tbuckley/cabot-search huggingface dataset:
27078 Mediation analysis of independent treatment effect of guselkumab on health-related quality of life in patients with moderate to severe plaque-type psoriasis: Results from 2 phase 3 studies VOYAGE-1&amp;2
Authors: April W. Armstrong, Yan Liu, Nan Li, Kristian Reich, Peter Foley, Shu Li, Michael Song, Steven Fakharzadeh, Kim A. Papp, Chenglong Han
Journal: Journal of the American Academy of Dermatology (2021)
Key Role of Personalized Dosimetry in Dose Adjustment for Selective Internal Radiotherapy
Authors: Celine Subreville, Jean-Baptiste Pinaquy, Bruno Lapuyade, Jean-Frederic Blanc, Laurence Bordenave, Panteleimon Papadopoulos, Frederic Debordeaux
Journal: Clinical Nuclear Medicine (2021)

Purpose Selective internal radiotherapy with 90 Y microspheres is widely used for the treatment of patients with liver cancer. A dosimetric analysis using the dosimetry software Simplicit90y (Boston Scientific, Natick, MA) was conducted to define doses to the tumor and healthy liver, and to determine a threshold tumor dose that could predict progression-free survival. Methods Patients experiencing hepatocellular carcinoma and treated with 90 Y-labeled resin microspheres were included in a retrospective study. The time-to-progression of the target lesions (TTPLs) and overall survival (OS) were evaluated using Kaplan-Meier tests, and this comparison was based on a log-rank test. Results Twenty-four procedures for patients with portal vein thrombosis were realized. Median follow-up was 16 months. A threshold tumor dose of 125 Gy was determined with a sensitivity of 89% and a specificity of 100%. For patients with a tumor dose of less than 125 Gy, the median OS was 7.5 months (95% confidence interval [CI], 5–14 months) and the TTPL was 3 months (95% CI, 2–6 months) versus 33 months (95% CI, 22–39 months) and 23 months (95% CI, 7–38 months), respectively, for those with a tumor dose of 125 Gy or more ( P = 0.002 and P = 0.0004). Conclusions Personalized dosimetry based on 99m Tc-MAA SPECT/CT is predictive of TTPL and OS in patients with hepatocellular carcinoma. Customized dosimetry software is essential to optimize treatment planning.
GAPIT Version 3: Boosting Power and Accuracy for Genomic Association and Prediction
Authors: Jiabo Wang, Zhiwu Zhang
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Genome-wide association study (GWAS) and genomic prediction/selection (GP/GS) are the two essential enterprises in genomic research. Due to the great magnitude and complexity of genomic and phenotypic data, analytical methods and their associated software packages are frequently advanced. GAPIT is a widely-used genomic association and prediction integrated tool as an R package. The first version was released to the public in 2012 with the implementation of the general linear model (GLM), mixed linear model (MLM), compressed MLM (CMLM), and genomic best linear unbiased prediction (gBLUP). The second version was released in 2016 with several new implementations, including enriched CMLM (ECMLM) and settlement of MLMs under progressively exclusive relationship (SUPER). All the GWAS methods are based on the single-locus test. For the first time, in the current release of GAPIT, version 3 implemented three multi-locus test methods, including multiple loci mixed model (MLMM), fixed and random model circulating probability unification (FarmCPU), and Bayesian-information and linkage-disequilibrium iteratively nested keyway (BLINK). Additionally, two GP/GS methods were implemented based on CMLM (named compressed BLUP; cBLUP) and SUPER (named SUPER BLUP; sBLUP). These new implementations not only boost statistical power for GWAS and prediction accuracy for GP/GS, but also improve computing speed and increase the capacity to analyze big genomic data. Here, we document the current upgrade of GAPIT by describing the selection of the recently developed methods, their implementations, and potential impact. All documents, including source code, user manual, demo data, and tutorials, are freely available at the GAPIT website (http://zzlab.net/GAPIT).
Diseases of the Aorta and Kidney Disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Pantelis Sarafidis, Sven Martens, Athanasios Saratzis, Daniella Kadian-Dodov, Patrick T Murray, Catherine M Shanahan, Allen D Hamdan, Daniel T Engelman, Ulf Teichgräber, Charles A Herzog, Michael Cheung, Michel Jadoul, Wolfgang C Winkelmayer, Holger Reinecke, Kirsten Johansen
Journal: Cardiovascular Research (2021)

Abstract Chronic kidney disease (CKD) is an independent risk factor for the development of abdominal aortic aneurysm (AAA), as well as for cardiovascular and renal events and all-cause mortality following surgery for AAA or thoracic aortic dissection. In addition, the incidence of acute kidney injury (AKI) after any aortic surgery is particularly high, and this AKI per se is independently associated with future cardiovascular events and mortality. On the other hand, both development of AKI after surgery and the long-term evolution of kidney function differ significantly depending on the type of AAA intervention (open surgery vs. the various subtypes of endovascular repair). Current knowledge regarding AAA in the general population may not be always applicable to CKD patients, as they have a high prevalence of co-morbid conditions and an elevated risk for periprocedural complications. This summary of a Kidney Disease: Improving Global Outcomes Controversies Conference group discussion reviews the epidemiology, pathophysiology, diagnosis, and treatment of Diseases of the Aorta in CKD and identifies knowledge gaps, areas of controversy, and priorities for future research.
Clonal hematopoiesis, myeloid disorders and <i>BAX</i>-mutated myelopoiesis in patients receiving venetoclax for CLL
Authors: Piers Blombery, Thomas E. Lew, Michael A. Dengler, Ella R. Thompson, Victor S. Lin, Xiangting Chen, Tamia Nguyen, Ashish Panigrahi, Sasanka M. Handunnetti, Dennis A. Carney, David A. Westerman, Constantine S. Tam, Jerry M. Adams, Andrew H. Wei, David C. S. Huang, John F. Seymour, Andrew W. Roberts, Mary Ann Anderson
Journal: Blood (2021)

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
Full SNO 2021 Abstracts PDF
Journal: Neuro-Oncology (2021)

Background: Since the preponderance of pediatric gliomas are mutationally 'bland,' immune checkpoint inhibitors are unlikely to mediate therapeutic benefit. Alternately, immunologic response can be induced de novo against pediatric gliomas with mRNA cancer vaccines. Messenger RNA represents a paradigm shift in vaccinology (i.e. COVID-19) given its flexibility, commercialization, and propensity to confer rapid protection with only a single vaccine. Objective: We sought to develop a new mRNA platform with an optimized backbone for insertion of both personalized and/or “off the shelf” (i.e. H3K27M) transcripts for rapid induction of anti-tumor activity against pediatric gliomas. Approach: We synthesized an mRNA backbone with optimized 5' and 3' UTRs for delivery of gene transcripts pertinent to pediatric brain tumors using a lipid-nanoparticle (NP) delivery vehicle. This vaccine utilizes a novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle (NP) “onion-like” or multi-lamellar package. Results: We demonstrate immunogenicity of RNA-NPs delivering either personalized glioma mRNA or H3K27M mRNA. RNA-NPs localize to myeloid cells in murine KR158b brain tumors and activate dendritic cells that supplant regulatory intratumoral myeloid populations inducing antigenrecall response with long-term survivor benefit. Our optimized mRNA backbone yielded significantly improved anti-tumor efficacy compared with commercial backbones. We have shown this approach can be refined for co-delivery of immunomodulatory RNAs (i.e. GM-CSF) and/or delivery of siRNAs targeting immunoregulatory axes (PD-L1) in murine brain tumors (GL261). We have since established safety of RNA-NPs in acute/chronic murine GLP toxicity studies without cross-reactivity to normal-brain, and launched a large-animal canine brain tumor trial which demonstrated RNANPs to be feasible, safe and immunologically active. Conclusion: RNA-NPs reprogram the brain tumor microenvironment while inducing a gliomaspecific immune response. We have since received FDA-IND approval for first-in-human trials.
The low advanced lung cancer inflammation index to predict poor prognosis of patients with metastatic non-small cell lung cancer.
Authors: Ping Lu, Yifei Ma, Jindan Kai, Jun Wang, Zhucheng Yin, Hongli Xu, Xinying Li, Xin Liang, Shaozhong Wei, Xinjun Liang
Journal: Journal of Clinical Oncology (2021)

e21132 Background: Inflammation plays a crucial role in cancers, in which the advanced lung cancer inflammation index (ALI) is considered to be a potential factor reflecting systemic inflammation. This work aimed to explore the prognostic value of ALI in metastatic non-small cell lung cancer (NSCLC) and classify patients according to their potential risks and different prognosis. Methods: Non-small cell lung cancer patients with stage IV were included in this retrospective study who were diagnosed pathologically in Hubei Cancer Hospital from June 2012 to December 2013. Combined with relevant imaging data and exfoliative cytology, patients with non-small cell lung cancer were staged according to the eighth edition of TNM staging criteria for non-small cell lung cancer. We screened 318 patients who met the inclusion and exclusion criteria requirements. The clinicopathological and therapeutic data of the patients were collected through medical records, including age, sex, smoking and drinking, tumor site, tumor family history, histology, metastatic site, chemotherapy, radiotherapy, anti-VEGF therapy and EGFR-TKI therapy. The formula of ALI is body mass index (BMI, Kg / m 2 ) × serum albumin (Alb, g / dl) / neutrophil-lymphocyte ratio (NLR). Categorical variables were analyzed by chi-square test or Fisher’s exact test. The OS rates was analyzed by Kaplan–Meier method and plotted with R language. Multivariate Cox proportional hazard model was used to analyze the relationship between ALI and OS. The nomogram based on the Multivariable Cox regression was establish, and the Harrell consistency index (C-index) was used to evaluate the predictive performance of the Cox regression model. Results: According to the optimal cut-off value determined by X-tile software, patients were divided into two groups: ALI &lt; 32.6 and ALI ≥ 32.6 and the median OS in the high ALI group were better than those in the low ALI group (39.97 vs 19.23 months, p &lt; 0.01). Local or distant metastases and some distant metastasis sites are related to prognosis. Multivariable Cox regression model confirmed that ALI (HR: 1.39; 95%CI: 1.03-1.89; P = 0.03) and chemotherapy (HR: 0.67; 95%CI: 0.49- 0.91; P = 0.01) were independent prognostic factors for OS in patients with metastatic non-small-cell lung cancer. Conclusions: The results of our study indicates that patients with low ALI tend to have lower OS in metastatic NSCLC, and ALI can serve as an effective prognostic factor for metastatic NSCLC patients.
Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial
Authors: Jesper H Svendsen, Søren Z Diederichsen, Søren Højberg, Derk W Krieger, Claus Graff, Christian Kronborg, Morten S Olesen, Jonas B Nielsen, Anders G Holst, Axel Brandes, Ketil J Haugan, Lars Køber
Journal: The Lancet (2021)
A Positively Selected <i>MAGEE2</i> LoF Allele Is Associated with Sexual Dimorphism in Human Brain Size and Shows Similar Phenotypes in <i>Magee2</i> Null Mice
Authors: Michał Szpak, Stephan C Collins, Yan Li, Xiao Liu, Qasim Ayub, Marie-Christine Fischer, Valerie E Vancollie, Christopher J Lelliott, Yali Xue, Binnaz Yalcin, Huanming Yang, Chris Tyler-Smith
Journal: Molecular Biology and Evolution (2021)

A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation, and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4×10-6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of gray matter in males (P = 0.00094), and smaller volumes of gray (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behavior or cognition, but it might have been the driving force underlying the positive selection in humans.
BCL6 controls contact-dependent help delivery during follicular T-B cell interactions
Authors: Dan Liu, Jiacong Yan, Jiahui Sun, Bo Liu, Weiwei Ma, Ye Li, Xingxing Shao, Hai Qi
Journal: Immunity (2021)

BCL6 is required for development of follicular T helper (Tfh) cells to support germinal center (GC) formation. However, it is not clear what unique functions programmed by BCL6 can explain its absolute essentiality in T cells for GC formation. We found that ablation of one Bcl6 allele did not appreciably alter early T cell activation and follicular localization but inhibited GC formation and Tfh cell maintenance. BCL6 impinged on Tfh calcium signaling and also controlled Tfh entanglement with and CD40L delivery to B cells. Amounts of BCL6 protein and nominal frequencies of Tfh cells markedly changed within hours after strengths of T-B cell interactions were altered in vivo, while CD40L overexpression rectified both defective GC formation and Tfh cell maintenance because of the BCL6 haploinsufficiency. Our results reveal BCL6 functions in Tfh cells that are essential for GC formation and suggest that BCL6 helps maintain Tfh cell phenotypes in a T cell non-autonomous manner.
P-252 Residual fibrosis after treatment with anti-epidermal growth factor receptor or bevacizumab in colorectal liver metastases and its correlation with survival: A retrospective pooled analysis
Authors: X. Hernández-Yagüe, S. Lopez-Ben, L. Llavata, G. Mateu Esquerda, M. Casellas-Robert, R. Ortiz-Duran, M. Buxó, M. Albiol-Quer, C. Meléndez-Muñoz, J. Brunet-Vidal, J. Figueras-Felip
Journal: Annals of Oncology (2021)
The Singapore Asymptomatic Narrow Angles Laser Iridotomy Study
Authors: Mani Baskaran, Rajesh S. Kumar, David S. Friedman, Qing-Shu Lu, Hon-Tym Wong, Paul T.K. Chew, Raghavan Lavanya, Arun Narayanaswamy, Shamira A. Perera, Paul J. Foster, Tin Aung
Journal: Ophthalmology (2021)
A New World Monkey Resembles Human in Bitter Taste Receptor Evolution and Function via a Single Parallel Amino Acid Substitution
Authors: Hui Yang, Songlin Yang, Fei Fan, Yun Li, Shaoxing Dai, Xin Zhou, Cynthia C Steiner, Bretton Coppedge, Christian Roos, Xianghai Cai, David M Irwin, Peng Shi
Journal: Molecular Biology and Evolution (2021)

Abstract Bitter taste receptors serve as a vital component in the defense system against toxin intake by animals, and the family of genes encoding these receptors has been demonstrated, usually by family size variance, to correlate with dietary preference. However, few systematic studies of specific Tas2R to unveil their functional evolution have been conducted. Here, we surveyed Tas2R16 across all major clades of primates and reported a rare case of a convergent change to increase sensitivity to β-glucopyranosides in human and a New World monkey, the white-faced saki. Combining analyses at multiple levels, we demonstrate that a parallel amino acid substitution (K172N) shared by these two species is responsible for this functional convergence of Tas2R16. Considering the specialized feeding preference of the white-faced saki, the K172N change likely played an important adaptive role in its early evolution to avoid potentially toxic cyanogenic glycosides, as suggested for the human TAS2R16 gene.
Gut microbiota associations with metabolic syndrome and relevance of its study in pediatric subjects
Authors: Ana K. Carrizales-Sánchez, Tomás García-Cayuela, Carmen Hernández-Brenes, Carolina Senés-Guerrero
Journal: Gut Microbes (2021)

Childhood obesity and T2DM have shown a recent alarming increase due to important changes in global lifestyle and dietary habits, highlighting the need for urgent and novel solutions to improve global public health. Gut microbiota has been shown to be relevant in human health and its dysbiosis has been associated with MetS, a health condition linked to the onset of relevant diseases including T2DM. Even though there have been recent improvements in the understanding of gut microbiota–host interactions, pediatric gut microbiota has been poorly studied compared to adults. This review provides an overview of MetS and its relevance in school-age children, discusses gut microbiota and its possible association with this metabolic condition including relevant emerging gut microbiome-based interventions for its prevention and treatment, and outlines future challenges and perspectives in preventing microbiota dysbiosis from the early stages of life.
Abstract 14607: mRNA Sequencing of Lung-Educated Platelets as a Powerful Diagnostic Biomarker for Pulmonary Hypertension
Authors: Josien Smits, Mo Arkani, Sjors In ’t Veld, Myron Best, Anna Huis in ’t Veld, Nik Sol, Jose Gomez-Arroy, Anton Vonk-Noordegraaf, Harm Jan Bogaard
Journal: Circulation (2018)

Introduction: Discriminating between biomarkers with true pathophysiological meaning from unrelated epiphenomena in pulmonary hypertension (PH) has proven challenging. Minimally invasive biomarkers...
Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions
Authors: Kelly M. Girskis, Andrew B. Stergachis, Ellen M. DeGennaro, Ryan N. Doan, Xuyu Qian, Matthew B. Johnson, Peter P. Wang, Gabrielle M. Sejourne, M. Aurel Nagy, Elizabeth A. Pollina, André M.M. Sousa, Taehwan Shin, Connor J. Kenny, Julia L. Scotellaro, Brian M. Debo, Dilenny M. Gonzalez, Lariza M. Rento, Rebecca C. Yeh, Janet H.T. Song, Marc Beaudin, Jean Fan, Peter V. Kharchenko, Nenad Sestan, Michael E. Greenberg, Christopher A. Walsh
Journal: Neuron (2021)
ACP provided 2 conditional recommendations on use of high-flow nasal oxygen in acute respiratory failure
Authors: Maitri Munsif, Christine F. McDonald
Journal: Annals of Internal Medicine (2021)

Source Citation Qaseem A, Etxeandia-Ikobaltzeta I, Fitterman N, et al. Appropriate use of high-flow nasal oxygen in hospitalized patients for initial or postextubation management of acute respiratory failure: a clinical guideline from the American College of Physicians. Ann Intern Med. 2021;174:977-84. 33900796
Reduced Exercise Capacity in Adults Born at Very Low Birth Weight: A Population-based Cohort Study
Authors: Jun Yang, Michael J. Epton, Sarah L. Harris, John Horwood, Rachel A. Kingsford, Richard Troughton, Charlotte Greer, Brian A. Darlow
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Population-based data regarding the consequences of very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) on adult exercise capacity are limited. Objectives: To compare exercise capacity in a national VLBW cohort with term-born controls and explore factors contributing to the differences. Methods: At 26–30 years of age, 228 VLBW survivors and 100 controls underwent lung function tests, cardiopulmonary exercise testing, and assessment of resting cardiac structure and function using echocardiography. Data on self-reported physical activity were collected. Measurements and Main Results: Compared with controls, adults with VLBW demonstrated reduced oxygen uptake, work rate, and oxygen pulse at peak exercise (9.3%, 10.7%, and 10.8% lower, respectively) and earlier anaerobic threshold (all P < 0.0001), with all mean values within normal range. VLBW survivors showed reduced physical activity, impaired lung function (reduced FEV1, FEV1/FVC, and DlCO), altered left ventricular structure and function (reduced mass, size, stroke volume, and cardiac output), and reduced right atrial and ventricular size. Adjustment for the combination of three sets of covariates (physical activity with body mass index, lung function, and cardiac structure and function) explained most of the exercise group differences. Beyond the effects of physical activity and body mass index, lung function and cardiac structure and function contributed approximately equally. BPD with other prematurity-related perinatal factors (ventilation, antenatal steroids, extremely low birth weight, and extreme preterm) were not associated with a reduced exercise capacity. Conclusions: Exercise capacity was significantly reduced in adults with VLBW, which we speculate is from combined effects of impaired lung function, altered heart structure and function, and reduced physical activity. Perinatal factors including BPD were not associated with a reduced exercise capacity.