tbuckley/cabot-search huggingface dataset:
Surfaceome CRISPR screen identifies OLFML3 as a rhinovirus-inducible IFN antagonist
Authors: Hong Mei, Zhao Zha, Wei Wang, Yusang Xie, Yuege Huang, Wenping Li, Dong Wei, Xinxin Zhang, Jieming Qu, Jia Liu
Journal: Genome biology (2021)

Abstract Background Rhinoviruses (RVs) cause more than half of common colds and, in some cases, more severe diseases. Functional genomics analyses of RVs using siRNA or genome-wide CRISPR screen uncovered a limited set of host factors, few of which have proven clinical relevance. Results Herein, we systematically compare genome-wide CRISPR screen and surface protein-focused CRISPR screen, referred to as surfaceome CRISPR screen, for their efficiencies in identifying RV host factors. We find that surfaceome screen outperforms the genome-wide screen in the success rate of hit identification. Importantly, using the surfaceome screen, we identify olfactomedin-like 3 (OLFML3) as a novel host factor of RV serotypes A and B, including a clinical isolate. We find that OLFML3 is a RV-inducible suppressor of the innate immune response and that OLFML3 antagonizes type I interferon (IFN) signaling in a SOCS3-dependent manner. Conclusion Our study suggests that RV-induced OLFML3 expression is an important mechanism for RV to hijack the immune system and underscores surfaceome CRISPR screen in identifying viral host factors.
P10.06 Affiliation to the Labour Market in Denmark for Patients Under 60 Years of Age After Diagnosis and Treatment for ALK-Positive NSCLC
Authors: J. Andersen, J. Johansen, E. Urbanska, P. Meldgaard, P. Hansen, C. Kristiansen, M. Stelmach, E. Santoni-Rugiu, B. Højgaard, M. Jensen, C. Dünweber, K. Hansen
Journal: Journal of Thoracic Oncology (2021)
Leveraging immune memory against measles virus as an antitumor strategy in a preclinical model of aggressive squamous cell carcinoma
Authors: Victoria M Leb-Reichl, Melanie Kienzl, Anna Kaufmann, Angelika Stoecklinger, Birgit Tockner, Sophie Kitzmueller, Nadja Zaborsky, Markus Steiner, Gabriele Brachtl, Lisa Trattner, Patrick Kreideweiss, Christian Reinsch, Steffen Panzner, Richard Greil, Dirk Strunk, Johann W Bauer, Iris K Gratz, Christina Guttmann-Gruber, Josefina Piñón Hofbauer
Journal: Journal for ImmunoTherapy of Cancer (2021)

Viral antigens are among the strongest elicitors of immune responses. A significant proportion of the human population already carries pre-existing immunity against several childhood viruses, which could potentially be leveraged to fight cancer. We sought to provide proof of concept in mouse models that a pre-existing measles virus (MeV) immunity can be redirected to inhibit tumor growth by directly forcing expression of cognate antigens in the tumor. To this end, we designed DNA vaccines against known MeV cytotoxic and helper T epitopes, and administered these intradermally to mice that were subsequently challenged with syngeneic squamous cancer cells engineered to either express the cognate antigens or not. Alternatively, established wild-type tumors in vaccinated animals were treated intratumorally with in vitro transcribed mRNA encoding the cognate epitopes. Vaccination generated MeV cytotoxic T lymphocyte (CTL) immunity in mice as demonstrated by enhanced interferon gamma production, antigen-specific T cell proliferation, and CTL-mediated specific killing of antigen-pulsed target cells. When challenged with syngeneic tumor cells engineered to express the cognate antigens, 77% of MeV-vaccinated mice rejected the tumor versus 21% in control cohorts. Antitumor responses were largely dependent on the presence of CD8+ cells. Significant protection was observed even when only 25% of the tumor bulk expressed cognate antigens. We therefore tested the strategy therapeutically, allowing tumors to develop in vaccinated mice before intratumoral injection with Viromer nanoparticles complexed with mRNA encoding the cognate antigens. Treatment significantly enhanced overall survival compared with controls, including complete tumor regression in 25% of mice. Our results indicate that redirecting pre-existing viral immunity to fight cancer is a viable alternative that could meaningfully complement current cancer immune therapies such as personalized cancer vaccines and checkpoint inhibitor blockade.
Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia
Authors: Tiago Oliveira, Mingfeng Zhang, Eun Ji Joo, Hisham Abdel-Azim, Chun-Wei Chen, Lu Yang, Chih-Hsing Chou, Xi Qin, Jianjun Chen, Kathirvel Alagesan, Andreia Almeida, Francis Jacob, Nicolle H Packer, Mark von Itzstein, Nora Heisterkamp, Daniel Kolarich
Journal: Theranostics (2021)

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi-omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi-omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi-omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.
37P Prognostic significance of immune checkpoint molecule expression in resectable gastric adenocarcinoma
Authors: V.M. Croitoru, A. Filippi, I.M. Cazacu, S. Kitahara, A. Matsui, G. Lauwers, A. Sorop, L.G. Necula, L. Matei, C. Pechianu, A.E. Croitoru, V. Herlea, A. Saftoiu, M. Chivu-Economescu, S. Dima, D.G. Duda, I. Popescu
Journal: Annals of Oncology (2021)
P45.18 NSCLC Patients With ALK Gene Rearrangement – Croatian Experience
Authors: L. Bitar, F. Seiwerth, G. Glodić, F. Džubur, D. Srdić, S. Smojver Ježek, L. Batelja Vuletić, M. Samaržija, M. Jakopović
Journal: Journal of Thoracic Oncology (2021)
P56.03 Prognostic Value of Tumor Spread Through Air Spaces in Patients With Lung Adenocarcinoma after Radical Surgery
Authors: S. Chen, T. Ye, F. Fu, C. Deng, H. Hu, Y. Sun, Y. Pan, Y. Zhang, J. Xiang, Y. Zhang, X. Shen, S. Wang, Z. Wang, Y. Li, H. Chen
Journal: Journal of Thoracic Oncology (2021)
MA02.05 A Phase I Study of Afatinib in Combination With Osimertinib in Patients After Failure of Prior Osimertinib
Authors: S. Miura, K. Azuma, H. Yoshioka, S. Teraoka, H. Ishii, K. Koyama, K. Kibata, Y. Ozawa, T. Tokito, Y. Koh, T. Shimokawa, T. Kurata, N. Yamamoto, H. Tanaka
Journal: Journal of Thoracic Oncology (2021)
The EHA Research Roadmap: Infections in Hematology
Authors: C Cordonnier, P Ljungman, S Cesaro, HH Hirsch, G Maschmeyer, von, Lilienfeld-Toal, M, M Vehreschild, M Mikulska, M Emonts, AR Gennery, D Neofytos, PY Bochud, H Einsele, J Maertens
Journal: HemaSphere (2021)
Relationship of 5Â-nuclotidase and deoxynucleoside kinase activity to the clinical activity of cladribine and fludarabine.
Authors: Freidoun Albertioni, Karin Karlsson, Gunnar Juliusson, Kourosh Lotfi
Journal: Cancer Research (2007)

941  In the present study we measured the basal activity of 5-nucleotidase using natural substrates and also cladribine monophosphate and fludarabine monophosphate as substrate in peripheral lymphocytes from 62 CLL patients (collected from an open randomized phase III study to evaluate the efficacy and toxicity of chlorambucil, fludarabine and cladribine as primary treatment of previously untreated patients with symptomatic B-cell CLL study), to define the relative importance and potential role of these enzymes and its connection to drug resistance. These studies show 20 fold variation in cN-1 degrading activity but the variation of cN-II was even greater, almost 50 fold. In correlating 5-nucleotidase activity to clinical outcome, we observed that those patient with high ratio of kinase activity, primarily dCK to specific nucleotidase activity (cladribine and fludarabine monophosphate degrading activity), are in remission while those who have low enzyme ratios were resistant to cladribine and fludarabine therapy. Thus the present study show that the clinical outcome of therapy in patients with CLL may be related to both enzymes. Compounds with 5-nucleotidase inhibitory effects could be interesting candidates for treatment of tumors with elevated 5-nucleotidase activity in combination with nucleoside analogues
Effects of anti-seizure medications on sleep architecture and daytime sleepiness in patients with epilepsy: A literature review
Authors: Claudio Liguori, Manuel Toledo, Sanjeev Kothare
Journal: Sleep Medicine Reviews (2021)

Anti-seizure medications (ASMs) may improve or be detrimental to sleep. A literature review (as an update to the 2014 review by Jain and Glauser [https://doi.org/10.1111/epi.12478]) of 25 ASMs of interest (articles from 12 ASMs included) on the effect of ASMs/non-drug treatments on sleep in patients with epilepsy was conducted. The most common objective instrument was polysomnography, and the most common subjective measures were the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index. Eslicarbazepine acetate, lacosamide, and perampanel improved or had no effect on sleep. Perampanel was associated with low incidence of insomnia, and lacosamide with low incidence of daytime sleepiness adverse events. Clonazepam, felbamate, lamotrigine, oxcarbazepine, and phenobarbital worsened or had no effect on sleep. Lamotrigine may be associated with insomnia risk and phenobarbital with daytime sleepiness. Data for valproic acid were mixed. Overall, cannabidiol, carbamazepine, and levetiracetam had no effect on sleep. Epilepsy surgery may benefit sleep in patients with a good surgical outcome. Some ASMs, and, possibly, epilepsy surgery, may have positive effects on sleep, possibly linked to achieving seizure control. Nonetheless, other ASMs may worsen sleep in some settings. Clinicians should consider such observations when making treatment decisions, particularly for patients with comorbid sleep disorders.
How to Interpret and Use a Clinical Practice Guideline or Recommendation
Authors: Romina Brignardello-Petersen, Alonso Carrasco-Labra, Gordon H. Guyatt
Journal: JAMA (2021)

Clinicians may rely on recommendations from clinical practice guidelines for management of patients.A clinical practice guideline is a published statement that includes recommendations that are intended to optimize patient care. In the guideline development process, a panel of experts formulates recommendation questions that guide the retrieval of evidence that is used to inform the recommendations. Typically, methods of guideline development, a summary of the supporting evidence, and a justification of the panel's decisions accompany the recommendations. To use such guidelines optimally, clinicians must understand the implications of the recommendations, assess the trustworthiness of the development process, and evaluate the extent to which the recommendations are applicable to patients in their practice settings. Helpful recommendations are clear and actionable, and explicitly specify whether they are strong or weak, are appropriate for all patients, or depend on individual patients' circumstances and values. Rigorous guidelines and recommendations are informed by appropriately conducted, up-to-date systematic reviews that consider outcomes important to patients. Because judgments are involved in the interpretation of the evidence and the process of moving from evidence to recommendations, useful guidelines consider all relevant factors that have a bearing in a clinical decision and are not influenced by conflicts of interest.In considering a guideline's recommendations, clinicians must decide whether there are important differences between the factors the guideline panel has considered in making recommendations and their own practice setting.
David Oliver: When doctors are accused of faking covid experiences
Authors: David Oliver
Journal: BMJ (2021)

In the pandemic we’ve seen repeated instances in social media, radio phone-ins, and newspapers where some members of the public, with little healthcare experience or specialist knowledge, deny point blank and challenge the stories and professional expertise of clinical staff who have cared for patients with covid-19. It’s part of a wider pattern described by leaders of the clinical royal colleges as a “sinister tide of abuse” towards NHS clinical staff,1 compounded by violence.2

Among the people admitted to hospital with severe respiratory failure from covid-19 pneumonia who have subsequently died, some had previously held strong …
Upregulated NMDAR-enhanced GABAergic transmission underlies autistic-like deficits in <i>Htr3a</i> knockout mice
Authors: Lang Huang, Jing Wang, Guanmei Liang, Yue Gao, Shi-Yang Jin, Jian Hu, Xiaoxue Yang, Jianpei Lao, Jinfa Chen, Zhou-Cai Luo, Cuixia Fan, Li Xiong, Xinhong Zhu, Tian-Ming Gao, Mei Zhong, Xinping Yang
Journal: Theranostics (2021)

Mutations in serotonin pathway genes, especially the serotonergic receptor subunit gene HTR3A, are associated with autism. However, the association of HTR3A deficiency with autism and the underlying mechanisms remain unknown. Methods: The Htr3a knockout (KO) mice were generated using transcription activator-like effector nuclease technology. Various behavior tests, including social interaction, social approach task, olfactory habituation/dishabituation, self-grooming, novel object recognition, contextual fear conditioning, elevated plus maze, open field and seizure susceptibility, were performed to assess the phenotypes. Transcriptome sequencing was carried out to search for molecular network and pathways underlying the phenotypes. Electrophysiological recordings, immunoblotting, immunofluorescence staining, immunoprecipitation, and quantitative real-time PCR were performed to verify the potential mechanisms. The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine was used to treat the KO mice for rescuing the phenotypes. Results: The Htr3a KO mouse model showed three phenotypic domains: autistic-like behaviors (including impaired social behavior, cognitive deficits, and increased repetitive self-grooming), impaired memory, and attenuated susceptibility to pentylenetetrazol-induced seizures. We observed enhanced action potential-driven γ-aminobutyric acid-ergic (GABAergic) transmission in pyramidal neurons and decreased excitatory/inhibitory (E/I) ratio using the patch-clamp recording. Transcriptome sequencing on the hippocampus revealed the converged pathways of the dysregulated molecular networks underlying three phenotypic domains with upregulation of NMDAR. We speculated that Htr3a KO promotes an increase in GABA release through NMDAR upregulation. The electrophysiological recordings on hippocampal parvalbumin-positive (PV+) interneuron revealed increased NMDAR current and NMDAR-dependent excitability. The NMDAR antagonist memantine could rescue GABAergic transmission in the hippocampus and ameliorate autistic-like behaviors of the KO mice. Conclusion: Our data indicated that upregulation of the NMDAR in PV+ interneurons may play a critical role in regulating GABAergic input to pyramidal neurons and maybe involve in the pathogenesis of autism associated with HTR3A deficiency. Therefore, we suggest that the NMDAR system could be considered potential therapeutic target for autism.
P06.02 Incorporating Surgical Collapse in the Pathological Assessment of Resected Adenocarcinoma in situ of the Lung. A Proof of Principle Study
Authors: H. Blaauwgeers, T. Radonic, B. Lissenberg-Witte, I. Bahce, J. Vincenten, C. Dickhoff, E. Thunnissen
Journal: Journal of Thoracic Oncology (2021)
MTAP gene deletions in mantle cell lymphoma are associated with lack of protein expression and shorter survival
Authors: Olga Balague, Silvia Marce, Lluis Colomo, German Ott, Lorenzo Leoni, Dolors Colomer, Elias Campo
Journal: Cancer Research (2005)

4898  Methylthioadenosine phosphorylase (MTAP) is a key enzyme of the purine salvage pathway necessary for the synthesis of AMP. The MTAP gene is located at 9p21 in proximity to the p16 gene, which is deleted in about 30% of mantle cell lymphomas (MCL). SDX-102 (L-alanosine) is a selective, non-folate inhibitor of the de novo purine biosynthesis. Tumor cells lacking MTAP rely on de novo AMP synthesis to produce ATP, and, therefore, are more sensitive to SDX-102. We have investigated the frequency of MTAP deletion in MCL, correlated the results with MTAP protein expression, and evaluated the potential prognostic value of MTAP alterations in these patients. MTAP and p16 gene deletions were examined by quantitative PCR (qPCR) in 59 MCL, 45 typical and 14 blastoid variants. MTAP protein expression was examined immunohistochemically in 24 cases using an anti-human MTAP monoclonal antibody. MTAP deletions were detected in 10 (17%) MCL, 5 (11%) typical and 5 (36%) blastoid variants. p16 gene deletions were observed in 9 (15%) primary MCL cases, all of them with codeletion of MTAP. MTAP protein was expressed in 19 tumors, all of them with wild type MTAP whereas no protein expression was detected in 5 (21%) cases. Three of them showed codeletion of MTAP and p16 genes, one case had a deletion of MTAP but not p16, and the fifth case did not show deletions of any of these genes. Patients with MTAP deletions had a significant shorter overall survival (mean 14.7 months) than patients with wild type MTAP (mean 71.7 months) (p
Agony and holiness—an alternative perspective
Authors: Ashish MacAden
Journal: BMJ (2021)

Notwithstanding the quote from Ecclesiasticus—“Death is better than a miserable life, and eternal rest than chronic sickness”—and consequent argument,1 I am compelled to counter Romain and Carey’s article on assisted dying with the disability paradox2 and my 30 years of experiences of enduring, awe inspiring, resilient holiness in scores of people with disability, including people with spinal cord injury who …
Association of Immediate Release of Test Results to Patients With Implications for Clinical Workflow
Authors: Bryan D. Steitz, Lina Sulieman, Adam Wright, Samuel Trent Rosenbloom
Journal: JAMA Network Open (2021)

This cross-sectional study assesses changes in the volume of patient-initiated messages to clinicians associated with release of test results before and after implementation of the 21st Century Cures Act.
The Saga of Thalidomide
Authors: Gilbert W. Mellin, Michael Katzenstein
Journal: New England Journal of Medicine (1962)

THE Fetal Life Study received an inquiry early in 1962 concerning the incidence of phocomelia in relation to a recent increase that had been observed in West Germany. The Fetal Life Study1 , 2 was established in 1946 in a selected population at the Columbia–Presbyterian Medical Center as a long-term prospective epidemiologic investigation of human reproduction, to determine the incidence of fetal deaths, neonatal deaths and congenital malformations and to delineate associated factors. From more than 10,000 pregnancies prospectively followed in the years 1946 to 1960, and more than 2000 followed in 1961, we were unable to find any cases of phocomelia . . .
Mechanisms of action of duodenal mucosal resurfacing in insulin resistant women with polycystic ovary syndrome
Authors: Vasha Kaur, Georgios K. Dimitriadis, Belen Pérez-Pevida, Davinder Singh Bansi, Channa Jayasena, Danielle Bate, Rhian Houghton, Barbara A. Fielding, Danai Balfoussia, Lisa Webber, Yun Miao, Frederick Mears, Nicola Jackson, Lucy Coppin, Jeremiah Perez, Megan Williams, Brett Johnson, Anne Margot Umpleby, Harpal S. Randeva, Alexander Dimitri Miras
Journal: Metabolism (2021)
Abstract P103: Genetic Analysis of Admixed US Populations Identifies Associations with Mean Corpuscular Volume
Authors: Chani J Hodonsky, Katherine K Nishimura, Ran Tao, Steve Buyske, Myriam Fornage, Lucia A Hindorff, Jonathan Kocarnik, Yun Li, Danyu Lin, Ruth J Loos, Weihong Tang, Bharat Thyagarajan, Christina L Wassel, Alex P Reiner, Kari E North, Charles L Kooperberg, Christy L Avery
Journal: Circulation (2017)

Introduction: Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index commonly used in clinical workup of anemia. Macrocytosis, or high MCV, is associated with cardiovascular events in chronic kidney disease patients and all-cause mortality. Genome-wide association studies (GWAS) of MCV have been conducted primarily in European and Asian populations; few have included populations of African or American ancestry. The Multiethnic Genotyping Array (MEGA) was designed to improve variant discovery and fine-mapping in US minorities by better capturing population-specific genetic variation. To identify novel MCV loci and examine evidence of generalization of previously reported MCV loci to populations with African and Amerindian genetic admixture, we conducted a GWAS of African American and Hispanic/Latino Population Architecture using Genomics and Epidemiology (PAGE II) participants on the MEGA array. Methods: We employed Illumina MEGA genotype data to evaluate the association between ~1.5 million SNPs and MCV. Generalized estimating equation models were adjusted for age, sex, current smoking status, study, study center, and the top 10 study-specific principal components of genetic ancestry. Race/ethnic-stratified analyses were combined using inverse-variance weighted fixed-effects meta-analysis to evaluate the entire study sample. Significance thresholds of 1.8x10 -3 and 5x10 -8 were used to define generalization and genome-wide significance, respectively. Results: The study population of 3,734 African Americans and 15,505 Hispanic/Latinos was 62% female with a mean age of 50 (range: 18 to 94 years); 19% of participants were current smokers. Trans-ethnic meta-analysis identified 12 genome-wide significant loci for MCV, including two associations at previously unreported loci: FIGNL1/IKZF1 (chromosome 7p12.2, coded allele frequency [CAF] range=51 to 57%), and LRP6 (chromosome 12p13.2, CAF range=0.3 to 1.7%). FIGNL1 is involved in DNA double-strand-break repair, and IKZF1 is a zinc-finger protein that functions in the hemo-lymphopoetic system. LRP6 encodes an LDL receptor involved in the Wnt/beta-catenin signaling cascade. Ninety-three percent of previously reported MCV loci generalized to the combined PAGE study population, ten at genome-wide significant levels. No previously unreported MCV loci were detected in race/ethnic stratified analyses. Conclusion: Generalization of previously reported MCV loci to African Americans and Hispanic/Latinos highlights the shared genetic architecture of MCV. The potentially novel associations identified at chromosomes 7p12.2 and 12p13.2 also underscore the benefits of performing GWAS in ancestrally diverse populations using arrays that better capture global genetic variation.