tbuckley/cabot-search huggingface dataset:
The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity
Authors: Bernhard Moser, Bernhard Hochreiter, José Basílio, Viola Gleitsmann, Anja Panhuber, Alan Pardo-Garcia, Bastian Hoesel, Manuel Salzmann, Ulrike Resch, Mamoona Noreen, Johannes A. Schmid
Journal: Molecular Cancer (2021)

Abstract Background The IκB kinase (IKK) complex, comprising the two enzymes IKKα and IKKβ, is the main activator of the inflammatory transcription factor NF-κB, which is constitutively active in many cancers. While several connections between NF-κB signaling and the oncogene c-Myc have been shown, functional links between the signaling molecules are still poorly studied. Methods Molecular interactions were shown by co-immunoprecipitation and FRET microscopy. Phosphorylation of c-Myc was shown by kinases assays and its activity by improved reporter gene systems. CRISPR/Cas9-mediated gene knockout and chemical inhibition were used to block IKK activity. The turnover of c-Myc variants was determined by degradation in presence of cycloheximide and by optical pulse-chase experiments.. Immunofluorescence of mouse prostate tissue and bioinformatics of human datasets were applied to correlate IKKα- and c-Myc levels. Cell proliferation was assessed by EdU incorporation and apoptosis by flow cytometry. Results We show that IKKα and IKKβ bind to c-Myc and phosphorylate it at serines 67/71 within a sequence that is highly conserved. Knockout of IKKα decreased c-Myc-activity and increased its T58-phosphorylation, the target site for GSK3β, triggering polyubiquitination and degradation. c-Myc-mutants mimicking IKK-mediated S67/S71-phosphorylation exhibited slower turnover, higher cell proliferation and lower apoptosis, while the opposite was observed for non-phosphorylatable A67/A71-mutants. A significant positive correlation of c-Myc and IKKα levels was noticed in the prostate epithelium of mice and in a variety of human cancers. Conclusions Our data imply that IKKα phosphorylates c-Myc on serines-67/71, thereby stabilizing it, leading to increased transcriptional activity, higher proliferation and decreased apoptosis.
Covalent Organic Frameworks for Biomedical Applications
Authors: Arezoo Esrafili, Avery Wagner, Sahil Inamdar, Abhinav P. Acharya
Journal: Advanced Healthcare Materials (2021)

Abstract Covalent organic frameworks (COFs) are porous organic polymeric materials that are composed of organic elements and linked together by the thermodynamically stable covalent bonds. The applications of COFs in energy sector and drug delivery are afforded because of the desirable properties of COFs, such as high stability, low density, large surface area, multidimensionality, porosity, and high‐ordered crystalline structure expanded. In this review COFs are reviewed, from the perspective of different types of reported COFs, different methods for their synthesis, and their potential applications in the biomedical field. The main goal of this review is to introduce COFs as a biomaterial and to identify specific advantages of different types of COFs that can be exploited for specialized biomedical applications, such as immune engineering.
Intake of <i>n</i>-3 polyunsaturated fatty acids in childhood, <i>FADS</i> genotype and incident asthma
Authors: Mohammad Talaei, Emmanouela Sdona, Philip C. Calder, Louise R. Jones, Pauline M. Emmett, Raquel Granell, Anna Bergström, Erik Melén, Seif O. Shaheen
Journal: European Respiratory Journal (2021)

Longitudinal evidence on the relation between dietary intake of n -3 (ω-3) very-long-chain polyunsaturated fatty acids, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mid-childhood and asthma risk is scarce. We aimed to investigate whether a higher intake of EPA and DHA from fish in childhood is associated with a lower risk of incident asthma. In the Avon Longitudinal Study of Parents and Children, dietary intakes of EPA and DHA from fish were estimated by food frequency questionnaire at 7 years of age. We used logistic regression, controlling for confounders, to analyse associations between intake of EPA and DHA (quartiles) and incidence of doctor-diagnosed asthma at age 11 or 14 years, and explored potential effect modification by a fatty acid desaturase ( FADS ) polymorphism (rs1535). Replication was sought in the Swedish BAMSE birth cohort. There was no evidence of association between intake of EPA plus DHA from fish and incident asthma overall (n=4543). However, when stratified by FADS genotype, the odds ratio comparing the top versus bottom quartile among the 2025 minor G allele carriers was 0.49 (95% CI 0.31–0.79; p trend =0.006), but no inverse association was observed in the homozygous major A allele group (OR 1.43, 95% CI 0.83–2.46; p trend =0.19) (p interaction =0.006). This gene–nutrient interaction on incident asthma was replicated in BAMSE. In children with a common FADS variant, higher intake of EPA and DHA from fish in childhood was strongly associated with a lower risk of incident asthma up to mid-adolescence.
Sex bias in COVID-19-associatedIllness severity and mortality in cancer patients: Asystematic review and meta-analysis
Authors: R. Park, A. Chidharla, K. Mehta, W. Sun, A. Kasi
Journal: Clinical Cancer Research (2020)

Importance: There is strong evidence that COVID-19 is associated with higher morbidity and mortality in malescompared to females in the general population  However, whether the same sex bias exists in the cancer patientpopulation is unknown  Several published studies have examined this question, but the results are inconclusive andinconsistent and the association remains unclear  Objective: To evaluate the sex differences in the risk of severe illness and mortality attributable to COVID-19 in thecancer patient population  Data Sources: Published articles that evaluated clinical outcomes associated with severe illness or deathattributable to COVID-19 in the cancer patient population from inception to June 1, 2020, were identified bysearching PubMed and EMBASE, as well as the ASCO 2020 Virtual Annual Conference, ESMO conferences heldfrom January 2020 to June 1, 2020, and the preprint databases medRxiv and bioRxiv  Study Selection: Prospective or retrospective analyses, studies published in English, providing clinical outcomesdata with sex differences in the cancer patient population  Data Extraction and Synthesis: Author, date of publication, country, type of studies, median and range of age, cancer types included in the studies, definitions of clinical outcomes, and the odds ratios (OR) for severe illness ordeath attributable to COVID-19 were retrieved  Where OR data were not available, raw data were used to calculatethe OR in a univariate analysis model and included in the meta-analysis  Main Outcome(s) and Measure(s): The primary outcome of interest was OR of (1) severe illness, (2) death, and(3) composite outcome of severe illness and death attributable to COVID-19 in males versus females  Results: Overall, 2,764 patients (9 studies) were analyzed in retrospective study settings  Of the included studies, two studies were multinational whereas the rest were conducted in China (4), France (1), United Kingdom (1), andUnited States (1)  Median ages were similar across studies (range 62-70)  Three studies reported outcomes fordeath and six studies reported outcomes for severe illness  Of the seven studies, all but one defined severe illnessas illness requiring ICU admission or leading to death and attributable to COVID-19  Pooled ORs for the compositeoutcome was 1 68 (95% CI, 1 27-2 24), death was 1 98 (95% CI, 1 21-3 26), and severe illness was 1 48 (95% CI,1 05-2 10), all disfavoring males  Random effects model was used with the Dersimonian-Laird Model throughoutanalyses and significant heterogeneity was subsequently confirmed (I2, 48 1%;tau2, 0 0816)  No significantbetween-study bias was detected per Begg's funnel plot  Conclusions and Relevance: The male sex was associated with higher risk of severe illness, death, and thecomposite outcome of both attributable to COVID-19  This finding has implications in informing the clinical prognosisand decision making regarding oncologic patients
The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk
Authors: Matthew Nayor, Kemar J. Brown, Ramachandran S. Vasan
Journal: Circulation Research (2021)

Atherosclerotic cardiovascular disease (ASCVD) proceeds through a series of stages: initiation, progression (or regression), and complications. By integrating known biology regarding molecular signatures of each stage with recent advances in high-dimensional molecular data acquisition platforms (to assay the genome, epigenome, transcriptome, proteome, metabolome, and gut microbiome), snapshots of each phase of atherosclerotic cardiovascular disease development can be captured. In this review, we will summarize emerging approaches for assessment of atherosclerotic cardiovascular disease risk in humans using peripheral blood molecular signatures and molecular imaging approaches. We will then discuss the potential (and challenges) for these snapshots to be integrated into a personalized movie providing dynamic readouts of an individual's atherosclerotic cardiovascular disease risk status throughout the life course.
Addressing Systemic Racism Through Clinical Preventive Service Recommendations From the US Preventive Services Task Force
Authors: Chyke A. Doubeni, Melissa Simon, Alex H. Krist
Journal: JAMA (2021)

Recommendations From the US Preventive Services Task ForceWellness and disease prevention are the foundations of health.The US Preventive Services Task Force (USPSTF) is congressionally mandated to make evidence-based recommendations about clinical preventive services, which, if delivered equitably to the intended population, can prevent many premature deaths.All USPSTF recommendations are based on a rigorous and objective methodology that has been continually refined since 1982.This methodology was cited by the Institute of Medicine as a gold standard for making guidelines. 1 In addition, the Patient Protection and Affordable Care Act mandated coverage by private insurers without cost sharing for USPSTF grade A and B recommended clinical preventive services, reflecting the importance of these recommendations.However, when making recommendations, the USPSTF often finds substantial data that potential lifesaving benefits of recommended services are not equitably available to Black, Indigenous, and Hispanic/Latino people.For instance, the 2020 systematic review to inform modeling for the USPSTF colorectal cancer screening recommendation found consistent evidence of inequities across the screening-to-treatment continuum that encompassed access to screening, quality of screening, time from diagnosis to treatment, and quality of treatment. 2This underscores the need to improve systems of care to ensure consistent delivery of highquality preventive and treatment services, with special attention to groups experiencing worse health outcomes.As described in the 2003 Institute of Medicine report Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, health inequities emerged from a "historic context in which healthcare has been differentially allocated on the basis of social class, race, and ethnicity" 3 and are sustained by systemic racism.The USPSTF considers systemic racism to be a pervasive set of societal and interpersonal practices within and outside health care institutions that foster discriminatory practices to create systematic disadvantage and health inequities in a racial group.Health inequities manifest as disproportionate risk, incidence, morbidity, or mortality.These inequities are due to social, economic, and structural factors stemming from systems in which public policies, institutional practices, and other norms work to perpetuate systemic racism.Even when deemed unintentional, well-documented structural inequities are evident within the health care ecosystem that span the entire prevention-to-treatment continuum.Being a member of a racial ethnic minority group is associated with multiple dimensions of social disadvantage, which in turn is associated with worse health care access, affordability, and quality of care.
The Landscape of Recombination Events That Create Nonribosomal Peptide Diversity
Authors: Martin Baunach, Somak Chowdhury, Pierre Stallforth, Elke Dittmann
Journal: Molecular Biology and Evolution (2021)

Abstract Nonribosomal peptides (NRP) are crucial molecular mediators in microbial ecology and provide indispensable drugs. Nevertheless, the evolution of the flexible biosynthetic machineries that correlates with the stunning structural diversity of NRPs is poorly understood. Here, we show that recombination is a key driver in the evolution of bacterial NRP synthetase (NRPS) genes across distant bacterial phyla, which has guided structural diversification in a plethora of NRP families by extensive mixing and matching of biosynthesis genes. The systematic dissection of a large number of individual recombination events did not only unveil a striking plurality in the nature and origin of the exchange units but allowed the deduction of overarching principles that enable the efficient exchange of adenylation (A) domain substrates while keeping the functionality of the dynamic multienzyme complexes. In the majority of cases, recombination events have targeted variable portions of the Acore domains, yet domain interfaces and the flexible Asub domain remained untapped. Our results strongly contradict the widespread assumption that adenylation and condensation (C) domains coevolve and significantly challenge the attributed role of C domains as stringent selectivity filter during NRP synthesis. Moreover, they teach valuable lessons on the choice of natural exchange units in the evolution of NRPS diversity, which may guide future engineering approaches.
Global patterns and trends in incidence and mortality of thyroid cancer in children and adolescents: a population-based study
Authors: Salvatore Vaccarella, Joannie Lortet-Tieulent, Murielle Colombet, Louise Davies, Charles A Stiller, Joachim Schüz, Kayo Togawa, Freddie Bray, Silvia Franceschi, Luigino Dal Maso, Eva Steliarova-Foucher
Journal: The Lancet Diabetes & Endocrinology (2021)
Ginkgo and Memory—Reply
Authors: Paul R. Solomon, Richard DeVeaux
Journal: JAMA (2003)

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Polypills — A Central Strategy for Improving Cardiovascular Health
Authors: Mark D. Huffman, Anushka Patel
Journal: New England Journal of Medicine (2021)

The polypill concept garnered substantial attention in 2003 after the publication of a modeling analysis that proposed that the use of fixed-dose combination therapy in persons with established atherosclerotic cardiovascular disease and in all other adults 55 years of age or older could reduce disease burden by 80% or more.1 Notably, these models overestimated the effects of aspirin and folic acid and assumed full long-term adherence to the regimen. Subsequent randomized trials testing the effects of different polypills in small populations over short periods of time showed reductions in the cholesterol level and blood pressure and increases in the percentages . . .
Outcomes in refractory diffuse large B‐cell lymphoma: results from a multicenter real‐world study in China
Authors: Shuo Wang, Li Wang, Jianda Hu, Wenbin Qian, Xi Zhang, Yu Hu, Qi Zhu, Bobin Chen, Depei Wu, Chung‐Chou H. Chang, Pengpeng Xu, Xiaoyun Zheng, Juying Wei, Yao Liu, Guohui Cui, Yong Tang, Yan Ma, Haiwen Huang, Hongmei Yi, Weili Zhao
Journal: Cancer Communications (2021)

Abstract Background Diffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study. Methods The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model. Results A total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors. Conclusions This is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.
OP0120 Cause of death in a prospective study of ra patients: do rheumatology drugs play a part?
Authors: S Stafford, CA Mayes, A Young, P Williams
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Few prospective studies in RA have reported on the occurrence of comorbid conditions and mortality, and what proportion could be either disease or treatment related. The Early Rheumatoid Arthritis Study (ERAS) has prospective outcome data on patients followed for as long as 13 years. <h3>Objectives</h3> To classify the cause of death and investigate any possible relationship with second line (disease modifying), steriodal or non steroidal anti-inflammatory drugs (NSAIDs). <h3>Methods</h3> Consecutive patients with RA of less than two years duration have been recruited into an inception cohort from 9 rheumatology units. 1500 patients have been recruited into the study, prior to the use of second line drugs within 2 years of onset of symptoms of RA. Standard clinical and laboratory data were recorded yearly. Details of medication have been collected prospectively. Nearly all patients received non steriodal anti-inflammatory drugs (NSAIDs) at some stage, 84% received second line (disease modifying) drugs and 4% steroids alone. 166 deaths have been recorded from clinical notes, death certificates and the NHS Central Register (NHSCR). Cause of death has been catergorised according to both aetiology and main organ involvement. <h3>Results</h3> Major causes of death in 166 patients (males n = 71 and females n = 95) were as follows: cardiovascular disease (n = 56,33.7%), cerebrovascular (n = 14,8.4%), malignancy (n = 45,27.1%) and respiratory (n = 32,19.3%). Pulmonary infections were recorded in 22 of the latter, Pulmonary Fibrosis in 6 (2 on methotrexate, but present prior to start of therapy), and others (n = 4). 19 miscellaneous conditions included gastrointestinal haemorrhage (n = 4, NSAID related in 3) and septicaemia (n = 5, 2 on steroids and 1 with neutropenia probably methotrexate induced). <h3>Conclusion</h3> No direct link could be established between cause of death and rheumatoid disease or drug therapy in most patients, except those with Pulmonary Fibrosis (4%), and in 6 patients where drug therapy could have been a contributory factor to cause of death.