tbuckley/cabot-search huggingface dataset:
Abstract B13: Characterization of the global proteome and phosphoproteome in cisplatin-resistant bladder cancers revealed the CDK2 network as a potential therapeutic target
Authors: Jae Hun Jung, Sungyong You, Jae Won Oh, Junhee Yoon, Austin Yeon, Muhammad Shahid, Eunho Cho, Vikram Sairam, Taeeun Park, Kwang Pyo Kim, Jayoung Kim
Journal: Clinical Cancer Research (2020)

Abstract Introduction and Objective: Cisplatin-based chemotherapy is currently part of the standard of care for bladder cancer (BC). Unfortunately, some patients respond poorly to chemotherapy and have acquired or developed resistance. The molecular mechanisms underlying this resistance remain unclear. Here, we introduce a multidimensional proteomic analysis of a cisplatin-resistant BC model that provides different levels of protein information, including that of the global proteome and phosphoproteome. Methods: To characterize the global proteome and phosphoproteome in cisplatin-resistant BC cells, liquid chromatography-mass spectrometry/mass spectrometry experiments combined with comprehensive bioinformatics analysis were performed. Perturbed expression and phosphorylation levels of key kinases associated with cisplatin resistance were further studied using various cell biology assays, including Western blot analysis. Results: Analyses of protein expression and phosphorylation identified significantly altered proteins, which were also EGF dependent and independent. This suggests that protein phosphorylation plays a significant role in cisplatin-resistant BC. Additional network analysis of significantly altered proteins revealed CDK2, CHEK1, and ERBB2 as central regulators mediating cisplatin resistance. In addition to this, we identified the CDK2 network, which consists of CDK2 and its five substrates, as being significantly associated with poor survival after cisplatin chemotherapy. Conclusions: Collectively, these findings potentially provide a novel way of classifying higher-risk patients and may guide future research in developing therapeutic targets. Citation Format: Jae Hun Jung, Sungyong You, Jae Won Oh, Junhee Yoon, Austin Yeon, Muhammad Shahid, Eunho Cho, Vikram Sairam, Taeeun Park, Kwang Pyo Kim, Jayoung Kim. Characterization of the global proteome and phosphoproteome in cisplatin-resistant bladder cancers revealed the CDK2 network as a potential therapeutic target [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B13.
Evaluating the Indirect Costs of Care Associated with Salvage Chemotherapy for Relapsed and Refractory Aggressive-Histology Lymphoma: A Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial
Authors: Anca Prica, Annette E Hay, Michael Crump, Nicole Mittman, Lois E. Shepherd, Ralph Meyer, Kevin Imrie, Nancy A. Risebrough, Marina S Djurfeldt, Bingshu E. Chen, Matthew Cheung
Journal: Blood (2017)
Abstract 10765: Improvement of Endothelial Dysfunction is Mediated Through Reduction of Remnant Lipoprotein After Statin Therapy in Patients With Coronary Artery Disease
Authors: Takamitsu Nakamura, Manabu Uematsu, Toru Yoshizaki, Tsuyoshi Kobayashi, Takeo Horikoshi, Yosuke Watanabe, Kiyotaka Kugiyama
Journal: Circulation (2019)

Introduction: Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for...
Effective Population Size Predicts Local Rates but Not Local Mitigation of Read-through Errors
Authors: Alexander T Ho, Laurence D Hurst
Journal: Molecular Biology and Evolution (2020)

In correctly predicting that selection efficiency is positively correlated with the effective population size (Ne), the nearly neutral theory provides a coherent understanding of between-species variation in numerous genomic parameters, including heritable error (germline mutation) rates. Does the same theory also explain variation in phenotypic error rates and in abundance of error mitigation mechanisms? Translational read-through provides a model to investigate both issues as it is common, mostly nonadaptive, and has good proxy for rate (TAA being the least leaky stop codon) and potential error mitigation via "fail-safe" 3' additional stop codons (ASCs). Prior theory of translational read-through has suggested that when population sizes are high, weak selection for local mitigation can be effective thus predicting a positive correlation between ASC enrichment and Ne. Contra to prediction, we find that ASC enrichment is not correlated with Ne. ASC enrichment, although highly phylogenetically patchy, is, however, more common both in unicellular species and in genes expressed in unicellular modes in multicellular species. By contrast, Ne does positively correlate with TAA enrichment. These results imply that local phenotypic error rates, not local mitigation rates, are consistent with a drift barrier/nearly neutral model.
Functional connectivity within glioblastoma impacts overall survival
Authors: Andy G S Daniel, Ki Yun Park, Jarod L Roland, Donna Dierker, James Gross, Joseph B Humphries, Carl D Hacker, Abraham Z Snyder, Joshua S Shimony, Eric C Leuthardt
Journal: Neuro-Oncology (2020)

Glioblastoma (GBM; World Health Organization grade IV) assumes a variable appearance on MRI owing to heterogeneous proliferation and infiltration of its cells. As a result, the neurovascular units responsible for functional connectivity (FC) may exist within gross tumor boundaries, albeit with altered magnitude. Therefore, we hypothesize that the strength of FC within GBMs is predictive of overall survival.We used predefined FC regions of interest (ROIs) in de novo GBM patients to characterize the presence of within-tumor FC observable via resting-state functional MRI and its relationship to survival outcomes.Fifty-seven GBM patients (mean age, 57.8 ± 13.9 y) were analyzed. Functionally connected voxels, not identifiable on conventional structural images, can be routinely found within the tumor mass and was not significantly correlated to tumor size. In patients with known survival times (n = 31), higher intranetwork FC strength within GBM tumors was associated with better overall survival even after accounting for clinical and demographic covariates.These findings suggest the possibility that functionally intact regions may persist within GBMs and that the extent to which FC is maintained may carry prognostic value and inform treatment planning.
Diabetic Foot Ulcers: A Neglected Complication of Lipodystrophy
Authors: Onur Saydam, Basak Ozgen Saydam, Cem Suleyman Adiyaman, Melda Sonmez Ince, Mehmet Ali Eren, Fatma Ela Keskin, Habib Bilen, Murat Dagdeviren, Seher Kaya, Gulcin Akinci, Ali Balci, Canan Altay, Firat Bayraktar, Elif Arioglu Oral, Baris Akinci
Journal: Diabetes Care (2020)

Lipodystrophy is a group of rare disorders characterized by generalized or partial loss of adipose tissue. Diabetes secondary to lipodystrophy is hardly responsive to standard treatment modalities and may lead to microvascular and macrovascular complications (1). Diabetic foot ulcers (DFUs) are a chronic complication of diabetes and a leading cause of lower-limb loss due to amputations. DFUs are an important cause of diabetes-related mortality (2).

In this observational retrospective cohort study, we report on 18 DFU episodes that developed in metreleptin-naive patients with lipodystrophy. These DFU episodes were compared with a series of DFUs ( n = 399) that occurred in a well-established cohort of patients with type 2 diabetes ( n = 290). The study was approved by the Dokuz Eylul University ethical review board.

Among 206 patients with lipodystrophy registered in our national cohort, DFUs were observed in 9 of 90 subjects with diabetes (10%). Four of these patients (44.4%) had multiple DFU episodes. Six patients had generalized lipodystrophy: five congenital generalized lipodystrophy (CGL) type 1 caused by AGPAT2 p.R68X (c.202C>T), p.E229X (c.685G>T), p.K216X (c.646A>T), and p.D180PfsX5 (c.538_539delGA) variants, and one CGL type 2 caused by BSCL2 p.Q94X (c.280C>T) variant. Three patients had partial lipodystrophy: one familial partial lipodystrophy (FPLD) type 1, one FPLD type 2 caused by LMNA p.R482W (c.144C>T) variant, …
ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection
Authors: Asmaa Hachim, Niloufar Kavian, Carolyn A. Cohen, Alex W. H. Chin, Daniel K. W. Chu, Chris K. P. Mok, Owen T. Y. Tsang, Yiu Cheong Yeung, Ranawaka A. P. M. Perera, Leo L. M. Poon, J. S. Malik Peiris, Sophie A. Valkenburg
Journal: Nature Immunology (2020)

The SARS-CoV-2 virus emerged in December 2019 and has caused a worldwide pandemic due to the lack of any pre-existing immunity. Accurate serology testing is urgently needed to help diagnose infection, determine past exposure of populations and assess the response to a future vaccine. The landscape of antibody responses to SARS-CoV-2 is unknown. In this study, we utilized the luciferase immunoprecipitation system to assess the antibody responses to 15 different SARS-CoV-2 antigens in patients with COVID-19. We identified new targets of the immune response to SARS-CoV-2 and show that nucleocapsid, open reading frame (ORF)8 and ORF3b elicit the strongest specific antibody responses. ORF8 and ORF3b antibodies, taken together as a cluster of points, identified 96.5% of COVID-19 samples at early and late time points of disease with 99.5% specificity. Our findings could be used to develop second-generation diagnostic tests to improve serological assays for COVID-19 and are important in understanding pathogenicity.
Publisher Correction: Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types
Authors: Tamás Laszlovszky, Dániel Schlingloff, Panna Hegedüs, Tamás F. Freund, Attila Gulyás, Adam Kepecs, Balázs Hangya
Journal: Nature Neuroscience (2020)
Predicting persistence of atopic dermatitis in children using clinical attributes and serum proteins
Authors: Felix Lauffer, Veronika Baghin, Marie Standl, Sebastian P. Stark, Manja Jargosch, Julius Wehrle, Jenny Thomas, Carsten B. Schmidt‐Weber, Tilo Biedermann, Stefanie Eyerich, Kilian Eyerich, Natalie Garzorz‐Stark
Journal: Allergy (2020)

Atopic dermatitis (AD) is the most common inflammatory skin disease in children, with 30% of all those diagnosed developing chronic or relapsing disease by adolescence. Such disease persistence cannot yet be predicted. The aim of the present study was to predict the natural course of AD using clinical parameters and serum proteins.Sera of 144 children with AD (age 0-3 years) were analyzed for IgE and 33 cytokines, chemokines, and growth factors. Patient disease course until the age of 7 years was assessed retrospectively. Unsupervised k-means clustering was performed to define disease endotypes. Identified factors associated with AD persistence at the age of 7 years were validated in children with AD in an independent cohort (LISA Munich; n = 168). Logistic regression and XGBoosting methods followed by cross-validation were applied to predict individual disease outcomes.Three distinct endotypes were found in infancy, characterized by a unique inflammatory signature. Factors associated with disease persistence were disease score (SCORAD), involvement of the limbs, flexural lesion distribution at the age of 3 years, allergic comorbidities, and disease exacerbation by the trigger factors stress, pollen exposure, and change in weather. Persistence was predicted with a sensitivity of 81.8% and a specificity of 82.4%. Factors with a high impact on the prediction of persistence were SCORAD at the age of 3 years, trigger factors, and low VEGF serum levels.Atopic dermatitis in infancy comprises three immunological endotypes. Disease persistence can be predicted using serum cytokines and clinical variables.
Distribution of the dermoscopic features of melanoma of trunk and extremities according to the anatomic sublocation
Authors: Juta Maskalane, Eliza Salijuma, Konstantinos Lallas, Chryssoula Papageorgiou, Theodosia Gkentsidi, Magdalini-Sofia Manoli, Ioannis Spyridis, Ilias Papadimitriou, Elizabeth Lazaridou, Elena Sotiriou, Efstratios Vakirlis, Dimitrios Ioannides, Zoe Apalla, Aimilios Lallas
Journal: Journal of the American Academy of Dermatology (2020)
Racial and Ethnic Disparities Among COVID-19 Cases in Workplace Outbreaks by Industry Sector — Utah, March 6–June 5, 2020
Authors: David P. Bui, Keegan McCaffrey, Michael Friedrichs, Nathan LaCross, Nathaniel M. Lewis, Kylie Sage, Bree Barbeau, Dede Vilven, Carolyn Rose, Sara Braby, Sarah Willardson, Amy Carter, Christopher Smoot, Andrea Winquist, Angela Dunn
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Improved understanding of the overall distribution of workplace coronavirus disease 2019 (COVID-19) outbreaks by industry sector could help direct targeted public health action; however, this has not been described. The Utah Department of Health (UDOH) analyzed COVID-19 surveillance data to describe workplace outbreaks by industry sectors. In this report, workplaces refer to non-health care, noncongregate-living, and noneducational settings. As of June 5, 2020, UDOH reported 277 COVID-19 outbreaks, 210 (76%) of which occurred in workplaces. Approximately 12% (1,389 of 11,448) of confirmed COVID-19 cases in Utah were associated with workplace outbreaks. The 210 workplace outbreaks occurred in 15 of 20 industry sectors;* nearly one half of all workplace outbreaks occurred in three sectors: Manufacturing (43; 20%), Construction (32; 15%) and Wholesale Trade (29; 14%); 58% (806 of 1,389) of workplace outbreak-associated cases occurred in these three sectors. Although 24% of Utah's workforce in all 15 affected sectors identified as Hispanic or Latino (Hispanic) or a race other than non-Hispanic white (nonwhite†) (1), 73% (970 of 1,335) of workplace outbreak-associated COVID-19 cases were in persons who identified as Hispanic or nonwhite. Systemic social inequities have resulted in the overrepresentation of Hispanic and nonwhite workers in frontline occupations where exposure to SARS-CoV-2, the virus that causes COVID-19, might be higher (2); extra vigilance in these sectors is needed to ensure prevention and mitigation strategies are applied equitably and effectively to workers of racial and ethnic groups disproportionately affected by COVID-19. Health departments can adapt workplace guidance to each industry sector affected by COVID-19 to account for different production processes and working conditions.
AB0178 On the diagnostics of possibly inherited osteoporosis
Authors: É Lányi, B Gömör, I Ratkó
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Osteoporosis (OP) is a disease of high occurrence in the older-aged population. Early diagnosis may trigger an efficient medication, which could slow down or even stop the decrease of bone mineral density (BMD), leading so to a noticeably decrease of the risk for bone fracture in old age. Reducing the incidence of osteoporosis is of utmost importance for both the individuals and the society, so it is not only of medical importance to identify individuals with a higher-than-average risk of developing osteoporosis. <h3>Objectives</h3> The aim of this work is to investigate the role of inheritance in osteoporosis as mirrored by basic diagnostic methods. It is also of practical interest to establish the applicability of the by now routinely applied dual energy X-ray absorption (DEXA) method for early diagnostics of BMD for patient groups with a suspected tendency to inherited osteoporosis. <h3>Methods</h3> The patient study group consisted of 28 mother- daughter pairs. The mothers (age group: 60–85 y) were suffering in a severe form of osteoporosis as shown for each of them by crush fractures of the vertebrae. The study of the BMD values was directed to the group of daughters of mothers suffering from osteoporosis (DMO). For the daughters (29–58 y, average age: 49 y), medication and coexistence of other diseases influencing BMD were excluded. The control group consisted of healthy reference persons, matched to persons in the DMO group. BMD values were determined by DEXA measurements on the lumbal spine (L2–4) and on the femoral neck, employing a Norland XR-26 densitometer, with an excellent coefficient of reproducibility (0.77%) over the 1.5 y of the investigations. Data significance was established by the t-probe analysis. <h3>Results</h3> BMD values referring to L2–4 were significantly lower for the DMO (0.86 ± 0.15 g/cm<sup>2</sup>) as for the control group (1.02 ± 0.16 g/cm<sup>2</sup>), whereas BMD results for the femoral neck were (0.76 ± 0.11 g/cm<sup>2</sup>) and (0.90 ± 0.14 g/cm<sup>2</sup>), respectively. The difference of the BMD values for L2–4 was about 20%, whereas for the femoral neck it amounted to 21%. There is an indication that the peak BMD values for the DMO groupremain lower than those for the control group. <h3>Conclusion</h3> These findings point strongly to the role of inheritance in the epigenesis of osteoporosis. It is concluded that for individuals with increased genetic risk of osteoporosis an appropriate strategy, combining increased calcium uptake with an educated application of physical exercise, should be worked out. Such a complex treatment could also increase the BMD values before menopause.
Tapering antirheumatic drugs in a resource-poor setting: real-world evidence
Authors: Muhammad Haroon, Zara Khan, Maryam Aamer
Journal: Annals of the Rheumatic Diseases (2020)

Introduction of biological agents has undoubtedly revolutionised the management of different inflammatory rheumatic conditions; however, for Pakistani patients, it comes with a significant cost burden. We read with interest the article by van Mulligen et al ,1 and we concur with their conclusion that ‘financial arguments may influence the decision to taper tumour necrosis factor-inhibitors first’. Being in a resource-poor country, the access to biological therapies is limited in our part of the world, and we would like to share our experience of tapering antirheumatic drugs.

After achieving remission or low disease activity (LDA), dosage reduction of biological disease-modifying antirheumatic drugs (bDMARDs) is an important topic in light of, not only the significant economic burden, but also as increasing number of patients who reach remission or LDA along with carrying the risk of unnecessary adverse events due to overtreatment. Hence, …
Daratumumab‐lenalidomide‐dexamethasone vs standard‐of‐care regimens: Efficacy in transplant‐ineligible untreated myeloma
Authors: Brian G. M. Durie, Shaji K. Kumar, Saad Z. Usmani, Bareng A. S. Nonyane, Eric M. Ammann, Annette Lam, Rachel Kobos, Eric M. Maiese, Thierry Facon
Journal: American Journal of Hematology (2020)

Daratumumab in combination with lenalidomide-dexamethasone (D-Rd) recently received FDA approval for the treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The present PEGASUS study compared progression-free survival (PFS) in patients treated with D-Rd in the MAIA trial and patients treated with common standard-of-care regimens from the Flatiron Health electronic health record-derived deidentified database, which has data from patients treated primarily at community-based oncology practices in the United States. Individual-level patient data from both data sources were used to perform an anchored indirect treatment comparison (ITC) of D-Rd to bortezomib-lenalidomide-dexamethasone (VRd) and bortezomib-dexamethasone (Vd); lenalidomide-dexamethasone (Rd) was the common anchor for the ITC. Hazard ratios (HRs) reflecting direct comparisons of PFS within MAIA (D-Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used to make ITCs for D-Rd vs VRd and Vd, respectively. After application of MAIA inclusion/exclusion criteria and propensity-score weighting, the Flatiron Health patients resembled the MAIA trial population on measured baseline characteristics. Based on the direct comparison within MAIA, treatment with D-Rd was associated with a significantly lower risk of progression or death compared to Rd (HR 0.54; 95% CI 0.42, 0.71). Based on the ITCs, D-Rd was associated with a significantly lower risk of progression or death compared to VRd (HR 0.68; 95% CI 0.48, 0.98) and Vd (HR 0.48; 95% CI 0.33, 0.69). In the absence of head-to-head trials comparing D-Rd to VRd or Vd, the present ITC may help inform treatment selection in transplant-ineligible patients with NDMM.
Abstract A04: DNA damage repair gene mutations and associated tumor immune landscape as biomarkers of response to immunotherapy in muscle-invasive urothelial cancer
Authors: Thiago Vidotto, Sarah Nersesian, Charles Graham, David Robert Siemens, Madhuri Koti
Journal: Clinical Cancer Research (2020)

Abstract Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behavior of cancer cells and their adaptation to the coevolving microenvironment and response to treatment. In alignment with this concept, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR). A comprehensive understanding of DDR mutation-associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments. We thus investigated the pretreatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle-invasive urothelial cancer (MIUC; n=408) from the Genomic Data Commons, to determine subtype-specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene mutation profiles. Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune-stimulatory and -inhibitory genes showed significant associations with subtypes and DDR mutation status. Findings from our study provide compelling evidence for coexpression of multiple immune checkpoint genes including PD-1, PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies. Citation Format: Thiago Vidotto, Sarah Nersesian, Charles Graham, David Robert Siemens, Madhuri Koti. DNA damage repair gene mutations and associated tumor immune landscape as biomarkers of response to immunotherapy in muscle-invasive urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A04.
Abstract 14530: Brown Adipose Tissue, a Novel Therapeutic Modality for Impaired Exercise Capacity
Authors: Marko Oydanich, Jie Zhang, Dorothy E Vatner, Stephen F Vatner
Journal: Circulation (2019)

Exercise has been shown to induce changes in brown adipose tissue (BAT) that lead to better performance. There have been no studies that have looked at the converse, i.e. whether BAT can improve ex...