tbuckley/cabot-search huggingface dataset:
A novel PLK1 inhibitor onvansertib effectively sensitizes MYC-driven medulloblastoma to radiotherapy
Authors: Dong Wang, Bethany Veo, Angela Pierce, Susan Fosmire, Krishna Madhavan, Ilango Balakrishnan, Andrew Donson, Irina Alimova, Kelly D Sullivan, Molishree Joshi, Mark Erlander, Maya Ridinger, Nicholas K Foreman, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2021)

Group 3 medulloblastoma (MB) is often accompanied by MYC amplification. PLK1 is an oncogenic kinase that controls cell cycle and proliferation and has been preclinically validated as a cancer therapeutic target. Onvansertib (PCM-075) is a novel, orally available PLK1 inhibitor, which shows tumor growth inhibition in various types of cancer. We aim to explore the effect of onvansertib on MYC-driven medulloblastoma as a monotherapy or in combination with radiation.Crisper-Cas9 screen was used to discover essential genes for MB tumor growth. Microarray and immunohistochemistry on pediatric patient samples were performed to examine the expression of PLK1. The effect of onvansertib in vitro was measure by cell viability, colony-forming assays, extreme limiting dilution assay, and RNA-Seq. ALDH activity, cell-cycle distribution, and apoptosis were analyzed by flow cytometry. DNA damage was assessed by immunofluorescence staining. Medulloblastoma xenografts were generated to explore the monotherapy or radio-sensitizing effect.PLK1 is overexpressed in Group 3 MB. The IC50 concentrations of onvansertib in Group 3 MB cell lines were in a low nanomolar range. Onvansertib reduced colony formation, cell proliferation, stem cell renewal and induced G2/M arrest in vitro. Moreover, onvansertib in combination with radiation increased DNA damage and apoptosis compared with radiation treatment alone. The combination radiotherapy resulted in marked tumor regression in xenografts.These findings demonstrate the efficacy of a novel PLK1 inhibitor onvansertib in vitro and in xenografts of Group 3 MB, which suggests onvansertib is an effective strategy as monotherapy or in combination with radiotherapy in MB.
Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia
Authors: David R. Collins, Jonathan M. Urbach, Zachary J. Racenet, Umar Arshad, Karen A. Power, Ruchi M. Newman, Geetha H. Mylvaganam, Ngoc L. Ly, Xiaodong Lian, Anna Rull, Yelizaveta Rassadkina, Adrienne G. Yanez, Michael J. Peluso, Steven G. Deeks, Francesc Vidal, Mathias Lichterfeld, Xu G. Yu, Gaurav D. Gaiha, Todd M. Allen, Bruce D. Walker
Journal: Immunity (2021)
Single-cell RNA-seq reveals functionally distinct biomaterial degradation-related macrophage populations
Authors: Jiayun Huang, Chunmei Fan, Yangwu Chen, Jinchun Ye, Yuwei Yang, Chenqi Tang, Hong Zhang, Yang Fei, Chengrui An, Yuanhao Xie, Hua Liu, Zi Yin, Weishan Chen, Boon Chin Heng, Hongwei Ouyang, Xiao Chen, Weiliang Shen
Journal: Biomaterials (2021)
Guidelines for Lipid-Lowering Therapy Intensification Rarely Followed
Authors: Anita Slomski
Journal: JAMA (2021)

A multisite registry study involving 5000 US patients showed that clinicians often don’t treat patients with atherosclerotic cardiovascular disease according to recommendations for intensive medication if low-density lipoprotein cholesterol (LDL-C) levels are 70 mg/dL or more.
Development of a biomechanical model for dynamic occlusal stress analysis
Authors: Zheng Duanmu, Lu Liu, Qi Deng, Yuanyuan Ren, Meiqing Wang
Journal: International Journal of Oral Science (2021)

The use of traditional finite element method (FEM) in occlusal stress analysis is limited due to the complexity of musculature simulation. The present purpose was to develop a displacement boundary condition (DBC)-FEM, which evaded the muscle factor, to predict the dynamic occlusal stress. The geometry of the DBC-FEM was developed based on the scanned plastic casts obtained from a volunteer. The electrognathographic and video recorded jaw positional messages were adopted to analyze the dynamic occlusal stress. The volunteer exhibited asymmetrical lateral movements, so that the occlusal stress was further analyzed by using the parameters obtained from the right-side eccentric movement, which was 6.9 mm long, in the stress task of the left-side eccentric movement, which was 4.1 mm long. Further, virtual occlusion modification was performed by using the carving tool software aiming to improve the occlusal morphology at the loading sites. T-Scan Occlusal System was used as a control of the in vivo detection for the location and strength of the occlusal contacts. Data obtained from the calculation using the present developed DBC-FEM indicated that the stress distribution on the dental surface changed dynamically with the occlusal contacts. Consistent with the T-Scan recordings, the right-side molars always showed contacts and higher levels of stress. Replacing the left-side eccentric movement trace by the right-side one enhanced the simulated stress on the right-side molars while modification of the right-side molars reduced the simulated stress. The present DBC-FEM offers a creative approach for pragmatic occlusion stress prediction.
The growing field of digital psychiatry: current evidence and the future of apps, social media, chatbots, and virtual reality
Authors: John Torous, Sandra Bucci, Imogen H. Bell, Lars V. Kessing, Maria Faurholt‐Jepsen, Pauline Whelan, Andre F. Carvalho, Matcheri Keshavan, Jake Linardon, Joseph Firth
Journal: World Psychiatry (2021)

As the COVID‐19 pandemic has largely increased the utilization of telehealth, mobile mental health technologies – such as smartphone apps, vir­tual reality, chatbots, and social media – have also gained attention. These digital health technologies offer the potential of accessible and scalable interventions that can augment traditional care. In this paper, we provide a comprehensive update on the overall field of digital psychiatry, covering three areas. First, we outline the relevance of recent technological advances to mental health research and care, by detailing how smartphones, social media, artificial intelligence and virtual reality present new opportunities for “digital phenotyping” and remote intervention. Second, we review the current evidence for the use of these new technological approaches across different mental health contexts, covering their emerging efficacy in self‐management of psychological well‐being and early intervention, along with more nascent research supporting their use in clinical management of long‐term psychiatric conditions – including major depression; anxiety, bipolar and psychotic disorders; and eating and substance use disorders – as well as in child and adolescent mental health care. Third, we discuss the most pressing challenges and opportunities towards real‐world implementation, using the Integrated Promoting Action on Research Implementation in Health Services (i‐PARIHS) framework to explain how the innovations themselves, the recipients of these innovations, and the context surrounding innovations all must be considered to facilitate their adoption and use in mental health care systems. We conclude that the new technological capabilities of smartphones, artificial intelligence, social media and virtual reality are already changing mental health care in unforeseen and exciting ways, each accompanied by an early but promising evidence base. We point out that further efforts towards strengthening implementation are needed, and detail the key issues at the patient, provider and policy levels which must now be addressed for digital health technologies to truly improve mental health research and treatment in the future.
Bottom-up inputs are required for establishment of top-down connectivity onto cortical layer 1 neurogliaform cells
Authors: Leena Ali Ibrahim, Shuhan Huang, Marian Fernandez-Otero, Mia Sherer, Yanjie Qiu, Spurti Vemuri, Qing Xu, Robert Machold, Gabrielle Pouchelon, Bernardo Rudy, Gord Fishell
Journal: Neuron (2021)
GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism
Authors: Luc Rochette, Marianne Zeller, Yves Cottin, Catherine Vergely
Journal: Trends in Endocrinology and Metabolism (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-β (TGF-β) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.
Safety and tolerability of the <scp>COVID</scp>‐19 messenger <scp>RNA</scp> vaccine in adolescents with juvenile idiopathic arthritis treated with tumor necrosis factor inhibitors
Authors: Dimitra Dimopoulou, Nikos Spyridis, George Vartzelis, Maria N. Tsolia, Despoina N. Maritsi
Journal: Arthritis & Rheumatology (2021)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men
Authors: Beckey Trinh, Merel Peletier, Casper Simonsen, Peter Plomgaard, Kristian Karstoft, Bente Klarlund Pedersen, Gerrit van Hall, Helga Ellingsgaard
Journal: Cell Reports Medicine (2021)

In briefTrinh et al. show that, in humans, less free fatty acids are mobilized when endogenous IL-6 signaling is blocked.Their findings highlight a possible mechanism by which treatment with IL-6 receptor blockade leads to expansion of fat mass and potentially affects the metabolic health of affected individuals.
Maternal diet in pregnancy and child's respiratory outcomes: an individual participant data meta-analysis of 18 000 children
Authors: Sara M. Mensink-Bout, Evelien R. van Meel, Johan C. de Jongste, Isabella Annesi-Maesano, Adrien M. Aubert, Jonathan Y. Bernard, Ling-Wei Chen, Cyrus Cooper, Sarah R. Crozier, Wojciech Hanke, Nicholas C. Harvey, James R. Hébert, Barbara Heude, Joanna Jerzynska, Cecily C. Kelleher, John Mehegan, Fionnuala M. McAuliffe, Catherine M. Phillips, Kinga Polanska, Caroline L. Relton, Nitin Shivappa, Matthew Suderman, Vincent W.V. Jaddoe, Liesbeth Duijts
Journal: European Respiratory Journal (2021)

Rationale Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health. Methods We performed an individual participant meta-analysis among 18 326 mother–child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using questionnaires and lung function by spirometry. Results After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower forced vital capacity (FVC) in children (z-score difference −0.05, 95% CI −0.08– −0.02, per interquartile range increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. In an exploratory examination of the extremes, a very low DASH score (&lt;10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low forced expiratory volume in 1 s/FVC (z-score &lt;−1.64) (OR 1.20, 95% CI 1.06–1.36 and z-score difference 1.40, 95% CI 1.06–1.85, compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%, respectively. Conclusion The main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.
Immunomics-guided discovery of serum and urine antibodies for diagnosing urogenital schistosomiasis: a biomarker identification study
Authors: Mark S Pearson, Bemnet A Tedla, Gebeyaw G Mekonnen, Carla Proietti, Luke Becker, Rie Nakajima, Al Jasinskas, Denise L Doolan, Abena S Amoah, Stefanie Knopp, David Rollinson, Said M Ali, Fatma Kabole, Cornelis H Hokke, Akim A Adegnika, Matt A Field, Govert van Dam, Paul L A M Corstjens, Takafira Mduluza, Francisca Mutapi, Claude Oeuvray, Beatrice Greco, Sujittra Chaiyadet, Thewarach Laha, Pengfei Cai, Donald P McManus, Maria Elena Bottazzi, Philip L Felgner, Javier Sotillo, Alex Loukas
Journal: The Lancet Microbe (2021)

Sensitive diagnostics are needed for effective management and surveillance of schistosomiasis so that current transmission interruption goals set by WHO can be achieved. We aimed to screen the Schistosoma haematobium secretome to find antibody biomarkers of schistosome infection, validate their diagnostic performance in samples from endemic populations, and evaluate their utility as point of care immunochromatographic tests (POC-ICTs) to diagnose urogenital schistosomiasis in the field.We did a biomarker identification study, in which we constructed a proteome array containing 992 validated and predicted proteins from S haematobium and screened it with serum and urine antibodies from endemic populations in Gabon, Tanzania, and Zimbabwe. Arrayed antigens that were IgG-reactive and a select group of antigens from the worm extracellular vesicle proteome, predicted to be diagnostically informative, were then evaluated by ELISA using the same samples used to probe arrays, and samples from individuals residing in a low-endemicity setting (ie, Pemba and Unguja islands, Zanzibar, Tanzania). The two most sensitive and specific antigens were incorporated into POC-ICTs to assess their ability to diagnose S haematobium infection from serum in a field-deployable format.From array probing, in individuals who were infected, 208 antigens were the targets of significantly elevated IgG responses in serum and 45 antigens were the targets of significantly elevated IgG responses in urine. Of the five proteins that were validated by ELISA, Sh-TSP-2 (area under the curve [AUC]serum=0·98 [95% CI 0·95-1·00]; AUCurine=0·96 [0·93-0·99]), and MS3_01370 (AUCserum=0·93 [0·89-0·97]; AUCurine=0·81 [0·72-0·89]) displayed the highest overall diagnostic performance in each biofluid and exceeded that of S haematobium-soluble egg antigen in urine (AUC=0·79 [0·69-0·90]). When incorporated into separate POC-ICTs, Sh-TSP-2 showed absolute specificity and a sensitivity of 75% and MS3_01370 showed absolute specificity and a sensitivity of 89%.We identified numerous biomarkers of urogenital schistosomiasis that could form the basis of novel antibody diagnostics for this disease. Two of these antigens, Sh-TSP-2 and MS3_01370, could be used as sensitive, specific, and field-deployable diagnostics to support schistosomiasis control and elimination initiatives, with particular focus on post-elimination surveillance.Australian Trade and Investment Commission and Merck Global Health Institute.
Transformation from non-small cell lung cancer to small cell lung cancer: A report of clinicopathological characteristics and prognoses.
Authors: Jun Wang, Qing Liu, Yanhong Shang, Linlin Xiao, Ran Huo
Journal: Journal of Clinical Oncology (2021)

e15084 Background: The transformation to small cell lung cancer (SCLC) is one of the mechanisms of drug resistance in non-small cell lung cancer (NSCLC). However, there are few reports on it. The study aims to analyze the clinicopathological characteristics of the patients, to explore the transformation factors and reasonable treatment strategy for them. Methods: A total of 9 patients with pathologically diagnosed NSCLC transformed into SCLC after first-line or multi-line treatment were involved in the study. Results: Among the 9 patients, there were 8 adenocarcinomas (ADC) and 1 squamous cell carcinoma (SCC), 7 of them were non-smokers. Epidermal growth factor receptor (EGFR) mutations were present in all ADC patients, including 7 with exon19 deletion (87.5%) and 1 with exon21 mutation (12.5%). All of them received EGFR tyrosine kinase inhibitors (TKIs) before the transformation, and the median transformation time was 19.5 months (95% CI, 14.1-32.7months). After first-line chemotherapy with paclitaxel and cisplatin, one SCC patient transformed to SCLC within 5 months. EGFR mutation was still maintained in 6 ADC patients when transformation occurred, of which 2 patients had a new TP53 mutation and 1 had RB1 gene mutation. Serum tumor markers were monitored in 6 patients, of them, progastrin releasing peptide (Pro-GRP) increased apparently at the time of disease progression in 5 patients, and neuron-specific enolase (NSE) also increased in 3 patients. This phenomenon occurred three to six months earlier than the transformation. The median survival time (MST) was 37 months from the initial diagnosis of NSCLC and 13 months after transformation. The median progression-free survival (mPFS) was only 2 months for those treated with chemotherapy (CT) after transformation, whereas 6 months treated with CT combined with TKIs as the first-line treatment. Three patients who received chemotherapy combined with programmed death receptor-1 (PD-1) inhibitor after multi-line therapy underwent progress within 2 months, nevertheless, 1 patient treated with the EP regimen combined with pembrolizumab as the first line treatment after transformation had a PFS of 12 months. After re-progression, the patients got another PFS of 5 months with a pemetrexed-platinum combined with atezolizumab. Conclusions: Phenotypic transformation is one of the mechanisms of drug resistance for NSCLC patients, especially for those with EFGR exon19 deletion received EGFR-TKIs. Tumor heterogeneity, TP53 gene and Rb gene mutation may be responsible for the transformation. The serum Pro-GRP over expression could as an early predictor of transformation. Classical chemotherapy is ineffective after SCLC transformation patients who still have sensitive mutation, it might be suitable to combine with EGFR-TKIs. The early application of immunotherapy could be attempted, but still needs to be explored further.
scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in T <sub>reg</sub> function
Authors: Kyle J. Gellatly, James P. Strassner, Kingsley Essien, Maggi Ahmed Refat, Rachel L. Murphy, Anthony Coffin-Schmitt, Amit G. Pandya, Andrea Tovar-Garza, Michael L. Frisoli, Xueli Fan, Xiaolan Ding, Evangeline E. Kim, Zainab Abbas, Patrick McDonel, Manuel Garber, John E. Harris
Journal: Science Translational Medicine (2021)

scRNA-seq of human vitiligo samples reveals complex autoimmune networks, including a role for CCR5 in T reg function.
Evaluation of Dietary Patterns and All-Cause Mortality
Authors: Laural K. English, Jamy D. Ard, Regan L. Bailey, Marlana Bates, Lydia A. Bazzano, Carol J. Boushey, Clarissa Brown, Gisela Butera, Emily H. Callahan, Janet de Jesus, Richard D. Mattes, Elizabeth J. Mayer-Davis, Rachel Novotny, Julie E. Obbagy, Elizabeth B. Rahavi, Joan Sabate, Linda G. Snetselaar, Eve E. Stoody, Linda V. Van Horn, Sudha Venkatramanan, Steven B. Heymsfield
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The 2020 Dietary Guidelines Advisory Committee conducted a systematic review of existing research on diet and health to inform the current Dietary Guidelines for Americans. The committee answered this public health question: what is the association between dietary patterns consumed and all-cause mortality (ACM)? <h3>Objective</h3> To ascertain the association between dietary patterns consumed and ACM. <h3>Evidence Review</h3> Guided by an analytical framework and predefined inclusion and exclusion criteria developed by the committee, the US Department of Agriculture’s Nutrition Evidence Systematic Review (NESR) team searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase and dual-screened the results to identify articles that were published between January 1, 2000, and October 4, 2019. These studies evaluated dietary patterns and ACM in participants aged 2 years and older. The NESR team extracted data from and assessed risk of bias in included studies. Committee members synthesized the evidence, developed conclusion statements, and graded the strength of the evidence supporting the conclusion statements. <h3>Findings</h3> A total of 1 randomized clinical trial and 152 observational studies were included in the review. Studies enrolled adults and older adults (aged 17-84 years at baseline) from 28 countries with high or very high Human Development Index; 53 studies originated from the US. Most studies were well designed, used rigorous methods, and had low or moderate risks of bias. Precision, directness, and generalizability were demonstrated across the body of evidence. Results across studies were highly consistent. Evidence suggested that dietary patterns in adults and older adults that involved higher consumption of vegetables, fruits, legumes, nuts, whole grains, unsaturated vegetable oils, fish, and lean meat or poultry (when meat was included) were associated with a decreased risk of ACM. These healthy patterns were also relatively low in red and processed meat, high-fat dairy, and refined carbohydrates or sweets. Some of these dietary patterns also included intake of alcoholic beverages in moderation. Results based on additional analyses with confounding factors generally confirmed the robustness of main findings. <h3>Conclusions and Relevance</h3> In this systematic review, consuming a nutrient-dense dietary pattern was associated with reduced risk of death from all causes.
Gramtools enables multiscale variation analysis with genome graphs
Authors: Brice Letcher, Martin Hunt, Zamin Iqbal
Journal: Genome biology (2021)

Abstract Genome graphs allow very general representations of genetic variation; depending on the model and implementation, variation at different length-scales (single nucleotide polymorphisms (SNPs), structural variants) and on different sequence backgrounds can be incorporated with different levels of transparency. We implement a model which handles this multiscale variation and develop a JSON extension of VCF (jVCF) allowing for variant calls on multiple references, both implemented in our software . We find outperforms existing methods for genotyping SNPs overlapping large deletions in M. tuberculosis and is able to genotype on multiple alternate backgrounds in P. falciparum , revealing previously hidden recombination.