bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion
Authors: Bishop Michael R. , Maziarz Richard T. , Waller Edmund K. , Jäger Ulrich , Westin Jason R. , McGuirk Joseph P. , Fleury Isabelle , Holte Harald , Borchmann Peter , del Corral Christopher , Tiwari Ranjan , Anak Özlem , Awasthi Rakesh , Pacaud Lida , Romanov Vadim V. , Schuster Stephen J. 
Published: July 2019

Abstract
Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free &gt;12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient required tocilizumab or steroids for CRS management. These data provide preliminary evidence of tisagenlecleucel efficacy in patients with r/r DLBCL without detectable disease after bridging or salvage therapies and warrant further investigation of tisagenlecleucel as consolidative therapy in future trials. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
Unstable control of breathing can lead to ineffective noninvasive ventilation in amyotrophic lateral sclerosis
Authors: Sancho Jesús , Burés Enric , Ferrer Santos , Ferrando Ana , Bañuls Pilar , Servera Emilio 
Published: July 2019

Upper airway obstruction with decreased central drive (ODCD) is one of the causes of ineffective noninvasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). The aim of this study is to determine the mechanism responsible for ODCD in ALS patients using NIV.This is a prospective study that included ALS patients with home NIV. Severity of bulbar dysfunction was assessed with the Norris scale bulbar subscore; data on upper or lower bulbar motor neuron predominant dysfunction on physical examination were collected. Polysomnography was performed on every patient while using NIV and the ODCD index (ODCDI: number of ODCD events/total sleep time) was calculated. To determine the possible central origin of ODCD, controller gain was measured by inducing a hypocapnic hyperventilation apnoea. Sonography of the upper airway during NIV was performed to determine the location of the ODCD.30 patients were enrolled; three (10%) had ODCDI >5 h−1. The vast majority of ODCD events were produced during non-rapid eye movement sleep stages and were a consequence of an adduction of the vocal folds. Patients with ODCDI >5 h−1had upper motor neuron predominant dysfunction at the bulbar level, and had greater controller gain (1.97±0.33versus0.91±0.36 L·min−1·mmHg−1; p<0.001) and lower carbon dioxide (CO2) reserve (4.00±0.00versus10.37±5.13 mmHg; p=0.043). ODCDI was correlated with the severity of bulbar dysfunction (r= −0.37; p=0.044), controller gain (r=0.59; p=0.001) and CO2reserve (r= −0.35; p=0.037).ODCD events in ALS patients using NIV have a central origin, and are associated with instability in the control of breathing and an upper motor neuron predominant dysfunction at the bulbar level.
Reducing the frequency of respiratory tract infections in severe neurological disorders by inhaled antibiotics: a retrospective data analysis
Authors: Eckerland Maximilian , Bock Claudia , Olivier Margarete , Pichlmaier Leopold , Steindor Mathis , Stehling Florian 
Published: July 2019

BackgroundIn patients with severe neurological impairment, recurrent respiratory tract infections frequently occur as a result of impaired clearance of airway secretions and microbial airway colonisation. We hypothesised that inhaled antibiotic therapy may improve the morbidity of these patients.MethodsA retrospective data analysis of 20 patients (11 nontracheotomised and nine tracheotomised) with neurological impairment and microbial airway colonisation was carried out at a children's university hospital. Two questionnaires that asked about the number of respiratory tract infections, antibiotic therapies and hospitalisations were distributed to the patients/caregivers: a first questionnaire representing the 12 months prior to the initiation of inhaled antibiotics and a second questionnaire describing the first 12 months under therapy.ResultsDuring the first 12 months of therapy, the frequency of respiratory tract infections among all participants was reduced from a mean of 6.8 episodes (median (interquartile range (IQR)) 6.0 (4.0–10.0) episodes) to a mean of 2.5 episodes (median (IQR) 2.0 (1.0–3.0) episodes; p<0.001). In addition, a significant decrease of systemic antibiotic therapies (mean 7.7, median (IQR) 6.0 (4.0–10.0)versus2.5, 2.5 (0.0–3.75) episodes; p<0.001) and hospitalisations (mean 3.9, median (IQR) 3.5 (1.0–5.0)versus0.9, 0.0 (0.0–1.0) episodes; p<0.001) was noted. This significant therapeutic effect could be demonstrated in a subgroup analysis in both tracheotomised and nontracheotomised subjects. The reduction of respiratory tract infections and systemic antibiotic therapies (and thus the therapeutic success) was significantly greater in the nontracheotomised group compared with the tracheotomised group.ConclusionsThe presented data suggest that inhaled antibiotics might play a role in treating recurrent respiratory tract infections in neuromuscular diseases.
ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer
Authors: Armstrong Andrew J. , Szmulewitz Russell Z. , Petrylak Daniel P. , Holzbeierlein Jeffrey , Villers Arnauld , Azad Arun , Alcaraz Antonio , Alekseev Boris , Iguchi Taro , Shore Neal D. , Rosbrook Brad , Sugg Jennifer , Baron Benoit , Chen Lucy , Stenzl Arnulf 
Published: July 2019

PURPOSE Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). METHODS ARCHES (ClinicalTrials.gov identifier: NCT02677896 ) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival. RESULTS As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT ( P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events. CONCLUSION Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.
Model systems for regeneration: salamanders
Authors: Joven Alberto , Elewa Ahmed , Simon András 
Published: July 2019

ABSTRACT
Salamanders have been hailed as champions of regeneration, exhibiting a remarkable ability to regrow tissues, organs and even whole body parts, e.g. their limbs. As such, salamanders have provided key insights into the mechanisms by which cells, tissues and organs sense and regenerate missing or damaged parts. In this Primer, we cover the evolutionary context in which salamanders emerged. We outline the varieties of mechanisms deployed during salamander regeneration, and discuss how these mechanisms are currently being explored and how they have advanced our understanding of animal regeneration. We also present arguments about why it is important to study closely related species in regeneration research.
Sirtuin 7 promotes 45S pre-rRNA cleavage at site 2 and determines the processing pathway
Authors: Sirri Valentina , Grob Alice , Berthelet Jérémy , Jourdan Nathalie , Roussel Pascal 
Published: July 2019

ABSTRACT
In humans, ribosome biogenesis mainly occurs in nucleoli following two alternative pre-rRNA processing pathways differing in the order in which cleavages take place but not by the sites of cleavage. To uncover the role of the nucleolar NAD+-dependent deacetylase sirtuin 7 in the synthesis of ribosomal subunits, pre-rRNA processing was analyzed after sirtinol-mediated inhibition of sirtuin 7 activity or depletion of sirtuin 7 protein. We thus reveal that sirtuin 7 activity is a critical regulator of processing of 45S, 32S and 30S pre-rRNAs. Sirtuin 7 protein is primarily essential to 45S pre-rRNA cleavage at site 2, which is the first step of processing pathway 2. Furthermore, we demonstrate that sirtuin 7 physically interacts with Nop56 and the GAR domain of fibrillarin, and propose that this could interfere with fibrillarin-dependent cleavage. Sirtuin 7 depletion results in the accumulation of 5′ extended forms of 32S pre-rRNA, and also influences the localization of fibrillarin. Thus, we establish a close relationship between sirtuin 7 and fibrillarin, which might determine the processing pathway used for ribosome biogenesis.
Colocation of Tpm3.1 and myosin IIa heads defines a discrete subdomain in stress fibres
Authors: Meiring Joyce C. M. , Bryce Nicole S. , Lastra Cagigas Maria , Benda Aleš , Whan Renee M. , Ariotti Nicholas , Parton Robert G. , Stear Jeffrey H. , Hardeman Edna C. , Gunning Peter W. 
Published: July 2019

ABSTRACT
Co-polymers of tropomyosin and actin make up a major fraction of the actin cytoskeleton. Tropomyosin isoforms determine the function of an actin filament by selectively enhancing or inhibiting the association of other actin binding proteins, altering the stability of an actin filament and regulating myosin activity in an isoform-specific manner. Previous work has implicated specific roles for at least five different tropomyosin isoforms in stress fibres, as depletion of any of these five isoforms results in a loss of stress fibres. Despite this, most models of stress fibres continue to exclude tropomyosins. In this study, we investigate tropomyosin organisation in stress fibres by using super-resolution light microscopy and electron microscopy with genetically tagged, endogenous tropomyosin. We show that tropomyosin isoforms are organised in subdomains within the overall domain of stress fibres. The isoforms Tpm3.1 and 3.2 (hereafter Tpm3.1/3.2, encoded by TPM3) colocalise with non-muscle myosin IIa and IIb heads, and are in register, but do not overlap, with non-muscle myosin IIa and IIb tails. Furthermore, perturbation of Tpm3.1/3.2 results in decreased myosin IIa in stress fibres, which is consistent with a role for Tpm3.1 in maintaining myosin IIa localisation in stress fibres.
Depletion of phosphatidylinositol 4-phosphate at the Golgi translocates K-Ras to mitochondria
Authors: Miller Taylor E. , Henkels Karen M. , Huddleston Mary , Salisbury Richard , Hussain Saber M. , Sasaki Atsuo T. , Cho Kwang-Jin 
Published: July 2019

ABSTRACT
Ras proteins are small GTPases localized to the plasma membrane (PM), which regulate cellular proliferation, apoptosis and differentiation. After a series of post-translational modifications, H-Ras and N-Ras traffic to the PM from the Golgi via the classical exocytic pathway, but the exact mechanism of K-Ras trafficking to the PM from the ER is not fully characterized. ATP5G1 (also known as ATP5MC1) is one of the three proteins that comprise subunit c of the F0 complex of the mitochondrial ATP synthase. In this study, we show that overexpression of the mitochondrial targeting sequence of ATP5G1 perturbs glucose metabolism, inhibits oncogenic K-Ras signaling, and redistributes phosphatidylserine (PtdSer) to mitochondria and other endomembranes, resulting in K-Ras translocation to mitochondria. Also, it depletes phosphatidylinositol 4-phosphate (PI4P) at the Golgi. Glucose supplementation restores PtdSer and K-Ras PM localization and PI4P at the Golgi. We further show that inhibition of the Golgi-localized PI4-kinases (PI4Ks) translocates K-Ras, and PtdSer to mitochondria and endomembranes, respectively. We conclude that PI4P at the Golgi regulates the PM localization of PtdSer and K-Ras.
This article has an associated First Person interview with the first author of the paper.
Dissection of GTPase-activating proteins reveals functional asymmetry in the COPI coat of budding yeast
Authors: Arakel Eric C. , Huranova Martina , Estrada Alejandro F. , Rau E-Ming , Spang Anne , Schwappach Blanche 
Published: July 2019

ABSTRACT
The Arf GTPase controls formation of the COPI vesicle coat. Recent structural models of COPI revealed the positioning of two Arf1 molecules in contrasting molecular environments. Each of these pockets for Arf1 is expected to also accommodate an Arf GTPase-activating protein (ArfGAP). Structural evidence and protein interactions observed between isolated domains indirectly suggest that each niche preferentially recruits one of the two ArfGAPs known to affect COPI, i.e. Gcs1/ArfGAP1 and Glo3/ArfGAP2/3, although only partial structures are available. The functional role of the unique non-catalytic domain of either ArfGAP has not been integrated into the current COPI structural model. Here, we delineate key differences in the consequences of triggering GTP hydrolysis through the activity of one versus the other ArfGAP. We demonstrate that Glo3/ArfGAP2/3 specifically triggers Arf1 GTP hydrolysis impinging on the stability of the COPI coat. We show that the Snf1 kinase complex, the yeast homologue of AMP-activated protein kinase (AMPK), phosphorylates the region of Glo3 that is crucial for this effect and, thereby, regulates its function in the COPI-vesicle cycle. Our results revise the model of ArfGAP function in the molecular context of COPI.
This article has an associated First Person interview with the first author of the paper.
Protective and curative effects of Beta vulgaris on dimethyl 2,2-dichlorovinyl phosphate-exposed albino rats
Authors: Nwaichi Eucharia O. , Essien Eka B. , Ibe Uzoamaka Chinonso 
Published: July 2019

Background: This study evaluated the effect of Beta vulgaris (beetroot) smoothie on some biochemical parameters on dimethyl 2,2-dichlorovinyl phosphate (DDVP, known as dichlorvos)-exposed albino Wistar rats. Methods: A total of 30 rats of both sexes were grouped into five groups of six animals each. Group I served as the negative control and were not exposed to dichlorvos. Group II served as the positive control and were exposed to dichlorvos but received no smoothie. Group III received 500 mg/kg body weight beetroot smoothie and was not exposed to dichlorvos. Groups IV and V were exposed to dichlorvos but received beetroot before and after exposure, respectively. At the end of the 6-week experiment, the animals were euthanized, the blood samples collected for some biochemical assays while the organs (kidney and liver) were harvested and subjected to histopathological examination. Results: From the biochemical assay, it was observed that the beetroot smoothies regulated and significantly reduced the elevated levels of AST, ALT, urea and creatinine observed in the animals that were exposed to dichlorvos. Additionally, the beetroot was able to regenerate the liver and kidney organs that were damaged on exposure to dichlorvos. Conclusion: This study concluded that beetroot smoothie possesses hepato-protective, hepato-curative as well as nephro-curative properties.
Evaluation of benefits and harms of surgical treatments for post-radical prostatectomy urinary incontinence: a systematic review and meta-analysis protocol
Authors: Choiniere Roselyne , Richard Patrick O. , Morin Melanie , Tu Le-Mai , Guyatt Gordon H. , Violette Philippe D. 
Published: July 2019

Background: Post-radical prostatectomy urinary incontinence (PPI) is a frequent and feared complication that can affect approximately 25% of patients. Between 1 and 10% of patients suffering from PPI will require surgery. The effectiveness of the available surgical interventions has only been compared in a few randomized controlled trials and the available reviews have important limitations regarding both benefits and harms that make them insufficient to inform decision-making. The aim of the study is to provide systematic summaries of benefits and harms of contemporary surgical treatment options for PPI through systematic review and meta-analysis using GRADE methodology and reporting in accord with the PRISMA-P statement. Methods: Studies pertaining to bulking agents, male synthetic slings, compressive balloon systems (ProACT) or artificial urinary sphincters (AUS) used for the treatment of patients suffering from PPI will be included. A systematic search will be conducted using the OVID and PubMED platforms in MEDLINE, Embase and Cochrane databases, and reference lists of relevant reviews and guidelines. Trained independent reviewers will conduct study selection and data extraction. Outcomes will include the number of pads used per day, the 24-h pad weight test, the Patient Global Impression of Improvement (PGI-I) and the Incontinence Quality of Life (IQOL) as possible benefits and the reoperations, the Clavien-Dindo complications and the other reported adverse events as the harms. When possible, pooled analyses will be completed. Risk of bias will be assessed using the CLARITY tools and a new tool for the before-and-after studies without a control group. Finally, study heterogeneity will be assessed, publication bias will be evaluated with funnel plots and quality of evidence rated for each outcome. Discussion: Our study will address patient-important outcomes and will be useful in clinical decision-making as well as identifying key elements for future research. Study registration: PROSPERO: CRD42018073923 05/12/2018
Case Report: Don’t chew the fufu: a case report of suspected drug bodystuffing
Authors: Jimenez Naya , Tran Nguyen Toan , Poletti Pierre-Alexandre , Platon Alexandra , Meach Francesco , Juillerat André , Getaz Laurent , Wolff Hans 
Published: July 2019

Background: Intrabody concealment of illicit substances is a common practice in the trafficking chain. Bodystuffing, which consists of precipitously swallowing packets of substances for concealment from law-enforcement officers in anticipation of impending search or arrest, is particularly dangerous. There is a risk of rupture of the loosely wrapped drug packets, which could lead to substance intoxication or even death. Case presentation: This article reports the case of a young man who was taken by law enforcement authorities to our Emergency Department for investigation of bodystuffing. Although the patient denied the facts, the initial reading of the computed tomography (CT) scan confirmed the presence of multiple images compatible with drug packets, which were mostly in the stomach. Upon admission to our secured inpatient ward for clinical surveillance of packet evacuation, the patient denied again having ingested such packets, and declared that he only ate ‘fufu’. Fufu is a traditional food of central and western Africa consisting of a starchy preparation compacted by hand into small balls. Fufu balls are usually swallowed without chewing to allow a sensation of stomach fullness throughout the day. Considering the fufu intake history, a careful reassessment of the imaging confirmed the presence of food content. Conclusions: This case study offers an example of bodystuffing false positive due to fufu. It illustrates the importance of a history of food intake that could bias the interpretation of CT scan images.
The negative health effects of hostile environment policies on migrants: A cross-sectional service evaluation of humanitarian healthcare provision in the UK
Authors: Weller Sophie J. , Crosby Liam J. , Turnbull Eleanor R. , Burns Rachel , Miller Anna , Jones Lucy , Aldridge Robert W. 
Published: July 2019

Background: Recent UK ‘hostile environment’ immigration policies, including obligatory charging and sharing of confidential data between NHS Digital and the Home Office, have created an atmosphere of fear and exposed already highly marginalised and vulnerable groups to significant health risks by increasing barriers to accessing NHS care. Methods: This is a cross-sectional observational study of patients accessing healthcare at Doctors of the World (DOTW) in the UK. DOTW is a humanitarian organisation, providing care to those excluded from NHS healthcare. We aimed to describe population characteristics of individuals using DOTW services and identify groups at greatest risk of facing ‘hostile environment’-related barriers to NHS care, specifically being denied healthcare or fear of arrest. Results: A total of 1474 adults were seen in 2016. Nearly all were non-EU/EEA nationals (97.8%; 1441/1474), living in poverty (68.6%; 1011/1474). DOTW saw a large number of undocumented migrants (57.1%; 841/1474) and asylum seekers (18.2%; 268/1474). 10.2% (151/1474) of adults seen had been denied NHS healthcare and 7.7% (114/1474) were afraid to access NHS services. Asylum seeker status was associated with the highest risk (adjusted odds ratio (OR): 2.48; 95% confidence interval (CI): 1.48-4.14) of being denied NHS healthcare and being undocumented was associated with the highest risk of fearing arrest (adjusted OR: 3.03; 95% CI: 1.70-5.40). Conclusions: Our findings make visible the multiple and intersecting vulnerabilities of individuals forced to seek care outside of the NHS, underlining the public health imperative for the government to urgently withdraw its ‘hostile environment’ policies and address their negative health impacts.