bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for a feasibility randomised controlled trial of a musculoskeletal exercise intervention versus usual care for children with haemophilia
Authors: Hashem Ferhana , Bladen Melanie , Carroll Liz , Dodd Charlene , Drechsler Wendy I , Lowery David , Patel Vishal , Pellatt-Higgins T , Saloniki Eirini , Stephensen David 
Published: August 2019

IntroductionHaemophilia is a rare, inherited disorder in which blood does not clot normally, resulting in bleeding into joints and muscles. Long-term consequence is disabling joint pain, stiffness, muscle weakness, atrophy and reduced mobility. The purpose of this proposed feasibility of a randomised controlled trial (RCT) is to test the feasibility of an age-appropriate physiotherapy intervention designed to improve muscle strength, posture and the way boys use their joints during walking and everyday activities.Methods and analysisA small-scale two-centre RCT of a 12-week muscle strengthening exercise intervention versus usual care for young children with haemophilia will be conducted. Primary outcomes will be safety and adherence to the exercise intervention. Secondary outcomes will include recruitment, retention and adverse event rates, clinical data, muscle strength, joint biomechanics and foot loading patterns during walking, 6 min timed walk, timed-up-and-down-stairs, EQ-5D-Y, participants’ perceptions of the study, training requirements and relevant costs. Recruitment, follow-up, safety and adherence rates will be described as percentages. Participant diary and interview data will be analysed using a framework analysis. Demographic and disease variable distributions will be analysed for descriptive purposes and covariant analysis. Estimates of differences between treatment arms (adjusted for baseline) and 75% and 95% CIs will be calculated.Ethics and disseminationThe study has ethical approval from the London—Fulham Research Ethics Committee (17/LO/2043) as well as Health Research Authority approval. As well as informing the design of the definitive trial, results of this study will be presented at local, national and international physiotherapy and haemophilia meetings as well as manuscripts submitted to peer-reviewed journals. We will also share the main findings of the study to all participants and the Haemophilia Society.
Optimized protocols for isolation, fixation, and flow cytometric characterization of leukocytes in ischemic hearts
Authors: Covarrubias Roman , Ismahil Mohamed Ameen , Rokosh Gregg , Hamid Tariq , Accornero Federica , Singh Harpreet , Gumina Richard J. , Prabhu Sumanth D. , Bansal Shyam S. 
Published: August 2019

Immune activation post-myocardial infarction is an orchestrated sequence of cellular responses to effect tissue repair and healing. However, excessive and dysregulated inflammation can result in left ventricular remodeling and pathological alterations in the structural and mechanical attributes of the heart. Identification of key pathways and critical cellular mediators of inflammation is thus essential to design immunomodulatory therapies for myocardial infarction and ischemic heart failure. Despite this, the experimental approaches to isolate mononuclear cells from the heart are diverse, and detailed protocols to enable maximum yield of live cells in the shortest time possible are not readily available. Here, we describe optimized protocols for the isolation, fixation, and flow cytometric characterization of cardiac CD45+leukocytes. These protocols circumvent time-consuming coronary perfusion and density-mediated cell-separation steps, resulting in high cellular yields from cardiac digests devoid of contaminating intravascular cells. Moreover, in contrast to methanol and acetone, we show that cell fixation using 1% paraformaldehyde is most optimal as it does not affect antibody binding or cellular morphology, thereby providing a considerable advantage to study activation/infiltration-associated changes in cellular granularity and size. These are highly versatile methods that can easily be streamlined for studies requiring simultaneous isolation of immune cells from different tissues or deployment in studies containing a large cohort of samples with time-sensitive constraints.NEW & NOTEWORTHY In this article, we describe optimized protocols for the isolation, fixation, and flow cytometric analysis of immune cells from the ischemic/nonischemic hearts. These protocols are optimized to process several samples/tissues, simultaneously enabling maximal yield of immune cells in the shortest time possible. We show that the low-speed centrifugation can be used as an effective alternative to lengthy coronary perfusion to remove intravascular cells, and sieving through 40-μm filter can replace density-mediated mononuclear cell separation which usually results in 50–70% cell loss in the sedimented pellets. We also show that cell fixation using 1% paraformaldehyde is better than the organic solvents such as methanol and acetone for flow cytometric analysis.
A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors
Authors: Aloia Andrea , Müllhaupt Daniela , Chabbert Christophe D. , Eberhart Tanja , Flückiger-Mangual Stefanie , Vukolic Ana , Eichhoff Ossia , Irmisch Anja , Alexander Leila T. , Scibona Ernesto , Frederick Dennie T. , Miao Benchun , Tian Tian , Cheng Chaoran , Kwong Lawrence N. , Wei Zhi , Sullivan Ryan J. , Boland Genevieve M. , Herlyn Meenhard , Flaherty Keith T. , Zamboni Nicola , Dummer Reinhard , Zhang Gao , Levesque Mitchell P. , Krek Wilhelm , Kovacs Werner J. 
Published: August 2019

Abstract

Purpose:
Treatment of BRAFV600E-mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi.

Experimental Design:
By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor specimens.

Results:
Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARα-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E-mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo.

Conclusions:
Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E-mutant melanoma.
Tumor Growth Rate as a Validated Early Radiological Biomarker Able to Reflect Treatment-Induced Changes in Neuroendocrine Tumors: The GREPONET-2 Study
Authors: Lamarca Angela , Ronot Maxime , Moalla Salma , Crona Joakim , Opalinska Marta , Lopez Lopez Carlos , Pezzutti Daniela , Najran Pavan , Carvhalo Luciana , Bezerra Regis Otaviano Franca , Borg Philip , Vietti Violi Naik , Vidal Trueba Hector , de Mestier Louis , Scaefer Niklaus , Baudin Eric , Sundin Anders , Costa Frederico , Pavel Marianne , Dromain Clarisse 
Published: August 2019

Abstract

Purpose:
Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET).

Experimental Design:
Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3(±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL; paired T test), and Aim-2: validate TGR3m (&lt;0.8%/m vs. ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan–Meier/Cox regression).

Results:
Of 785 patients screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and −1.4%/m (11.8), respectively. Mean (SD) ΔTGR3m-BL paired-difference was −6.8%/m (19.3; P &lt; 0.001). Most marked ΔTGR3m-BL [mean (SD)] were identified with targeted therapies [−11.3%/m (4.7); P = 0.0237] and chemotherapy [−7.9%/m (3.4); P = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31–16.52; P = 0.018) and low TGR3m (continuous variable; OR 1.09; 95% CI, 1.01–1.19; P = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade (P = 0.004) and stage (P = 0.017), TGR3m ≥ 0.8 (vs. &lt;0.8) maintained its significance as a prognostic factor (P &lt; 0.001), whereas TGR0 and ΔTGR3m-BL did not. TGR3m ≥ 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21–3.70; P = 0.003)].

Conclusions:
TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response.
Antitumor T-cell Homeostatic Activation Is Uncoupled from Homeostatic Inhibition by Checkpoint Blockade
Authors: Marshall Netonia , Hutchinson Keino , Marron Thomas U. , Aleynick Mark , Hammerich Linda , Upadhyay Ranjan , Svensson-Arvelund Judit , Brown Brian D. , Merad Miriam , Brody Joshua D. 
Published: August 2019

Abstract

T-cell transfer into lymphodepleted recipients induces homeostatic activation and potentiates antitumor efficacy. In contrast to canonical T-cell receptor–induced activation, homeostatic activation yields a distinct phenotype and memory state whose regulatory mechanisms are poorly understood. Here, we show in patients and murine models that, following transfer into lymphodepleted bone marrow transplant (BMT) recipients, CD8+ T cells undergo activation but also simultaneous homeostatic inhibition manifested by upregulation of immune-checkpoint molecules and functional suppression. T cells transferred into BMT recipients were protected from homeostatic inhibition by PD-1/CTLA4 dual checkpoint blockade (dCB). This combination of dCB and BMT—”immunotransplant”—increased T-cell homeostatic activation and antitumor T-cell responses by an order of magnitude. Like homeostatic activation, homeostatic inhibition is IL7/IL15-dependent, revealing mechanistic coupling of these two processes. Marked similarity in ex vivo modulation of post-BMT T cells in mice and patients is promising for the clinical translation of immunotransplant (NCT03305445) and for addressing homeostatic inhibition in T-cell therapies.

Significance:
For optimal anticancer effect, T-cell therapies including chimeric antigen receptor T-cell, tumor-infiltrating lymphocyte, and transgenic T-cell therapies require transfer into lymphodepleted recipients and homeostatic activation; however, concomitant homeostatic inhibition mitigates T-cell therapies' efficacy. Checkpoint blockade uncouples homeostatic inhibition from activation, amplifying T-cell responses. Conversely, tumors nonresponsive to checkpoint blockade or BMT are treatable with immunotransplant.
See related commentary by Ansell, p. 1487.
This article is highlighted in the In This Issue feature, p. 1469
POUR LA TRADUCTION
Authors: Riaudel Michel 
Published: August 2019

Dans le présent exposé, nous traiterons des voies possibles que nous offre la traduction : parler dans sa langue, dans la langue de l’autre ; parler dans ma langue ; adopter une langue tierce, une sorte de lingua franca. Comprendre la langue de l’autre ne peut nous dispenser de traduire, c’est-à-dire d’acclimater, de s’approprier, mais de mobiliser et de confronter des épistémologies, faire jouer des mondes entre eux et contre eux. Pour ce faire, nous convoquerons, d’un côté, l’anthropologie d’Eduardo Viveiros de Castro et le concept de « transduction » et, de l’autre, Antoine Berman et le lien entre le travail critique d’interprétation et la traduction.
EROS E A GRÉCIA NO CORAÇÃO DE TRÊS CONTOS DE MARGUERITE YOURCENAR
Authors: Chauvel Thaïs 
Published: August 2019

Este artigo propõe analisar o tratamento da temática eróticoamorosa nas seguintes nouvelles de Marguerite Yourcenar: “Le sourire de Marko”, “Le dernier amour du prince Genghi” e “La veuve Aphrodissia”. Escritas e publicadas originalmente de forma separada, em 1938 essas narrativas foram reunidas numa antologia organizada pela autora e intitulada Nouvelles Orientales. Trata-se de uma de suas obras de juventude na qual eros é um dos temas principais. O objetivo desse estudo é mostrar de que maneira a paixão e o amor retratados por Yourcenar nestes textos dialoga intimamente com representação de eros na poesia grega arcaica, notadamente com a lírica de Safo, no intuito de verificar o modo como a escritora apropria-se, em pleno século XX, de uma representação clássica do amor, legitimando, assim, o tratamento da paixão e do amor carnal.
The Badoh-Pathari Saptamātṛ Panel Inscription
Authors: Balogh Dániel 
Published: August 2019

Abstract
Located in Vidisha District, Madhya Pradesh, the area of Badoh-Pathari is home to a rock shelter with a sculpted panel depicting seven mother goddesses. A weathered inscription next to the sculptures was reported as early as 1926. The inscription is dateable to the fifth century on the basis of its palaeography and the art-historical dating of the site. Though partly effaced beyond hope of decipherment, roughly half of the text can be read with confidence, while some of the rest may be restored conjecturally, and some speculatively. The epigraph pays homage to Rudra and Skanda in addition to the Mothers themselves, and is thus a key resource concerning mātṛ worship in the Gupta period. It mentions the otherwise unknown local ruler Jayatsena of Avamukta (a region also named in the Allahabad pillar inscription), and may refer to the reign of Kumāragupta (I).
Alpheus perlas, sp. nov., a new infaunal snapping shrimp from the Pacific coast of Panama (Malacostraca: Decapoda: Alpheidae)
Authors: ANKER ARTHUR , PACHELLE PAULO P.G. 
Published: August 2019

A new snapping shrimp, Alpheus perlas sp. nov., is described based on a single complete male specimen collected on a shallow mudflat at Casayeta Island in the Las Perlas Archipelago, Gulf of Panama. The new species belongs to the large A. edwardsii (Audouin, 1821) species group characterised essentially by the presence of two notches on the major chela palm, with the dorsal notch extending posteriorly on the mesial surface. Within the eastern Pacific members of the A. edwardsii group, A. perlas sp. nov. appears to be morphologically closest to A. latus Kim & Abele, 1988 and A. burukovskyi Anker & Pachelle, 2015. Alpheus perlas sp. nov. does not seem to be specially adapted for digging and may be inquiline of a larger burrowing host, which currently remains unknown.
Professional liability and patient safety in thromboembolic disease
Authors: Oller-Grau Mar , Gómez-Durán Esperanza L , Martin-Fumadó Carles , Roche Enric , Arimany-Manso Josep 
Published: August 2019

Objectives As a potentially preventable severe event, venous thromboembolism can lead to malpractice claims. We aim to identify characteristics of claimed events and to assess possible association between guidelines compliance and professional liability. Methods We analyzed every claim of alleged medical negligence following venous thromboembolism registered at the Catalan Council of Medical Colleges from 1986 to 2014. Results A total of 100 claims related to venous thromboembolism were identified. In 24 cases, out of 95 closed-claims, medical professional liability was the outcome. The specialty with more complaints was Orthopaedic Surgery. In 43 cases, venous thromboembolism occurred in low-risk patients with no prophylaxis prescribed. Professionals’ conduct followed the official guidelines in 73 cases but still 11 of them ended up in professional liability. Nevertheless, liability outcome was significantly associated with non-compliance of guidelines, as well as the absence of a prophylaxis ( p < 0.001). Conclusions Guidelines should be considered not only a patient safety measure but also a relevant issue towards determining the standard of care required in law. However, guidelines compliance does not qualify automatically as an affirmative defense in claims. It is individualized prophylaxis and protocols compliance that makes clinical practice safe and at the same time avoids medical professional liability.
Feasibility, acceptability and potential effectiveness of an occupation-focused cognitive self-management program for breast cancer survivors
Authors: Newman Robin , Lyons Kathleen Doyle , Coster Wendy J , Wong Jasin , Festa Kate , Ko Naomi Y 
Published: August 2019

Introduction The purpose of this research was to assess the feasibility, acceptability and potential effectiveness of a program to support the occupational performance of urban breast cancer survivors living with cancer-related cognitive impairment. Method Participants ( n = 15) reporting cognitive changes following breast cancer treatment were enrolled in an occupation-focused self-management program. Occupational performance challenges, activity level, subjective cognitive function and quality of life were measured at the beginning, end and 3 months after completion of the program. Results Participants reported high satisfaction with the program and high confidence in their problem-solving and goal-setting skills. The 11 participants who completed the post-program assessment showed significant increases in self-perceived performance and satisfaction in daily living, participation, physical and functional wellbeing and perceived cognitive impairment. Conclusion The program was feasible for a vulnerable, socio-economically diverse patient population, acceptable to participants and may have positive effects on occupational performance.
Current understanding of pineal gland structure and function in headache
Authors: Peres Mario FP , Valença Marcelo M , Amaral Fernanda G , Cipolla-Neto José 
Published: August 2019

Purpose The pineal gland plays an important role in biological rhythms, circadian and circannual variations, which are key aspects in several headache disorders. Overview Melatonin, the main pineal secreting hormone, has been extensively studied in primary and secondary headache disorders. Altered melatonin secretion occurs in many headache syndromes. Experimental data show pineal gland and melatonin both interfere in headache animal models, decreasing trigeminal activation. Melatonin has been shown to regulate CGRP and control its release. Discussion Melatonin has been used successfully as a treatment for migraine, cluster headaches and other headaches. There is a rationale for including the pineal gland as a relevant brain structure in the mechanisms of headache pathophysiology, and melatonin as a treatment option in primary headache.
Comparative Clinical Outcomes After Intra-articular Injection With Adipose-Derived Cultured Stem Cells or Noncultured Stromal Vascular Fraction for the Treatment of Knee Osteoarthritis
Authors: Yokota Naomasa , Hattori Mari , Ohtsuru Tadahiko , Otsuji Masaki , Lyman Stephen , Shimomura Kazunori , Nakamura Norimasa 
Published: August 2019

Background: Intra-articular injection of adipose-derived stem cells (ASCs) has shown promise for improving symptoms and cartilage quality in the treatment of osteoarthritis (OA). However, while most preclinical studies have been performed with plastic-adherent ASCs, most clinical trials are being conducted with the stromal vascular fraction (SVF), prepared from adipose tissue without prior culture. Purpose: To directly compare clinical outcomes of intra-articular injection with ASCs or SVF in patients with knee OA. Study Design: Cohort study; Level of evidence, 3. Methods: The authors retrospectively compared 6-month outcomes in 42 patients (59 knees) receiving intra-articular injection with 12.75 million ASCs and 38 patients (69 knees) receiving a 5-mL preparation of SVF. All patients had Kellgren-Lawrence grade 2, 3, or 4 knee OA and had failed standard medical therapy. The visual analog scale (VAS) pain score and Knee injury and Osteoarthritis Outcome Score (KOOS) at baseline and 1, 3, and 6 months after injection were considered as outcomes. Outcome Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) criteria were also used to assess positive response. A repeated measures analysis of variance was used for comparison between the treatment groups. Results: No major complications occurred in either group. The SVF group had a higher frequency of knee effusion (SVF 8%, ASC 2%) and minor complications related to the fat harvest site (SVF 34%, ASC 5%). Both groups reported improvements in pain VAS and KOOS domains. Specifically, in the ASC group, symptoms improved earlier (by 3 months; P < .05) and pain VAS decreased to a greater degree (55%; P < .05) compared with the SVF group (44%). The proportion of OMERACT-OARSI responders in the ASC group was slightly higher (ASCs, 61%; SVF, 55%; P = .25). Conclusion: It was observed that both ASCs and SVF resulted in clinical improvement in patients with knee OA, but that ASCs outperform SVF in the early reduction of symptoms and pain with less comorbidity.