tbuckley/cabot-search huggingface dataset:
Temporal airway microbiome changes related to ventilator-associated pneumonia in children
Authors: Peter M. Mourani, Marci K. Sontag, Kayla M. Williamson, J. Kirk Harris, Ron Reeder, Chris Locandro, Todd C. Carpenter, Aline B. Maddux, Katherine Ziegler, Eric A.F. Simões, Christina M. Osborne, Lilliam Ambroggio, Matthew K. Leroue, Charles E. Robertson, Charles Langelier, Joseph L. DeRisi, Jack Kamm, Mark W. Hall, Athena F. Zuppa, Joseph Carcillo, Kathleen Meert, Anil Sapru, Murray M. Pollack, Patrick McQuillen, Daniel A. Notterman, J. Michael Dean, Brandie D. Wagner
Journal: European Respiratory Journal (2020)

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children. Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for &gt;72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case–control comparisons and unsupervised clustering. Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3–5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of Streptococcus , Lactobacillales and Prevotella were lower for VAP subjects versus non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23–0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included Prevotella species (19%), Pseudomonas aeruginosa (14%) and Streptococcus mitis / pneumoniae (10%). Mycoplasma and Ureaplasma were also identified as dominant organisms in several subjects. In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.
Mustache: multi-scale detection of chromatin loops from Hi-C and Micro-C maps using scale-space representation
Authors: Abbas Roayaei Ardakany, Halil Tuvan Gezer, Stefano Lonardi, Ferhat Ay
Journal: Genome biology (2020)

We present MUSTACHE, a new method for multi-scale detection of chromatin loops from Hi-C and Micro-C contact maps. MUSTACHE employs scale-space theory, a technical advance in computer vision, to detect blob-shaped objects in contact maps. MUSTACHE is scalable to kilobase-resolution maps and reports loops that are highly consistent between replicates and between Hi-C and Micro-C datasets. Compared to other loop callers, such as HiCCUPS and SIP, MUSTACHE recovers a higher number of published ChIA-PET and HiChIP loops as well as loops linking promoters to regulatory elements. Overall, MUSTACHE enables an efficient and comprehensive analysis of chromatin loops. Available at: https://github.com/ay-lab/mustache .
Subvoxel vessel wall thickness measurements of the intracranial arteries using a convolutional neural network
Authors: Kees M. van Hespen, Jaco J.M. Zwanenburg, Jeroen Hendrikse, Hugo J. Kuijf
Journal: Medical Image Analysis (2020)

Vessel wall thickening of the intracranial arteries has been associated with cerebrovascular disease and atherosclerotic plaque development. Visualization of the vessel wall has been enabled by recent advancements in vessel wall MRI. However, quantifying early wall thickening from these MR images is difficult and prone to severe overestimation, because the voxel size of clinically used acquisitions exceeds the wall thickness of the intracranial arteries. In this study, we aimed for accurate and precise subvoxel vessel wall thickness measurements. A convolutional neural network was trained on MR images of 34 ex vivo circle of Willis specimens, acquired with a clinically used protocol (isotropic acquired voxel size: 0.8 mm). Ground truth measurements were performed on images acquired with an ultra-high-resolution protocol (isotropic acquired voxel size: 0.11 mm) and were used for evaluation. Additionally, we determined the robustness of our method by applying Monte Carlo dropout and test time augmentation. Lastly, we applied our method on in vivo images of three intracranial aneurysms to measure their wall thickness. Our method shows resolvability of different vessel wall thicknesses, well below the acquired voxel size. The method described may facilitate quantitative measurements on MRI data for a wider range of clinical applications.
Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer
Authors: Claire F Friedman, Alexandra Snyder Charen, Qin Zhou, Michael A Carducci, Alexandre Buckley De Meritens, Bradley R Corr, Siqing Fu, Travis J Hollmann, Alexia Iasonos, Jason A Konner, Panagiotis A Konstantinopoulos, Susan C Modesitt, Elad Sharon, Carol Aghajanian, Dmitriy Zamarin
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background There are limited treatment options for patients with metastatic or recurrent cervical cancer. Platinum-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab remains the mainstay of advanced treatment. Pembrolizumab is Food and Drug Agency approved for programmed death ligand 1 (PD-L1) positive cervical cancer with a modest response rate. This is the first study to report the efficacy and safety of the PD-L1 antibody atezolizumab in combination with bevacizumab in advanced cervical cancer. Methods We report the results from a phase II, open-label, multicenter study ( NCT02921269 ). Patients with advanced cervical cancer were treated with bevacizumab 15 mg/kg intravenous every 3 weeks and atezolizumab 1200 mg intravenous every 3 weeks. The primary objective was to measure the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results In the total evaluable population (n=10), zero patients achieved an objective response as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1, resulting in a confirmed ORR of 0%. Of note, there were two patients who achieved an unconfirmed PR. The DCR by RECIST V.1.1 was 60% (0% complete response, 0% partial response, 60% stable disease). Median PFS was 2.9 months (95% CI, 1.8 to 6) and median OS was 8.9 months (95% CI, 3.4 to 21.9). Safety results were generally consistent with the known safety profile of both drugs, notably with two high-grade neurologic events. Conclusions The combination of bevacizumab and atezolizumab did not meet the predefined efficacy endpoint, as addition of bevacizumab to PD-L1 blockade did not appear to enhance the ORR in cervical cancer.
Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma
Authors: Jason Yongsheng Chan, Jing Quan Lim, Joe Yeong, Vinod Ravi, Peiyong Guan, Arnoud Boot, Timothy Kwang Yong Tay, Sathiyamoorthy Selvarajan, Nur Diyana Md Nasir, Jie Hua Loh, Choon Kiat Ong, Dachuan Huang, Jing Tan, Zhimei Li, Cedric Chuan-Young Ng, Thuan Tong Tan, Mikio Masuzawa, Ken Wing-Kin Sung, Mohamad Farid, Richard Hong Hui Quek, Ngian Chye Tan, Melissa Ching Ching Teo, Steven George Rozen, Patrick Tan, Andrew Futreal, Bin Tean Teh, Khee Chee Soo
Journal: Journal of Clinical Investigation (2020)

Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non-UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15+), macrophages (CD68+), cytotoxic T cells (CD8+), Tregs (FOXP3+), and PD-L1+ cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.
Tralokinumab for moderate‐to‐severe atopic dermatitis: results from two 52‐week, randomized, double‐blind, multicentre, placebo‐controlled phase III trials (ECZTRA 1 and ECZTRA 2)*
Authors: A. Wollenberg, A. Blauvelt, E. Guttman‐Yassky, M. Worm, C. Lynde, J.‐P. Lacour, L. Spelman, N. Katoh, H. Saeki, Y. Poulin, A. Lesiak, L. Kircik, S.H. Cho, P. Herranz, M.J. Cork, K. Peris, L.A. Steffensen, B. Bang, A. Kuznetsova, T.N. Jensen, M.L. Østerdal, E.L. Simpson
Journal: British Journal of Dermatology (2020)

Background Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. Objectives To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. Methods In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. Results At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1–13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8–16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5–17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8–27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. Conclusions Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.
Abstract A28: Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma
Authors: Victor Lin, Ashwini Zolekar, Nigam Mishra, Yin Ying Ho, Hamed Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle Emmitte, Yu-Chieh Wang
Journal: Cancer Research (2020)

Abstract Although NGLY1 is known as a pivotal enzyme that catalyzes the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. While studying the NGLY1 deficiency-caused neurodevelopmental variations in patients with a congenital deglycosylation disorder, we made an intriguing discovery that the expression of NGLY1 appears to be dysregulated in human melanoma cells. We have examined how NGLY1 expression affects viability, tumor growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumors. NGLY1 knockdown caused melanoma cell death and tumor growth retardation. Targeting NGLY1 in melanoma cells induced pleiotropic responses, predominantly stress signaling-associated apoptosis and cytokine surges, which synergize with the antimelanoma activity of standard chemotherapy and targeted therapy agents. Pharmacologic and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel antimelanoma strategy with the opportunity of a broad therapeutic window. Citation Format: Victor Lin, Ashwini Zolekar, Nigam Mishra, Yin Ying Ho, Hamed Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle Emmitte, Yu-Chieh Wang. Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A28.
AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-xL, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia
Authors: Srividya B. Balachander, Steven W. Criscione, Kate F. Byth, Justin Cidado, Ammar Adam, Paula Lewis, Terry Macintyre, Shenghua Wen, Deborah Lawson, Kathleen Burke, Tristan Lubinski, Jeffrey W. Tyner, Stephen E. Kurtz, Shannon K. McWeeney, Jeffrey Varnes, R. Bruce Diebold, Thomas Gero, Stephanos Ioannidis, Edward J. Hennessy, William McCoull, Jamal C. Saeh, Areya Tabatabai, Omid Tavana, Nancy Su, Alwin Schuller, Mathew J. Garnett, Patricia Jaaks, Elizabeth A. Coker, Gareth P. Gregory, Andrea Newbold, Ricky W. Johnstone, Eric Gangl, Martin Wild, Michael Zinda, J. Paul Secrist, Barry R. Davies, Stephen E. Fawell, Francis D. Gibbons
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. Results: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-xL–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. Conclusions: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
Response to: ‘Correspondence on ‘Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis’’ by Jeny<i>et al</i>
Authors: Andrea Hermina Györfi, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2020)

We thank Cohen Aubart et al for their correspondence.1 Their study on 36 patients with sarcoidosis and COVID-19 from 15 French centres provides interesting insights on the outcome of COVID-19 in this group of patients. These data provide evidence that a higher percentage of patients with sarcoidosis with COVID-19 might require intensive care support than in the general population. In contrast, sarcoidosis does not seem to affect the severity of COVID-19, and patients with sarcoidosis-associated interstitial lung disease (ILD) are not admitted more often to the intensive care unit (ICU) than patients without ILD.

The data by Cohen Aubart et al 1 show that 85% of the patients with sarcoidosis with COVID-19 admitted to …
Environment Influences Tumor Progression and Transcriptional Subtype in a New Model of Pancreatic Cancer
Authors: Karen A. Pickering, Jennifer P. Morton
Journal: Cancer Discovery (2020)

Abstract Summary: In this issue, Miyabayashi and colleagues describe a novel intraductal model of pancreatic cancer that allows modeling of the transcriptional subtypes of pancreatic cancer. Using this model, they are able to observe subtype switching driven by the microenvironment, a process at least partially mediated by RAS signaling. See related article by Miyabayashi et al., p. 1566.
mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer
Authors: Gal Cafri, Jared J. Gartner, Tal Zaks, Kristen Hopson, Noam Levin, Biman C. Paria, Maria R. Parkhurst, Rami Yossef, Frank J. Lowery, Mohammad S. Jafferji, Todd D. Prickett, Stephanie L. Goff, Christine T. McGowan, Samantha Seitter, Mackenzie L. Shindorf, Anup Parikh, Praveen D. Chatani, Paul F. Robbins, Steven A. Rosenberg
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.
Biomechanical Footwear for Osteoarthritic Knee Pain
Authors: Yiting Lei, Danli Cui, Wei Huang
Journal: JAMA (2020)

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Novel Therapeutic Approach for Excitatory/Inhibitory Imbalance in Neurodevelopmental and Neurodegenerative Diseases
Authors: Swagata Ghatak, Maria Talantova, Scott R. McKercher, Stuart A. Lipton
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Excitatory/inhibitory (E/I) balance, defined as the balance between excitation and inhibition of synaptic activity in a neuronal network, accounts in part for the normal functioning of the brain, controlling, for example, normal spike rate. In many pathological conditions, this fine balance is perturbed, leading to excessive or diminished excitation relative to inhibition, termed E/I imbalance, reflected in network dysfunction. E/I imbalance has emerged as a contributor to neurological disorders that occur particularly at the extremes of life, including autism spectrum disorder and Alzheimer's disease, pointing to the vulnerability of neuronal networks at these critical life stages. Hence, it is important to develop approaches to rebalance neural networks. In this review, we describe emerging therapies that can normalize the E/I ratio or the underlying abnormality that contributes to the imbalance in electrical activity, thus improving neurological function in these maladies.
An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy
Authors: Cong Wang, Wanbing Sun, Jun Zhang, Jianping Zhang, Qinghua Guo, Xingyu Zhou, Dandan Fan, Haoran Liu, Ming Qi, Xihui Gao, Haiyan Xu, Zhaobing Gao, Mei Tian, Hong Zhang, Jianhong Wang, Zixuan Wei, Nicholas J. Long, Ying Mao, Cong Li
Journal: Nature Biomedical Engineering (2020)
The role of T cell based interferon-gamma release assays in the evaluation of patients with suspected active tuberculosis
Authors: Hinks Tsc., Dosanjh Dps., J A Innes, J Deeks, G Pasvol, S Hackforth, H Varia, X Q Liu, K Millington, R Gunatheesan, V Guyot-Revol, A Lalvani
Journal: Thorax (2007)