bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jack of All
Authors: Gunn James E. 
Published: March 2020

This article is basically a scientific autobiography from a long and very rewarding career, covering childhood, education, theoretical work, observations, instrumentation, and some social activities. It is not meant to be a review of anything except an incomplete picture of my life, and the relatively few references are to some of my work, work related to mine, and work that had a very large influence on my life and research, so apologies in advance to those I left out in subjects I discuss. I have not in any way attempted to discuss scientific results; those you can go read. I have used more words on old things than new, with the idea that most readers of this article are much more familiar with the field in the last couple of decades than before. My career spans almost six, and there may be things to learn from antiquity.
RNF168-Mediated Ubiquitin Signaling Inhibits the Viability of BRCA1-Null Cancers
Authors: Krais John J. , Wang Yifan , Bernhardy Andrea J. , Clausen Emma , Miller Jessica A. , Cai Kathy Q. , Scott Clare L. , Johnson Neil 
Published: March 2020

Abstract

BRCA1 gene mutations impair homologous recombination (HR) DNA repair, resulting in cellular senescence and embryonic lethality in mice. Therefore, BRCA1-deficient cancers require adaptations that prevent excessive genomic alterations from triggering cell death. RNF168-mediated ubiquitination of γH2AX at K13/15 (ub-H2AX) serves as a recruitment module for the localization of 53BP1 to DNA break sites. Here, we found multiple BRCA1-mutant cancer cell lines and primary tumors with low levels of RNF168 protein expression. Overexpression of ectopic RNF168 or a ub-H2AX fusion protein induced cell death and delayed BRCA1-mutant tumor formation. Cell death resulted from the recruitment of 53BP1 to DNA break sites and inhibition of DNA end resection. Strikingly, reintroduction of BRCA1 or 53BP1 depletion restored HR and rescued the ability of cells to maintain RNF168 and ub-H2AX overexpression. Thus, downregulation of RNF168 protein expression is a mechanism for providing BRCA1-null cancer cell lines with a residual level of HR that is essential for viability. Overall, our work identifies loss of RNF168 ubiquitin signaling as a proteomic alteration that supports BRCA1-mutant carcinogenesis. We propose that restoring RNF168-ub-H2AX signaling, potentially through inhibition of deubiquitinases, could represent a new therapeutic approach.

Significance:
This study explores the concept that homologous recombination DNA repair is not an all-or-nothing concept, but a spectrum, and that where a tumor stands on this spectrum may have therapeutic relevance.
See related commentary by Wang and Wulf, p. 2720
HER2-Mediated Internalization of Cytotoxic Agents inERBB2Amplified or Mutant Lung Cancers
Authors: Li Bob T. , Michelini Flavia , Misale Sandra , Cocco Emiliano , Baldino Laura , Cai Yanyan , Shifman Sophie , Tu Hai-Yan , Myers Mackenzie L. , Xu Chongrui , Mattar Marissa , Khodos Inna , Little Megan , Qeriqi Besnik , Weitsman Gregory , Wilhem Clare J. , Lalani Alshad S. , Diala Irmina , Freedman Rachel A. , Lin Nancy U. , Solit David B. , Berger Michael F. , Barber Paul R. , Ng Tony , Offin Michael , Isbell James M. , Jones David R. , Yu Helena A. , Thyparambil Sheeno , Liao Wei-Li , Bhalkikar Anuja , Cecchi Fabiola , Hyman David M. , Lewis Jason S. , Buonocore Darren J. , Ho Alan L. , Makker Vicky , Reis-Filho Jorge S. , Razavi Pedram , Arcila Maria E. , Kris Mark G. , Poirier John T. , Shen Ronglai , Tsurutani Junji , Ulaner Gary A. , de Stanchina Elisa , Rosen Neal , Rudin Charles M. , Scaltriti Maurizio 
Published: March 2020

AbstractAmplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627
Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8+ T Cells to Memory T Cells
Authors: Wang Junmei , Hasan Farah , Frey Amanda C. , Li Haiyan S. , Park Jungsun , Pan Ke , Haymaker Cara , Bernatchez Chantale , Lee Dean A. , Watowich Stephanie S. , Yee Cassian 
Published: March 2020

Abstract
Clinical response rates after adoptive cell therapy (ACT) are highly correlated with in vivo persistence of the infused T cells. However, antigen-specific T cells found in tumor sites are often well-differentiated effector cells with limited persistence. Central memory CD8+ T cells, capable of self-renewal, represent desirable ACT products. We report here that exposure to a histone deacetylase inhibitor (HDACi) and IL21 could reprogram differentiated human CD8+ T cells into central memory–like T cells. Dedifferentiation of CD8+ T cells was initiated by increased H3 acetylation and chromatin accessibility at the CD28 promoter region. This led to IL21-mediated pSTAT3 binding to the CD28 region, and subsequent upregulation of surface CD28 and CD62L (markers of central memory T cells). The reprogrammed cells exhibited enhanced proliferation in response to both IL2 and IL15, and a stable memory-associated transcriptional signature (increased Lef1 and Tcf7). Our findings support the application of IL21 and HDACi for the in vitro generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.
Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells
Authors: Wijewarnasuriya Dinali , Bebernitz Christina , Lopez Andrea V. , Rafiq Sarwish , Brentjens Renier J. 
Published: March 2020

AbstractAlthough clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Previous studies have identified a role for sustained CAR CD3ζ signaling in CAR T-cell dysfunction. Here, we demonstrate a mechanism that drives dysfunction in CAR T cells through excessive costimulation. Fully activated CD19-targeted CAR T cells were rendered dysfunctional upon stimulation with both endogenous CD28 stimulation and CAR-mediated CD28 costimulation. Costimulation-driven dysfunction of CAR T cells was demonstrated in a syngeneic immunocompetent mouse model, in which CAR T cells were activated with signals 1 (CD3ζ), 2 (CD28), and 3 (IL12). Thus, we show that CAR T-cell dysfunction can be driven through excessive CD28 and 4-1BB costimulation.See related article by Drakes et al., p. 743
PCSK9 Protein and rs562556 Polymorphism Are Associated With Arterial Plaques in Healthy Middle‐Aged Population: The STANISLAS Cohort
Authors: Ferreira João Pedro , Xhaard Constance , Lamiral Zohra , Borges‐Canha Marta , Neves João Sérgio , Dandine‐Roulland Claire , LeFloch Edith , Deleuze Jean‐François , Bacq‐Daian Delphine , Bozec Erwan , Girerd Nicolas , Boivin Jean‐Marc , Zannad Faiez , Rossignol Patrick 
Published: March 2020

Background
PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds low‐density lipoprotein receptor, preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis. The PCSK9‐rs562556 variant has been reported as a gain‐of‐function mutation. The aim of this study was to determine whether the PCSK9–low‐density lipoprotein receptor–rs562556 axis is associated with carotid artery plaques between 2 visits separated by almost 20 years in a longitudinal population cohort.

Methods and Results

The STANISLAS (Suivi Temporaire Annuel Non‐Invasif de la Santé des Lorrains Assurés Sociaux) cohort is a longitudinal familial cohort from the Lorraine region of France. Participants attending 2 visits (visit 1 and visit 4) separated by 18.5 years (mean) were included (n=997). Carotid artery plaques were determined with standardized vascular echography. The mean age of the adult population at visit 1 was 42±5 years. At visit 4, 203 (20.4%) participants had arterial plaques. Participants who developed arterial plaques were older (42.7±5.4 versus 41.7±4.7 years), more often male (60% versus 49%), smokers (29% versus 18%), with diabetes mellitus (6% versus 3%), and higher cholesterol levels (low‐density lipoprotein cholesterol, 1.6±0.4 versus 1.5±0.3 g/L) (all
P
<0.05). The independent factors associated with arterial plaques were age, smoking, and low‐density lipoprotein cholesterol. Higher PCSK9 levels were associated with arterial plaques on top of the clinical model (odds ratio, 2.14; 95% CI,= 1.28–3.58); the missense mutation coding the single‐nucleotide polymorphism rs562556 was associated with both higher PCSK9 concentration and incident carotid arterial plaques.

Conclusions
Higher PCSK9 concentration was associated with the development of arterial plaques almost 20 years in advance in a healthy middle‐aged population. Mutations of the single‐nucleotide polymorphism rs562556 associated with both PCSK9 levels and arterial plaques reinforce the potential causality of our findings. PCSK9 inhibitors could be useful for primary cardiovascular prevention.
Coronary Angiography and Intervention in Women Resuscitated From Sudden Cardiac Death
Authors: May Teresa , Skinner Kristina , Unger Barbara , Mooney Michael , Patel Nainesh , Dupont Allison , McPherson John , McMullan Paul , Nielsen Niklas , Seder David B. , Kern Karl B. 
Published: March 2020

Background
Coronary artery disease is the primary etiology for sudden cardiac arrest in adults, but potential differences in the incidence and utility of invasive coronary testing between resuscitated men and women have not been extensively evaluated. Our aim was to characterize angiographic similarities and differences between men and women after cardiac arrest.

Methods and Results

Data from the International Cardiac Arrest Registry–Cardiology database included patients resuscitated from out‐of‐hospital cardiac arrest of presumed cardiac origin, admitted to 7 academic cardiology/resuscitation centers during 2006 to 2017. Demographics, clinical factors, and angiographic findings of subjects were evaluated in relationship to sex and multivariable logistic regression models created to predict both angiography and outcome. Among 966 subjects, including 277 (29%) women and 689 (71%) men, fewer women had prior coronary artery disease and more had prior congestive heart failure (
P
=0.05). Women were less likely to have ST‐segment–elevation myocardial infarction (32% versus 39%,
P
=0.04). Among those with ST‐segment–elevation myocardial infarctions, identification and distribution of culprit arteries was similar between women and men, and there were no differences in treatment or outcome. In patients without
ST
‐segment elevation post‐arrest, women were overall less likely to undergo coronary angiography (51% versus 61%,
P
<0.02), have a culprit vessel identified (29% versus 45%,
P
=0.03), and had fewer culprits acutely occluded (17% versus 28%,
P
=0.03). Women were also less often re‐vascularized (44% versus 52%,
P
<0.03).

Conclusions
Among cardiac arrest survivors, women are less likely to undergo angiography or percutaneous coronary intervention than men. Sex disparities for invasive therapies in post‐cardiac arrest care need continued attention.
Stroke Prognostic Scores and Data-Driven Prediction of Clinical Outcomes After Acute Ischemic Stroke
Authors: Matsumoto Koutarou , Nohara Yasunobu , Soejima Hidehisa , Yonehara Toshiro , Nakashima Naoki , Kamouchi Masahiro 
Published: March 2020

Background and Purpose—
Several stroke prognostic scores have been developed to predict clinical outcomes after stroke. This study aimed to develop and validate novel data-driven predictive models for clinical outcomes by referring to previous prognostic scores in patients with acute ischemic stroke in a real-world setting.

Methods—
We used retrospective data of 4237 patients with acute ischemic stroke who were hospitalized in a single stroke center in Japan between January 2012 and August 2017. We first validated point-based stroke prognostic scores (preadmission comorbidities, level of consciousness, age, and neurological deficit [PLAN] score, ischemic stroke predictive risk score [IScore], and acute stroke registry and analysis of Lausanne [ASTRAL] score in all patients; Houston intraarterial recanalization therapy [HIAT] score, totaled health risks in vascular events [THRIVE] score, and stroke prognostication using age and National Institutes of Health Stroke Scale-100 [SPAN-100] in patients who received reperfusion therapy) in our cohort. We then developed predictive models using all available data by linear regression or decision tree ensembles (random forest and gradient boosting decision tree) and evaluated their area under the receiver operating characteristic curve for clinical outcomes after repeated random splits.

Results—
The mean (SD) age of the patients was 74.7 (12.9) years and 58.3% were men. Area under the receiver operating characteristic curves (95% CIs) of prognostic scores in our cohort were 0.92 PLAN score (0.90–0.93), 0.86 for IScore (0.85–0.87), 0.85 for ASTRAL score (0.83–0.86), 0.69 for HIAT score (0.62–0.75), 0.70 for THRIVE score (0.64–0.76), and 0.70 for SPAN-100 (0.63–0.76) for poor functional outcomes, and 0.87 for PLAN score (0.85–0.90), 0.88 for IScore (0.86–0.91), and 0.88 ASTRAL score (0.85–0.91) for in-hospital mortality. Internal validation of data-driven prediction models showed that their area under the receiver operating characteristic curves ranged between 0.88 and 0.94 for poor functional outcomes and between 0.84 and 0.88 for in-hospital mortality. Ensemble models of a decision tree tended to outperform linear regression models in predicting poor functional outcomes but not in predicting in-hospital mortality.

Conclusions—
Stroke prognostic scores perform well in predicting clinical outcomes after stroke. Data-driven models may be an alternative tool for predicting poststroke clinical outcomes in a real-world setting.
Trends in Stroke Incidence in High-Income Countries in the 21st Century
Authors: Li Linxin , Scott Catherine A. , Rothwell Peter M. ,   on behalf of the Oxford Vascular Study
Published: March 2020

Background and Purpose—
Population-based studies provide the most reliable data on stroke incidence. A previous systematic review of population-based studies suggested that stroke incidence in high-income countries decreased by 42% between the 1970s and early 2000s. However, it is uncertain whether this trend of steady decline has been maintained in more recent periods.

Methods—
Data from OCSP (Oxfordshire Community Stroke Project; 1981–1986) and OXVASC (Oxford Vascular Study; 2002–2017) along with other published population-based stroke incidence studies that reported temporal trends of stroke incidence since 1990 in high-income countries were included. Age-standardized relative incidence rate ratios were calculated for each study and then pooled with inverse-variance weighted random-effects meta-analysis. Projection estimates were calculated for the number of incident stroke patients in the United Kingdom from year 2015 to 2045.

Results—

In Oxfordshire, stroke incidence fell by 32% from OCSP to OXVASC, with a similar trend before or after year 2000. With the projected aging population, if the age-specific stroke incidence continued to decrease at its current rate (6% every 5 years), there would still be a 13% increase of the number of first-ever strokes in the United Kingdom up to year 2045. Incorporating the Oxfordshire data with other 12 population-based studies, stroke incidence declined steadily between the 1990s and 2010s within each study, resulting in a 28% decline over an average period of 16.5 years (pooled incidence rate ratio, 0.72 [95% CI, 0.66–0.79];
P
<0.0001). The trend was the same for men (0.69 [95% CI, 0.61–0.77];
P
<0.0001) and women (0.66 [95% CI, 0.59–0.74];
P
<0.0001) and remained consistent after year 2010 in OXVASC. Proportion of disabling or fatal stroke also decreased over time (early versus later period, 53.6% versus 46.1%;
P
=0.02).

Conclusions—
Stroke incidence is continuing to decline with steady rate in Oxfordshire and in other high-income settings. However, the absolute number of strokes occurring is not falling.
On Anatomical Enumeration and Difference in Early Sanskrit Medical Literature
Authors: Selby Martha Ann 
Published: March 2020

Abstract
What does it mean to inventory all the components of the human body, and what do those inventories tell us about medical ideas and practice? I compare the lists of body parts in the śārīra-sthānas (sections relating to the body) of the Caraka-saṃhitā (ca. first century CE) and the Suśruta-saṃhitā (ca. second century CE). Rather than provide a detailed list of differences, I contemplate what these differences “mean” in terms of counting as a practice and of how we might think about these two texts as articulations of the concerns of the “theorist-physicians” of the Caraka-saṃhitā and the “anatomist-surgeons” of the Suśruta-saṃhitā. How might a close comparative reading of these passages—an “emic” reading, if you will—shed light on medical practice in early India and its relationship with metaphysical concerns, issues of selfhood, sexual “difference,” and the problem of understanding what cannot be seen with the naked eye?
The Gendered Networking of Diplomats
Authors: Niklasson Birgitta 
Published: March 2020

Summary
The aim of this study is to contribute to a deeper understanding of the gendered condi- tions under which diplomats network. We still have limited knowledge of how female diplomats network when serving abroad in strongly male-dominated contexts. To what extent do they experience token tendencies (visibility, assimilation and contrast) and how are these tendencies perceived to affect their access to important contacts? Based on 28 interviews with diplomats and civil servants from the Swedish Ministry for Foreign Affairs (MFA), this study compares how female and male diplomats are expected and perceived to network. The results indicate that the greater visibility of female diplomats makes them assimilate to a stereotypical gender role that closely resembles that of diplomatic wives. Women thus legitimise their presence in the MFA and make it less intrusive. Still, they experience contrast in silent resistance and con- stant reminders of their presence in a gender-inappropriate profession.
A Synoptic Climatological Analysis of the Atmospheric Drivers of Water Clarity Variability in the Great Lakes
Authors: Smith Erik T. , Lee Cameron C. , Barnes Brian B. , Adams Ryan E. , Pirhalla Douglas E. , Ransibrahmanakul Varis , Hu Chuanmin , Sheridan Scott C. 
Published: March 2020

AbstractA historical water clarity index (Kd index or KDI) was developed through the use of satellite-derived and validated diffuse light attenuation (Kd; m−1) for each of the Great Lakes (and subbasins) on a daily level from 1998 to 2015. A statistical regionalization was performed with monthly level KDI using k-means clustering to subdivide the Great Lakes into regions with similar temporal variability in water clarity. The KDI was then used to assess the relationship between water clarity and atmospheric circulation patterns and stream discharge. An artificial neural-network-based self-organized map data reduction technique was used to classify atmospheric patterns using four atmospheric variables: mean sea level pressure, 500-hPa geopotential heights, zonal and meridional components of the wind at 10 m, and 850-hPa temperature. Stream discharge was found to have the strongest relationship with KDI, suggesting that sediments and dissolved matter from land runoffs are the key factors linking the atmosphere to water clarity in the Great Lakes. Although generally lower in magnitude than stream discharge, atmospheric circulation patterns associated with increased precipitation tended to have stronger positive correlations with KDI. With no long-range forecasts of stream discharge, the strong relationship between atmospheric circulation patterns and stream discharge may provide an avenue to more accurately model water clarity on a subseasonal-to-seasonal time scale.
Atlantic–Pacific Links in Observed Multidecadal SST Variability: Is the Atlantic Multidecadal Oscillation’s Phase Reversal Orchestrated by the Pacific Decadal Oscillation?
Authors: Nigam Sumant , Sengupta Agniv , Ruiz-Barradas Alfredo 
Published: March 2020

AbstractThe Atlantic and Pacific basin are found linked in the context of multidecadal SST variability from analyses of 118 years of observational data. Recurrent spatiotemporal variability, including multidecadal modes, was identified using the extended-EOF technique in a longitudinally global domain, allowing unfettered expression of interbasin interactions. The physicality of the obtained decadal modes was assessed using fishery records and analog counts.A three-mode structure with bi-directional interbasin links frames the new perspective on the cycling of multidecadal SST variability. The three modes are the Atlantic multidecadal oscillation (AMO), low-frequency North Atlantic Oscillation (LF-NAO), and North Pacific decadal variability [PDV-NP; resembling negative (–ve) PDO]. The two previously documented links AMO→PDV-NP (with ~12.5-yr lead) and LF-NAO→AMO (with 16-yr lead) are corroborated, while a third one, PDV-NP→(−LF-NAO) with ~6.5-yr lead, is uncovered. The interaction triad closes the loop on the cycling of multidecadal SST variability, generating AMO’s phase reversal in ~35 years, consistent with its widely noted ~70-yr time scale. The two previously noted links—one intrabasin and one interbasin—were unsuccessful in this regard.Other findings include the deeper subsurface extensions of Atlantic multidecadal SST variability, and the hitherto unrecognized similarity of Pan-Pacific decadal variability and North Pacific Gyre Oscillation. Instrumental records, albeit short in the context of multidecadal variability, must continue to be mined for insights into the functioning of the climate system as its model representations while improving, remain inadequate.