bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atopic dermatitis in West Highland white terriers – Part III: early life peripheral blood regulatory T cells are reduced in atopic dermatitis
Authors: Rostaher Ana , Rodriguez‐Campos Sabrina , Deplazes Peter , Zwickl Lena , Akdis A. Cezmi , Urwyler Adrian , Wheeler David W. , Audergon Sabrina , Fischer Nina Maria , Favrot Claude 
Published: February 2021

BackgroundRegulatory T (Treg) cells are involved in homeostasis of immune regulation and suppression of inflammation and T‐cell polarisation. Current knowledge regarding the role of Treg cells in the initiation of allergic disease is limited for both people and dogs.ObjectivesTo explore the role of circulating Treg cells and their possible influencing factors, on the development of atopic dermatitis (AD).Methods and materialsThis study followed part of a birth cohort of West Highland white terrier dogs and classified them according to eventual clinical signs of AD (i.e. allergic versus healthy). The Treg phenotypes were assessed longitudinally by flow cytometry at 3, 3–12 and 12–36 months of age, and associated with development of AD. Different early life antigenic factors [endotoxins and allergens in house dust, Toxocara canis‐specific immunoglobulin (Ig)E/IgG, allergen‐specific and total IgE, skin microbiota] were measured at three months of age, and a possible association with Treg cell levels was assessed.ResultsThe percentages of CD4+CD25+Foxp3+ Treg cells in healthy dogs were significantly higher at in 3‐month‐old (mean 4.5% healthy versus 3.3% allergic; P = 0.021) and <1‐year‐old (4.0% healthy versus 2.9% allergic; P = 0.028) dogs when compared to percentages of Treg cells in dogs that developed AD. There was a significantly positive correlation between the relative abundance of Lachnospiraceae on the skin and CD4+CD25+Foxp3+ Treg cells in puppies that became allergic (r = 0.568, P = 0.017).Conclusion and clinical importanceFurther large‐scale studies are needed to identify the practical value of these findings in AD diagnosis, treatment and prevention.
Adaptation of a hands‐on veterinary surgical training course from a traditionally taught laboratory to a remotely taught laboratory during a global pandemic
Authors: Thieman Mankin Kelley M. , Cornell Karen , Peycke Laura , Dickerson Vanna , Scallan Elizabeth 
Published: February 2021

AbstractObjectiveThe goal of this study was to evaluate and report details of a remotely taught surgical laboratory.Study designObservational.Sample populationSecond‐year veterinary students (n = 143) enrolled in a surgical laboratory; 9 weeks were taught traditionally, and 6 weeks were taught remotely.MethodsBecause of the global pandemic, remote laboratories were developed and delivered. Students performed surgical procedures in model organs remotely while being observed by and receiving feedback from instructors on an internet‐based video platform. Methods for remote surgical teaching were explored, and successes and challenges were detailed. Surveys were administered to the students and faculty to gather perspectives on their experience and subsequent confidence.ResultsSurveys were completed by 81 of 143 (57%) students and seven of seven (100%) instructors. The mean overall student satisfaction score (1 not at all satisfied, 10 very satisfied) for in‐person instruction was 8.2, and the mean score for remote instruction was 6.2 (P < .001). Overall, the instructors had a mean satisfaction score of 8 for in‐person laboratories and a mean satisfaction score of 6 for remotely taught laboratories. Most students had a perception of greater one‐on‐one instructor attention in remote laboratories. Students reported similar confidence levels for three surgical procedures.ConclusionThe described remote teaching method resulted in the perception of greater instructor attention given to students. Student and instructor satisfaction was lower with remote teaching than with in‐person teaching.ImpactThe described method of remote teaching may be applied to teaching surgical students in settings when face‐to‐face instruction cannot be achieved and may be developed further to create an experience equivalent to face‐to‐face instruction.
The Role of the Centerbody Wake on the Precessing Vortex Core Dynamics of a Swirl Nozzle
Authors: Mukherjee Arnab , Muthichur Nishanth , More Chaitali , Gupta Saarthak , Hemchandra Santosh 
Published: February 2021

Abstract
The precessing vortex core (PVC) phenomenon in swirling jets is a helical instability in the flow driven by the coherent precession of the vortex breakdown bubble (VBB) around the flow axis, resulting in the helical rollup of the shear layer. This instability is driven by flow processes in the region upstream of the VBB. Centerbodies, commonly employed in combustor nozzles, create a centerbody wake recirculation zone (CWRZ) that can interfere with VBB precession and hence suppress the PVC. We study this phenomenon in a swirl nozzle with a centerbody whose end face is flush with the nozzle exit plane, using large eddy simulations (LES) and linear hydrodynamic stability analysis for flow Reynolds numbers Re = 48,767 and 82,751, based on nozzle exit diameter and bulk flow velocity. For one of the Re = 82,751 cases, the centerbody end face diameter is halved, resulting in the onset of coherent VBB precession. Linear stability analysis reveals a marginally unstable mode in this case. The same mode is found to be stable in the nominal cases. Structural sensitivity analysis shows that the VBB precession eigenmode is sensitive to changes in the time-averaged flow in the VBB-CWRZ merger region. This suggests that the reduction in CWRZ length due to halving the centerbody end face diameter is the reason for the onset of VBB precession. These results suggest that in general, spatial separation between the CWRZ and VBB can result in the onset of VBB precession and the emergence of PVC oscillations in flows with swirl.
Carbon isotope and sequence stratigraphy of the upper Isachsen Formation on Axel Heiberg Island (Nunavut, Canada): High Arctic expression of oceanic anoxic event 1a in a deltaic environment
Authors: Dummann W. , Schröder-Adams C. , Hofmann P. , Rethemeyer J. , Herrle J.O. 
Published: February 2021

Abstract
The Early Cretaceous oceanic anoxic event (OAE) 1a documents a major perturbation of the global carbon cycle with severe consequences for the ocean-climate-biosphere system. While numerous studies over the past decades have provided a relatively detailed picture of the environmental repercussions of OAE 1a at low and mid-latitudes, studies from high latitudes, in particular the High Arctic, are limited. In this study, we present a high-resolution carbon isotopic and sequence stratigraphic framework for the lower to lower upper Aptian interval of the Isachsen Formation of the High Arctic Sverdrup Basin (Canada). These data enable us to precisely locate the stratigraphic position of OAE 1a in a deltaic sedimentary environment. The carbon isotope record allows, for the first time, identification of the different carbon isotope segments (CISs) of OAE 1a in the Sverdrup Basin and thereby correlation of the High Arctic record with sections from lower latitudes. Based on this improved chemostratigraphy, we revise the age of upper Paterson Island, Rondon, and Walker Island Members, important regional lithostratigraphic marker units. Whole-rock geochemical data record two episodes of marine incursion into the Sverdrup Basin during OAE 1a (CISs Ap3 and Ap6), which are interpreted as regional maximum flooding surfaces. This information is used in conjunction with detailed sedimentological logs and geochemical grain-size proxies to refine the sequence stratigraphic framework for the upper Isachsen Formation. We propose that transgressive-regressive cycles in the Sverdrup Basin were controlled mainly by the combined effects of eustatic sea-level changes and regional tectonic uplift, potentially related to the emplacement of Alpha Ridge, which culminated at ca. 122 Ma during CIS Ap9.
Cardiac arrest after severe traumatic brain injury can be survivable with good outcomes
Authors: Zhao Zirun , Liang Justine J , Wang Zhe , Winans Nathan J , Morris Matthew , Doyle Stephen , Fry Adam , Fiore Susan M , Mofakham Sima , Mikell Charles B 
Published: February 2021

BackgroundResuscitation for traumatic cardiac arrest (TCA) in patients with severe traumatic brain injury (sTBI) has historically been considered futile. There is little information on the characteristics and outcomes of these patients to guide intervention and prognosis. The purpose of the current study is to report the clinical characteristics, survival, and long-term neurological outcomes in patients who experienced TCA after sTBI and analyze the factors contributing to survival.MethodsA retrospective review identified 42 patients with TCA from a total of 402 patients with sTBI (Glasgow Coma Scale (GCS) score ≤8) who were admitted to Stony Brook University Hospital, a level I trauma center, from January 2011 to December 2018. Patient demographics, clinical characteristics, survival, and neurological functioning during hospitalization and at follow-up visits were collected.ResultsOf the 42 patients, the average age was 45 years and 21.4% were female. Eight patients survived the injury (19.0%) to discharge and seven survived with good neurological function. Admission GCS score and bilateral pupil reactivity were found to be significant indicators of survival. The mean GCS score was 5.3 in survivors and 3.2 in non-survivors (p=0.020). Age, Injury Severity Score, or cardiac rhythm was not associated with survival. Frequent neuroimaging findings included subarachnoid hemorrhage, subdural hematoma, and diffuse axonal injury.DiscussionTCA after sTBI is survivable and seven out of eight patients in our study recovered with good neurological function. GCS score and pupil reactivity are the best indicators of survival. Our results suggest that due to the possibility of recovery, resuscitation and neurosurgical care should not be withheld from this patient population.Level of evidenceLevel IV, therapeutic/care management.
Two approaches that prove divergence free nature of non-local gravity
Authors: Hameeda M. , Pourhassan B. , Rocca M. C. , Brzo Aram Bahroz 
Published: February 2021

AbstractThis paper is an attempt to study the thermodynamics of the structure formation in the large scale universe in the non local gravity using Boltzmann statistics and the Tsallis statistics. The partition function is obtained in both the approaches and the corresponding thermodynamics properties are evaluated. The important thing about the paper is that we surprisingly get the divergence free integrals and thus stress upon the fact that the nonlocal gravity is the singularity free model of gravity.
Effect of Naringin Treatment on Postmenopausal Osteoporosis in Ovariectomized Rats: A Meta-Analysis and Systematic Review
Authors: Zhu Zhu , Xie Wenjing , Li Yanyan , Zhu Zaiou , Zhang Wei 
Published: February 2021

Background. Osteoporosis is a major disease that affects the quality of life of middle-aged and old people, so it is very important to find efficient and safe drugs to treat osteoporosis. The purpose of this study was to investigate the therapeutic effect of naringin on postmenopausal osteoporosis in ovariectomized (OVX) rats. Methods. Chinese biomedical databases, CNKI, PubMed, EMBASE, and Wan Fang were searched for articles from inception to March 2020. Two independent researchers screened articles according to inclusion criteria. RevMan 5.3 was used for data analysis. Results. Ten studies were included in the systematic review. The bone mineral density (BMD) significantly increased after naringin treatment (weighted mean difference, 0.06; 95% CI, 0.03–0.09;

P

< 0.01). There was no significant increase in BMD after estrogen treatment compared with naringin (weighted mean difference, 0.00; 95% CI, −0.00 to 0.01;

P

= 0.06). The trabecular bone volume (BV/TV) (weighted mean difference, 2.09; 95% CI, 1.85–2.34;

P

< 0.01) and trabecular thickness (Tb.Th) (weighted mean difference, 6.65; 95% CI, 6.55–6.74;

P

< 0.01) significantly increased after using naringin. Conclusions. Naringin had been shown to promote bone formation in OVX rats. However, the mechanism of naringin needs more research to confirm.
Data-Driven Computational Modeling Identifies Determinants of Glioblastoma Response to SHP2 Inhibition
Authors: Day Evan K. , Zhong Qing , Purow Benjamin , Lazzara Matthew J. 
Published: February 2021

AbstractOncogenic protein tyrosine phosphatases have long been viewed as drug targets of interest, and recently developed allosteric inhibitors of SH2 domain–containing phosphatase-2 (SHP2) have entered clinical trials. However, the ability of phosphatases to regulate many targets directly or indirectly and to both promote and antagonize oncogenic signaling may make the efficacy of phosphatase inhibition challenging to predict. Here we explore the consequences of antagonizing SHP2 in glioblastoma, a recalcitrant cancer where SHP2 has been proposed as a useful drug target. Measuring protein phosphorylation and expression in glioblastoma cells across 40 signaling pathway nodes in response to different drugs and for different oxygen tensions revealed that SHP2 antagonism has network-level, context-dependent signaling consequences that affect cell phenotypes (e.g., cell death) in unanticipated ways. To map specific signaling consequences of SHP2 antagonism to phenotypes of interest, a data-driven computational model was constructed based on the paired signaling and phenotype data. Model predictions aided in identifying three signaling processes with implications for treating glioblastoma with SHP2 inhibitors. These included PTEN-dependent DNA damage repair in response to SHP2 inhibition, AKT-mediated bypass resistance in response to chronic SHP2 inhibition, and SHP2 control of hypoxia-inducible factor expression through multiple MAPKs. Model-generated hypotheses were validated in multiple glioblastoma cell lines, in mouse tumor xenografts, and through analysis of The Cancer Genome Atlas data. Collectively, these results suggest that in glioblastoma, SHP2 inhibitors antagonize some signaling processes more effectively than existing kinase inhibitors but can also limit the efficacy of other drugs when used in combination.Significance:These findings demonstrate that allosteric SHP2 inhibitors have multivariate and context-dependent effects in glioblastoma that may make them useful components of some combination therapies, but not others.
Inflammation and Apolipoproteins Are Potential Biomarkers for Stratification of Cutaneous Melanoma Patients for Immunotherapy and Targeted Therapy
Authors: Karlsson Max J. , Costa Svedman Fernanda , Tebani Abdellah , Kotol David , Höiom Veronica , Fagerberg Linn , Edfors Fredrik , Uhlén Mathias , Egyhazi Brage Suzanne , Maddalo Gianluca 
Published: February 2021

Abstract

Malignant cutaneous melanoma is one of the most common cancers in young adults. During the last decade, targeted and immunotherapies have significantly increased the overall survival of patients with malignant cutaneous melanoma. Nevertheless, disease progression is common, and a lack of predictive biomarkers of patient response to therapy hinders individualized treatment strategies. To address this issue, we performed a longitudinal study using an unbiased proteomics approach to identify and quantify proteins in plasma both before and during treatment from 109 patients treated with either targeted or immunotherapy. Linear modeling and machine learning approaches identified 43 potential prognostic and predictive biomarkers. A reverse correlation between apolipoproteins and proteins related to inflammation was observed. In the immunotherapy group, patients with low pretreatment expression of apolipoproteins and high expression of inflammation markers had shorter progression-free survival. Similarly, increased expression of LDHB during treatment elicited a significant impact on response to immunotherapy. Overall, we identified potential common and treatment-specific biomarkers in malignant cutaneous melanoma, paving the way for clinical use of these biomarkers following validation on a larger cohort.

Significance:
This study identifies a potential biomarker panel that could improve the selection of therapy for patients with cutaneous melanoma.
PINK1-Mediated Inhibition of EGFR Dimerization and Activation Impedes EGFR-Driven Lung Tumorigenesis
Authors: Lin Emily Pei-Ying , Huang Bo-Tsang , Lai Wei-Yun , Tseng Yi-Ting , Yang Shuenn-Chen , Kuo Hao-Cheng , Yang Pan-Chyr 
Published: February 2021

Abstract

EGFR is established as a driver of lung cancer, yet the regulatory machinery underlying its oncogenic activity is not fully understood. PTEN-induced kinase 1 (PINK1) kinase is a key player in mitochondrial quality control, although its role in lung cancer and EGFR regulation is unclear. In this study, we show that PINK1 physically directly interacts with EGFR via the PINK1 C-terminal domain (PINK1-CTD) and the EGFR tyrosine kinase domain. This interaction constituted an endogenous steric hindrance to receptor dimerization and inhibited EGFR-mediated lung carcinogenesis. Depletion of PINK1 from lung cancer cells promoted EGFR dimerization, receptor activation, EGFR downstream signaling, and tumor growth. In contrast, overexpression of PINK1 or PINK1-CTD suppressed EGFR dimerization, activation, downstream signaling, and tumor growth. These findings identify key elements in the EGFR regulatory cascade and illustrate a new direction for the development of anti-EGFR therapeutics, suggesting translational potential of the PINK1-CTD in lung cancer.

Significance:
This study identifies PINK1 as a critical tumor suppressor that impedes EGFR dimerization and highlights PINK1-CTD as a potential therapeutic agent in EGFR-driven lung cancer.
PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma
Authors: Shami Shah Adnan , Cao Xiaofu , White Andrew C. , Baskin Jeremy M. 
Published: February 2021

Abstract

Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro decreased Dishevelled levels, attenuated Wnt/β-catenin signaling, and blocked progression through the G1–S cell-cycle transition. In mouse xenograft and allograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid- and protein-binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation.

Significance:
This study establishes that melanoma cell proliferation requires the protein PLEKHA4 to promote pathologic Wnt signaling for proliferation, highlighting PLEKHA4 inhibition as a new avenue for the development of targeted therapies.
Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression
Authors: Kurebayashi Yutaka , Olkowski Colleen P. , Lane Kelly C. , Vasalatiy Olga V. , Xu Biying C. , Okada Ryuhei , Furusawa Aki , Choyke Peter L. , Kobayashi Hisataka , Sato Noriko 
Published: February 2021

AbstractRegulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab′)2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies.Significance:Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature.
YAP and β-Catenin Cooperate to Drive Oncogenesis in Basal Breast Cancer
Authors: Quinn Hazel M. , Vogel Regina , Popp Oliver , Mertins Philipp , Lan Linxiang , Messerschmidt Clemens , Landshammer Alexandro , Lisek Kamil , Château-Joubert Sophie , Marangoni Elisabetta , Koren Elle , Fuchs Yaron , Birchmeier Walter 
Published: February 2021

AbstractTargeting cancer stem cells (CSC) can serve as an effective approach toward limiting resistance to therapies. While basal-like (triple-negative) breast cancers encompass cells with CSC features, rational therapies remain poorly established. We show here that the receptor tyrosine kinase Met promotes YAP activity in basal-like breast cancer and find enhanced YAP activity within the CSC population. Interfering with YAP activity delayed basal-like cancer formation, prevented luminal to basal transdifferentiation, and reduced CSC. YAP knockout mammary glands revealed a decrease in β-catenin target genes, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, nuclear YAP interacted with β-catenin and TEAD4 at gene regulatory elements. Proteomic patient data revealed an upregulation of the YAP signature in basal-like breast cancers. Our findings demonstrate that in basal-like breast cancers, β-catenin activity is dependent on YAP signaling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal-like breast cancers.Significance:These findings show that YAP cooperates with β-catenin in basal-like breast cancer to regulate CSCs and that targeting this interaction may be a novel CSC therapy for patients with basal-like breast cancer.