bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-molecule optical mapping enables quantitative measurement of D4Z4 repeats in facioscapulohumeral muscular dystrophy (FSHD)
Authors: Dai Yi , Li Pidong , Wang Zhiqiang , Liang Fan , Yang Fan , Fang Li , Huang Yu , Huang Shangzhi , Zhou Jiapeng , Wang Depeng , Cui Liying , Wang Kai 
Published: September 2019

PurposeFacioscapulohumeral muscular dystrophy (FSHD) is a common adult muscular dystrophy. Over 95% of FSHD cases are associated with contraction of the D4Z4 tandem repeat (~3.3 kb per unit) at 4q35 with a specific genomic configuration (haplotype) called 4qA. Molecular diagnosis of FSHD typically requires pulsed-field gel electrophoresis with Southern blotting. We aim to develop novel genomic and computational methods for characterising D4Z4 repeat numbers in FSHD.MethodsWe leveraged a single-molecule optical mapping platform that maps locations of restriction enzyme sites on high molecular weight (>150 kb) DNA molecules. We developed bioinformatics methods to address several challenges, including the differentiation of 4qA with 4qB alleles, the differentiation of 4q35 and 10q26 segmental duplications, the quantification of repeat numbers with different enzymes that may or may not have recognition sites within D4Z4 repeats. We evaluated the method on 25 human subjects (13 patients, 3 individual control subjects, 9 control subjects from 3 families) labelled by the Nb.BssSI and/or Nt.BspQI enzymes.ResultsWe demonstrated that the method gave a direct quantitative measurement of repeat numbers on D4Z4 repeats with 4qA allelic configuration and the levels of postzygotic mosaicism. Our method had high concordance with Southern blots from several cohorts on two platforms (Bionano Saphyr and Bionano Irys), but with improved quantification of repeat numbers.ConclusionWhile the study is limited by small sample size, our results demonstrated that single-molecule optical mapping is a viable approach for more refined analysis on genotype-phenotype relationships in FSHD, especially when postzygotic mosaicism is present.
Reactions to electronic nicotine delivery system (ENDS) prevention messages: results from qualitative research used to inform FDA’s first youth ENDS prevention campaign
Authors: Roditis Maria L , Dineva Atanaska , Smith Alexandria , Walker Matthew , Delahanty Janine , D'lorio Emily , Holtz Kristen D 
Published: September 2019

BackgroundYouth e-cigarette use is a major public health concern. Large-scale tobacco prevention campaigns are a proven strategy to prevent tobacco use. There is a gap in understanding what types of e-cigarette prevention messages might be most effective. This study addresses this gap by reporting youth reactions to health messages aimed at preventing e-cigarette use.MethodsIn 2018, twenty-four focus groups, with 159 teens (12–17) at risk for or experimenting with e-cigarettes were conducted in four cities across the USA. During focus groups, youth responded to creative concepts dealing with (1) the addictive nature of e-cigarettes, (2) the fact that e-cigarettes come in flavours, which may encourage youth initiation, and nicotine which may lead to addiction, or (3) that youth who use e-cigarettes are more likely to use cigarettes. Youth also gave feedback to specific facts about harmful and potentially harmful chemicals in e-cigarettes. Transcripts were analysed using thematic analysis.ResultsMessages focusing on addiction alone did not resonate with participants. While youth found the idea that e-cigarettes may contain nicotine and can be addictive believable, with many describing personal experiences of addiction, they questioned how bad this really was, comparing addiction to e-cigarettes to things like being addicted to food. Participants wanted more information about negative consequences of vaping. Concepts paired with strong health effects messages resonated with participants.ConclusionThese focus groups clarified which e-cigarette prevention messages might be most persuasive to teens. Youth in this study responded favourably to messages stating specific health consequences of e-cigarette use.
DeepNavi
Authors: Niu Qun , Liu Ning , Huang Jianjun , Luo Yangze , He Suining , He Tao , Chan S.-H. Gary , Luo Xiaonan 
Published: September 2019

Indoor navigation plays a crucial role in indoor location-based services. Single signal-based navigation systems, however, are prone to sensor noises, signal ambiguities and are specific to trial sites. To address these, existing work fuses different signals with user trajectories. Despite their accuracy, many of them are specific to input signals and navigation modes (e.g., spot-based or sequence-based) and are computationally expensive in large sites. Additionally, they do not give predictive uncertainty estimations, leading to a lack of trust in navigation instructions.
In this paper, we propose a unified framework for accurate indoor navigation in various modes with different inputs, termed DeepNavi. We exploit either convolutional or recurrent neural networks for initial feature extraction. Afterwards, we insert fully connected layers to generalize extracted signal-dependent features to a shared domain before fusion. Then, we leverage state-of-the-art ensemble learning to learn multiple predictive models. By combining them together, we further reduce the impact of signal noises and achieve high accuracy. Finally, we insert mixture density networks to model more generalized data distributions and provide uncertainty estimations. We have implemented DeepNavi and conducted extensive experiments in two different trial sites with different signal combinations. Experimental results show that DeepNavi reduces location errors by more than 20% with comparable orientation accuracy.
Oncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4–Induced Metabolic and Oxidative Stress
Authors: Hong Beom-Jin , Park Woo-Yong , Kim Hwa-Ryeon , Moon Jin Woo , Lee Ho Yeon , Park Jun Hyung , Kim Seon-Kyu , Oh Youngbin , Roe Jae-Seok , Kim Mi-Young 
Published: September 2019

Abstract

Genetic and epigenetic changes (e.g., histone methylation) contribute to cancer development and progression, but our understanding of whether and how specific mutations affect a cancer's sensitivity to histone demethylase (KDM) inhibitors is limited. Here, we evaluated the effects of a panel of KDM inhibitors on lung adenocarcinomas (LuAC) with various mutations. Notably, LuAC lines harboring KRAS mutations showed hypersensitivity to the histone H3K27 demethylase inhibitor GSK-J4. Specifically, GSK-J4 treatment of KRAS mutant–containing LuAC downregulated cell-cycle progression genes with increased H3K27me3. In addition, GSK-J4 upregulated expression of genes involved in glutamine/glutamate transport and metabolism. In line with this, GSK-J4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate α-ketoglutarate (αKG) and of the antioxidant glutathione, leading to reduced cell viability. Supplementation with an αKG analogue or glutathione protected KRAS-mutant LuAC cells from GSK-J4–mediated reductions in viability, suggesting GSK-J4 exerts its anticancer effects by inducing metabolic and oxidative stress. Importantly, KRAS knockdown in mutant LuAC lines prevented GSK-J4–induced decrease in glutamate levels and reduced their susceptibility to GSK-J4, whereas overexpression of oncogenic KRAS in wild-type LuAC lines sensitized them to GSK-J4. Collectively, our study uncovers a novel association between a genetic mutation and KDM inhibitor sensitivity and identifies the underlying mechanisms. This suggests GSK-J4 as a potential treatment option for cancer patients with KRAS mutations.

Significance:
This study not only provides a novel association between KRAS mutation and GSK-J4 sensitivity but also demonstrates the underlying mechanisms, suggesting a potential use of GSK-J4 in cancer patients with KRAS mutations.
A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation–Positive Solid Tumors
Authors: Kieran Mark W. , Geoerger Birgit , Dunkel Ira J. , Broniscer Alberto , Hargrave Darren , Hingorani Pooja , Aerts Isabelle , Bertozzi Anne-Isabelle , Cohen Kenneth J. , Hummel Trent R. , Shen Violet , Bouffet Eric , Pratilas Christine A. , Pearson Andrew D.J. , Tseng Lillian , Nebot Noelia , Green Steven , Russo Mark W. , Whitlock James A. 
Published: September 2019

Abstract

Purpose:
The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600–mutated cancers.

Patients and Methods:
This phase I dose-finding part treated patients ages 1 to &lt;18 years with BRAF V600 mutation–positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.

Results:
Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1–17 years)] with BRAF V600–mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6–148.7 weeks), with 63% treated for &gt;52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0–12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age &lt;12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.

Conclusions:
In this first clinical trial in pediatric patients with pretreated BRAF V600–mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was &gt;1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.
NKG2D Controls Natural Reactivity of Vγ9Vδ2 T Lymphocytes against Mesenchymal Glioblastoma Cells
Authors: Chauvin Cynthia , Joalland Noémie , Perroteau Jeanne , Jarry Ulrich , Lafrance Laura , Willem Catherine , Retière Christelle , Oliver Lisa , Gratas Catherine , Gautreau-Rolland Laetitia , Saulquin Xavier , Vallette François M. , Vié Henri , Scotet Emmanuel , Pecqueur Claire 
Published: September 2019

Abstract

Purpose:
Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of nonalloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, in vitro and in vivo, in the absence of any prior sensitization.

Experimental Design:
Through functional and transcriptomic analyses, we extensively characterized the immunoreactivity of human Vγ9Vδ2 T lymphocytes against various primary GBM cultures directly derived from patient tumors.

Results:
We evidenced that GBM cells displaying a mesenchymal signature are spontaneously eliminated by allogeneic human Vγ9Vδ2 T lymphocytes, a reactivity process being mediated by γδ T-cell receptor (TCR) and tightly regulated by cellular stress–associated NKG2D pathway. This led to the identification of highly reactive Vγ9Vδ2 T lymphocyte populations, independently of a specific TCR repertoire signature. Moreover, we finally provide evidence of immunotherapeutic efficacy in vivo, in the absence of any prior tumor cell sensitization.

Conclusions:
By identifying pathways implicated in the selective natural recognition of mesenchymal GBM cell subtypes, accounting for 30% of primary diagnosed and 60% of recurrent GBM, our results pave the way for novel targeted cellular immunotherapies.
Cisplatin Facilitates Radiation-Induced Abscopal Effects in Conjunction with PD-1 Checkpoint Blockade Through CXCR3/CXCL10-Mediated T-cell Recruitment
Authors: Luo Ren , Firat Elke , Gaedicke Simone , Guffart Elena , Watanabe Tsubasa , Niedermann Gabriele 
Published: September 2019

Abstract

Purpose:
Localized radiotherapy can cause T-cell–mediated abscopal effects on nonirradiated metastases, particularly in combination with immune checkpoint blockade (ICB). However, results of prospective clinical trials have not met the expectations. We therefore investigated whether additional chemotherapy can enhance radiotherapy-induced abscopal effects in conjunction with ICB.

Experimental Design:
In three different two-tumor mouse models, triple therapy with radiotherapy, anti–PD-1, and cisplatin (one of the most widely used antineoplastic agents) was compared with double or single therapies.

Results:
In these mouse models, the response of the nonirradiated tumor and the survival of the mice were much better upon triple therapy than upon radiotherapy + anti–PD-1 or cisplatin + anti–PD-1 or the monotherapies; complete regression of the nonirradiated tumor was usually only observed in triple-treated mice. Mechanistically, the enhanced abscopal effect required CD8+T cells and relied on the CXCR3/CXCL10 axis. Moreover, CXCL10 was found to be directly induced by cisplatin in the tumor cells. Furthermore, cisplatin-induced CD8+T cells and direct cytoreductive effects of cisplatin also seem to contribute to the enhanced systemic effect. Finally, the results show that the abscopal effect is not precluded by the observed transient radiotherapy-induced lymphopenia.

Conclusions:
This is the first report showing that chemotherapy can enhance radiotherapy-induced abscopal effects in conjunction with ICB. This even applies to cisplatin, which is not classically immunogenic. Whereas previous studies have focused on how to effectively induce tumor-specific T cells, this study highlights that successful attraction of the induced T cells to nonirradiated tumors is also crucial for potent abscopal effects.
Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
Authors: Georgiadis Andrew , Durham Jennifer N. , Keefer Laurel A. , Bartlett Bjarne R. , Zielonka Magdalena , Murphy Derek , White James R. , Lu Steve , Verner Ellen L. , Ruan Finey , Riley David , Anders Robert A. , Gedvilaite Erika , Angiuoli Sam , Jones Siân , Velculescu Victor E. , Le Dung T. , Diaz Luis A. , Sausen Mark 
Published: September 2019

Abstract

Purpose:
Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients.

Experimental Design:
We developed an approach that utilized a hybrid-capture–based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA).

Results:
Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of &gt;99% (n = 163) and sensitivities of 78% (n = 23) and 67% (n = 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P = 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade.

Conclusions:
These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade.
See related commentary by Wang and Ajani, p. 6887
Realidades em transformação
Authors: Murrace Thays Bueno 
Published: September 2019

Este artigo visa relatar as experiências vividas nos quilombos de Mandira e Ivaporundva – localizados no Vale do Ribeira – durante a excursão didática realizada no curso História da África e dos Afrodescendentes no Brasil: conteúdos e ferramentas didáticas para a formação de professores do Ensino Médio e Fundamental, ministrado pela professora doutora Maria Cristina Cortez Wissenbach, ao longo do primeiro semestre de 2018, de modo a evidenciar as narrativas construídas acerca da identidade quilombola em cada uma das comunidades e as transformações destas comunidades no tempo.
O Vale do Ribeira contém cerca de oitenta comunidades quilombolas reconhecidas pelo Instituto Palmares, mas que em sua totalidade ainda não receberam a sua titulação. O local apresenta um grande potencial hidrelétrico e mineral, sendo assim alvo de constantes disputas, gerando o Movimento dos Ameaçados por Barragens (MOAB).
Grid Mapping Catheter for Ventricular Tachycardia Ablation
Authors: Okubo Kenji , Frontera Antonio , Bisceglia Caterina , Paglino Gabriele , Radinovic Andrea , Foppoli Luca , Calore Federico , Della Bella Paolo 
Published: September 2019

Background:
A new grid mapping catheter (GMC)—allowing for bipolar recordings of the electrograms in each orthogonal direction—became available. The aim of the current study is to evaluate the utility of the GMC in creating substrate and ventricular tachycardia (VT) activation maps during VT ablation procedures.

Methods:
From December 2017 to July 2018, 41 consecutive patients undergoing a VT ablation procedure using a GMC were studied. During the substrate mapping, 3 different maps were created using the 3 GMC bipolar configurations (along the spline, across the spline, HD wave solution); the low voltage area and late potential areas were compared. In case of inducible VTs, the GMC was used to create the VT activation maps focusing on the diastolic interval. The relation between diastolic activities during VT and substrate abnormality during sinus rhythm was also investigated.

Results:

The median low-voltage area drawn by the HD wave configuration was 28.9 cm
2
, 13% and 15% smaller than the low-voltage areas identified by the along and across configuration, respectively (33.1 and 33.9 cm
2
;
P
<0.0001). The late potential areas obtained with the 3 GMC configuration did not differ (
P
>0.05). VT activation mappings using the GMC were performed in 40 VTs, visualizing the full diastolic pathway in 22 (55%) of them. While the latest late potential areas were included in VT diastolic pathway in 17 VTs, the other 6 VTs showed mismatching of them. Identifying the full diastolic pathway led to a higher ongoing VT termination rate during the ablation than in case of partial recordings (88% versus 45%;
P
=0.03); furthermore, in the former situation, the noninducibility of the targeted VTs was achieved in all cases.

Conclusions:
The GMC is a useful tool for performing substrate and VT activation mappings during the VT ablation procedure, precisely identifying the low-voltage areas and quickly visualizing the diastolic pathways.
Duration of Heart Failure and Effect of Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure
Authors: Elming Marie Bayer , Thøgersen Anna M. , Videbæk Lars , Bruun Niels E. , Eiskjær Hans , Haarbo Jens , Egstrup Kenneth , Gustafsson Finn , Hastrup Svendsen Jesper , Høfsten Dan E. , Pehrson Steen , Nielsen Jens C. , Køber Lars , Jakob Thune Jens 
Published: September 2019

Background:
Patients with nonischemic systolic heart failure (HF) have increased risk of sudden cardiac death (SCD) and death from progressive pump failure. Whether the risk of SCD changes over time is unknown. We seek here to investigate the relation between duration of HF, mode of death, and effect of implantable cardioverter-defibrillator implantation.

Methods and Results:

We examined the risk of all-cause death and SCD according to the duration of HF among patients with nonischemic systolic HF enrolled in the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality). In all, 1116 patients were included. Patients were divided according to quartiles of HF duration (≤8, 9≤18, 19≤65, and ≥66 months). Patients with the longest duration of HF were older, more often men, had more comorbidity, and more often received a cardiac resynchronization therapy device. Doubling of HF duration was an independent predictor of both all-cause mortality (hazard ratio [HR], 1.27; 95% CI, 1.17–1.38;
P
<0.0001), and SCD (HR, 1.29; 95% CI, 1.11–1.50;
P
=0.0007). The proportion of deaths caused by SCD was not different between HF quartiles (
P
=0.91), and the effect of implantable cardioverter-defibrillator implantation on all-cause mortality was not modified by the duration of HF (
P
=0.59).

Conclusions:
Duration of HF predicted both all-cause mortality and risk of SCD independently of other risk indicators. However, the proportion of death caused by SCD did not change with longer duration of HF, and the effect of implantable cardioverter-defibrillator was not modified by the duration of HF.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00542945.
The View from the Monasteries: Taxes, Muslims and Converts in the “Pseudepigrapha” from Middle Egypt
Authors: Palombo Cecilia 
Published: September 2019

Abstract
This paper analyzes a group of homilies composed in Middle Egypt around the early ninth century CE by monastic leaders who had to cope with unsettling changes in local politics and society. The corpus deals with issues of taxation, economic distress and conversion to Islam in subtle and indirect ways, showing the inside perspective of Christian leaders on developments on which we are informed primarily from documentary papyri and historical works. It highlights the view of a certain segment of Egyptian Christianity on Islam and ongoing processes of Islamization, adding to the better-known literary sources from the area of Alexandria, and revealing the existence of internal tensions within the monastic world.
Abraham Ibn Ezra as the Translator of Astrological and Astronomical Texts from Arabic into Hebrew: Sources and Methods
Authors: Sela Shlomo 
Published: September 2019

Abstract
Abraham Ibn Ezra (ca. 1089–ca. 1161) was born in Muslim Spain, but his extensive scientific corpus, dealing mainly with astrology and astronomy, was composed in Latin Europe and written almost exclusively in Hebrew. Recent work on Reshit Ḥokhmah (Beginning of Wisdom), an introduction to astrology that is considered to be the zenith of Ibn Ezra’s astrological work, revealed that at least one-fourth of this text consists of translations or close paraphrases from identifiable and available Arabic astrological and astronomical texts. Relying on these findings, this paper identifies the Arabic texts Ibn Ezra drew on, shows where their Hebrew translations were incorporated into Reshit Ḥokhmah, and then scrutinizes his translation methods.