bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPR15 Facilitates Recruitment of Regulatory T Cells to Promote Colorectal Cancer
Authors: Adamczyk Alexandra , Pastille Eva , Kehrmann Jan , Vu Vivian P. , Geffers Robert , Wasmer Marie-Hélène , Kasper Stefan , Schuler Martin , Lange Christian M. , Muggli Beat , Rau Tilman T. , Klein Diana , Hansen Wiebke , Krebs Philippe , Buer Jan , Westendorf Astrid M. 
Published: March 2021

Abstract

Colorectal cancer is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, particularly in advanced colorectal cancer. Regulatory T cells (Treg) are increased in the peripheral blood and tumor tissue of patients with colorectal cancer. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8+ T-cell–mediated antitumoral immunity in murine colorectal cancer models. However, before considering therapies on targeting Tregs in patients with cancer, detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here, we demonstrate in a murine model of inflammation-induced colorectal cancer that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human colorectal cancer lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15+ Tregs have a Th17-like phenotype, thereby producing IL17 and TNFα. Gpr15 deficiency repressed Treg infiltration in colorectal cancer, which paved the way for enhanced antitumoral CD8+ T-cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T-cell–mediated antitumoral immunity in colorectal cancer.

Significance:
The G protein–coupled receptor 15, an unconventional chemokine receptor, directs Tregs into the colon, thereby modifying the tumor microenvironment and promoting intestinal tumorigenesis.
See related commentary by Chakraborty and Zappasodi, p. 2817
Phase II Clinical Trial of Everolimus in a Pan-Cancer Cohort of Patients with mTOR Pathway Alterations
Authors: Adib Elio , Klonowska Katarzyna , Giannikou Krinio , Do Khanh T. , Pruitt-Thompson Solida , Bhushan Ketki , Milstein Matthew I. , Hedglin Jennifer , Kargus Katherine E. , Sholl Lynette M. , Tsuji Junko , Hyman David M. , Sisk Anne , Shapiro Geoffrey I. , Vargas Hebert A. , Harding James J. , Voss Martin H. , Iyer Gopa , Kwiatkowski David J. 
Published: March 2021

AbstractPurpose:This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations.Patients and Methods:Patients with tumors with inactivating TSC1/TSC2 or activating MTOR mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.Results:Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30), or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%–22%]. Median progression-free survival was 2.3 months (95% CI, 1.8–3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5–12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of TSC1 and high tumor mutation burden, and the other had uterine carcinoma with biallelic TSC2-inactivating mutations and PEComa-like pathologic features.Conclusions:Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.See related commentary by Kato and Cohen, p. 3807
Proteomic Analysis of Src Family Kinase Phosphorylation States in Cancer Cells Suggests Deregulation of the Unique Domain
Authors: Ruiz-Saenz Ana , Zahedi Farima , Peterson Elliott , Yoo Ashley , Dreyer Courtney A. , Spassov Danislav S. , Oses-Prieto Juan , Burlingame Alma , Moasser Mark M. 
Published: March 2021

Abstract

The Src family kinases (SFK) are homologs of retroviral oncogenes, earning them the label of proto-oncogenes. Their functions are influenced by positive and negative regulatory tyrosine phosphorylation events and inhibitory and activating intramolecular and extramolecular interactions. This regulation is disrupted in their viral oncogene counterparts. However, in contrast to most other proto-oncogenes, the genetic alteration of these genes does not seem to occur in human tumors and how and whether their functions are altered in human cancers remain to be determined. To look for proteomic-level alterations, we took a more granular look at the activation states of SFKs based on their two known regulatory tyrosine phosphorylations, but found no significant differences in their activity states when comparing immortalized epithelial cells with cancer cells. SFKs are known to have other less well-studied phosphorylations, particularly within their unstructured N-terminal unique domains (UD), although their role in cancers has not been explored. In comparing panels of epithelial cells with cancer cells, we found a decrease in S17 phosphorylation in the UD of Src in cancer cells. Dephosphorylated S17 favors the dimerization of Src that is mediated through the UD and suggests increased Src dimerization in cancers. These data highlight the important role of the UD of Src and suggest that a deeper understanding of proteomic-level alterations of the unstructured UD of SFKs may provide considerable insights into how SFKs are deregulated in cancers.

Implications:
This work highlights the role of the N-terminal UD of Src kinases in regulating their signaling functions and possibly in their deregulation in human cancers.
Surface Proteomics Reveals CD72 as a Target for In Vitro–Evolved Nanobody-Based CAR-T Cells in KMT2A/MLL1-Rearranged B-ALL
Authors: Nix Matthew A. , Mandal Kamal , Geng Huimin , Paranjape Neha , Lin Yu-Hsiu T. , Rivera Jose M. , Marcoulis Makeba , White Kristie L. , Whitman Jeffrey D. , Bapat Sagar P. , Parker Kevin R. , Ramirez Jonathan , Deucher Anne , Phojanokong Paul , Steri Veronica , Fattahi Faranak , Hann Byron C. , Satpathy Ansuman T. , Manglik Aashish , Stieglitz Elliot , Wiita Arun P. 
Published: March 2021

Abstract

Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully in vitro system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL.

Significance:
Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully in vitro nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development.
This article is highlighted in the In This Issue feature, p. 1861
Um panorama dos museus universitários mais visitados no Brasil, entre 2014 e 2018
Authors: Fernandes Ana Veronica Cook 
Published: March 2021

A compreensão do papel atualmente desempenhado pelos museus universitários no Brasil passa pela identificação e caracterização dessas instituições, bem como pela análise dos resultados obtidos através das ações por elas empreendidas. Neste sentido, o presente trabalho apresenta um panorama quali-quantitativo dos museus universitários que estiveram presentes na lista dos 100 museus mais visitados no Brasil, conforme levantamento do Formulário de Visitação Anual compilado pelo Instituto Brasileiro de Museus, referente aos anos de 2014 a 2018. Foram analisados dados referentes à quantidade de museus universitários, a sua distribuição geográfica no país, ao seu vínculo institucional, às temáticas às quais se dedicam, ao ano de criação da instituição e à condição de preexistência e tombamento ou não de sua sede, realizando-se alguns cruzamentos dos dados para extrair informações adicionais. Não obstante seja um recorte numericamente restrito, ao contemplar as instituições que obtiveram melhor resultado de público nos cinco anos estudados, consideramos se tratar de uma amostragem qualitativamente significativa. Através desse panorama, podemos não apenas visualizar similaridades, mas também lacunas no cenário nacional, como a localização quase exclusiva nas regiões Sul e Sudeste do país; a maior incidência numérica e maior recorrência na lista dos museus vinculados a universidades públicas; e a predominância da temática científica. Esta é certamente uma abordagem parcial do tema dos museus universitários no país, que poderá complementar outras abordagens e apontar caminhos que poderão ser aprofundados em futuras investigações, de forma a possibilitar uma compreensão mais plena do papel que essas instituições desempenham no Brasil.
Arte moderna no campus da USP: o projeto de recepção do antigo MAM-SP na Universidade
Authors: Magalhães Ana Gonçalves , Brognara Gustavo 
Published: March 2021

Durante a década de 1960, a Universidade de São Paulo (USP) tornou-se responsável por um conjunto de coleções histórico-artísticas de grande relevância com a recepção dos acervos que integram seus museus estatutários. No caso do Museu de Arte Contemporânea (MAC-USP), instituído em 1963 a partir da doação das chamadas Coleções Matarazzo, formadas por Francisco Matarazzo Sobrinho (1898-1977) e Yolanda Penteado (1903-1983), havia um projeto anterior ao implantado: o de receber o antigo Museu de Arte Moderna de São Paulo (MAM-SP) na Cidade Universitária. O presente artigo busca apresentar indícios desse projeto através da relação da Universidade com seus interlocutores, com especial atenção ao envolvimento de Mário Pedrosa (1900-1981). Entende-se aqui a criação do MAC-USP como resultante da tentativa de incorporação do MAM-SP e parte integrante de um processo de modernização do país de que a Universidade se firmava como expoente. O artigo é o primeiro resultado da pesquisa de Gustavo Brognara no PPGMus-USP sob orientação de Ana Gonçalves Magalhães. O tema central da dissertação é a história da recepção das obras que fundam o MAC-USP, buscando esclarecer os motivos e os significados da destinação da coleção do antigo MAM-SP para a Universidade de São Paulo, bem como os projetos e os interesses desta ao recebê-la.
Patterns of Care for Atrial Fibrillation Before, During, and at Discharge From Hospitalization
Authors: Desai Nihar R. , Sciria Christopher T. , Zhao Xin , Piccini Jonathan P. , Turakhia Mintu P. , Matsouaka Roland , Fonarow Gregg C. , Lewis William R. 
Published: March 2021

Background:
Atrial fibrillation (AF) is the most common arrhythmia encountered in the hospital. However, contemporary treatment of patients hospitalized with AF, including stroke prevention, switching between these therapies, and rhythm control interventions are not well studied. We aimed to examine trends in inpatient interventions for AF, including switching oral anticoagulation (warfarin to direct oral anticoagulants [DOACs]), cardioversion, catheter ablation, and amiodarone use in hospitalized patients with AF.

Methods:
Using data from the Get With The Guidelines—AFIB registry from the American Heart Association, we analyzed patterns of medication and procedure use among hospitalized patients with AF from January 3, 2013, to March 28, 2017. To identify significant predictors of switching, multivariable hierarchical regression models were developed with patient baseline characteristics and comorbidities.

Results:

Among 31 280 patients with AF from 97 participating hospitals, 47.1% were on anticoagulation at presentation (6695 warfarin and 7393 DOAC) and the majority were continued at discharge (91.1%). Of those who were not receiving anticoagulation before hospitalization, 60.6% started anticoagulation at discharge (25.0% warfarin and 75.0% DOAC). The prevalence of switching from warfarin to DOAC was 4.0% and was more likely with younger age and lower CHA
2
DS
2
-VASc. Among 28 143 patients (excluding those discharged from the emergency department or observation status), 32.0% underwent cardioversion (56.1% chemically assisted and 49.4% electrical), 6.4% AF ablation, and 1.0% left atrial appendage occlusion device implantation. Patients of White race, younger age, and lower CHA
2
DS
2
-VASc were significantly more likely to undergo cardioversion or AF ablation, while older patients with higher CHA
2
DS
2
-VASc were significantly more likely to be initiated on amiodarone.

Conclusions:
Despite guideline recommendations prioritizing DOAC therapy, there are relatively low rates of switching from warfarin to DOAC in patients hospitalized with AF. Moreover, there is substantial variation in switching and utilization of rhythm control strategies, highlighting opportunities for performance improvement.

Graphic Abstract:

A
graphic abstract
is available for this article.
Phenology and temperature are the main drivers shaping the detection probability of the common wall lizard
Authors: Falaschi Mattia 
Published: March 2021

Abstract
Measuring the abundance of organisms is essential to provide information to ecology and biodiversity conservation. Hardly ever, the probability of detecting an animal during a survey is near one. Overlooking this observational process can lead to biased estimates of population size and vital rates. In this study, through Bayesian modeling, I evaluated the effects of temperature, precipitation, wind, humidity, and phenology in determining changes in the detection probability of the common wall lizard, for which studies on the factors determining detection probability are currently not available. Additionally, I tested for two possible interactions: date-temperature and date-humidity, in order to assess if the relationships of these variables with detection probability vary through the sampling season. Detection probability was highest earlier in the season (April) and between 24 and 28 degrees. Rainfall during the survey showed a negative effect on detection probability. In contrast, cumulative precipitation in the 24 hours before the survey showed a positive relationship, indicating that lizards are easier to detect in surveys after rainy days. Furthermore, date and temperature showed a positive interaction, indicating that the relationship between detectability and temperature changed over the sampling season. Date and humidity showed a negative interaction: late in the sampling season, detectability was higher with lower humidity, however, this relationship was not found in the early season. Future studies can consider multiple sites to evaluate the extent of variation in the drivers of detection probability and to assess the factors related to abundance.
Hobbes on Property: Between Legal Certainty and Sovereign Discretion
Authors: van Apeldoorn Laurens 
Published: March 2021

Abstract
Hobbes treats individual property as regulated by stable law, yet dependent on the arbitrary will of the sovereign. In this paper I catalogue the different definitions of property present in his main political and legal works – The Elements of Law (1640), De Cive (1642, 2nd ed. 1647), Leviathan (1651) and A Dialogue between a philosopher and a student (1681) – with the aim of showing how he attempted to square those commitments. I record how the definitions of property affect his views about how sovereigns hold property, the nature of the liability of subjects to having their property confiscated by the sovereign, and the legal conflicts that may arise between subjects and their rulers regarding such confiscations.
Foreign Military Adventurers in the Taiping Rebellion, 1860–1864
Authors: Orbach Danny 
Published: March 2021

Abstract
Using Western and Chinese archival sources, the following paper explores the military intervention of freelance foreign adventurers, particularly a militia eventually known as the Ever-Victorious Army, in the waning years of the Taiping Rebellion (1860–1864). My goal here is not merely to retell the story of this force, or to reassess its contribution to the subjugation of the Taipings, a question already studied by several historians. Instead, I will analyze the complicated and ever-changing relationship between these adventurers and the powers around them: Qing local authorities, the imperial court in Beijing, and the various foreign countries, especially Great Britain. I argue that the opening for such a force as the Ever-Victorious Army was created by the need of all parties for informal cooperation against the Taiping while maintaining plausible deniability. Once this need had passed, the foreign military adventurers became redundant and could be discarded by their former sponsors.
A Climatology of Unstable Layers in the Troposphere and Lower Stratosphere: Some Early Results
Authors: Geller Marvin A. , Love Peter T. , Wang Ling 
Published: March 2021

AbstractThe 1-s-resolution U.S. radiosonde data are analyzed for unstable layers, where the potential temperature decreases with increasing altitude, in the troposphere and lower stratosphere (LS). Care is taken to exclude spurious unstable layers arising from noise in the soundings and also to allow for the destabilizing influence of water vapor in saturated layers. Riverton, Wyoming, and Greensboro, North Carolina, in the extratropics, are analyzed in detail, where it is found that the annual and diurnal variations are largest, and the interannual variations are smallest in the LS. More unstable layer occurrences in the LS at Riverton are found at 0000 UTC, while at Greensboro, more unstable layer occurrences in the LS are at 1200 UTC, consistent with a geographical pattern where greater unstable layer occurrences in the LS are at 0000 UTC in the western United States, while greater unstable layer occurrences are at 1200 UTC in the eastern United States. The picture at Koror, Palau, in the tropics is different in that the diurnal and interannual variations in unstable layer occurrences in the LS are largest, with much smaller annual variations. At Koror, more frequent unstable layer occurrences in the LS occur at 0000 UTC. Also, a “notch” in the frequencies of occurrence of thin unstable layers at about 12 km is observed at Koror, with large frequencies of occurrence of thick layers at that altitude. Histograms are produced for the two midlatitude stations and one tropical station analyzed. The log–log slopes for troposphere histograms are in reasonable agreement with earlier results, but the LS histograms show a steeper log–log slope, consistent with more thin unstable layers and fewer thick unstable layers there. Some radiosonde stations are excluded from this analysis since a marked change in unstable layer occurrences was identified when a change in radiosonde instrumentation occurred.
Factors Associated With Clinical Improvement and the Disappearance of Calcifications After Ultrasound-Guided Percutaneous Lavage of Rotator Cuff Calcific Tendinopathy: A Post Hoc Analysis of a Randomized Controlled Trial
Authors: Dumoulin Nicolas , Cormier Grégoire , Varin Stéphane , Coiffier Guillaume , Albert Jean-David , Le Goff Benoit , Darrieutort-Laffite Christelle 
Published: March 2021

Background: Calcific tendinitis of the rotator cuff is a frequent cause of shoulder pain. Ultrasound-guided percutaneous lavage (UGPL) is an effective treatment, but factors associated with good clinical and radiological outcomes still need to be identified. Purpose: To study the clinical, procedural, and radiological characteristics associated with improved shoulder function and the disappearance of calcification on radiograph after UGPL. Study Design: Case-control study; Level of evidence, 3. Methods: This is a post hoc analysis of the CALCECHO trial, a double-blinded randomized controlled trial conducted on 132 patients. The trial assessed the effect of corticosteroid injections after UGPL, and patients were randomly assigned to receive either corticosteroid or saline solution in the subacromial bursa. We analyzed all patients included in the randomized controlled trial as 1 cohort. We collected the patients’ clinical, procedural, and radiological characteristics at baseline and during follow-up (3, 6, and 12 months). Univariable analysis, followed by multivariable stepwise regression through forward elimination, was performed to identify the factors associated with clinical success (Disabilities of the Arm, Shoulder and Hand [DASH] score <15) or the disappearance of calcification. Results: Good clinical outcomes at 3 months were associated with steroid injections after the procedure (odd ratio [OR], 3.143; 95% CI, 1.105-8.94). At 6 months, good clinical evolution was associated with a lower DASH score at 3 months (OR, 0.92; 95% CI, 0.890-0.956) and calcium extraction (OR, 10.7; 95% CI, 1.791-63.927). A lower DASH at 6 months was also associated with a long-term favorable outcome at 12 months (OR, 0.939; 95% CI, 0.912-0.966). Disappearance of calcification at 3 and 12 months occurred more frequently in patients in whom communication was created between the calcification and the subacromial bursa during the procedure (OR, 2.728 [95% CI, 1.194-6.234] at 3 months; OR, 9.835 [95% CI, 1.977-48.931] at 12 months). Importantly, an association between calcification resorption and good clinical outcome was found at each time point. Conclusion: Assessing patients at 3 months seems to be an essential part of their management strategy. Calcium extraction and creating a communication between the calcific deposits and subacromial bursa are procedural characteristics associated with good clinical and radiological evolution.