bluuebunny/crossref_metadata_2025_split huggingface dataset:
MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer
Authors: Lee Jia-Ying Lloyd , Ekambaram Prasanna , Carleton Neil M. , Hu Dong , Klei Linda R. , Cai Zongyou , Myers Max I. , Hubel Nathaniel E. , Covic Lidija , Agnihotri Sameer , Krappmann Daniel , Bornancin Frédéric , Lee Adrian V. , Oesterreich Steffi , McAllister-Lucas Linda M. , Lucas Peter C. 
Published: November 2021

Abstract

MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein–coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs.

Implications:
This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.
Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition
Authors: Eisenmann Eric D. , Fu Qiang , Muhowski Elizabeth M. , Jin Yan , Uddin Muhammad Erfan , Garrison Dominique A. , Weber Robert H. , Woyach Jennifer A. , Byrd John C. , Sparreboom Alex , Baker Sharyn D. 
Published: November 2021

Ibrutinib (Imbruvica; PCI-32765) is an orally administered inhibitor of Bruton's tyrosine kinase that has transformed the treatment of B-cell malignancies. However, ibrutinib has very low oral bioavailability that contributes to significant variability in systemic exposure between patients, and this has the potential to affect both efficacy and toxicity. We hypothesized that the oral bioavailability of ibrutinib is limited by CYP3A isoform–mediated metabolism, and that this pathway can be inhibited to improve the pharmacokinetic properties of ibrutinib. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms (CYP3A−/−) that received ibrutinib alone or in combination with CYP3A inhibitors cobicistat or ketoconazole. Computational modeling was performed to derive doses of ibrutinib that, when given after a CYP3A inhibitor, results in therapeutically relevant drug levels. Deficiency of CYP3A in mice was associated with an approximately 10-fold increase in the AUC of ibrutinib. This result could be phenocopied by administration of cobicistat before ibrutinib in wild-type mice, but cobicistat did not influence levels of ibrutinib in CYP3A−/− mice. Population pharmacokinetic and prospectively validated physiologically based pharmacokinetic models established preclinical and clinical doses of ibrutinib that could be given safely in combination with cobicistat without negatively affecting antileukemic properties. These findings signify a dominant role for CYP3A-mediated metabolism in the elimination of ibrutinib, and suggest a role for pharmacologic inhibitors of this pathway to intentionally modulate the plasma levels and improve the therapeutic use of this clinically important agent.Significance:Ibrutinib has limited oral bioavailability, which contributes to significant interindividual pharmacokinetic variability. Using engineered mouse models, we here report a causal relationship between CYP3A-mediated metabolism and ibrutinib's bioavailability and drug–drug interaction with cobicistat. These results offer a mechanistic basis for reported pharmacokinetic interactions with ibrutinib, and in conjunction with a newly developed computational model, allow for the rational design of clinical trials aimed at improving the therapeutic use of ibrutinib.
Large Diameter Advanta V12 Covered Stent Trial for Coarctation of the Aorta: COARC Study
Authors: Bruckheimer Elchanan , Birk Einat , Benson Lee , Butera Gianfranco , Martin Robin , Roberts Philip A. , Schneider Martin B.E. , Schubert Stephan , Sievert Horst , Pedra Carlos C.A. 
Published: November 2021

Background:
Covered stent implantation for treatment of coarctation of the aorta (CoA) is effective and can prevent aortic wall injury. Prospective studies with long-term follow-up, including imaging, are lacking. We report the acute and long-term outcomes for use of the Large Diameter Advanta V12 covered stent for treatment of native and recurrent CoA.

Methods:
A prospective, multicenter, nonrandomized study was performed including 70 patients (43 male), median age 17 years, median weight 57.4 kg with CoA who underwent implantation of the Large Diameter Advanta V12 covered stent. Annual follow-up for 5 years included Doppler echocardiography to calculate diastolic velocity: systolic velocity ratio.

Results:

CoA diameter increased from 5.6±3.6 to 14.9±3.9 mm (
P
<0.0001) and the pressure gradient decreased from 35.8±16.2 to 5.6±7.9 mm Hg (
P
<0.0001). Preimplantation diastolic velocity:systolic velocity of 0.6±0.16 dropped to 0.34±0.13 (
P
<0.0001) and was maintained at 5 years. Computed tomography angiograms at 12 months postimplantation demonstrated the stent:transverse arch diameter to be similar, 0.91±0.09 to postprocedure 0.86±0.14. Major adverse vascular events at 30 days and 12 months were 1.4% and 4.3%, respectively. Significant adverse events included three patients who required stent implantation to treat infolding. There were no mortalities.

Conclusions:
The Large Diameter Advanta V12 covered stent is safe and effective for the treatment of CoA with an immediate and sustained reduction of the pressure gradient over 12 months and 5 years as assessed by preimplantation and postimplantation Doppler echocardiography and 12-month computed tomography angiography.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00978952. URL:
http://www.anzctr.org.au
; Unique identifier: ACTRN12612000013864.
A regression framework for brain network distance metrics
Authors: Tomlinson Chal E. , Laurienti Paul J. , Lyday Robert G. , Simpson Sean L. 
Published: November 2021

Abstract
Analyzing brain networks has long been a prominent research topic in neuroimaging. However, statistical methods to detect differences between these networks and relate them to phenotypic traits are still sorely needed. Our previous work developed a novel permutation testing framework to detect differences between two groups. Here we advance that work to allow both assessing differences by continuous phenotypes and controlling for confounding variables. To achieve this, we propose an innovative regression framework to relate distances (or similarities) between brain network features to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. We explore several similarity metrics for comparing distances (or similarities) between connection matrices, and adapt several standard methods for estimation and inference within our framework: standard F test, F test with individual level effects (ILE), feasible generalized least squares (FGLS), and permutation. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing multivariate distance matrix regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.
Minority Actorness Through a Non-Europeanised Policy Area
Authors: Huseyinoglu Ali , Hoch Tamara 
Published: November 2021

Abstract
By bringing together the literatures on Europeanisation and minority studies, this article illustrates the centrality of actors representing national minorities as a key to understand Europeanisation of minority politics today. Minority politics is becoming Europeanised indeed, however, not in the ways commonly expected. And although the EU repeatedly fails to develop a clear minority policy, an actor-centred approach adopted in this study helps to reveal how minority actors extend their political strategies to the European level through different channels and how they exploit various opportunities stemming from European-level politics. Jacquot and Woll’s concept of ‘usages of Europe’ not only enables us to trace how actors multiply channels and arenas of participation, but it also helps to spot the emergence of tactics of experimentation with European-level norms and rules, contributing to an acquisition of new roles among minority actors and supporting an actorness formation among those active. As the actors engage in criticising EU institutions, they develop tactics of responsibilising which in turn affects their minority agendas and the actors themselves. In this respect, this study contributes to developing the weakly studied literature about minority agency and Europeanisation.
The Worse than Nothing Account of Harm and the Preemption Problem
Authors: Immerman Daniel 
Published: November 2021

Abstract
Because harm is an important notion in ethics, it’s worth investigating what it amounts to. The counterfactual comparative account of harm, commonly thought to be the most promising account of harm, analyzes harm by comparing what actually happened with what would have happened in some counterfactual situation. But it faces the preemption problem, a problem so serious that it has driven some to suggest we abandon the counterfactual comparative account and maybe even abandon the notion of harm altogether. This paper defends a version of the counterfactual comparative account that solves the preemption problem, a version called the “worse than nothing account.” It says that you harm someone just in case you leave them worse off than if you’d done nothing at all.
Consenting Under Third-Party Coercion
Authors: Kiener Maximilian 
Published: November 2021

Abstract
This paper focuses on consent and third-party coercion, viz. cases in which a person consents to another person performing a certain act because a third party coerced her into doing so. I argue that, in these cases, the validity of consent depends on the behavior of the recipient of consent rather than the third party’s coercion taken separately, and I will specify the conditions under which consent is invalid. My view, which is a novel version of what I call a Recipient-Focus-View, holds that coercion invalidates consent only if consent was ‘obtained by’ coercion, but not if consent was ‘merely motivated by’ coercion. I explain and support my view on the basis that it best reconciles an unnoticed tension between two fundamental principles in the debate on consent (which I call the Coercion Principle and the Permissibility Principle) and that it can deal with cases that undermine other Recipient-Focus-Views.
Comparing Frontal Structures of Extratropical Cyclones in the Northwestern Pacific and Northwestern Atlantic Storm Tracks
Authors: Tochimoto Eigo , Niino Hiroshi 
Published: November 2021

Abstract
The frontal structures of extratropical cyclones developing in the northwestern Pacific storm track are relatively poorly understood compared with those in Europe and the Atlantic Ocean, for which representative conceptual models have been developed. In this paper, the structures of cyclones and their associated fronts in the northwestern Pacific (NP), as well as in the Okhotsk Sea and Sea of Japan (OJ), are examined at their developing and mature stages using Japanese 55-year Reanalysis dataset. Furthermore, the frontal structures in the NP are compared with those in the northwestern Atlantic (NA). At the time of maximum deepening rate, cyclones in the NP are accompanied by strong warm and cold fronts, whereas cyclones in the OJ are more frequently accompanied by cold fronts than by warm fronts and tend to have stronger cold fronts than warm fronts. The weaker warm fronts than cold fronts to the east and northeast of cyclones in the OJ is likely due to the cyclones developing to the north and away from the region where the horizontal gradient of environmental potential temperature is strong. A comparison between mature cyclones in the NP and NA shows that the warm fronts in the NA tend to extend northeastward, whereas those in the NP extend more southeastward. These differences in warm fronts between NP and NA are suggested to be due to the difference in the horizontal structures of the warm currents between NP and NA.
Survival Associated With Consolidated Multidisciplinary Care in Head and Neck Cancer: A Retrospective Cohort Study
Authors: Meltzer Charles , Nguyen Nathalie T. , Zhang Jie , Aguilar Jillian , Blatchins Maruta A. , Quesenberry Charles P. , Wang Yan , Sakoda Lori C. 
Published: November 2021

AbstractObjectiveTo compare survival among patients with head and neck cancer before and after implementing a weekly multidisciplinary clinic and case conference.MethodsA retrospective cohort study with chart review was conducted of 3081 patients (1431 preimplementation, 1650 postimplementation) diagnosed with stage I‐IVB tumors in the oral cavity, oropharynx, hypopharynx, nasopharynx, or larynx. Pre‐ and postimplementation differences in overall and disease‐specific survival 1, 2, and 3 years after diagnosis were assessed with unadjusted Kaplan‐Meier curves and multivariable Cox proportional hazard regression models adjusted for demographic characteristics, comorbidity burden, smoking status, tumor site and stage, p16 status for oropharyngeal squamous cell cancer, and initial treatment modality.ResultsPatients less commonly presented with oropharyngeal squamous cell cancer and advanced tumors (III‐IVB) and received primary treatment with surgery alone or with adjuvant therapy preimplementation than postimplementation. Overall survival at 3 years was 77.1% and 79.9% (P = .07) and disease‐specific survival was 84.9% and 87.5% (P = .05) among pre‐ and postimplementation patients, respectively. At 3 years, preimplementation patients had slightly poorer overall (hazard ratio, 1.20; 95% CI, 1.02‐1.40) and disease‐specific (hazard ratio, 1.26; 95% CI, 1.03‐1.54) adjusted survival than postimplementation patients. In unadjusted and adjusted analyses, survival improvements were more pronounced among patients with advanced disease.DiscussionA multidisciplinary clinic and case conference were associated with improved outcomes among patients with head and neck cancer, especially those with advanced tumors.Implications for PracticeAll patients with head and neck cancer should receive multidisciplinary team management, especially those with advanced tumors.
Impact of Powered Air‐Purifying Respirator Devices on Word Recognition in Health Care Providers
Authors: Moldoff Emily J. , Eubank Miranda K. , Feng Anne Y. , Corrales C. Eduardo , Shin Jennifer J. 
Published: November 2021

The coronavirus 2019 pandemic has increased the use of powered air‐purifying respirator (PAPR) devices, which produce appreciable noise levels during filtration. Our objective was to determine if active PAPR usage significantly impairs auditory communication in health care providers. We additionally sought to assess what volume of speech presentation was required for adequate communication with providers wearing a PAPR. In subjects with normal hearing at baseline, audiometric data demonstrated a 93% (95% CI, 86%‐99%) decrease in word recognition scores during active PAPR usage. Presentation at 85 to 90 dB was needed to obtain word recognition scores similar to baseline in subjects with normal hearing without a PAPR. Pure tone averages also significantly decreased with PAPR usage, by 54 dB (95% CI, 46‐62). Active PAPR usage has a substantial impact on auditory perception when utilized by health care providers. The potential longer‐term effect of these devices on providers with regular active usage is of interest for future study.
Acral Lentiginous Melanoma: A United States Multi-Center Substage Survival Analysis
Authors: Kolla Avani M. , Vitiello Gerardo A. , Friedman Erica B. , Sun James , Potdar Aishwarya , Daou Hala , Farrow Norma E. , Farley Clara R. , Vetto John T. , Han Dale , Tariq Marvi , Beasley Georgia M , Contreras Carlo M. , Lowe Michael , Zager Jonathan S. , Osman Iman , Berman Russell S. , Liebman Tracey N. , Stein Jennifer A. , Lee Ann Y. 
Published: November 2021

Background Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. Objectives To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. Methods Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. Results Of the 433 primary acral lentiginous melanoma patients identified (median [range] age: 66 [8–97] years; 53% female, 83% white), 66% presented with stage 0–2 disease and the median time of follow-up for the 392 patients included in the survival analysis was 32.5 months (range: 0–259). The 5-year melanoma-specific survivals by stage were 0 = 100%, I = 93.8%, II = 76.2%, III = 63.4%, IIIA = 80.8%, and IV = 0%. Thicker Breslow depth ((HR) = 1.13; 95% CI = 1.05–1.21; P < .001)) and positive nodal status ((HR) = 1.79; 95% CI = 1.00–3.22; P = .050)) were independent prognostic factors for melanoma-specific survival. Breslow depth ((HR = 1.13; 95% CI = 1.07–1.20; P < .001), and positive nodal status (HR = 2.12; 95% CI = 1.38–3.80; P = .001) were also prognostic factors for recurrence-free survival. Conclusion In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.
Application of the Failure Mode and Effects Analysis (FMEA) to identify vulnerabilities and opportunities for improvement prior to implementing a computerized prescription order entry (CPOE) system in a university hospital oncology clinic
Authors: Joly-Mischlich Thomas , Maltais Serge , Tétu Amélie , Delorme Marie-Noëlle , Boilard Brigitte , Pavic Michel 
Published: November 2021

Introduction Prior to implementing a new computerized prescription order entry (CPOE) application, the potential risks associated with this system were assessed and compared to those of paper-based prescriptions. The goal of this study is to identify the vulnerabilities of the CPOE process in order to adapt its design and prevent these potential risks. Methods and materials Failure mode and effects analysis (FMEA) was used as a prospective risk-management technique to evaluate the chemotherapy medication process in a university hospital oncology clinic. A multidisciplinary team assessed the process and compared the critical steps of a newly developed CPOE application versus paper-based prescriptions. The potential severity, occurrence and detectability were assessed prior to the implementation of the CPOE application in the clinical setting. Results The FMEA led to the identification of 24 process steps that could theoretically be vulnerable, therefore called failure modes. These failure modes were grouped into four categories of potential risk factors: prescription writing, patient scheduling, treatment dispensing and patient follow-up. Criticality scores were calculated and compared for both strategies. Three failure modes were prioritized and led to modification of the CPOE design. Overall, the CPOE pathway showed a potential risk reduction of 51% compared to paper-based prescriptions. Conclusion FMEA was found to be a useful approach to identify potential risks in the chemotherapy medication process using either CPOE or paper-based prescriptions. The e-prescription mode was estimated to result in less risk than the traditional paper mode.
Clinical approach to skin eruptions induced by anti-TNF agents among patients with inflammatory bowel diseases: insights from a multidisciplinary IBD-DERMA clinic
Authors: Yanai Henit , Amir Barak Hadar , Ollech Jacob E , Avni Biron Irit , Goren Idan , Snir Yifat , Banai Eran Hagar , Broitman Yelena , Aharoni Golan Maya , Didkovsky Elena , Amitay-Laish Iris , Ollech Ayelet , Hodak Emmilia , Dotan Iris , Pavlovsky Lev 
Published: November 2021

Background and Aims: Skin eruptions are prevalent among patients with inflammatory bowel diseases (IBD), often associated with therapies and frequently leading to dermatological consults and treatment interruptions. We aimed to assess the impact of joint shared decision-making in a multidisciplinary (MDT) IBD-DERMA clinic. Methods: This retrospective cohort study assessed a consecutive group of patients with IBD who were referred for consultation in an MDT clinic at a tertiary referral center in Israel. Results: Over 1 year, 118 patients were evaluated in the MDT-IBD-DERMA clinic: 68 (57.6%) males; age – 35.2 ± 13.5 years, disease duration – 7.1 (interquartile range: 3.7–13.9) years; Crohn’s disease – 94/118 (79.6%). Skin eruption induced by an anti–tumor necrosis factor (TNF) were the most common diagnoses [46/118 (39%)], including psoriasiform dermatitis (PD) – 31/46 (67.4%) and inflammatory alopecia (IA) – 15/46 (32.6%). Of these, 18 patients (39.1%) continued the anti-TNF agent concomitantly with a topical or systemic anti-inflammatory agent to control the eruption. The remaining 28 patients (60.9%) discontinued the anti-TNF, of whom 16/28 (57.1%) switched to ustekinumab. These strategies effectively treated the majority [38/46 (82.6%)] of patients. Continuation of the anti-TNF was possible in a significantly higher proportion of patients with PD: 12/31 (38.7%) than only one in the IA group, p = 0.035. There was a higher switch to ustekinumab among the IA 7/15 (46.6%) compared with the PD 7/31 (22.6%) group, P = .09. Following IBD-DERMA advised intervention, IBD deteriorated in 9/4 6(19.5%) patients, 5/9 on ustekinumab (PD versus IA, P = NS). Conclusion: Shared decision-making in an integrated IBD-DERMA clinic allowed successful control of skin eruptions while preserving control of the underlying IBD in more than 80% of cases. Patients with IA profited from a switch to ustekinumab.