bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCT-06. PRECISION ONCOLOGY IN THE PEDIATRIC TARGETED THERAPY 2.0 PROGRAM
Authors: Ecker Jonas , Selt Florian , Korshunov Andrey , Capper David , Dikow Nicola , Hirsch Steffen , Sutter Christian , van Tilburg Cornelis , von Deimling Andreas , Jones David T W , Pfister Stefan M , Sahm Felix , Witt Olaf , Milde Till 
Published: June 2021

Abstract

Introduction
Precise diagnoses and robust detection of actionable alterations is required for individualized treatments. By using extended molecular diagnostics, the Pediatric Targeted Therapy (PTT) 2.0 program aims at the improvement of diagnostic accuracy and detection of actionable alterations for pediatric high-risk patients. The impact of these analyses on clinical management is reported.

Methods
Pediatric patients with relapsed or progressive tumors after standard of care treatment were included, independent of histological diagnosis. Formalin fixed paraffin embedded material and a blood sample for germline correction were requested. DNA methylation array, targeted gene panel sequencing (130 genes), RNA and Sanger sequencing in selected cases, and immunohistochemistry (IHC) of selected markers (pERK, pAKT, pS6, PD-L1) were performed. A questionnaire-based follow-up was used to determine the clinical impact of the analysis.

Results
We enrolled n=263 patients from February 2017 to February 2019. Complete molecular analysis was possible for n=260 cases (99%). The most common entities were brain tumors (n=172/260, 65%). In brain tumors, DNA methylation array alone allowed robust diagnostic classification (score of &gt;=0.9) in n=104/172 cases (60%). Actionable targets as detected by copy number calculation, gene panel sequencing, RNA sequencing and IHC were found in n=94/172 (55%) brain tumor cases. The most common actionable targets in brain tumors were MAPK (pERK, BRAF fusions, BRAF V600E), mTOR (pS6), PI3K (pAKT), CDK4/6 (CDKN2A/B loss), and immune checkpoints (PD-L1). Pathogenic germline alterations with clinical relevance were identified in n=12/172 brain tumor cases (6.9%) and were confirmed by Sanger sequencing, 5/12 (41%) of which were previously unknown. Clinical follow-up of subsequent treatment and outcome are ongoing.

Conclusion
The combination of next-generation diagnostics such as methylation arrays and targeted sequencing in addition to selected IHC markers added robust information with regard to diagnosis and actionable alterations. The impact on clinical decision-making and on outcome is currently being evaluated.
EPCT-15. RAPID EPIGENOMIC CLASSIFICATION OF BRAIN TUMORS ENABLES INTRAOPERATIVE NEUROSURGICAL RISK MODULATION
Authors: Djirackor Luna , Halldorsson Skarphedinn , Niehusmann Pitt , Leske Henning , Kuschel Luis P , Pahnke Jens , Due-Tønnessen Bernt J , Langmoen Iver A , Sandberg Cecilie J , Euskirchen Philipp , Vik-Mo Einar O 
Published: June 2021

Abstract

Background
Clear identification of tumor subtype is the main predictor of patient outcome and ultimately what is considered an adequate level of surgical risk. At brain tumor resection, imaging modalities and intraoperative histology often give an ambigious diagnosis, complicating intraoperative surgical decision-making. Here, we report a nanopore DNA methylation analysis (NDMA) sequencing approach combined with machine learning for classification of tumor entities that could be used intraoperatively.

Methods
We analyzed 50 biopsies obtained from biobanked tissue (43, prospective) or sampled at surgery (7, intraoperative) from 20 female and 30 male patients with a median age of 8 years. DNA was extracted using spin columns, quantified on a Qubit fluorometer and assessed for purity using NanoDrop spectrophotometer. DNA was then barcoded with the Rapid Barcoding kit from Oxford Nanopore technologies and loaded onto a MinION flow cell. Sequencing was performed for 3 hours (intraoperative) and 24 hours (prospective). Raw reads were basecalled using the Guppy algorithm, then fed into a snakemake workflow (nanoDx pipeline). This generated a report showing the copy number profile, genome-wide methylation status and subclassification of the tumor according to the Heidelberg reference cohort.

Results
Twelve different tumor classes were discovered within our cohort spanning from WHO Grade I to Grade IV. The results generated by NDMA were concordant with standard neuropathological diagnosis in 43 out of 50 cases (86%). Of the discordant cases, six were due to the biological complexity of the tumor and one case was misclassified by the pipeline. NDMA enabled correct subclassification of 6/7 intraop cases within a mean of 129 minutes.

Conclusion
NDMA can accurately subclassify tumor entities intraoperatively and guide surgical procedures when preoperative imaging and frozen section evaluation are unclear.
EPCT-17. DEVELOPING EYA PHOSPHATASE INHIBITORS WITH ON-TARGET EFFECTS IN SHH-MEDULLOBLASTOMA
Authors: H. Hwang Grace , Scott David A , Segal Rosalind A 
Published: June 2021

Abstract
Medulloblastoma, one of the most frequent malignant pediatric brain tumors, encompasses four molecularly and clinically distinct cancers. Sonic hedgehog (SHH)-subtype medulloblastoma constitutes about 30% of medulloblastomas, and therapies targeting the SHH pathway can lead to new highly selective treatment. The haloacid dehalogenase (HAD) phosphatase Eyes Absent 1 (EYA1) is critically involved in the development and progression of SHH-medulloblastoma: Eya1 is highly expressed in SHH-medulloblastomas, and single cell sequencing indicates that Eya1 is a consistent feature that can be detected in every individual cancer cell. Inhibition of EYA1 interrupts SHH pathway signaling. During normal development, EYA1 promotes symmetric division of cerebellar granule cell precursors (GCPs), the cells of origin for SHH-subtype medulloblastoma, and reduced levels of EYA1 decrease medulloblastoma mortality rates in mouse models. Therefore, targeting EYA1 may be a novel therapeutic avenue for these pediatric cancers. Benzarone derivatives have been suggested as allosteric EYA-inhibitors, and benzarone provides a promising platform for chemical derivatives. Here, we develop 60 novel benzarone derivatives and assess their efficacy in inhibiting SHH-medulloblastoma growth through the inhibition of EYA1. Several of the new compounds inhibit EYA1 phosphotyrosine phosphatase activity in a cell-based assay, interrupt SHH pathway, and prevent SHH-medulloblastoma growth in vitro. Our results show that these novel benzarone derivatives are a new promising avenue for developing therapeutics for pediatric SHH-medulloblastoma via inhibition of EYA phosphatases.
Humoral Immune Response to Clostridioides difficile Toxins A and B in Hospitalized Immunocompromised Patients With C difficile Infection
Authors: Alonso Carolyn D , Papamichael Konstantinos , Sprague Rebecca , Barrett Caitlin , Gonzales-Luna Anne J , Daugherty Kaitlyn , Garey Kevin W , Villafuerte-Gálvez Javier , Xu Hua , Lin Qianyun , Wang Lamei , Chen Xinhua , Pollock Nira R , Kelly Ciarán P 
Published: June 2021

Abstract

Background
The humoral immune response to Clostridioides difficile toxins in C difficile infection (CDI) is incompletely characterized in immunocompromised hosts (ICHs).

Methods
We conducted a prospective study of hospitalized adults with CDI, with and without immunosuppression (hematologic malignancy, active solid tumor, solid organ or stem cell transplant, inflammatory bowel disease, autoimmune disease, congenital or acquired immunodeficiency, asplenia, chronic receipt of high-dose steroids, or receipt of immunosuppressing medications within 12 months). Serum and stool antibody concentrations of immunoglobulin (Ig)M, IgG, and IgA to C difficile toxins A and B at treatment days 0, 3, and 10–14 were compared.

Results
Ninety-eight subjects (47 ICH; 51 non-ICH) were enrolled. Baseline serum antitoxin A and B antibody levels were similar. At day 3, ICHs demonstrated lower serum levels of antitoxin A IgG, antitoxin A IgA, and antitoxin B IgA (all P &lt; .05). At day 10–14, lower antitoxin A IgG concentrations were observed in ICHs (ICH, 21 enzyme-linked immunosorbent assay [ELISA] units; interquartile range [IQR], 16.4–44.6) compared with non-ICH subjects (49.0 ELISA units; IQR, 21.5–103; P = .045). In stool, we observed lower concentrations of antitoxin B IgA antibodies at baseline and at day 3 for ICH subjects, with a notable difference in concentrations of antitoxin B IgA at day 3 (ICH, 6.7 ELISA units [IQR, 1.9–13.9] compared with non-ICH, 18.1 ELISA units [IQR, 4.9–31.7]; P = .003).

Conclusions
The ICHs with CDI demonstrated lower levels of C difficile antitoxin antibodies in serum and stool during early CDI therapy compared with non-ICHs. These data provide insight into the humoral response to CDI in ICHs.
Reciprocal adaptation of rice and Xanthomonas oryzae pv. oryzae: cross-species 2D GWAS reveals the underlying genetics
Authors: Zhang Fan , Hu Zhiqiang , Wu Zhichao , Lu Jialing , Shi Yingyao , Xu Jianlong , Wang Xiyin , Wang Jinpeng , Zhang Fan , Wang Mingming , Shi Xiaorong , Cui Yanru , Vera Cruz Casiana , Zhuo Dalong , Hu Dandan , Li Min , Wang Wensheng , Zhao Xiuqin , Zheng Tianqing , Fu Binying , Ali Jauhar , Zhou Yongli , Li Zhikang 
Published: June 2021

Abstract
A 1D/2D genome-wide association study strategy was adopted to investigate the genetic systems underlying the reciprocal adaptation of rice (Oryza sativa) and its bacterial pathogen, Xanthomonas oryzae pv. oryzae (Xoo) using the whole-genome sequencing and large-scale phenotyping data of 701 rice accessions and 23 diverse Xoo strains. Forty-seven Xoo virulence-related genes and 318 rice quantitative resistance genes (QR-genes) mainly located in 41 genomic regions, and genome-wide interactions between the detected virulence-related genes and QR genes were identified, including well-known resistance genes/virulence genes plus many previously uncharacterized ones. The relationship between rice and Xoo was characterized by strong differentiation among Xoo races corresponding to the subspecific differentiation of rice, by strong shifts toward increased resistance/virulence of rice/Xoo populations and by rich genetic diversity at the detected rice QR-genes and Xoo virulence genes, and by genome-wide interactions between many rice QR-genes and Xoo virulence genes in a multiple-to-multiple manner, presumably resulting either from direct protein–protein interactions or from genetic epistasis. The observed complex genetic interaction system between rice and Xoo likely exists in other crop–pathogen systems that would maintain high levels of diversity at their QR-loci/virulence-loci, resulting in dynamic coevolutionary consequences during their reciprocal adaptation.
A plant-specific syntaxin-6 protein contributes to the intracytoplasmic route for the begomovirus CabLCV
Authors: Gouveia-Mageste Bianca Castro , Martins Laura Gonçalves Costa , Dal-Bianco Maximiller , Machado João Paulo Batista , da Silva José Cleydson Ferreira , Kim Alice Y. , Yazaki Junshi , dos Santos Anésia Aparecida , Ecker Joseph R. , Fontes Elizabeth Pacheco Batista 
Published: June 2021

Abstract
Because of limited free diffusion in the cytoplasm, viruses must use active transport mechanisms to move intracellularly. Nevertheless, how the plant single-stranded DNA begomoviruses hijack the host intracytoplasmic transport machinery to move from the nucleus to the plasmodesmata remains enigmatic. Here, we identified nuclear shuttle protein (NSP)-interacting proteins from Arabidopsis (Arabidopsis thaliana) by probing a protein microarray and demonstrated that the cabbage leaf curl virus NSP, a facilitator of the nucleocytoplasmic trafficking of viral (v)DNA, interacts in planta with an endosomal vesicle-localized, plant-specific syntaxin-6 protein, designated NSP-interacting syntaxin domain-containing protein (NISP). NISP displays a proviral function, unlike the syntaxin-6 paralog AT2G18860 that failed to interact with NSP. Consistent with these findings, nisp-1 mutant plants were less susceptible to begomovirus infection, a phenotype reversed by NISP complementation. NISP-overexpressing lines accumulated higher levels of vDNA than wild-type. Furthermore, NISP interacted with an NSP-interacting GTPase (NIG) involved in NSP–vDNA nucleocytoplasmic translocation. The NISP–NIG interaction was enhanced by NSP. We also showed that endosomal NISP associates with vDNA. NISP may function as a docking site for recruiting NIG and NSP into endosomes, providing a mechanism for the intracytoplasmic translocation of the NSP–vDNA complex toward and from the cell periphery.
HIV persistence in lymph nodes
Authors: Banga Riddhima , Munoz Olivia , Perreau Matthieu 
Published: June 2021

Purpose of review
HIV persists in distinct cellular and anatomical compartments in the body including blood, Central nervous system, and lymphoid tissues (spleen, lymph nodes [LNs], gut-associated lymphoid tissue) by diverse mechanisms despite antiretroviral therapy. Within LNs, human and animal studies have highlighted that a specific CD4 T cell subset - called T follicular helper cells locating in B cell follicles is enriched in cells containing replication-competent HIV as compared to extra-follicular CD4 T cells. Therefore, the objective of the present review is to focus on the potential mechanisms allowing HIV to persist within LN microenvironment.

Recent findings
The combination of factors that might be involved in the regulation of HIV persistence within LNs remain to be fully identified but may include - the level of activation, antiretroviral drug concentrations, presence of cytolytic mechanisms and/or regulatory cells, in addition to cell survival and proliferation propensity which would ultimately determine the fate of HIV-infected cells within LN tissue areas.

Summary
HIV persistence in blood and distinct body compartments despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on composition, viral diversity, distribution, replication competence, migration dynamics across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.
New findings bearing on the prevention, detection and management of high blood pressure
Authors: Carey Robert M. , Whelton Paul K. 
Published: June 2021

Purpose of review
Hypertension is the foremost risk factor for cardiovascular disease (CVD) and death. This review highlights recent findings that apply to the prevention, detection, and management of high blood pressure (BP), in the context of the 2017 American College of Cardiology/American Heart Association BP guideline.

Recent findings
Several new findings on the association of BP measurement with CVD outcomes are now available. (1) Beginning with a systolic BP (SBP) as low as 90 mm Hg, coronary artery calcium deposition and the risk of incident atherosclerotic CVD (ASCVD) increased in stepwise fashion with increasing SBP levels within the normal range in adults at low risk for ASCVD. (2) Isolated diastolic hypertension was not associated with ASCVD, heart failure, or chronic kidney disease. (3) Nocturnal BP appeared to be better associated with CVD outcomes than office or daytime BP. (4) In a head-to-head comparison, home BP monitoring had higher reliability and predictive value than office or ambulatory BP to detect left ventricular hypertrophy, an intermediate form of hypertension-related target organ damage. In addition, new information indicates that autonomous aldosterone production is present in a substantially larger percentage of adults with hypertension than previously recognized. Finally, intensive BP lowering is associated with a significant reduction in the incidence of mild cognitive impairment, a precursor of dementia.

Summary
Ongoing research has made significant progress in the prevention, detection, and management of high BP, clarifying, amplifying, and/or supporting the 2017 ACC/AHA BP guideline recommendations.
Medical management of resistant hypertension: the role of sodium-glucose cotransporter 2 inhibitors (SGLT2i)
Authors: Alqudsi Muhannad , Velez Juan Carlos Q. , Navarrete Jose 
Published: June 2021

Purpose of review
Controlling hypertension to the desired target is commonly unsuccessful and requires multi-drug regimen, which can lead to undesirable side effects. Resistant hypertension (RH) is more cumbersome to deal with and has robust morbidity and mortality burden even with current multiple medical options. Herein, we review the literature for the potential role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a treatment option for hypertension and RH.

Recent findings
With more recent randomized controlled trials (RCTs), SGLT2i have gained more recognition for their renal and cardiovascular protection as well as mortality benefit that are believed to be medication class-related effects. Multiple RCTs have evaluated blood pressure (BP) lowering properties of SGLT2i, as a primary or secondary end point, in diabetic and nondiabetic patients, yet trials are scarce in studying SGLT2i as first-line antihypertensives, or as add-on agents for treating RH.

Summary
Finding the right medical therapy in treating hypertension, especially RH, is commonly onerous when it comes to achieving BP targets, avoiding medication side effects, and aiming for the best outcomes. Utilizing existing drugs like SGLT2i or exploring other novel agents with more RCTs for these purposes will be beneficial. The addition of SGLT2i to the therapeutic armamentarium in patients with RH should be considered as a target for upcoming RCTs.
New targets in inflammatory bowel disease therapy: 2021
Authors: Cohen Nathaniel A. , Rubin David T. 
Published: June 2021

Purpose of review
In the rapidly progressing world of inflammatory bowel disease, this review discusses and summarizes new drug targets and results from major clinical trials in order to provide an update to physicians treating patients with inflammatory bowel diseases (IBD).

Recent findings
Multiple new mechanisms in the treatment of IBD are being developed and many are showing promising results in both ulcerative colitis and Crohn's disease patients. In addition to efficacy, some of these treatments may provide safety benefits over existing therapies.

Summary
The IBD physicians’ therapeutic armamentarium is rapidly expanding and keeping abreast of these developments is required in order to provide patients with optimized individualized care.
The role of the allergist in the management of eosinophilic esophagitis
Authors: Woo Wonhee , Aceves Seema S. 
Published: June 2021

Purpose of review
The purpose of this review is to provide the current understanding of the role of allergens/antigens, the use of allergy testing, and to elucidate the role of the allergist in the management of eosinophilic esophagitis (EoE).

Recent findings
EoE is a T2 immune disorder that is part of the atopic march. EoE patients commonly have multiple concurrent allergic disorders. Recent studies demonstrate that, like other allergic diseases, epithelial barrier dysfunction plays a key role in EoE pathogenesis. Aero- and food allergens have been identified as EoE triggers. EoE management includes the assessment and avoidance of its instigating antigens. Due to the integrated T2 immune response in an allergic individual, proper EoE care should include the control of underlying atopic disorders. EoE is a complex disease that is optimally managed by a multidisciplinary approach.

Summary
This review provides an update on the role of the allergist in the clinical management of EoE.
Incorporating a Civility Program Into a Healthcare System
Authors: Garcia Mayra G. , Allen Stephanie , Griffis Leigh , Tidwell Jerithea , Watt Jennifer 
Published: June 2021

Purpose/Objectives
Incivility contributes to employee dissatisfaction, turnover, patient errors, and a disrespectful culture. Turnover rates and employee exit interviews alerted hospital leaders to uncivil behaviors exhibited by staff. A clinical nurse specialist (CNS) team captured this as an opportunity to create a civility program to develop team cohesiveness and improve patient safety. The purpose of this process improvement project was to identify uncivil behaviors in a pediatric hospital.

Description of the Project/Program
Using the Plan-Do-Study-Act model, an interprofessional team led by CNSs collaborated on a program to assess, intervene, and evaluate a program to improve civility. A preprogram survey, the Negative Acts Questionnaire-Revised, was used to assess staff perceptions of their work environment. Staff attended an education program on ways to recognize and intervene in situations involving less than standard civil behavior. Classes included communication application in uncivil situations using scenarios paired with evidence-based practice articles. Unit leaders reset behavioral expectations learned from a leader-specific class on managing unproductive behaviors.

Outcome
Staff completed a postprogram Negative Acts Questionnaire-Revised survey 6 months after conclusion of classes. Survey results indicated the civility program effected a reduction in frequency of negative behaviors indicating an overall positive shift in workplace civility.

Conclusion
The program provided staff with tools to recognize and intervene for improving civility, which impacted the overall work environment and patient safety.
Establishing Performance Evaluation for Quality Inspection of Specialty Nurses
Authors: Cai Xinying , Zheng Shaoyan , Huang Jiajia , Zheng Zeli , Xu Manqing , Wu Xiaoying , Zhou Yuhua 
Published: June 2021

Purpose
The present study aimed to establish an index system for the performance evaluation of specialty nurses (SNs) in tertiary hospitals.

Background
An objective index system for performance evaluation of SN has not yet been established in China.

Design
A 2-round Delphi survey sought opinions from experts about the index system for SNs' performance evaluation in tertiary hospitals in China.

Methods
Delphi survey was used to inquire approximately 20 experts from the fields of nursing management, nursing education, and clinical nursing. We determined the weight coefficient of each index of performance evaluation based on the opinion. Finally, the index of the quality evaluation was established for SN.

Results
A total of 20 experts from 10 provinces in China reached a consensus on the tertiary indexes of the assessment model. The indexes contained first-level (4), second-level (16), and third-level (24) indicators. The 4 aspects of the performance evaluation, including clinical specialist practice assessment, nursing research, education assessment, medical cooperation recognition, and personal comprehensive ability assessment, reached consensus.

Conclusion
Establishing the performance evaluation for SNs aided the SNs in achieving the best clinical practice after training. The performance evaluation still needed to be continuously improved.