bluuebunny/crossref_metadata_2025 huggingface dataset:
OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME
Authors: Michaeli Orli , Ladany Hagay , Maruvka Yosef E , Erez Ayelet , Shachar Shay Ben , Izraeli Shai , Goldberg Yael , Toledano Helen
Published: June 2021

Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.
OMIC-14. OPENPBTA: AN OPEN PEDIATRIC BRAIN TUMOR ATLAS
Authors: Shapiro Joshua , Savonen Candace , Bethell Chante , Gaonkar Krutika , Zhu Yuankun , Brown Miguel , Duong Nhat , Rathi Komal , Noureen Nighat , Zhang Bo , Ennis Brian , Spielman Stephanie , Farrow Bailey , Van Kuren Nicolas , Koganti Tejaswi , Kannan Shrivats , Raman Pichai , Miller Daniel , Jain Payal , Guo Yiran , Huang Xiaoyan , Kraya Adam , Heath Allison , Koptyra Mateusz , Wong Jessica , Mason Jennifer , Robbins Shannon , Santi Mariarita , Viaene Angela , Waanders Angela , Hanson Derek , Scolaro Laura , Xie Hongbo , Zheng Siyuan , Kline Cassie , Lilly Jena , Storm Philip , Resnick Adam , Rokita Jo Lynne , Greene Casey , Taroni Jaclyn
Published: June 2021

Pediatric brain tumors comprise a heterogeneous molecular and histological landscape that challenges most current precision-medicine approaches. While recent large-scale efforts to molecularly characterize distinct histological entities have dramatically advanced the field’s capacity to classify and further define molecular subtypes, developing therapeutic and less toxic molecularly-defined clinical approaches remains a challenge. To define new approaches to meet these challenges and advance scalable, shared biospecimen- and data-resources for pediatric brain tumors, the Children’s Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium, in partnership with the Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, launched OpenPBTA, a global open science Pediatric Brain Tumor Atlas initiative to comprehensively define the molecular landscape of pediatric brain tumors. The initiative contains multi-modal analyses of research- and clinical-trial based DNA and RNA sequences from nearly 1,000 subjects (with 1,256 tumors) along with their longitudinal clinical data. The OpenPBTA’s open science framework for analysis tests the capacity of crowd-sourced collaborative architectures to advance more rapid, iterative and integrated discovery of the underlying mechanisms of disease across pediatric brain and spinal cord tumors. Since the launch of the project, OpenPBTA has collaboratively created reproducible workflows for integrated consensus SNV, CNV, and fusion calling, enabled RNA-Seq-based classification of medulloblastoma subtypes, and more than 25 additional DNA- and RNA-based analyses. The open-science platform and associated datasets and processed results provide a continuously updated, global view of the integrated cross-disease molecular landscape of pediatric brain tumors. Such biospecimen- and clinically-linked scalable data resources provide unprecedented collaborative opportunities for precision-based, personalized therapeutic discovery and drug development with the upcoming further integration of proteomic sample data (N >300) and drug response datasets, additionally diversifying the multimodal discovery potential of crowd-sourced approaches for accelerated impact for children with brain tumors.
RARE-18. NF1-MUTATED TUMORS EXHIBIT INCREASED SENSITIVITY TO AUTOPHAGY INHIBITION ALONE AND IN COMBINATION WITH MEK INHIBITION
Authors: Baird-Daniel Eliza , Zahedi Shadi , Morin Andrew , Desmarais Michelle , Williams Kyle , Williams Rory , Vibhakar Rajeev , Foreman Nicholas , Mulcahy-Levy Jean
Published: June 2021

Background

Autophagy inhibition is a potential treatment for central nervous system (CNS) tumors. Autophagy, a heavily regulated process by which cellular waste is transferred to lysosomes for degradation and processing, is an integral part of tumor cell survival under stressful conditions including nutrient deprivation and chemotherapy. While the efficacy of autophagy inhibition has been demonstrated in CNS tumors with BRAFV600e mutations, it has yet to be explored in other CNS tumor types with MAPK pathway dysregulation including NF1-mutated tumors. Many tumors associated with the NF1 phenotype can be difficult to treat surgically thus development of further pharmacologic interventions is necessary.

Methods

A CRISPR/Cas9 mediated NF1 KO was derived from human immortalized Schwann cells and utilized as a tumor model. Autophagy inhibition was achieved pharmacologically by chloroquine (CQ) and genetically via shRNAi of ATG5 and ATG7. Trametinib was used for MEK inhibition. Cell growth and viability were determined by Incucyte, Cell Titer-Glo luminescent assay, and colony-formation assays. Protein expression was measured by western blot.

Results

We demonstrate increased autophagic activity in NF1 KO cell as compared to control lines both at baseline and in response to cellular stress. Furthermore, we describe that NF1 KO cells exhibit increased sensitivity to CQ alone, CQ in combination with trametinib, and shRNAi-mediated autophagy inhibition in combination with trametinib.

Conclusion

Here, we describe increased autophagic dependence of NF1 mutated tumors and demonstrate increased tumor sensitivity to autophagy inhibition both alone and in combination with MEK inhibition. These findings indicate that autophagy inhibition via CQ may be an effective adjunctive treatment for NF1 mutated tumors and suggests that diverse CNS tumor types with MAPK pathway dysregulation are susceptible to autophagy inhibition. Clinical investigation of combined MEK and autophagy inhibition has the potential to improve outcomes for NF1 patients with CNS tumors.
RARE-21. A RARE CASE OF PEDIATRIC SPINDLE CELL ONCOCYTOMA WITH EML4-ALK FUSION
Authors: Michaiel George , Hawes Debra , Guzman Samuel , Margol Ashley , Biegel Jaclyn , Ji Jianling
Published: June 2021

A 12 year-old male presented with a 2-month history of intermittent headaches, nausea, and vomiting. Magnetic resonance imaging (MRI) of the brain revealed a 2.2 x 3.5 x 2.6 cm lobulated, sellar/suprasellar mass, mildly T1/T2 hyperintense, with mild homogeneous enhancement and diffusion restriction. He underwent transsphenoidal and right craniotomies for gross total resection of the mass. Pathology demonstrated a hypercellular neoplasm with spindled to ovoid tumor cells arranged in fascicles and tight whirls, consistent with a spindle cell oncocytoma. OncoKids, a DNA- and RNA-based next generation sequencing panel, demonstrated an in-frame EML4 exon 2-ALK exon 19 fusion with a total of 179,872 supporting reads. The EML4-ALK fusion gene is predicted to encode a chimeric tyrosine kinase that facilitates multimerization and autophosphorylation of ALK, and activates its downstream targets, such as RAS/ERK, PI3K/AKT, and JAK/STAT pathways. This fusion is found in approximately 5% of patients with non-small cell lung cancer, a subset of inflammatory myofibroblastic tumors, as well as single cases of pulmonary atypical carcinoid, cholangiocarcinoma, and high-grade glioma. However, it has not been previously described in oncocytoma. Chromosomal microarray analysis demonstrated two interstitial non-contiguous deletions in 2p, and an interstitial deletion in 18q that does not include any known cancer-related genes. The deleted segment in 2p23.3p23.2 includes DNMT3A, which mediates DNA methylation and functions in modification of gene expression. DNMT3A mutations are frequent in hematological malignancies, however their role in oncocytoma is currently unknown. The proximal breakpoint of the deletion in 2p23.3p23.2 is in close proximity to but does not reside within ALK. Spindle cell oncocytoma is rarely reported in the pediatric population, with only one case described in the literature. This is the first case report of an oncocytoma with an EML4-ALK fusion. Additional studies are warranted to confirm its functional effect.
EPCT-01. A NOVEL PEPTIDE VACCINE DIRECTED TO CMV PP65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL
Authors: Thompson Eric , Landi Daniel , Archer Gerald , Lipp Eric , Walter Ashley , Archambault Bridget , Balajonda Bea , Flahiff Charlene , Jaggers Denise , Herndon James , Buckley Evan , Schroeder Kristin , Randazzo Dina , Desjardins Annick , Johnson Margaret , Peters Katherine , Khasraw Mustafa , Malinzak Michael , Michell Duane , Ashley David , Sampson John
Published: June 2021

Introduction

The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma.

Methods

Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly.

Results

To date, 22 patients have been enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=12), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=3), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 45% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 1.7,4.5) and median OS is 6.5 months (95% CI 3.3, 7.9). Immune response to pp65 as determined by ELISpot was found in 75% of patients. On MRI 6 of the 11 evaluable patients have had at least stable disease with three of those having a partial response.

Conclusions

Preliminary results demonstrate that PEP-CMV is well-tolerated and elicits an immune response in heavily pretreated, multiply recurrent patients. A multi-institutional Phase II trial is scheduled to open fall 2021.
EPCT-16. LENALIDOMIDE ACTIVITY IN PILOCYTIC ASTROCYTOMA AND OPTIC PATHWAY GLIOMAS: REPORT ON CHILDREN’S ONCOLOGY GROUP ACNS1022
Authors: Warren Katherine , Vezina Gilbert , Springer Linda , Buxton Allen , Peer Cody , Figg W Douglas , Fouladi Maryam , Gajjar Amar , Krailo Mark , Bowers Daniel
Published: June 2021

Children with low-grade glioma have excellent survival rates but often suffer from the morbidity of treatment, particularly from cytotoxic chemotherapies. Targeted agents appear to have some activity but the long-term effects of inhibiting normal developmental pathways are unknown. Lenalidomide is an oral immunomodulatory agent with additional properties including anti-angiogenesis. Phase I studies indicated greater tolerability of this agent compared to adults, and a potential dose-response effect. We performed a Phase 2 trial of lenalidomide in children with pilocytic astrocytoma and optic pathway gliomas who failed initial therapy. The primary objective was to determine the objective response rate of children randomized to Regimen A low-dose (20 mg/m2 /dose) or Regimen B high-dose (115 mg/m2 /dose) lenalidomide, each administering lenalidomide daily x 21 days of each 28-day course. Secondary objectives included estimation of event-free survival (EFS) in this population and correlation of plasma lenalidomide concentration with toxicity and outcome.

Results

74 eligible patients were enrolled (n=37 to each arm). The pre-defined activity level of interest was achieved for both arms. Objective responses were observed in both arms, with 4 partial responses in each. A total of n=18 patients completed 26 courses of therapy (Arm A, n=12, Arm B, n=6) The median number of courses on each arm was 14 (range 2–26) for Arm A and 11 for Arm B (range 1- 26). Of the 74 eligible patients who received study drug, 30 required a dose reduction for toxicity (Arm A, n=6, Arm B, n=24) and 16 discontinued treatment on protocol due to toxicity (Arm A, n=2, Arm B, n=14).

Conclusion

Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration in Phase 3 studies. Low-dose (20 mg/m2) lenalidomide appears to have better tolerability.
EPCT-18. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY FOR RECURRENT, REFRACTORY, OR PROGRESSIVE EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG) AND NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Plant Ashley , Goldman Stewart , Lam Sandi , DeCuypere Michael , Stein Gregory , Brenner Andrew
Published: June 2021

Ependymoma, HGG, and DIPG are gliomas that are often difficult to treat, frequently aggressive, and often carry an extremely poor prognosis. While external beam radiation therapy (EBRT) remains a central component of the management of pediatric gliomas, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. In a Phase 1 trial in adults with recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor when coverage was 75% or greater (n=10) was 392 Gy (CI 306 – 478). Thus far, the therapy has been well tolerated, no dose-limiting toxicity has been observed, and no treatment-related serious adverse events have occurred despite markedly higher absorbed doses than typically delivered by EBRT (n=18).

Methods

This is a two-part, Phase 1 dose-finding study followed by an expansion cohort to explore efficacy. Part 1 will enroll up to 18 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by convection enhanced delivery (CED). Tumor size will be limited to a diameter of 4 cm in the longest axis and a volume of 34 mL. The dose limiting toxicity period (DLT) is 28 days post infusion. Part 2 will independently evaluate 186RNL in 3 different cohorts: Cohort A: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive ependymoma; Cohort B: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive HGG; Cohort C: up to 15 subjects with newly diagnosed DIPG. The primary endpoint is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. Secondary endpoints are PFS-24 and OS-24 in Cohort A and PFS-12 and OS-12 in Cohorts B and C. Planned enrollment will begin in H2 2021.
EPCT-21. NEXT-GENERATION SEQUENCING OF CEREBROSPINAL FLUID FOR CLINICAL MOLECULAR DIAGNOSTICS IN ADOLESCENT AND YOUNG ADULT (AYA) BRAIN TUMOR PATIENTS
Authors: Miller Alexandra , Szalontay Luca , Bouvier Nancy , Ahmed Hamza , Hill Katherine , Rafailov Johnathan , Lee Alex , Rodriguez-Sanchez Irene , Yildirim Onur , Patel Arti , Bale Tejus , Benayed Ryma , Arcila Maria , Donzelli Maria , Dunkel Ira , Gilheeney Stephen , Khakoo Yasmin , Kramer Kim , Sait Sameer F , Greenfield Jeffrey , Souweidane Mark , Haque Sofia , Mauguen Audrey , Berger Michael , Mellinghoff Ingo , Karajannis Matthias
Published: June 2021

Purpose

Pediatric central nervous system tumors remain a leading cause of cancer-related death in children and adolescents. Safe sampling of tumor tissue for diagnostic purposes may be challenging. Subclinical detection of disease prior to clinical or imaging progression may provide opportunity for earlier intervention and ultimately improve overall survival. Additionally, our understanding of molecular evolution in response to therapy remains limited, given the rarity of serial sampling of tumor tissue.

Methods

We report our experience with minimally invasive molecular diagnostics using a validated next generation sequencing assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) obtained at the time of surgery, by intraventricular catheter or lumbar puncture. All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families.

Results

We analyzed 64 CSF samples from 45 pediatric and adolescent and young adult (AYA) patients (pediatric=25; AYA=20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n=10), medulloblastoma (n=10), pineoblastoma (n=5), low grade glioma (n=4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n=4), metastatic retinoblastoma (n=4), ependymoma (n=3), and other (n=5). Somatic alterations were detected in 28/64 samples (44.4%) and in at least one sample per unique patient in 22/45 patients (48.8%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (86.3%). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient’s disease course.

Conclusion

We identified four general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: 1) diagnosis; 2) identification of actionable alterations; 3) track response to therapy; and 4) monitoring tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population that may improve care.
Plasma IL-8 and ICOSLG as prognostic biomarkers in glioblastoma
Authors: Holst Camilla Bjørnbak , Christensen Ib Jarle , Vitting-Seerup Kristoffer , Skjøth-Rasmussen Jane , Hamerlik Petra , Poulsen Hans Skovgaard , Johansen Julia Sidenius
Published: June 2021

Background

CNS immune privilege has been challenged in recent years. Glioblastoma (GBM) immune dysfunction includes complex interactions with the immune system outside the CNS. The aim of this study was to determine diagnostic and prognostic potential of immune-related proteins in plasma in GBM and interrogate biomarker presence in the brain tumor microenvironment (TME).

Methods

One hundred and fifty-eight patients with glioma WHO grade II–IV were included. Plasma collected at surgery was screened for 92 proteins using proximity extension assay technology and related to clinical outcome. Secretion and expression of candidate prognostic biomarkers were subsequently analyzed in 8 GBM cell lines and public RNAseq data.

Results

Plasma levels of 20 out of 92 screened proteins were significantly different in patients with GBM compared to patients with astrocytoma WHO grade II–III. High plasma interleukin-8 (IL-8) (hazard ratio [HR] = 1.52; P = .0077) and low CD244 (HR = 0.36; P = .0004) were associated with short progression-free survival and high plasma IL-8 (HR = 1.40; P = .044) and low ICOS ligand (ICOSLG) (HR = 0.17; P = .0003) were associated with short overall survival (OS) in newly diagnosed patients with GBM. A similar trend was found for ICOSLG (HR = 0.34; P = .053) in recurrent GBM. IL-8 was mostly secreted and expressed by mesenchymal GBM cell lines and expressed by vascular cells and immune cells in the TME. This was also the case for ICOSLG, although less consistent, and with additional expression in tumor-associated oligodendrocytes.

Conclusions

High plasma IL-8 and low ICOSLG at surgery are associated with short OS in newly diagnosed GBM. Source of plasma ICOSLG may be found outside the TME.
Waterpipe Tobacco Warnings: An Experimental Study Among a Nationally Representative Sample of US Young Adults
Authors: Sutfin Erin L , Lazard Allison J , Cornacchione Ross Jennifer , Noar Seth M , Reboussin Beth A
Published: June 2021

Background

Waterpipe tobacco (WT) smoking by young adults remains high and misperceptions are common. Product warnings can increase knowledge of harms and reduce use. The goal of this study was to test warning statements, including the FDA-required nicotine warning (prior to implementation), on young adults’ thinking about harms of and discouragement from WT smoking.

Methods

We conducted a between-subjects experiment in a nationally representative telephone survey of 1152 young adults aged 18–29. Participants were randomly assigned to hear one of five warning statements and reported how much, on a 4-point scale, the warning made them think about the harms and discouraged them from WT smoking.

Results

The sample was 36.8% female, 57.8% white, 20.2% Black, 24.1% Hispanic, with a mean age of 23.2 (SE = 0.25). Under half (43.5%) had ever smoked WT. There were significant differences among the statements on both thinking about harms (p < .0001) and discouragement (p < .0001). The FDA-required “nicotine” warning led to the lowest thinking about harms (M = 2.85, SE = 0.08) and was the least discouraging (M = 2.86, SE = 0.08), while the “100 cigarettes” warning resulted in the greatest thinking about harms (M = 3.62, SE = 0.05) and was the most discouraging (M = 3.56, SE = 0.06).

Conclusions

The nicotine warning resulted in the lowest levels of thinking about harms and discouragement from WT smoking, suggesting limited impact. However, a warning focused on comparing smoke inhalation from WT smoking to cigarettes seems promising. Warnings should cover a broad range of WT health effects, and possibly comparisons to cigarettes. Findings also have implications for the content of international waterpipe warnings.

Implications

This study indicates that the nicotine warning is the least effective at making young adults think about the harms of and discouraging WT smoking. The FDA and other countries should consider requiring warnings to cover a broader range of health harms, misperceptions, and possibly comparisons to cigarettes.
Comparative Analysis of Host Range, Ability to Infect Tomato Cultivars with Tm-22 Gene, and Real-Time Reverse Transcription PCR Detection of Tomato Brown Rugose Fruit Virus
Authors: Chanda Bidisha , Gilliard Andrea , Jaiswal Namrata , Ling Kai-Shu
Published: June 2021

Tomato (Solanum lycopersicum L.) is one of the most important vegetables in the world. However, tomato is also susceptible to many viral diseases. Several tobamoviruses, including tomato mosaic virus (ToMV), tomato mottle mosaic virus (ToMMV), and tomato brown rugose fruit virus (ToBRFV), are highly contagious pathogens that could result in significant economic losses if not controlled effectively. Tobamoviruses have been managed relatively well with broad adaptation of tomato cultivars with resistance genes. However, emergence of ToBRFV was shown to break down resistance conferred by the common resistance genes, resulting in serious outbreaks in many countries in Asia, Europe, and North America. The objective of this study was to conduct a comparative analysis of biological properties, including host range and disease resistance of ToMV, ToMMV, and ToBRFV. Results showed that despite many similarities in the host range, there were some unique host plant responses for each of the three viruses. In a comparative evaluation of disease resistance using the same tomato cultivars with or without Tm-22 gene, there was a striking difference in responses from tomato plants with Tm-22 gene inoculated with ToBRFV, ToMV, or ToMMV. Whereas these test plants were resistant to ToMV or ToMMV infection, all test plants were susceptible to ToBRFV. Further, for ToBRFV detection, a sensitive and reliable multiplex real-time reverse transcription (RT)-PCR assay using TaqMan probe with an internal 18S rRNA control was also developed. With simple modifications to RNA extraction and seed soaking, real-time RT-PCR could consistently detect the virus in single infested seed in varied levels of contamination, suggesting its usefulness for seed health assay.
The Aquaporin TaPIP2;10 Confers Resistance to Two Fungal Diseases in Wheat
Authors: Wang Xiaobing , Lu Kai , Yao Xiaohui , Zhang Liyuan , Wang Fubin , Wu Degong , Peng Jinfeng , Chen Xiaochen , Du Junli , Wei Jiankun , Ma Jingyu , Chen Lei , Zou Shenshen , Zhang Chunling , Zhang Meixiang , Dong Hansong
Published: June 2021

Plants employ aquaporins (AQPs) of the plasma membrane intrinsic protein (PIP) family to import environmental substrates, thereby affecting various processes, such as the cellular responses regulated by the signaling molecule hydrogen peroxide (H2O2). Common wheat (Triticum aestivum) contains 24 candidate members of the PIP family, designated as TaPIP1;1 to TaPIP1;12 and TaPIP2;1 to TaPIP2;12. None of these TaPIP candidates have been characterized for substrate selectivity or defense responses in their source plant. Here, we report that T. aestivum AQP TaPIP2;10 facilitates the cellular uptake of H2O2 to confer resistance against powdery mildew and Fusarium head blight, two devastating fungal diseases in wheat throughout the world. In wheat, the apoplastic H2O2 signal is induced by fungal attack, while TaPIP2;10 is stimulated to translocate this H2O2 into the cytoplasm, where it activates defense responses to restrict further attack. TaPIP2;10-mediated transport of H2O2 is essential for pathogen-associated molecular pattern-triggered plant immunity (PTI). Typical PTI responses are induced by the fungal infection and intensified by overexpression of the TaPIP2;10 gene. TaPIP2;10 overexpression causes a 70% enhancement in wheat resistance to powdery mildew and an 86% enhancement in resistance to Fusarium head blight. By reducing the disease severities, TaPIP2;10 overexpression brings about >37% increase in wheat grain yield. These results verify the feasibility of using an immunity-relevant AQP to concomitantly improve crop productivity and immunity.
Microsatellite Markers fromPeronospora tabacina, the Cause of Blue Mold of Tobacco, Reveal Species Origin, Population Structure, and High Gene Flow
Authors: Nowicki Marcin , Hadziabdic Denita , Trigiano Robert N. , Runge Fabian , Thines Marco , Boggess Sarah L. , Ristaino Jean , Spring Otmar
Published: June 2021

Peronospora tabacina is an obligate parasite that causes blue mold of tobacco. The pathogen reproduces primarily by sporangia, whereas the sexual oospores are rarely observed. A collection of 122 isolates of P. tabacina was genotyped using nine microsatellites to assess the population structure of individuals from subpopulations collected from central, southern, and western Europe; the Middle East; Central America; North America; and Australia. Genetic variations among the six subpopulations accounted for ∼8% of the total variation, including moderate levels of genetic differentiation, high gene flow among these subpopulations, and a positive correlation between geographic and genetic distance (r = 0.225; P < 0.001). Evidence of linkage disequilibrium (P < 0.001) showed that populations contained partially clonal subpopulations but that subpopulations from Australia and Mediterranean Europe did not. High genetic variation and population structure among samples could be explained by continuous gene flow across continents via infected transplant exchange and/or long-distance dispersal of sporangia via wind currents. This study analyzed the most numerous P. tabacina collection and allowed conclusions regarding the migration, mutation, and evolutionary history of this obligate biotrophic oomycete. The evidence pointed to the species origin in Australia and identified intracontinental and intercontinental migration patterns of this important pathogen.

[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
A Ricin B-Like Lectin Protein Physically Interacts with TaPFT and Is Involved in Resistance to Fusarium Head Blight in Wheat
Authors: Song Puwen , Zhang Lufan , Wu Liuliu , Hu Haiyan , Liu Qili , Li Dongxiao , Hu Ping , Zhou Feng , Bu Ruifang , Wei Qichao , Yu Yongang , Guan Yuanyuan , Chen Eryong , Su Xiaojia , Huang Zhongwen , Qiao Mei , Ru Zhengang , Li Chengwei
Published: June 2021

Fusarium head blight (FHB), mainly caused by Fusarium graminearum, has become one of the most serious diseases that damage wheat. The TaPFT (pore-forming toxin-like) and TaHRC (histidine-rich calcium-binding protein) genes at the quantitative trait locus Fhb1 were identified to confer resistance to FHB in the wheat cultivar Sumai 3. In this study, a wheat ricin B-like lectin gene (designated TaRBL) that interacted with TaPFT was isolated by a yeast two-hybrid screen of a wheat cDNA library. A yeast two-hybrid and bimolecular fluorescence complementation study further verified that TaRBL interacted with TaPFT but not with TaHRC. Gene expression studies showed that upon F. graminearum infection, TaRBL expression was upregulated in resistant cultivars but downregulated in susceptible cultivars. Furthermore, knockdown of TaRBL expression by barley stripe mosaic virus-induced gene silencing significantly reduced the resistance of wheat to FHB in both the resistant cultivar Sumai 3 and the susceptible cultivar Jimai 22. Thus, we conclude that TaRBL encodes a ricin B-like lectin protein that interacts with TaPFT and is involved in resistance to FHB in wheat.
Distal Transradial (Snuffbox) Access for Coronary Catheterization: A Systematic Review
Authors: Didagelos Matthaios , McEntegart Margaret , Kouparanis Antonios , Tsigkas Grigorios , Koutouzis Michael , Tsiafoutis Ioannis , Kassimis Georgios , Oldroyd Keith G. , Ziakas Antonios
Published: June 2021

Distal transradial access, through puncture of the radial artery at its course in the anatomical snuffbox, has emerged recently as an alternative approach for coronary catheterization. Several advantages of this approach seem promising and several studies are trying to elucidate its features. This review provides an overview of the snuffbox approach for coronary catheterization and summarizes the key results of the research conducted so far.
Goiter disease in traditional Chinese medicine: Modern insight into ancient wisdom
Authors: Lee Chen-Hsen , Chiu Jen-Hwey
Published: June 2021

Goiter is a disease with history perhaps as long as human has been around. Almost all the available references are in Western language works of literature while information concerning the occurrence of goiter disease in ancient China and the comparison between the treatment in traditional Chinese medicine (TCM) with current Western medicine remains lacking. In this article, the description of goiter, the history of surgical intervention for goiter disease, and the general concept of goiter disease treatment in ancient China literature such as seaweed decoction and acupuncture analgesia for surgery were reviewed.
The Value of Including the Nursing Perspective in the Boardroom
Authors: Harper Kimberly J. , Benson Laurie S.
Published: June 2021

In response to the Future of Nursing Report, the Nurses on Boards Coalition promotes the health of communities and the nation by engaging nurses in board service. Nurses possess knowledge and skills that when leveraged in boardroom discussions and decisions may impact the health of the populations served by the board. This article highlights the insights of organizational board leaders, as they describe the impact and influence of nurse board members within their organizations.
Malar stripe size and prominence in peregrine falcons vary positively with solar radiation: support for the solar glare hypothesis
Authors: Vrettos Michelle , Reynolds Chevonne , Amar Arjun
Published: June 2021

Many falcons (Falcospp.) exhibit a distinct dark plumage patch below the eye, termed the malar stripe. This stripe is hypothesized to reduce the amount of solar glare reflected into the eyes while foraging, thereby increasing hunting efficiency in bright conditions. Here, we use a novel, global-scale correlative approach to test this ‘solar glare hypothesis' in peregrine falcons (Falco peregrinus), the most widespread falcon species, using web-sourced photographs from across the species' global range. We found that the size and prominence of the malar stripe were positively associated with average annual solar radiation, but not with other environmental variables, such as temperature and rainfall. Our results provide the first published evidence for the hypothesis that this plumage feature functions to reduce the amount of solar glare reflected into the falcon's eyes, thereby improving the ability to pinpoint and target agile prey in bright conditions.
Health expenditure among the outpatient of type-2 diabetes in selected hospital of Kathmandu district: A cross sectional study
Authors: Shrestha Rasmita , Shakya Aditya
Published: June 2021

Introduction

Out of Pocket (OOP) expenditure is the dominant financing mechanism in the low and middle-income countries. In these countries the prevalence of diabetes has been rising more rapidly which can lead to various micro-vascular complications thus increasing the risk of dying prematurely.

Methods

A cross-sectional - comparative and hospital-based study was carried out in which OOP expenditure of diabetic patient treating in public and private hospital was compared. A total of 154 diabetic patients i.e.77 in each type of hospitals were selected purposively in consultation with attending physician and staffs. Face to face interview was done to diabetic patient with a minimum of one year of illness using structured questionnaire. Lorentz curve and concentration curve were prepared using income and expenditure of the patients.

Result

Among154 patients, 97.4% patients had paid out of pocket for the treatment of diabetes. Mean direct cost per month was NRs. 7312.17 in public and NRs. 10125.31 in private hospital. Direct medical cost had higher share in total direct cost i.e. 60.5% in public and 69.3 % in private hospital. Medicine cost had higher percentage share (50.9%) in public hospital and laboratory cost had higher percentage share (68%) in private hospital.

Conclusion

Direct medical cost was higher in private hospital as compared to public hospital. All the income groups have to pay similar amount of money for the treatment i.e. economic burden for the treatment of disease was found higher for the poor people as there was not any financial protection mechanism.
Policy and Effectiveness of Covid-19 Response
Authors: Dolgikh Serge
Published: June 2021

A comparative analysis of selected national jurisdictions with respect to Covid-19 policy response indicated that factors such as effective communications and effective targeted intervention in the environments of higher epidemiological risk can be the key factors in the overall effectiveness of the epidemiological response minimizing both the impact of the epidemics and disruptions in the life of the society.
Impact of vaccination and undetected cases on the COVID-19 pandemic dynamics in Qatar in 2021
Authors: Nesteruk Igor
Published: June 2021

The third COVID-19 pandemic wave in Qatar was simulated with the use of the generalized SIR-model and the accumulated number of cases reported by Johns Hopkins University for the period: April 25 - May 8, 2021. Comparison with the SIR-curves calculated before for the second wave showed that the effect of mass vaccination is not evident during 4 months after its onset in December 2020. Additional simulations have demonstrated that many COVID-19 cases are not detected. The real accumulated number of cases can exceed the laboratory-confirmed one more than 5 times. This fact drastically increases the probability of meeting an infectious person and the epidemic duration.
Development of a Deep Learning Model for Early Alzheimer’s Disease Detection from Structural MRIs and External Validation on an Independent Cohort
Authors: Liu Sheng , Masurkar Arjun V. , Rusinek Henry , Chen Jingyun , Zhang Ben , Zhu Weicheng , Fernandez-Granda Carlos , Razavian Narges ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2021

Early diagnosis of Alzheimer’s disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimer’s disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimer’s Coordinating Center (NACC). The deep-learning model is more accurate and significantly faster than the volume/thickness model. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimer’s disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimer’s disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimer’s disease, and leverage them to achieve accurate early detection of the disease.
A meta-analysis of polygenic risk scores for mood disorders, neuroticism, and schizophrenia in antidepressant response
Authors: Fanelli Giuseppe , Domschke Katharina , Minelli Alessandra , Gennarelli Massimo , Martini Paolo , Bortolomasi Marco , Maron Eduard , Squassina Alessio , Kasper Siegfried , Zohar Joseph , Souery Daniel , Montgomery Stuart , Albani Diego , Forloni Gianluigi , Ferentinos Panagiotis , Rujescu Dan , Mendlewicz Julien , Ronchi Diana De ,   European College of Neuropsychopharmacology (ECNP) Pharmacogenomics & Transcriptomics Thematic Working Group, Baune Bernhard T , Serretti Alessandro , Fabbri Chiara
Published: June 2021

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p=0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11-1.98, p=0.007). Nominal associations were also found between MDD-PRS and non-response (p=0.013), as well as between SCZ-PRS and non-remission (p=0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.
High concordance of 70-gene recurrence risk signature and 80-gene molecular subtyping signature between core needle biopsy and surgical resection specimens in early-stage breast cancer
Authors: Crozier Jennifer A. , Barone Julie , Whitworth Pat , Cheong Abraham , Maganini Robert , Falk Jeffrey , Wei Jia-Perng , Mee Sammy , Ruby Jake , Yang Suoyi , Huynh Yen , Witteveen Anke , Finn Christine , Corcoran Kate , Dreezen Christa , Dauer Patricia , Menicucci Andrea , Wang Shiyu , Tran Annie , Yoder Erin , van der Baan Bastiaan , Audeh William , Glas Annuska ,   FLEX Investigators Group
Published: June 2021

Introduction

With an increase in neoadjuvant therapy recommendations for most early-stage breast cancer patients due to the COVID-19 pandemic, it has become increasingly imperative to ensure that molecular diagnostic assays provide reliable results from preoperative core needle biopsies. Therefore, the objective of this study was to determine the concordance of MammaPrint results (70-gene signature) and BluePrint results (80-gene signature) between core needle biopsies (CNB) and surgical resection (SR) specimens using prospectively collected matched tissues from patients enrolled in the FLEX trial (NCT03053193).

Methods

We analyzed 113 matched CNB and SR tumor specimens from women with early-stage breast cancer enrolled in the FLEX trial. Each patient enrolled in the trial receives a MammaPrint recurrence risk classification test with or without BluePrint molecular subtyping. Concordance of MammaPrint is reported using overall percentage agreement, positive predictive value (PPV, High Risk), negative predictive value (NPV, Low Risk), and Cohen’s kappa coefficient. Additionally, correlations between sample types are reported using Pearson correlation coefficient.

Results

We found good concordance for MammaPrint results between CNB and SR tumor samples (90.3%, κ = 0.803), with a 95.1% NPV and 84.6% PPV. There was also a strong correlation of MammaPrint indices between CNB and SR specimens (r = 0.94). In addition to our primary objective, we determined the concordance of BluePrint subtyping in the matched tumor samples, and found excellent concordance (98.2%) and strong correlation of BluePrint scores within each subtype.

Conclusion

CNB samples demonstrated overall high concordance with paired SR samples for MammaPrint risk classification, ensuring that physicians are provided with accurate prognostic information for therapy decisions based on testing of core biopsy tissue. Further, BluePrint molecular subtyping also had good concordance between the sample types, outperforming concordance rates based on traditional IHC based classification. Overall, with an increase in neoadjuvant therapy, physicans and patients can be assured that MammaPrint and BluePrint provide reliable results that guide timely and appropriate therapies using preoperative CNB specimens.
Variation in the reporting of elective surgeries and its influence on patient safety indicators
Authors: Locey Kenneth J. , Webb Thomas A. , Farooqui Sana , Hota Bala
Published: June 2021

Background

US hospital safety is routinely measured via patient safety indicators (PSIs). Receiving a score for most PSIs requires a minimum number of qualifying cases, which are partly determined by whether the associated diagnosis-related group (DRG) was surgical and whether the surgery was elective. While these criteria can exempt hospitals from PSIs, it remains to be seen whether exemption is driven by low volume, small numbers of DRGs, or perhaps, policies that determine how procedures are classified as elective.

Methods

Using Medicare inpatient claims data from 4,069 hospitals between 2015 and 2017, we examined how percentages of elective procedures relate to numbers of surgical claims and surgical DRGs. We used a combination of quantile regression and machine learning based anomaly detection to characterize these relationships and identify outliers. We then used a set of machine learning algorithms to test whether outliers were explained by the DRGs they reported.

Results

Average percentages of elective procedures generally decreased from 100% to 60% in relation to the number of surgical claims and the number of DRGs among them. Some providers with high volumes of claims had anomalously low percentages of elective procedures (5% – 40%). These low elective outliers were not explained by the particular surgical DRGs among their claims. However, among hospitals exempted from PSIs, those with the greatest volume of claims were always low elective outliers.

Conclusion

Some hospitals with relatively high numbers of surgical claims may have classified procedures as non-elective in a way that ultimately exempted them from certain PSIs.
Disease correlates of quantitative susceptibility mapping rim lesions in multiple sclerosis
Authors: Marcille Melanie , Rúa Sandra Hurtado , Tyshkov Charles , Jaywant Abhishek , Comunale Joseph , Kaunzner Ulrike W. , Nealon Nancy , Perumal Jai S. , Zexter Lily , Zinger Nicole , Bruvik Olivia , Wang Yi , Sweeney Elizabeth , Kuceyeski Amy , Nguyen Thanh D. , Gauthier Susan A.
Published: June 2021

Objective

This study aimed to explore the association between chronic active rim+ lesions, identified as having a hyperintense rim on quantitative susceptibility mapping (QSM), on both clinical disability and imaging measures of neurodegeneration in patients with multiple sclerosis.

Methods

The patient cohort was composed of 159 relapsing remitting multiple sclerosis patients aged 42.17 ± 10.25 years and disease duration of 10.74 ± 7.51 years. The Brief International Cognitive Assessment for Multiple Sclerosis and Expanded Disability Status Scale (EDSS) were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration.

Results

A total of 4,469 multiple sclerosis lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.9%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p=0.010), California Verbal Learning Test-II (p=0.030), and EDSS (p=0.001). In a separate univariate regression model, controlling for age (p<0.001), having at least one rim+ lesion was related to more cortical thinning (p= 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p=0.038) and larger total lesion burden (p<0.001) however, the association did not remain significant with rim+ lesions (p=0.10).

Interpretation

Our findings demonstrate the significant impact of chronic active lesions, as identified on QSM, on both clinical disability and imaging measures of neurodegeneration in patients with multiple sclerosis.