tbuckley/cabot-search huggingface dataset:
Immunological effects of adjuvanted low‐dose allergoid allergen‐specific immunotherapy in experimental murine house dust mite allergy
Authors: Alexander Heldner, Francesca Alessandrini, Dennis Russkamp, Sonja Heine, Benjamin Schnautz, Adam Chaker, Juliet Mwange, Thalia L. Carreno Velazquez, Matthew D. Heath, Murray A. Skinner, Matthias F. Kramer, Ulrich M. Zissler, Carsten B. Schmidt‐Weber, Simon Blank
Journal: Allergy (2021)

Abstract Background Native allergen extracts or chemically modified allergoids are routinely used to induce allergen tolerance in allergen‐specific immunotherapy (AIT), although mechanistic side‐by‐side studies are rare. It is paramount to balance optimal dose and allergenicity to achieve efficacy warranting safety. AIT safety and efficacy could be addressed by allergen dose reduction and/or use of allergoids and immunostimulatory adjuvants, respectively. In this study, immunological effects of experimental house dust mite (HDM) AIT were investigated applying high‐dose HDM extract and low‐dose HDM allergoids with and without the adjuvants microcrystalline tyrosine (MCT) and monophosphoryl lipid A (MPL) in a murine model of HDM allergy. Methods Cellular, humoral, and clinical effects of the different AIT strategies were assessed applying a new experimental AIT model of murine allergic asthma based on physiological, adjuvant‐free intranasal sensitization followed by subcutaneous AIT. Results While low‐dose allergoid and high‐dose extract AIT demonstrated comparable potency to suppress allergic airway inflammation and Th2‐type cytokine secretion of lung‐resident lymphocytes and draining lymph node cells, low‐dose allergoid AIT was less effective in inducing a potentially protective IgG1 response. Combining low‐dose allergoid AIT with MCT or MCT and dose‐adjusted MPL promoted Th1‐inducing mechanisms and robust B‐cell activation counterbalancing the allergic Th2 immune response. Conclusion Low allergen doses induce cellular and humoral mechanisms counteracting Th2‐driven inflammation by using allergoids and dose‐adjusted adjuvants. In light of safety and efficacy improvement, future therapeutic approaches may use low‐dose allergoid strategies to drive cellular tolerance and adjuvants to modulate humoral responses.
Statins as adjunct therapy in COPD: is it time to target innate immunity and cardiovascular risk?
Authors: Robert P. Young, Raewyn J. Scott
Journal: European Respiratory Journal (2021)

<b>COPD exacerbations are associated with considerable morbidity and mortality. In a well-designed RCT, Schenk and colleagues show that simvastatin reduces COPD exacerbations by 23% relative to placebo in patients optimised on preventive inhaler therapy.</b>https://bit.ly/2NAFM2v
RETRACTED: Liposomal valinomycin mediated cellular K+ leak promoting apoptosis of liver cancer cells
Authors: Qian-Wen Zhang, Mirza Muhammad Faran Ashraf Baig, Tian-Qi Zhang, Ting-Ting Zhai, Xiang Qin, Xing-Hua Xia
Journal: Journal of Controlled Release (2021)
MO18-7 Combinatorial treatments of aspirin with glutaminolysis-targeting agents against PIK3CA-mutated colorectal cancer cells
Authors: Shogen Boku, Motoki Watanabe, Mamiko Sukeno, Takeshi Yaoi, Kiichi Hirota, Mahiro Iizuka, Kyoko Itoh, Yoshihiro Sowa, Yosuke Iizumi, Mitsuharu Masuda, Takumi Narita, Takahiro Hamoya, Toshiyuki Sakai, Michihiro Mutoh
Journal: Annals of Oncology (2021)
Covid-19: Experts condemn UK “freedom day” as dangerous and unethical
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: Experts condemn UK "freedom day" as dangerous and unethical Elisabeth MahaseInternational health leaders have raised significant concerns over the UK government's relaxation of all covid-19 restrictions, calling it "foolish" and "unethical" as new cases continue to rise to nearly 50 000 a day.Living with covid-19: Israel changes strategy as delta variant hits.Reuters.
IRE1α regulates skeletal muscle regeneration through myostatin mRNA decay
Authors: Shengqi He, Tingting Fu, Yue Yu, Qinhao Liang, Luyao Li, Jing Liu, Xuan Zhang, Qian Zhou, Qiqi Guo, Dengqiu Xu, Yong Chen, Xiaolong Wang, Yulin Chen, Jianmiao Liu, Zhenji Gan, Yong Liu
Journal: Journal of Clinical Investigation (2021)

Skeletal muscle can undergo a regenerative process from injury or disease to preserve muscle mass and function, which is critically influenced by cellular stress responses. Inositol-requiring enzyme 1 (IRE1) is an ancient endoplasmic reticulum (ER) stress sensor and mediates a key branch of the unfolded protein response (UPR). In mammals, IRE1α is implicated in the homeostatic control of stress responses during tissue injury and regeneration. Here, we show that IRE1α serves as a myogenic regulator in skeletal muscle regeneration in response to injury and muscular dystrophy. We found in mice that IRE1α was activated during injury-induced muscle regeneration, and muscle-specific IRE1α ablation resulted in impaired regeneration upon cardiotoxin-induced injury. Gain- and loss-of-function studies in myocytes demonstrated that IRE1αacts to sustain both differentiation in myoblasts and hypertrophy in myotubes through regulated IRE1-dependent decay (RIDD) of mRNA encoding Myostatin, a key negative regulator of muscle repair and growth. Furthermore, in the mouse model of Duchenne muscular dystrophy (DMD), loss of muscle IRE1α resulted in augmented Myostatin signaling and exacerbated the dystrophic phenotypes. Thus, these results reveal a pivotal role for the RIDD output of IRE1α in muscle regeneration, offering new insight into potential therapeutic strategies for muscle loss diseases.
P15-2 Risk factors and barriers of early breast cancer diagnosis and treatment outcome in Bangladesh
Authors: Abdullah Al Mamun Khan, Parveen Shahida Akhtar, Md Yeaqub Ali, Nazrina Khatun, Muhammed Jahangir Alam, Mosfika Rahman, Nahid Hossen, Narita Khurshid, Kazi Abdullah Arman, Md Rafiqul Islam, Mohammad Rafiqul Islam, Ferdous Ara, Tanzina Hossen, ATM Kamrul Hasan
Journal: Annals of Oncology (2021)
N6-methyladenosine methyltransferases: functions, regulation, and clinical potential
Authors: Wei Huang, Tian-Qi Chen, Ke Fang, Zhan-Cheng Zeng, Hua Ye, Yue-Qin Chen
Journal: Journal of Hematology & Oncology (2021)

Abstract N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.
Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial
Authors: Aditya H Gaur, Mark F Cotton, Carina A Rodriguez, Eric J McGrath, Elizabeth Helström, Afaaf Liberty, Eva Natukunda, Pope Kosalaraksa, Kulkanya Chokephaibulkit, Heather Maxwell, Pamela Wong, Danielle Porter, Sophia Majeed, Mun Sang Yue, Hiba Graham, Hal Martin, Diana M Brainard, Cheryl Pikora
Journal: The Lancet Child & Adolescent Health (2021)
Gadolinium-labeled affibody-XTEN recombinant vector for detection of HER2+ lesions of ovarian cancer lung metastasis using quantitative MRI
Authors: Alireza Nomani, Geng Li, Siavash Yousefi, Shawn Wu, Obeid M. Malekshah, Shahryar K. Nikkhoi, Mehrdad Pourfathi, Rahim Rizi, Arash Hatefi
Journal: Journal of Controlled Release (2021)
Annals Graphic Medicine - Dr. Mom: Mom in Medicine Bingo
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2021)

Web ExclusivesAugust 2021Annals Graphic Medicine - Dr. Mom: Mom in Medicine BingoFREEGrace E. Farris, MDGrace E. Farris, MDUniversity of Texas, Austin, Texas (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0043 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Anne Valaas-TurnerAllina Health26 July 2021 COVID-19 bonus row How about a COVID bonus row? May I suggest "School switches to distance learning with less than 24 hours' notice." "Son hits the nanny you hastily hired because school closed with less than 24 hours' notice." "You switch kid to daycare; kid refuses to do any distance learning." "School remains "distance" for 11 months" "School reopens but there is a COVID-19 case in your child's class so you have to stay home for ten days because nobody will take care of a child with a COVID-19 exposure and your husband's hospitalist job refuses to allow him leave to share childcare duties" Author, Article, and Disclosure InformationAffiliations: University of Texas, Austin, Texas (G.E.F.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0024.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Dell Medical School at the University of Texas in Austin, Texas. You can view her work at her website: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org.This article was published at Annals.org on 27 July 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics August 2021Volume 174, Issue 8Page: W79-W80 ePublished: 27 July 2021 Issue Published: August 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Discovery of Parkinson's disease states and disease progression modelling: a longitudinal data study using machine learning
Authors: Kristen A Severson, Lana M Chahine, Luba A Smolensky, Murtaza Dhuliawala, Mark Frasier, Kenney Ng, Soumya Ghosh, Jianying Hu
Journal: The Lancet Digital Health (2021)

BackgroundParkinson's disease is heterogeneous in symptom presentation and progression. Increased understanding of both aspects can enable better patient management and improve clinical trial design. Previous approaches to modelling Parkinson's disease progression assumed static progression trajectories within subgroups and have not adequately accounted for complex medication effects. Our objective was to develop a statistical progression model of Parkinson's disease that accounts for intra-individual and inter-individual variability and medication effects.MethodsIn this longitudinal data study, data were collected for up to 7-years on 423 patients with early Parkinson's disease and 196 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) longitudinal observational study. A contrastive latent variable model was applied followed by a novel personalised input-output hidden Markov model to define disease states. Clinical significance of the states was assessed using statistical tests on seven key motor or cognitive outcomes (mild cognitive impairment, dementia, dyskinesia, presence of motor fluctuations, functional impairment from motor fluctuations, Hoehn and Yahr score, and death) not used in the learning phase. The results were validated in an independent sample of 610 patients with Parkinson's disease from the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP).FindingsPPMI data were download July 25, 2018, medication information was downloaded on Sept 24, 2018, and PDBP data were downloaded between June 15 and June 24, 2020. The model discovered eight disease states, which are primarily differentiated by functional impairment, tremor, bradykinesia, and neuropsychiatric measures. State 8, the terminal state, had the highest prevalence of key clinical outcomes including 18 (95%) of 19 recorded instances of dementia. At study outset 4 (1%) of 333 patients were in state 8 and 138 (41%) of 333 patients reached stage 8 by year 5. However, the ranking of the starting state did not match the ranking of reaching state 8 within 5 years. Overall, patients starting in state 5 had the shortest time to terminal state (median 2·75 [95% CI 1·75–4·25] years).InterpretationWe developed a statistical progression model of early Parkinson's disease that accounts for intra-individual and inter-individual variability and medication effects. Our predictive model discovered non-sequential, overlapping disease progression trajectories, supporting the use of non-deterministic disease progression models, and suggesting static subtype assignment might be ineffective at capturing the full spectrum of Parkinson's disease progression.FundingMichael J Fox Foundation.
Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma
Authors: Alessandra Rossi, Stefania Orecchioni, Paolo Falvo, Valentina Tabanelli, Elena Baiardi, Claudio Agostinelli, Federica Melle, Giovanna Motta, Angelica Calleri, Stefano Fiori, Chiara Corsini, Beatrice Casadei, Saveria Mazzara, Umberto Vitolo, Francesco Bertolini, Pier Luigi Zinzani, Myriam Alcalay, Pier Giuseppe Pelicci, Stefano Pileri, Corrado Tarella, Enrico Derenzini
Journal: Leukemia (2021)

Abstract Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient’s population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2 -positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.
ATR/ATM-Mediated Phosphorylation of BRCA1 T1394 Promotes Homologous Recombinational Repair and G2–M Checkpoint Maintenance
Authors: Tzeh K. Foo, Gabriele Vincelli, Eric Huselid, Joonyoung Her, Haiyan Zheng, Srilatha Simhadri, Meiling Wang, Yanying Huo, Tao Li, Xiaochun Yu, Hong Li, Weixing Zhao, Samuel F. Bunting, Bing Xia
Journal: Cancer Research (2021)

Abstract BRCA1 maintains genome integrity and suppresses tumorigenesis by promoting homologous recombination (HR)–mediated repair of DNA double-strand breaks (DSB) and DNA damage-induced cell-cycle checkpoints. Phosphorylation of BRCA1 by ATM, ATR, CHK2, CDK, and PLK1 kinases has been reported to regulate its functions. Here we show that ATR and ATM-mediated phosphorylation of BRCA1 on T1394, a highly conserved but functionally uncharacterized site, is a key modification for its function in the DNA damage response (DDR). Following DNA damage, T1394 phosphorylation ensured faithful repair of DSBs by promoting HR and preventing single-strand annealing, a deletion-generating repair process. BRCA1 T1394 phosphorylation further safeguarded chromosomal integrity by maintaining the G2–M checkpoint. Moreover, multiple patient-derived BRCA1 variants of unknown significance were shown to affect T1394 phosphorylation. These results establish an important regulatory mechanism of BRCA1 function in the DDR and may have implications in the development or prognosis of BRCA1-associated cancers. Significance: This study identifies a BRCA1 phosphorylation event critical for its DNA repair function and reveals the functional defects of several BRCA1 variants of unknown significance.
Household Transmission of SARS-CoV-2 from Children and Adolescents
Authors: Victoria T. Chu, Anna R. Yousaf, Karen Chang, Noah G. Schwartz, Clinton J. McDaniel, Scott H. Lee, Christine M. Szablewski, Marie Brown, Cherie L. Drenzek, Emilio Dirlikov, Dale A. Rose, Julie Villanueva, Alicia M. Fry, Aron J. Hall, Hannah L. Kirking, Jacqueline E. Tate, Tatiana M. Lanzieri, Rebekah J. Stewart
Journal: New England Journal of Medicine (2021)

Household Transmission of SARS-CoV-2 from Children In an outbreak of Covid-19 at a summer camp, 224 confirmed cases in children and adolescents 7 to 19 years of age were identified. After the campe...
<i>TP53</i> Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia
Authors: Riccardo Bomben, Francesca Maria Rossi, Filippo Vit, Tamara Bittolo, Tiziana D'Agaro, Antonella Zucchetto, Erika Tissino, Federico Pozzo, Elena Vendramini, Massimo Degan, Eva Zaina, Ilaria Cattarossi, Paola Varaschin, Paola Nanni, Michele Berton, Alessandra Braida, Jerry Polesel, Jared A. Cohen, Enrico Santinelli, Annalisa Biagi, Massimo Gentile, Fortunato Morabito, Gilberto Fronza, Gabriele Pozzato, Giovanni D'Arena, Jacopo Olivieri, Pietro Bulian, Chris Pepper, Anna Hockaday, Anna Schuh, Peter Hillmen, Davide Rossi, Annalisa Chiarenza, Francesco Zaja, Francesco Di Raimondo, Giovanni Del Poeta, Valter Gattei
Journal: Clinical Cancer Research (2021)

Abstract Purpose: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. Experimental Design: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. Results: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P &amp;lt; 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. Conclusions: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
LSD1‐Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1‐Induced p62 Transcription in HCC
Authors: Luyuan Ma, An Xu, Lei Kang, Rui Cong, Zhongyi Fan, Xiang Zhu, Nan Huo, Wenpeng Liu, Chunyuan Xue, Quanbo Ji, Wenchao Li, Zhong Chu, Xiaofeng Kang, Yadong Wang, Zhijia Sun, Yuchen Han, Hanxiao Liu, Xiang Gao, Juqiang Han, Hua You, Caiyan Zhao, Xiaojie Xu
Journal: Hepatology (2021)

Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently.RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up-regulation in OXA resistance.LINC01134 was identified as one of the most up-regulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up-regulation in OXA-R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression.LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.
Covid-19: Longer interval between Pfizer doses results in higher antibody levels, research finds
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Longer interval between Pfizer doses results in higher antibody levels, research finds Elisabeth MahaseAn interval of at least six weeks between the two doses of the Pfizer-BioNTech covid-19 vaccine increased concentrations of neutralising antibodies, research funded by the Department of Health and Social Care for England has found. 1 1