bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of e-commerce pharmacy provision and acceptability of levonorgestrel 1.5 mg for pericoital use in urban and peri-urban settings in Kenya: a prospective cohort study
Authors: Odwe George , McCann Brent , Liambila Wilson , Vandermark Jessica , Mwanga Daniel , Anab Edna , Wanami Moses , Ramarao Saumya 
Published: November 2022

IntroductionAn ‘on-demand’ contraceptive pill may suit women having infrequent sex. We assessed the feasibility of e-commerce pharmacy provision and acceptability of levonorgestrel (LNG) 1.5 mg for pericoital use in Kenya.MethodsA 12-month prospective, single-arm, open-label, interventional study conducted from August 2020 to August 2021. A total of 897 women aged 18–49 years at risk of pregnancy and having infrequent sex (ie, six times or fewer coital frequency/month) were screened and enrolled. We undertook univariate and bivariate analysis on multiple data points: enrolment dataset, bimonthly surveys, extended survey around 6-month follow-up, and e-commerce pharmacy sales log.ResultsA total of 2291 pericoital LNG 1.5 mg pill doses were dispensed to 300 women over a 12-month period mainly via the USSD (Unstructured Supplementary Service Data) platform. Of the 266 women who obtained the pill and completed the survey, most (83%) were satisfied/very satisfied with e-commerce platform services, citing convenience and ease of use. The pill was also acceptable. Of the 266 women who used it at least once, 94% were satisfied/very satisfied, likely to continue using and would recommend it to others; 86% used it within 24 hours before/after sex as recommended and most of the time they had sex; and 147 (55%) experienced side effects, mainly nausea, headache, changes in menstrual pattern, cramps and dizziness that were mild and tolerable.ConclusionsE-commerce pharmacy provision of LNG 1.5 mg for pericoital use is feasible. In addition, a pericoital LNG 1.5 mg pill is acceptable among women having infrequent sex and could potentially address their unmet family planning needs.
Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
Authors: Hägerbrand Karin , Varas Laura , Deronic Adnan , Nyesiga Barnabas , Sundstedt Anette , Ljung Lill , Sakellariou Christina , Werchau Doreen , Thagesson Mia , Gomez Jimenez David , Greiff Lennart , Celander Mona , Smedenfors Kristine , Rosén Anna , Bölükbas Deniz , Carlsson Fredrika , Levin Mattias , Säll Anna , von Schantz Laura , Lindstedt Malin , Ellmark Peter 
Published: November 2022

BackgroundIndications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime.MethodsBispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models.ResultsThe results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM).ConclusionsThe data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8+T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization
Authors: Camviel Nicolas , Wolf Benita , Croce Giancarlo , Gfeller David , Zoete Vincent , Arber Caroline 
Published: November 2022

BackgroundChimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only).MethodsThree new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell–target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo.ResultsAPRIL-CAR T cells in a trimeric ligand binding conformation conferred fast but not sustained antitumor responses in vivo in mouse xenograft models. In vitro trimer-BBζ CAR T cells were more polyfunctional and formed stronger immune synapses than monomer-BBζ CAR T cells. After CAR T cell–myeloma cell contact, BCMA was rapidly downmodulated on target cells with all evaluated binding moieties. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during progression and persisting CAR T cells may not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell–MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo.ConclusionAntitumor responses with APRIL-CAR T cells were fast but not sustained. Rapid BCMA downmodulation occurred independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM when targeting BCMA and can inform the development of improved treatment strategies.
Body composition of extreme performers in the US Marine Corps
Authors: Potter Adam W , Soto L D , Friedl K E 
Published: November 2022

BackgroundThe creation of highly muscled and strong fighters is a recurring theme in human performance enhancement concepts. Physical readiness standards, intended to prevent obesity in the military, produce contradictory objectives, hounding large individuals to lose weight because of confusion between body size and body composition. Through selection, specialised training and policy exceptions the US Marine Corps has successfully developed a unique group of large (body mass index (BMI) >30 kg/m2) and strong individuals, the body bearers (BB) who carry coffins of Marines to their final resting place.MethodsWe examined the relationship between adiposity and body size from nine male BB (age 25.0±2.1, height: 1.84±0.04 (1.80–1.92) m, BMI: 33.0±2.1 (30–37) kg/m2). Body composition was assessed by dual-energy X-ray absorptiometry (DXA), bioelectrical impedance (BIA) and tape measured abdominal circumference (AC)-based equations and from three-dimensional scanning (3DS).ResultsMeasures were made of fat-free mass (FFM): 90.5±7.0 (82.0–106.7) kg, where FFM included total body water: 62.8±5.0 (55.8–71.8) L, representing 69±2 (67–73) % of FFM, along with calculated FFM index: 26.8±2.4 (24.4–32.9) kg/m2). DXA measures were made for bone mineral content 4.1±0.4 (3.5–4.9) kg, bone mineral density (BMD) 1.56±0.10 (1.37–1.76) g/cm2and %BF 19.5±6.6 (9.0–27.8). Additional measures of percent body fat (%BF) were made by AC: 20.3±2.9 (15.2–24.6), BIA: 23.7±6.4 (9.8–29.2) and 3DS: 25.5±4.7 (18.9–32.2). AC %BF reasonably matched DXA %BF, with expected overprediction and underprediction at low and high DXA %BF. BIA %BF was affected by deviations from assumed FFM hydration (72%–73%).ConclusionThese men are classified as obese by BMI but carried massive amounts of muscle and bone on their large frames, while presenting a range of %BF irrelevant to strength performance. BMI did not predict obesity and adiposity had no association with muscle mass and strength performance.
Fast food consumption in adults living in Canada: alternative measurement methods, consumption choices, and correlates
Authors: Seale Emily , de Groh Margaret , Greene-Finestone Linda 
Published: November 2022

Global industries and technological advancements have contributed to the proliferation of fast food (FF) establishments and ultraprocessed food, associated with poorer diet quality and health outcomes. To investigate FF as an indicator, we compared alternative methods to capture self-reported FF consumption and examined associated socio-demographic factors. We conducted a secondary analysis of the 2014–2015 Foodbook study, a cross-sectional survey on foods consumed by Canadians during the previous week. An embedded randomized design compared alternative FF intake questions of varying details. A total of 6062 participants aged 18+ were included, representing 24.7 million Canadian adults. Approximately 48% consumed FF in the past week, and of FF consumers, average frequency was twice. Asking broadly about FF intake without examples resulted in significantly lower reported FF intake compared with the two more detailed questions; the latter two were not significantly different. Burgers, pizza, and submarines/sandwiches were most commonly consumed. Men, younger age, higher BMI, women in central Canada (versus territorial regions), and men with income $30 000–$80 000 (versus >$80 000) were associated with higher FF consumption. Consumption of FF is common among Canadians; some associated factors are gender-specific. Further research examining FF as an indicator, and individual and societal implications of FF consumption, is recommended to inform programs and policies.
Test–retest repeatability of electrically evoked isotonic power and isometric torque in the plantar flexors
Authors: Paris Michael T. , Zero Alexander M. , Rice Charles L. 
Published: November 2022

Electrically evoked isometric torque has good to excellent repeatability, but the degree of repeatability for electrically evoked isotonic power is unknown. We evaluated the test–retest repeatability of plantar flexion isometric torque and isotonic power evoked using brief tetanic trains at 10 and 50 Hz. Both torque and power had excellent (intraclass correlation coefficient >0.9) repeatability at low and high frequencies. Similar to isometric torque, electrically evoked isotonic power is a stable measure for studying dynamic muscle function.
The SPHERE view of multiple star formation
Authors: Gratton Raffaele , Desidera Silvano , Marzari Francesco , Bonavita Mariangela 
Published: November 2022

AbstractWhile a large fraction of the stars are in multiple systems, our understanding of the processes leading to the formation of these systems is still inadequate. Given the large theoretical uncertainties, observation plays a basic role. Here we discuss the contribution of high contrast imaging, and more specifically of the SPHERE instrument at the ESO Very Large Telescope, in this area. SPHERE nicely complements other instruments such as Gaia or ALMA—in detecting and characterizing systems near the peak of the binary distribution with separation and allows to capture snapshots of binary formation within disks that are invaluable for the understanding of disk fragmentation.
First steps of planet formation around very low mass stars and brown dwarfs
Authors: Pinilla Paola 
Published: November 2022

AbstractBrown dwarfs and very low mass stars are a significant fraction of stars in our galaxy and they are interesting laboratories to investigate planet formation in extreme conditions of low temperature and densities. In addition, the dust radial drift of particles is expected to be a more difficult barrier to overcome during the first steps of planet formation in these disks. ALMA high-angular resolution observations of few protoplanetary disks around BDs and VLMS have shown substructures as in the disks around Sun-like stars. Such observations suggests that giant planets embedded in the disks are the most likely origin of the observed substructures. However, this type of planets represent less than 2% of the confirmed exoplanets so far around all stars, and they are difficult to form by different core accretion models (either pebble or planetesimal accretion). Dedicated deep observations of disks around BDs and VLMS with ALMA and JWST will provide significant progress on understanding the main properties of these objects (e.g., disk size and mass), which is crucial for determining the physical mechanisms that rule the evolution of these disks and the effect on the potential planets that may form in these environments.
C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan
Authors: Kohno Takashi , Kato Mamoru , Kohsaka Shinji , Sudo Tomohisa , Tamai Ikuo , Shiraishi Yuichi , Okuma Yusuke , Ogasawara Daisuke , Suzuki Tatsuya , Yoshida Teruhiko , Mano Hiroyuki 
Published: November 2022

Summary:
Since June 2019, under the umbrella of the national health insurance system, Japan has started cancer genomic medicine (CGM) with comprehensive genomic profiling (CGP) tests. The Ministry of Health, Labour and Welfare (MHLW) of Japan constructed a network of CGM hospitals (a total of 233 institutes as of July 1, 2022) and established the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter for CGM. Clinical information and genomic data from the CGP tests are securely transferred to C-CAT, which then generates “C-CAT Findings” reports containing information of clinical annotation and matched clinical trials based on the CGP data. As of June 30, 2022, a total of 36,340 datapoints of clinical/genomic information are aggregated in C-CAT, and the number is expected to increase swiftly. The data are now open for sharing with not only the CGM hospitals but also other academic institutions and industries.
Lung CAFs Show T Cells the Velvet Rope
Authors: Sherman Mara H. 
Published: November 2022

Summary:
Cancer-associated fibroblasts share defined features with fibroblasts in secondary lymphoid organs, including the ability to regulate immune cell localization. In this issue of Cancer Discovery, Grout and colleagues perform multimodal analysis of human lung cancer specimens and identify two distinct fibroblast populations associated with spatial exclusion of T cells from tumor cell nests.
See related article by Grout et al., p. 2606 (3).
A Therapeutically Targetable NOTCH1–SIRT1–KAT7 Axis in T-cell Leukemia
Authors: Lancho Olga , Singh Amartya , da Silva-Diz Victoria , Aleksandrova Maya , Khatun Jesminara , Tottone Luca , Nunes Patricia Renck , Luo Shirley , Zhao Caifeng , Zheng Haiyan , Chiles Eric , Zuo Zhenyu , Rocha Pedro P. , Su Xiaoyang , Khiabanian Hossein , Herranz Daniel 
Published: November 2022

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1–SIRT1–KAT7 link as a therapeutic vulnerability in T-ALL, in which the histone deacetylase SIRT1 is overexpressed downstream of a NOTCH1-bound enhancer. SIRT1 loss impaired leukemia generation, whereas SIRT1 overexpression accelerated leukemia and conferred resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, pharmacologic or genetic inhibition of SIRT1 resulted in significant antileukemic effects. Global acetyl proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene-expression profiling revealed metabolic changes together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a nonacetylatable KAT7-mutant partly rescued SIRT1 loss-induced proliferation defects. Overall, our results uncover therapeutic targets in T-ALL and reveal a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.

Significance:
We identify a T-ALL axis whereby NOTCH1 activates SIRT1 through an enhancer region, and SIRT1 deacetylates and activates KAT7. Targeting SIRT1 shows antileukemic effects, partly mediated by KAT7 inactivation. Our results reveal T-ALL therapeutic targets and uncover a rheostat mechanism between deacetylase/acetyltransferase activities with potentially broader cancer relevance.
This article is highlighted in the In This Issue feature, p. 1
2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines
Authors: Isselbacher Eric M. , Preventza Ourania , Hamilton Black James , Augoustides John G. , Beck Adam W. , Bolen Michael A. , Braverman Alan C. , Bray Bruce E. , Brown-Zimmerman Maya M. , Chen Edward P. , Collins Tyrone J. , DeAnda Abe , Fanola Christina L. , Girardi Leonard N. , Hicks Caitlin W. , Hui Dawn S. , Schuyler Jones William , Kalahasti Vidyasagar , Kim Karen M. , Milewicz Dianna M. , Oderich Gustavo S. , Ogbechie Laura , Promes Susan B. , Gyang Ross Elsie , Schermerhorn Marc L. , Singleton Times Sabrina , Tseng Elaine E. , Wang Grace J. , Woo Y. Joseph , Faxon David P. , Upchurch Gilbert R. , Aday Aaron W. , Azizzadeh Ali , Boisen Michael , Hawkins Beau , Kramer Christopher M. , Luc Jessica G.Y. , MacGillivray Thomas E. , Malaisrie S. Christopher , Osteen Kathryn , Patel Himanshu J. , Patel Parag J. , Popescu Wanda M. , Rodriguez Evelio , Sorber Rebecca , Tsao Philip S. , Santos Volgman Annabelle 
Published: November 2022

Aim:
The “2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease” provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes).

Methods:
A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate.

Structure:
Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.
The
FES
Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis
Authors: Karamanavi Elisavet , McVey David G. , van der Laan Sander W. , Stanczyk Paulina J. , Morris Gavin E. , Wang Yifan , Yang Wei , Chan Kenneth , Poston Robin N. , Luo Jun , Zhou Xinmiao , Gong Peng , Jones Peter D. , Cao Junjun , Kostogrys Renata B. , Webb Tom R. , Pasterkamp Gerard , Yu Haojie , Xiao Qingzhong , Greer Peter A. , Stringer Emma J. , Samani Nilesh J. , Ye Shu 
Published: November 2022

Background:

Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the
FES
(FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis.

Methods and Results:

Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed
FES
were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed
FES
. There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that
Fes
knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet.

Conclusions:
We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.