiple myeloma viability and drug sensitivity, we systematically deleted the major proteasome catalytic subunits. Multiple myeloma cells without PSMB5 were viable. Drug-resistant, PSMB5-mutated cell lines were resensitized to bortezomib by PSMB5 deletion, implying PSMB5 mutation is activating in its drug resistance function. In contrast, PSMB6 knockout was lethal to multiple myeloma cell lines. Depleting PSMB6 prevented splicing of the major catalytic subunits PSMB5, PSMB7, PSMB8, and PSMB10; however, PSMB6 engineered without splicing function or catalytic activity, also restored viability, inferring the contribution of PSMB6 to proteasome structure to be more important than functional activity. Supporting this, bortezomib sensitivity was restored in drug-resistant multiple myeloma cell lines by low level expression of mutated PSMB6 lacking splicing function. Loss of PSMB8 and PSMB9 was neither lethal nor restored bortezomib sensitivity. Significant codependency of PSMB5, PSMB6, and PSMB7 expression was observed. We demonstrated elevated levels of PSMB6 and 7, but not 8 and 9, in some, but not all, serial patient samples exposed to proteasome inhibitors. In summary, we show PSMB6 and PSMB7, but not PSMB5, to be essential for multiple myeloma cell survival, this dependency is structural and that upregulation or activating mutation of PSMB5, 6, and 7 confers proteasome inhibitor resistance, while depletion confers sensitivity.

Implications:
These findings support modulation of PSMB5, PSMB6, or PSMB7 expression as a new therapeutic strategy.
Identification of the Cryptic HLA-I Immunopeptidome
Authors: Erhard Florian , Dölken Lars , Schilling Bastian , Schlosser Andreas 
Published: June 2020

Abstract
The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often remain unidentified, it is generally assumed that neoantigens, due to tumor-specific mutations, are the most common targets. Here, we used a mass spectrometric approach to show an underappreciated class of epitopes that accounts for up to 15% of HLA-I peptides for certain HLA alleles in various tumors and patients. These peptides are translated from cryptic open reading frames in supposedly noncoding regions in the genome and are mostly unidentifiable with conventional computational analyses of mass spectrometry (MS) data. Our approach, Peptide-PRISM, identified thousands of such cryptic peptides in tumor immunopeptidomes. About 20% of these HLA-I peptides represented the C-terminus of the corresponding translation product, suggesting frequent proteasome-independent processing. Our data also revealed HLA-I allele–dependent presentation of cryptic peptides, with HLA-A*03 and HLA-A*11 presenting the highest percentage of cryptic peptides. Our analyses refute the reported frequent presentation of HLA peptides generated by proteasome-catalyzed peptide splicing. Thus, Peptide-PRISM represents an important step toward comprehensive identification of HLA-I immunopeptidomes and reveals cryptic peptides as an abundant class of epitopes with potential relevance for novel immunotherapeutic approaches.
Players in Drug-Resistant Leukemia Stem/Initiating Cells and Immunity in Patients with CML in Context of Oxygen Levels: Would Collecting/Processing Cells in Hypoxia Offer Additional Information? A Next Frontier of Investigation
Authors: Broxmeyer Hal 
Published: June 2020

Abstract

Summary:
Chronic myelogenous leukemia (CML) is a stem cell disorder once considered an eventual death sentence upon progression to the terminal acute/blastic cell phase, a terrible clinical outcome that has improved with the introduction of tyrosine kinase inhibitors. A major continuing problem with treating CML is the persistence of drug-resistant leukemia stem/initiating cells (LS/IC). In this issue of Blood Cancer Discovery, Silvestri and colleagues describe an incredibly in-depth mechanistic study using genetic and pharmacologic modulation of the miRNA MiR300 with and without treatment with activators of the serine-threonine protein phosphatase 2A (PP2A) in human cells. In vitro studies and in vivo mouse models of patient-derived xenografts were used to address the need to target LS/ICs and restore immunity of impaired natural killer cells for attenuation of CML progression.
See related article by Silvestri et al., p. 48.
Rates and Predictors of Patient Underreporting of Hospitalizations During Follow-Up After Acute Myocardial Infarction
Authors: Caraballo César , Khera Rohan , Jones Philip G. , Decker Carole , Schulz Wade , Spertus John A. , Krumholz Harlan M. 
Published: June 2020

Background:
Many clinical investigations depend on participant self-report as a principal method of identifying health care events. If self-report is used as the trigger to collect and adjudicate medical records, any event that is not reported by the patient will be missed by the investigators, reducing the power of the study and misrepresenting the risk of its participants. We sought to determine the rates and predictors of underreporting hospitalization events during the follow-up period of a prospective study of patients hospitalized with an acute myocardial infarction.

Methods and Results:
The TRIUMPH (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status) registry, a longitudinal multicenter cohort study of people with acute myocardial infarction in the United States, queried patients for hospitalization events during interviews at 1, 6, and 12 months. To validate these self-reports, medical records for all events at every hospital where the patient reported receiving care were acquired for adjudication, not just those for the reported events. Of the 4340 participants in TRIUMPH, 1209 (28%) reported at least one hospitalization. After medical records abstraction and adjudication, we identified 1086 hospitalizations from 639 participants (60.2±12 years of age, 38.2% women). Of these hospitalizations, 346 (31.9%) were underreported by the participants. Rates of underreporting ranged from 22.5% to 55.6% based on different patient characteristics. The odds of underreporting were highest for those not currently working (adjusted odds ratio, 1.66 [95% CI, 1.04–2.63]), lowest for those married (adjusted odds ratio, 0.50 [95% CI, 0.33–0.76]), and increased the longer the elapsed time between the admission and the patient’s follow-up interview (adjusted odds ratio per month, 1.16 [95% CI, 1.08–1.24]). There was a substantial within-individual variation on the accuracy of reporting.

Conclusions:
Hospitalizations after acute myocardial infarction are commonly underreported in interviews and should not be used alone to determine event rates in clinical studies.
A new structure on the frons of male adults of the Asian rice spittlebug Callitettix versicolor (Hemiptera: Auchenorrhyncha: Cercopidae)
Authors: LIANG AI-PING 
Published: June 2020

A new structure, here tentatively named the “frontal gland,” specifically found on frons of male adults of the Asian rice spittlebug, Callitettix versicolor (Fabricius, 1794) (Hemiptera: Auchenorrhyncha: Cercopidae), is reported. Adult C. versicolor is distinctly dimorphic in frons morphology. The frons in female adults, like that in most cercopid species, is normally swollen and nearly bulbose and is covered with short pilosity, while the frons in male adults is visibly different, with the lower 3/5 of the postclypeus and anteclypeus being centrally flat, bare and smooth on the surface. SEM observations revealed that the flat frons surface of the male adults is covered with numerous, very fine pores. In total, each frons has over 4500 pores on the central flat area, with an average density of 55.5 ± 1.50 pores per 100 µm2. The distance among the pores averages 10.63 ± 1.8 µm. Each pore unit is composed of a round, deep cavity in which one central conical process is set. The cavity is delimited by a cuticular rim and the opening of the cavity averages 2.89 ± 0.20 µm in diameter. The central, conical process has a sponge-like apex and measures 2.52–2.70 µm in diameter. In addition, one or two (two in most cases) extremely fine pits (0.42–0.56 µm in diameter) are located on the marginal cuticle rim surrounding the cavity and its central conical process. These cuticular, fine pits are located proximal to the pores, at a distance of 0.98–1.96 µm. These porous structures are not present on the frons in female adults. They are assumed to be an exocrine gland system and are possibly the male sex pheromone-releasing glands, as they are only present in male adults. Observations of mating behavior showed that it is likely that the secretions made by the frontal gland constitute short-range attractants and may fulfil aphrodisiac functions to stimulate mating. The species of Auchenorrhyncha were previously thought to communicate via acoustic signals, but the findings described here suggest that at least one Auchenorrhynchan species also uses chemicals for sexual communication.