bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small leucine zipper protein promotes the metastasis of castration-resistant prostate cancer through transcriptional regulation of matrix metalloproteinase-13
Authors: Kim Suhyun , Kang Minsoo , Ko Jesang 
Published: May 2021

Abstract
Matrix metalloproteinases (MMPs) function as central modulators of tissue remodeling. Abnormal expression and altered activity of MMPs result in excessive extracellular matrix degradation and increased tumor metastasis in various cancers. Small leucine zipper protein (sLZIP), belonging to the leucine zipper transcription factor family, functions as a transcriptional regulator of genes involved in various cellular processes. However, its role in MMP expression and castration-resistant prostate cancer (CRPC) metastasis remains unclear. In this study, we investigated the role of sLZIP in MMP-13 expression and its involvement in CRPC metastasis. sLZIP increased MMP-13 transcription by directly binding to its promoter in CRPC cells. We found that the expression levels of glucocorticoid receptor (GR), which represses MMP transcription, were elevated in CRPC cells. However, sLZIP suppressed the inhibitory effect of GR and enhanced the secretion of MMP-13 in CRPC cells. sLZIP promoted cell migration and invasion; however, a specific MMP-13 inhibitor blocked sLZIP-induced cell motility. Depletion of sLZIP using the CRISPR/Cas9 system downregulated MMP-13 messenger RNA expression in PC3 cells. Mice injected with sLZIP-depleted PC3 cells showed significantly reduced metastatic tumor volume in the lung compared with mice injected with control PC3 cells. Our findings suggest that sLZIP plays an important role in MMP-13 induction and CRPC metastasis. Therefore, sLZIP inhibition could be a novel therapeutic strategy for metastatic GR-enriched CRPC.
Climate Strikes in Millennial India: Social Capital and “On-Ground” Networks in Digital-First Movements
Authors: Khan Aasim , Natarajan Sarayu , Bhalla Sakshi 
Published: May 2021

Abstract
In September 2019, young people in India led a series of protest events, taking inspiration from a digital campaign for a series of Climate Strikes. Our article explores these events in the context of “millennial India,” particularly in terms of the networks that emerged in the course of climate action in two different regions. By using evidence from Delhi in the north and Bengaluru in the south, we also develop a comparative sociology of digital-first environmental movements and show how the significance of Twitter can only be understood in relation to the formations of social capital on the ground.
Chronicles of a Meme Foretold: Political Memes as Folk Memory in India
Authors: Baishya Anirban K 
Published: May 2021

Abstract
While memes evoke the idea of image (and text) based digital artifacts, memes are not merely visual or textual. Focusing on the demonetization drive undertaken by the BJP-led government in India in 2016, this forum piece makes the case for memes as a kind of memory culture. By this, I mean not only the representation of historical events in memes, but also memes themselves as memorial objects. Memes made in 2016 resurface even now as a form of humorous political critique and demonetization memes are further folded into critiques of current events such as the ongoing farmers' protests. Through an examination of such processes of recontextualization, repurposing and resurfacing, I demonstrate how the seemingly fragmented form of the meme impacts the way we remember through digital media. In effect, meme-culture in India accrues a “sticky” temporality that makes them powerful forms of digital “folk” archiving.
Emergence of the E484K Mutation in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Lineage B.1.1.345 in Upstate New York
Authors: Lesho Emil , Corey Brendan , Lebreton Francois , Ong Ana C , Swierczewski Brett E , Bennett Jason W , Walsh Edward E , McGann Patrick 
Published: May 2021

Abstract
A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.345 variant carrying the E484K mutation was detected in 4 patients with no apparent epidemiological association from a hospital network in upstate New York. Subsequent analysis identified an additional 11 B.1.1.345 variants from this region between December 2020 and February 2021.
Detecting Malicious Domain Names with Abnormal WHOIS Records Using Feature-Based Rules
Authors: Cheng Yanan , Chai Tingting , Zhang Zhaoxin , Lu Keyu , Du Yuejin 
Published: May 2021

Abstract
Millions of new domain names are registered every day, but a large proportion of them are malicious and usually discovered and blacklisted after the crime has been committed. In order to improve the security of domain name registration, this paper proposes a lightweight detection method based on the AdaBoost to identify malicious domain names, which focuses on proactively detecting malicious domain names by exploring the abnormal WHOIS records. The domain name registries and registrars can adopt the proposed method as the first layer of defense to identify malicious domains on the domain registration stage. Extensive experiments on a large-scale database demonstrate that the proposed approach achieves satisfactory results on various malicious domain names.
Favorable Outcomes Combining Vedolizumab With Other Biologics or Tofacitinib for Treatment of Inflammatory Bowel Disease
Authors: Llano Ernesto M , Shrestha Shreeju , Burstein Ezra , Boktor Moheb , Fudman David I 
Published: May 2021

Abstract

Background
Combining advanced therapies may improve outcomes in inflammatory bowel disease (IBD), but there are little data on the effectiveness and safety of this approach.

Methods
We examined outcomes of patients who received vedolizumab in combination with another biologic or tofacitinib between 2016 and 2020.

Results
Fourteen patients (10 ulcerative colitis [UC], 3 Crohn disease, 1 indeterminate colitis) received a combination of advanced therapies. Vedolizumab was combined with tofacitinib in 9 patients, ustekinumab in 3, and adalimumab in 2. Median follow-up on combination therapy was 31 weeks. Normalization of C-reactive protein (CRP) or fecal calprotectin (&lt;5 mg/L and &lt;150 µg/g, respectively) was achieved in 56% (5/9) and 50% (4/8) of patients. Paired median CRP decreased from 14 mg/L to &lt;5 mg/L with combination therapy (n = 9, P = 0.02), and paired median calprotectin from 594 µg/g to 113 µg/g (n = 8, P = 0.12). Among patients with UC, paired median Lichtiger score decreased from 9 to 3 (n = 7, P = 0.02). Prednisone discontinuation was achieved in 67% (4/6) of prednisone-dependent patients. There were 4 infections: 2 required hospitalization (rotavirus, Clostridium difficile), and 2 did not (pneumonia, sinusitis). During follow-up, 5/14 patients discontinued combination therapy (2 nonresponse; 1 improvement and de-escalation; 1 noninfectious adverse effect; 1 loss of coverage).

Conclusions
In this retrospective case series of a cohort with refractory IBD, combining vedolizumab with other biologics or tofacitinib improved inflammatory markers, reduced clinical disease activity and steroid use, and was well tolerated.
HIV infection is associated with thoracic and abdominal aortic aneurysms: a prospective matched cohort study
Authors: Høgh Julie , Pham Michael Huy Cuong , Knudsen Andreas Dehlbæk , Thudium Rebekka Faber , Gelpi Marco , Sigvardsen Per Ejlstrup , Fuchs Andreas , Kühl , Jørgen Tobias , Afzal Shoaib , Nordestgaard Børge Grønne , Benfield Thomas , Køber Lars , Gerstoft Jan , Kofoed Klaus Fuglsang , Nielsen Susanne Dam 
Published: May 2021

Abstract

Aims
Little is known about the prevalence of aortic aneurysms among people living with HIV (PLWH). We investigated whether HIV status is independently associated with having aortic aneurysms. Furthermore, we determined risk factors associated with aortic aneurysms in PLWH.

Methods and results
PLWH aged ≥40 years (n = 594) were recruited from the Copenhagen Comorbidity in HIV Infection study and matched for age and sex with uninfected controls (n = 1188) from the Copenhagen General Population Study. Aortic dimensions were assessed using contrast enhanced computed tomography. Aortic aneurysms were defined according to the European Society of Cardiology guidelines, i.e. an aortic dilation of ≥50% or an infrarenal aortic diameter of ≥30 mm. Among PLWH and uninfected controls, the median (interquartile range) age was 52 (47–60) and 52 (48–61) and 88% and 90% were male, respectively. We found 46 aneurysms in 42 (7.1%) PLWH and 31 aneurysms in 29 (2.4%) uninfected controls (P &lt; 0.001). PLWH had a significantly higher prevalence of ascending aortic aneurysms and infrarenal aortic aneurysms. In an adjusted model, HIV was independently associated with aortic aneurysms (adjusted odds ratio; 4.51 [95% confidence interval 2.56–8.08], P &lt; 0.001). Within PLWH, obesity and hepatitis B co-infection were associated with aortic aneurysms.

Conclusion
PLWH had four-fold higher odds of aortic aneurysms compared to uninfected controls, and HIV status was independently associated with aortic aneurysms. Among PLWH, age, obesity and hepatitis B co-infection were associated with higher odds of aortic aneurysms. Our findings suggest that increased attention to aortic aneurysms in PLWH may be beneficial.
Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial
Authors: Lam Carolyn S P , Ferreira João Pedro , Pfarr Egon , Sim David , Tsutsui Hiroyuki , Anker Stefan D , Butler Javed , Filippatos Gerasimos , Pocock Stuart J , Sattar Naveed , Verma Subodh , Brueckmann Martina , Schnee Janet , Cotton Daniel , Zannad Faiez , Packer Milton 
Published: May 2021

Abstract

Aims
The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial.

Methods and results
Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%.

Conclusions
There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.
Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study
Authors: Salem Joe-Elie , Nguyen Lee S , Moslehi Javid J , Ederhy Stéphane , Lebrun-Vignes Bénédicte , Roden Dan M , Funck-Brentano Christian , Gougis Paul 
Published: May 2021

Abstract

Aims
With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA).

Methods and results
We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 &gt;0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P &lt; 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P &lt; 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed.

Conclusion
This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements.

Clinical trial registration
NCT03530215.
Age Trends in Growth and Differentiation Factor-11 and Myostatin Levels in Healthy Men, and Differential Response to Testosterone, Measured Using Liquid Chromatography–Tandem Mass Spectrometry
Authors: Peng Liming , Gagliano-Jucá Thiago , Pencina Karol M , Krishnan Srinivasan , Li Zhuoying , Tracy Russell P , Jasuja Ravi , Bhasin Shalender 
Published: May 2021

Abstract

Background
Growth and differentiation factor (GDF)-11 controls embryonic development and has been proposed as an antiaging factor. GDF-8 (myostatin) inhibits skeletal muscle growth. Difficulties in accurately measuring circulating GDF-11 and GDF-8 have generated controversy.

Methods
We developed a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for simultaneous measurement of circulating GDF-8 and GDF-11 that employs denaturation, reduction, and alkylation; cation-exchange solid-phase extraction; tryptic digestion; followed by separation and quantification using 2 signature peptides for multiple reaction monitoring and C-terminal [13C615N4]-Arg peptides as internal standards. We evaluated age trends in serum GDF-11 and GDF-8 concentrations in community-dwelling healthy men, 19 years or older, and determined the effects of graded testosterone doses on GDF-8 and GDF-11 concentrations in healthy men in a randomized trial.

Results
The assay demonstrated linearity over a wide range, lower limit of quantitation 0.5 ng/mL for both proteins, and excellent precision, accuracy, and specificity (no detectable cross-reactivity of GDF-8 in GDF-11 assay or of GDF-11 in GDF-8 assay). Mean ± SD (median ± 1QR) GDF-8 and GDF-11 levels in healthy community-dwelling men, 19 years and older, were 7.2 ± 1.9 (6.8 ± 1.4) ng/mL. Neither GDF-8 nor GDF-11 levels were related to age or body composition. Testosterone treatment significantly increased serum GDF-8 but not GDF-11 levels.

Conclusions
The LC–MS/MS method for the simultaneous measurement of circulating total GDF-8 and GDF-11 demonstrates the characteristics of a valid assay. Testosterone treatment increased GDF-8 levels, but not GDF-11. Increase in GDF-8 levels by testosterone treatment, which increased muscle mass, suggests that GDF-8 acts as a chalone to restrain muscle growth.
Mobility of Older Adults: Gait Quality Measures Are Associated With Life-Space Assessment Scores
Authors: Suri Anisha , Rosso Andrea L , VanSwearingen Jessie , Coffman Leslie M , Redfern Mark S , Brach Jennifer S , Sejdić Ervin 
Published: May 2021

Abstract

Background
The relation of gait quality to real-life mobility among older adults is poorly understood. This study examined the association between gait quality, consisting of step variability, smoothness, regularity, symmetry, and gait speed, and the Life-Space Assessment (LSA).

Method
In community-dwelling older adults (N = 232, age 77.5 ± 6.6, 65% females), gait quality was derived from (i) an instrumented walkway: gait speed, variability, and walk ratio and (ii) accelerometer: signal variability, smoothness, regularity, symmetry, and time-frequency spatiotemporal variables during 6-minute walk. In addition to collecting LSA scores, cognitive functioning, walking confidence, and falls were recorded. Spearman correlations (speed as covariate) and random forest regression were used to assess associations between gait quality and LSA, and Gaussian mixture modeling (GMM) was used to cluster participants.

Results
Spearman correlations of ρ p = .11 (signal amplitude variability mediolateral [ML] axis), ρ p = .15 and ρ p = −.13 (symmetry anterior-posterior–vertical [AP–V] and ML–AP axes, respectively), ρ p = .16 (power V), and ρ = .26 (speed), all p &lt;.05 and marginally related, ρ p = −.12 (regularity V), ρ p = .11 (smoothness AP), and ρ p = −.11 (step-time variability), all p &lt;.1, were obtained. The cross-validated random forest model indicated good-fit LSA prediction error of 17.77; gait and cognition were greater contributors than age and gender. GMM indicated 2 clusters. Group 1 (n = 189) had better gait quality than group 2 (n = 43): greater smoothness AP (2.94 ± 0.75 vs 2.30 ± 0.71); greater similarity AP–V (.58 ± .13 vs .40 ± .19); lower regularity V (0.83 ± 0.08 vs 0.87 ± 0.10); greater power V (1.86 ± 0.18 vs 0.97 ± 1.84); greater speed (1.09 ± 0.16 vs 1.00 ± 0.16 m/s); lower step-time coefficient of variation (3.70 ± 1.09 vs 5.09 ± 2.37), and better LSA (76 ± 18 vs 67 ± 18), padjusted &lt; .004.

Conclusions
Gait quality measures taken in the clinic are associated with real-life mobility in the community.
Assessing What Matters Most in Older Adults With Multicomplexity
Authors: Moye Jennifer , Driver Jane A , Owsiany Montgomery T , Chen Li Qing , Whitley Jessica Cruz , Auguste Elizabeth J , Paik Julie M 
Published: May 2021

Abstract

Background and Objectives
Abilities and activities that are often simultaneously valued may not be simultaneously achievable for older adults with multicomplexity. Because of this, the Geriatrics 5Ms framework prioritizes care on “what matters most.” This study aimed to evaluate and refine the What Matters Most—Structured Tool (WMM-ST).

Research Design and Methods
About 105 older adults with an average of 4 chronic conditions completed the WMM-ST along with open-ended questions from the Serious Illness Conversation Guide. Participants also provided demographic and social information, completed cognitive screening with the Telephone-Montreal Cognitive Assessment-Short and frailty screening with the Frail scale. Quantitative and qualitative analyses aimed to (a) describe values; (b) evaluate the association of patient characteristics with values; and (c) assess validity via the tool’s acceptability, educational bias, and content accuracy.

Results
Older adults varied in what matters most. Ratings demonstrated modest associations with social support, religiosity, cognition, and frailty, but not with age or education. The WMM-ST was rated as understandable (86%) and applicable to their current situation (61%) independent of education. Qualitative analyses supported the content validity of WMM-ST, while revealing additional content.

Discussion and Implications
It is possible to assess what matters most to older adults with multicomplexity using a structured tool. Such tools may be useful in making an abstract process clearer but require further validation in diverse samples.
Cell surface integrin α5ß1 clustering negatively regulates receptor tyrosine kinase signaling in colorectal cancer cells via glycogen synthase kinase 3
Authors: Starchenko Alina , Graves-Deal Ramona , Brubaker Douglas , Li Cunxi , Yang Yuping , Singh Bhuminder , Coffey Robert J , Lauffenburger Douglas A 
Published: May 2021

Abstract
As a key process within the tissue microenvironment, integrin signaling can influence cell functional responses to growth factor stimuli. We show here that clustering of integrin α5ß1 at the plasma membrane of colorectal cancer-derived epithelial cells modulates their ability to respond to stimulation by receptor tyrosine kinase (RTK)-activating growth factors EGF, NRG and HGF, through GSK3-mediated suppression of Akt pathway. We observed that integrin α5ß1 is lost from the membrane of poorly organized human colorectal tumors and that treatment with the integrin-clustering antibody P4G11 is sufficient to induce polarity in a mouse tumor xenograft model. While adding RTK growth factors (EGF, NRG and HGF) to polarized colorectal cancer cells induced invasion and loss of monolayer formation in 2D and 3D, this pathological behavior could be blocked by P4G11. Phosphorylation of ErbB family members as well as MET following EGF, NRG and HGF treatment was diminished in cells pretreated with P4G11. Focusing on EGFR, we found that blockade of integrin α5ß1 increased EGFR phosphorylation. Since activity of multiple downstream kinase pathways were altered by these various treatments, we employed computational machine learning techniques to ascertain the most important effects. Partial least-squares discriminant analysis identified GSK3 as a major regulator of EGFR pathway activities influenced by integrin α5ß1. Moreover, we used partial correlation analysis to examine signaling pathway crosstalk downstream of EGF stimulation and found that integrin α5ß1 acts as a negative regulator of the AKT signaling cascade downstream of EGFR, with GSK3 acting as a key mediator. We experimentally validated these computational inferences by confirming that blockade of GSK3 activity is sufficient to induce loss of polarity and increase of oncogenic signaling in the colonic epithelial cells.
Two Kinds of “Bad” Musical Performance: Musical and Moral Mistakes
Authors: London Justin 
Published: May 2021

AbstractThere are many ways in which a musical performance can be “bad,” but here the focus is on two: those performances that make you laugh, and those that make you angry. These forms of musical badness, however, are not primarily compositional deficits, but either (a) that the performer simply cannot competently deliver the music to their audience, inducing laughter, or (b) that the performer exhibits some form of disrespect, provoking anger. Such laughter or anger stems from failure of the expected relationship between a performer and their audience, that is, a social failure. After surveying a range of musical faults, the article examines the causes of laughter in general and in relation to some of examples of risible “bad” music. Similarly, the causes of social and moral anger in general are examined, and several cases of anger-inducing musical performances are presented. The article concludes with a consideration of the broader implications of these responses to “bad” music for theories of emotional expression in music, the relationship between aesthetic and moral judgments, and the centrality of musical performances as opposed to works in discussions of musical expression and value.