bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer Analysis of Homologous Recombination Repair–associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score
Authors: Westphalen C. Benedikt , Fine Alexander D. , André Fabrice , Ganesan Shridar , Heinemann Volker , Rouleau Etienne , Turnbull Clare , Garcia Palacios Luis , Lopez Jorge-Antonio , Sokol Ethan S. , Mateo Joaquin 
Published: November 2021

AbstractPurpose:To study associations across tumor types between genome-wide loss of heterozygosity (gLOH) and alterations in homologous recombination repair (HRR)-associated genes beyond BRCA1 and BRCA2.Experimental Design:Genomic profiling using a targeted next-generation sequencing assay examining 324–465 genes (FoundationOne, FoundationOne Heme, and FoundationOne CDx; Foundation Medicine, Inc.) was performed in a cohort of 160,790 samples across different tumor types. Zygosity predictions and gLOH status were calculated and linked with alterations in 18 HRR-associated genes (BRCA1, BRCA2, PALB2, BARD1, ATR, ATRX, ATM, BAP1, RAD51B, RAD51C, RAD51D, BRIP1, NBN, CHEK1, CHEK2, FANCA, FANCC, MRE11) and other genomic features, using Fisher's exact test and Mann–Whitney U tests.Results:We identified a strong correlation between elevated gLOH and biallelic alterations in a core set of HRR-associated genes beyond BRCA1 and BRCA2, such as BARD1, PALB2, FANCC, RAD51C, and RAD51D (particularly in breast, ovarian, pancreatic, and prostate cancer). Monoallelic/heterozygous alterations in HRR-associated genes were not associated with elevated gLOH. gLOH was also independently associated with TP53 loss. Co-occurrence of TP53 loss and alterations in HRR-associated genes, and combined loss of TP53-PTEN or TP53-RB1, was associated with a higher gLOH than each of the events separately.Conclusions:Biallelic alterations in core HRR-associated genes are frequent, strongly associated with elevated gLOH, and enriched in breast, ovarian, pancreatic, and prostate cancer. This analysis could inform the design of the next generation of clinical trials examining DNA repair–targeting agents, including PARP inhibitors.
DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition
Authors: Izquierdo Elisa , Carvalho Diana M. , Mackay Alan , Temelso Sara , Boult Jessica K.R. , Pericoli Giulia , Fernandez Elisabet , Das Molina , Molinari Valeria , Grabovska Yura , Rogers Rebecca F. , Ajmone-Cat Maria Antonietta , Proszek Paula Z. , Stubbs Mark , Depani Sarita , O'Hare Patricia , Yu Lu , Roumelioti Georgia , Choudhary Jyoti S. , Clarke Matthew , Fairchild Amy R. , Jacques Thomas S. , Grundy Richard G. , Howell Lisa , Picton Susan , Adamski Jenny , Wilson Shaun , Gray Juliet C. , Zebian Bassel , Marshall Lynley V. , Carceller Fernando , Grill Jacques , Vinci Maria , Robinson Simon P. , Hubank Michael , Hargrave Darren , Jones Chris 
Published: November 2021

Abstract

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.

Significance:
We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic.
This article is highlighted in the In This Issue feature, p. 587
Framework of diacritic segmentation for Arabic handwritten document
Authors: Shiekh Ahmed Abdalla , Azmi Mohd Sanusi , Aziz Maslita Abd , Al-Mhiqani Mohammed Nasser , Bafjaish Salem Saleh 
Published: November 2021

<span lang="EN-US">In <span>recent Arabic standard language and Arabic dialectal texts, diacritics and short vowels are absent. There are some exceptions have been made for the Arabic beginner learner scripts, religious texts and as well as a significant political text. In addition, the text without diacritics is considered ambiguous due to numerous words with different diacritic marks seem identical. However, this paper we present a framework for segmenting diacritics from Arabic handwritten document by using region-based segmentation technique. Since Arabic handwritten and Mushaf Al-Quran contain many diacritical marks. Hence, the diacritics must be properly extracted from Arabic handwritten document to avoid losing some good features. Furthermore, the proposed framework is devised specifically to segment diacritics from Arabic handwritten image, thus there will be no feature extraction, feature selection, and classification processes included. Besides, we will present the methodology that is used to fulfil the objectives of this paper. The pre-processing phases will be explained and more specifically segmentation phase for segmenting diacritics which is the phase we concentrate more in this article. Lastly, we will identify the proposed technique region-based segmentation to facilitate our development throughout the experimental process.</span></span>
From Democratic Exception to State of Exception: Covid-19 in the Context of Tunisia’s State of Law
Authors: Guetat Meriem , Agrebi Meriem 
Published: November 2021

Abstract
Through an analysis of the early legal and institutional response to Covid-19 in Tunisia, this article demonstrates that the narrative of Tunisia’s democratic exceptionalism following the 2011 revolution is not translated into a liberal legal practice but is instead upheld by an authoritarian rationale that serves the role of a formal channel that legitimizes power discourse. Specifically, this article focuses on what the state of exception, which was declared during the ongoing state of emergency, reveals about the various uses of law in Tunisia. It argues that the state of emergency has become the norm to the Tunisian way of governance post-2011, allowing for the survival of past authoritarian practices where the legal apparatus is used and deployed as a tool of policing and control.
Observations and Simulated Mechanisms of Elevation-Dependent Warming over the Tropical Andes
Authors: Chimborazo Oscar , Minder Justin R. , Vuille Mathias 
Published: November 2021

Abstract
Many mountain regions around the world are exposed to enhanced warming when compared to their surroundings, threatening key environmental services provided by mountains. Here we investigate this effect, known as elevation-dependent warming (EDW), in the Andes of Ecuador, using observations and simulations with the Weather Research and Forecasting (WRF) Model. EDW is discernible in observations of mean and maximum temperature in the Andes of Ecuador, but large uncertainties remain due to considerable data gaps in both space and time. WRF simulations of present-day (1986–2005) and future climate (RCP4.5 and RCP8.5 for 2041–60) reveal a very distinct EDW signal, with different rates of warming on the eastern and western slopes. This EDW effect is the combined result of multiple feedback mechanisms that operate on different spatial scales. Enhanced upper-tropospheric warming projects onto surface temperature on both sides of the Andes. In addition, changes in the zonal mean midtropospheric circulation lead to enhanced subsidence and warming over the western slopes at high elevation. The increased subsidence also induces drying, reduces cloudiness, and results in enhanced net surface radiation receipts, further contributing to stronger warming. Finally, the highest elevations are also affected by the snow-albedo feedback, due to significant reductions in snow cover by the middle of the twenty-first century. While these feedbacks are more pronounced in the high-emission scenario RCP8.5, our results indicate that high elevations in Ecuador will continue to warm at enhanced rates in the twenty-first century, regardless of emission scenario.

Significance Statement
Mountains are often projected to experience stronger warming than their surrounding lowlands going forward, a phenomenon known as elevation-dependent warming (EDW), which can threaten high-altitude ecosystems and lead to accelerated glacier retreat. We investigate the mechanisms associated with EDW in the Andes of Ecuador using both observations and model simulations for the present and the future. A combination of factors amplify warming at mountain tops, including a stronger warming high in the atmosphere, reduced cloudiness, and a reduction of snow and ice at high elevations. The latter two factors also favor enhanced absorption of sunlight, which promotes warming. The degree to which this warming is enhanced at high elevations in the future depends on the greenhouse gas emission pathway.
Suicidality and Associated Factors Among Individuals Assessed for Fetal Alcohol Spectrum Disorder Across the Lifespan in Canada
Authors: Flannigan Katherine , McMorris Carly , Ewasiuk Amanda , Badry Dorothy , Mela Mansfield , Ben Gibbard W. , Unsworth Kathy , Cook Jocelynn , Harding Kelly D. 
Published: November 2021

Objective Individuals with fetal alcohol spectrum disorder (FASD) experience a range of complex neurodevelopmental, psychological, and socioenvironmental vulnerabilities. There is growing evidence that suicidal ideation, attempts, and death by suicide are significant concerns within this population. In this study, we (1) determined the rate of suicidal ideation/attempts in a large group of individuals with prenatal alcohol exposure (PAE) who were assessed for FASD in Canada and (2) investigated the associations between suicidal ideation/attempts and select demographic and biopsychosocial factors in this group. Method A secondary analysis of data from Canada's National FASD Database, a national repository of clinical information gathered through FASD assessment and diagnostic clinics across the country, was conducted. Descriptive analyses, chi-square/Fisher's exact tests, and binary logistic regression were used to examine demographic and biopsychosocial variables and their associations with suicidality. Results In our sample of 796 participants ( Mage = 17.7 years, range = 6–59; 57.6% male) assessed for FASD, 25.9% were reported to experience suicidal ideation/attempts. Numerous demographic and biopsychosocial factors were found to be significantly associated with suicidal ideation/attempts. The strongest associations with suicidal ideation/attempts were substance use, history of trauma/abuse, and impaired affect regulation. Conclusions With this study, we contribute to the emerging evidence of elevated risk of suicidality among individuals with PAE/FASD and improve our understanding of factors that may exacerbate this risk. Findings have relevance for improving screening, prevention, and proactive treatment approaches for individuals with PAE and FASD, their families, and wider support systems.
Analysis of predictors of mortality after surgical and non-surgical management in proximal humerus fractures
Authors: Garcia-Reza Alejandro , Dominguez-Prado Diego Matias , Iglesias-Nuñez Constantino , Alvarez-Alvarez Lucia , Hernandez-Gonzalez Beatriz , Balvis-Balvis Patricia , Fernandez-Fernandez Daniel , Castro-Menendez Manuel 
Published: November 2021

Abstract
Background
Proximal humerus fractures are one of the main osteoporotic fractures. Choosing between conservative or surgical treatment is a controversial topic in the literature, as is the functional impact. The main aim of our study was to analyse whether patient comorbidities should influence the final therapeutic decision for these fractures.

Material and methods
We collected data from 638 patients with proximal humerus fractures. The main variable collected was exitus. We also collected the following data: age, gender, type of fracture, laterality, type of treatment, production mechanism, comorbidities and the Charlson comorbidity index (CCI) for each patient. The therapeutic indication used the criteria established by the Upper Limb Unit in our centre. We performed chi-square tests, Fischer’s exact tests and Student’s t-tests to compare the variables. We used the Kaplan–Meier method to analyse both the overall and disease-specific survival rates. We employed the Cox regression model to analyse factors associated with mortality.

Results
Patients with a CCI greater than 5 showed greater mortality (HR  = 3.83; p  < 0.001) than those with a CCI lower than 5. Within the patients who underwent surgery, those with a CCI higher than 5 had an increased mortality rate (HR  = 22.6; p < 0.001) compared with those with a CCI lower than 5. Within the patients who received conservative treatment, those with a CCI over 5 showed greater mortality (HR  = 3.64; p  < 0.001) than those with a CCI under 5.

Conclusions
Patients with proximal humerus fractures and associated comorbidities (CCI > 5) presented higher mortality than healthier patients. This mortality risk was greater in patients with comorbidities if surgical treatment was indicated rather than conservative treatment. Patient’s comorbidities should be a fundamental parameter when planning the therapeutic strategy.

Level of evidence
Level 3.
Parent-reported measure of repetitive behavior in Phelan-McDermid syndrome
Authors: Srivastava Siddharth , Condy Emma , Carmody Erin , Filip-Dhima Rajna , Kapur Kush , Bernstein Jonathan A. , Berry-Kravis Elizabeth , Powell Craig M. , Soorya Latha , Thurm Audrey , Buxbaum Joseph D. , Sahin Mustafa , Kolevzon A﻿lexander ,   on behalf of Developmental Synaptopathies Consortium, Sahin Mustafa , Kolevzon Alexander , Buxbaum Joseph D. , Kravis Elizabeth Berry , Soorya Latha , Thurm Audrey , Powell Craig , Bernstein Jonathan A. , Warfield Simon , Dies Kira , Siper Paige , Hanson Ellen , Phillips Jennifer M. 
Published: November 2021

Abstract
Background
Phelan McDermid syndrome (PMS) is a neurogenetic condition associated with a high prevalence of intellectual disability (ID) and autism spectrum disorder (ASD). This study provides a more comprehensive and quantitative profile of repetitive behaviors within the context of ID seen with the condition.

Methods
Individuals age 3–21 years with a confirmed PMS diagnosis participated in a multicenter observational study evaluating the phenotype and natural history of the disorder. We evaluated data collected from this study pertaining to repetitive behaviors from the Repetitive Behavior Scales-Revised (RBS-R).

Results
There were n = 90 participants who were part of this analysis. Forty-seven percent (n = 42/90) were female, and the average age at baseline evaluation was 8.88 ± 4.72 years. The mean best estimate IQ of the cohort was 26.08 ± 17.67 (range = 3.4–88), with n = 8 with mild ID (or no ID), n = 20 with moderate ID, and n = 62 with severe-profound ID. The RBS-R total overall score was 16.46 ± 13.9 (compared to 33.14 ± 20.60 reported in previous studies of ASD) (Lam and Aman, 2007), and the total number of items endorsed was 10.40 ± 6.81 (range = 0–29). After statistical correction for multiple comparisons, IQ correlated with the RBS-R stereotypic behavior subscale score (rs = − 0.33, unadjusted p = 0.0014, adjusted p = 0.01) and RBS-R stereotypic behavior total number of endorsed items (rs = − 0.32, unadjusted p = 0.0019, adjusted p = 0.01). IQ did not correlate with any other RBS-R subscale scores.

Conclusions
The RBS-R total overall score in a PMS cohort appears milder compared to individuals with ASD characterized in previous studies. Stereotypic behavior in PMS may reflect cognitive functioning.
Measurement of the nociceptive flexion reflex threshold in critically ill patients – a randomized observational pilot study
Authors: Schick Benedikt , Mayer Benjamin , Walter Steffen , Gruss Sascha , Stitz Ronald , Stitz Pauline , Barth Eberhard 
Published: November 2021

Abstract
Background
Pain detection and treatment is a major challenge in the care of critically ill patients, rendered more complex by the need to take into consideration the risk of insufficient or excessive analgesia. The nociceptive flexion reflex threshold (NFRT) has become the established basis for measuring the level of analgesia in the perioperative context. However, it remains unclear whether NFRT measurement can be usefully applied to mechanically ventilated, analgosedated critically ill patients who are unable to communicate. Therefore, the aim of the present study was to investigate whether there is an association between the NFRT measurement and the Behavioral Pain Scale (BPS) in critically ill, analgosedated, and mechanically ventilated patients and whether the NFRT measurement can also detect potential excessive analgesia.

Methods
This prospective, observational, randomized single-center pilot study included patients admitted to the surgical Intensive Care Unit of University Hospital Ulm, Germany, all of whom were analgosedated and intubated. Major exclusion criteria were defined as the need for the administration of neuromuscular blocking agents or neurological diseases associated with peripheral nerve conduction restriction. Initial NFRT and BPS measurements were conducted within 12 h after admission. A structured pain assessment was performed at least twice daily until extubation throughout the observation period thereafter (Group A: BPS + NFRT, Group B: BPS).

Results
114 patients were included in the study. NFRT is associated negatively with BPS. NFRT was almost twice as high in patients with a Richmond Agitation Sedation Scale (RASS) score of -5 than in patients with a RASS score ≥ -4 (RASS -5 – NFRT: 59.40 vs. RASS -4 – NFRT: 29.00, p < 0.001).

Conclusions
NFRT measurement is associated negatively with the BPS in critically ill patients. NFRT measurement provides guidance for the evaluation of nociceptive processes in patients with RASS scores ≤ −4, in whom analgesia level is often difficult to assess. However, in order to identify excessive analgesia and derive therapeutic consequences, it is necessary to gradually decrease analgesics and sedatives until a stimulus threshold is reached at which the patient does not feel pain.

Trial Registration
Retrospectively registered in the German Clinical Trials Register, registration number DRKS00021149, date of registration: March 26, 2020. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021149.
Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial
Authors: Italiano Antoine , Dinart Derek , Soubeyran Isabelle , Bellera Carine , Espérou Hélène , Delmas Christelle , Mercier Noémie , Albert Sabrina , Poignie Ludivine , Boland Anne , Bourdon Aurélien , Geneste Damien , Cavaille Quentin , Laizet Yec’han , Khalifa Emmanuel , Auzanneau Céline , Squiban Barbara , Truffaux Nathalène , Olaso Robert , Gerber Zuzana , Wallet Cédrick , Bénard Antoine , Blay Jean-Yves , Laurent-Puig Pierre , Deleuze Jean-François , Lucchesi Carlo , Mathoulin-Pelissier Simone ,   the MULTISARC study group
Published: November 2021

Abstract
Background
Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant’s outcome.

Methods
This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm “NGS” and the standard “No NGS”. NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in “No NGS” arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator.

Discussion
The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale.

Trial registration
clinicaltrial.gov NCT03784014.
Molecular genetic analysis and growth hormone response in patients with syndromic short stature
Authors: Sun Huihui , Li Na , Wan Naijun 
Published: November 2021

Abstract
Background
Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response.

Methods
Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature.

Results
Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [− 5.05 standard deviation (SD)] to 100.4 cm (− 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (− 2.69 SD) to 145.0 cm (− 2.36 SD), and her increased height SDS was 0.33.

Conclusions
Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.