tbuckley/cabot-search huggingface dataset:
Trends in the global burden of paediatric lower respiratory infections
Authors: Carina King, Eric D McCollum
Journal: The Lancet Infectious Diseases (2019)

As the leading cause of infectious deaths in children, 1 Liu L Oza S Hogan D et al. Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016; 388: 3027-3035 Summary Full Text Full Text PDF PubMed Scopus (1723) Google Scholar reducing lower respiratory infections (LRIs) will be the key to achieving Sustainable Development Goal 3.2. However, of the biggest infectious killers, LRI remains the condition with the least funding on a global level. 2 Brown R Head M Sizing up pneumonia research: assessing global investments in pneumonia research 2000–2015. University of Southampton, Southampton2018 Google Scholar In The Lancet Infectious Diseases, the GBD 2017 Lower Respiratory Infections Collaborators 3 GBD 2017 Lower Respiratory Infections CollaboratorsQuantifying risks and interventions that have affected the burden of lower respiratory infections among children younger than 5 years: an analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019; (published online Oct 30)https://doi.org/10.1016/S1473-3099(19)30410-4 Google Scholar present modelled trends in LRI incident cases and mortality and estimate the role of 13 modifiable protective and preventive risk factors in these spatiotemporal changes using the Global Burden of Disease (GBD) dataset. Quantifying risks and interventions that have affected the burden of lower respiratory infections among children younger than 5 years: an analysis for the Global Burden of Disease Study 2017Our findings show that there have been substantial but uneven declines in LRI mortality among countries between 1990 and 2017. Although improvements in indicators of sociodemographic development could explain some of these trends, changes in exposure to modifiable risk factors are related to the rates of decline in LRI mortality. No single intervention would universally accelerate reductions in health loss associated with LRIs in all settings, but emphasising the most dominant risk factors, particularly in countries with high case fatality, can contribute to the reduction of preventable deaths. Full-Text PDF Open Access
pTuneos: prioritizing tumor neoantigens from next-generation sequencing data
Authors: Chi Zhou, Zhiting Wei, Zhanbing Zhang, Biyu Zhang, Chenyu Zhu, Ke Chen, Guohui Chuai, Sheng Qu, Lu Xie, Yong Gao, Qi Liu
Journal: Genome Medicine (2019)

Abstract Background Cancer neoantigens are expressed only in cancer cells and presented on the tumor cell surface in complex with major histocompatibility complex (MHC) class I proteins for recognition by cytotoxic T cells. Accurate and rapid identification of neoantigens play a pivotal role in cancer immunotherapy. Although several in silico tools for neoantigen prediction have been presented, limitations of these tools exist. Results We developed pTuneos , a computational pipeline for p rioritizing tu mor neo antigens from next-generation s equencing data. We tested the performance of pTuneos on the melanoma cancer vaccine cohort data and tumor-infiltrating lymphocyte (TIL)-recognized neopeptide data. pTuneos is able to predict the MHC presentation and T cell recognition ability of the candidate neoantigens, and the actual immunogenicity of single-nucleotide variant (SNV)-based neopeptides considering their natural processing and presentation, surpassing the existing tools with a comprehensive and quantitative benchmark of their neoantigen prioritization performance and running time. pTuneos was further tested on The Cancer Genome Atlas (TCGA) cohort data as well as the melanoma and non-small cell lung cancer (NSCLC) cohort data undergoing checkpoint blockade immunotherapy. The overall neoantigen immunogenicity score proposed by pTuneos is demonstrated to be a powerful and pan-cancer marker for survival prediction compared to traditional well-established biomarkers. Conclusions In summary, pTuneos provides the state-of-the-art one-stop and user-friendly solution for prioritizing SNV-based candidate neoepitopes, which could help to advance research on next-generation cancer immunotherapies and personalized cancer vaccines. pTuneos is available at https://github.com/bm2-lab/pTuneos , with a Docker version for quick deployment at https://cloud.docker.com/u/bm2lab/repository/docker/bm2lab/ptuneos .
Expectations of cancer patients about clinical trials in multidisciplinary clinics
Authors: G. H. Kloecker, M. Janjua, J. Day, D. Lee
Journal: Journal of Clinical Oncology (2009)

e17563 Background: Progress in cancer treatment is very much dependent on the effective interaction of several specialties. To facilitate the process, more and more multidisciplinary clinics have been created over the last decade, especially in academic settings. This approach has been more established in the academic setting to help facilitate better patient accrual to clinical trials. Although there are studies confirming the effectiveness of this approach in fulfilling practice guidelines, there is however no study of patients’ expectations at a multidisciplinary clinic, especially in regard to the patients’ attitude towards clinical trials. This study examines patients’ preferences for services offered in an academic Methods: Surveys were handed to patients at the time of the first clinic visit and at time of progressive disease. The surveys were designed as a self directed questionnaire with the following questions that were rated on an ordinate scale from not at all important (score 1) to extremely important value (score 7): to see all doctors the same day; to be treated at a university-based cancer center; to have everything completely explained; to have the first appointment within 10 days; to know your cases will be discussed at conference; to have help with transportation and medical costs; and to participate in clinical trials. Results: 94 patients were surveyed at the GI and Thoracic Multimodality Clinic. Among patients the highest preference was “to have every thing explained,” score 6.7 (6.5–7.0, CI), immediately followed by the discussion at the multidisciplinary conference, score 6.6 (6.5–6.8, CI). Clinical trials ranked lowest, score 4.8 (4.4–5.2,CI). The difference was statistically significant, p = 0.012. There was no difference between GI and Thoracic Multimodality Clinic patients. Patients with progressive cancers showed a slightly higher interest in clinical trials, but still ranking trials below most other services. Conclusions: Patients value complete explanations of the disease and management plan far more than they value clinical trials. Considering that nationwide less than 5% of cancer patients are enrolled in clinical studies, it is important for physicians to explain the merit of clinical trials to patients and public. No significant financial relationships to disclose.
Theranostics in immuno-oncology using nanobody derivatives
Authors: Quentin Lecocq, Yannick De Vlaeminck, Heleen Hanssens, Matthias D'Huyvetter, Geert Raes, Cleo Goyvaerts, Marleen Keyaerts, Nick Devoogdt, Karine Breckpot
Journal: Theranostics (2019)

Targeted therapy and immunotherapy have become mainstream in cancer treatment. However, only patient subsets benefit from these expensive therapies, and often responses are short-lived or coincide with side effects. A growing modality in precision oncology is the development of theranostics, as this enables patient selection, treatment and monitoring. In this approach, labeled compounds and an imaging technology are used to diagnose patients and select the best treatment option, whereas for therapy, related compounds are used to target cancer cells or the tumor stroma. In this context, nanobodies and nanobody-directed therapeutics have gained interest. This interest stems from their high antigen specificity, small size, ease of labeling and engineering, allowing specific imaging and design of therapies targeting antigens on tumor cells, immune cells as well as proteins in the tumor environment. This review provides a comprehensive overview on the state-of-the-art regarding the use of nanobodies as theranostics, and their importance in the emerging field of personalized medicine.
Determining factors related to poor quality of life in patients with axial spondyloarthritis: results from the British Society for Rheumatology Biologics Register (BSRBR-AS)
Authors: Gary J Macfarlane, Ovidiu Rotariu, Gareth T Jones, Ejaz Pathan, Linda E Dean
Journal: Annals of the Rheumatic Diseases (2019)

Objective To determine modifiable factors associated with poor quality of life (QoL) in patients with axial spondyloarthritis (axSpA). Methods Analysis of data from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS) and validation of a previous model using data from 1810 patients with axSpA recruited during 2012–2017. Data collected included clinical and patient-reported measures. QoL was assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) measure. Linear regression models predicting ASQoL scores were used first to validate a previous model from a national study, to extend this with additional information available in BSRBR-AS and finally to identify a ‘de novo’ model from BSRBR-AS of which factors impact on poor QoL. Results Four out of five factors included in a previous model of poor QoL in patients with axSpA were confirmed: Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index, fatigue and widespread pain, although the performance of the model was improved by the addition of measures of mood and sleep disturbance. In a de novo model in BSRBR-AS, there were six factors (other than disease activity and function) that predicted ASQoL: depression (β=0.16), sleep disturbance (β=0.08), activity impairment (β=0.04), fibromyalgia (Symptom Severity Scale (β=0.24) and Widespread Pain Index (β=0.10)) and tobacco smoking (β=0.66). Conclusion This study confirms that poor QoL in patients with axSpA, in addition to high disease activity and poor function, is independently influenced by sleep disturbance, mood and widespread pain. These additional factors are not considered targets for treatment in current European League Against Rheumatism (EULAR) guidelines for managing the condition.
Understanding and addressing social determinants to advance cancer health equity in the United States: A blueprint for practice, research, and policy
Authors: Kassandra I. Alcaraz, Tracy L. Wiedt, Elvan C. Daniels, K. Robin Yabroff, Carmen E. Guerra, Richard C. Wender
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract Although cancer mortality rates declined in the United States in recent decades, some populations experienced little benefit from advances in cancer prevention, early detection, treatment, and survivorship care. In fact, some cancer disparities between populations of low and high socioeconomic status widened during this period. Many potentially preventable cancer deaths continue to occur, and disadvantaged populations bear a disproportionate burden. Reducing the burden of cancer and eliminating cancer‐related disparities will require more focused and coordinated action across multiple sectors and in partnership with communities. This article, part of the American Cancer Society's Cancer Control Blueprint series, introduces a framework for understanding and addressing social determinants to advance cancer health equity and presents actionable recommendations for practice, research, and policy. The article aims to accelerate progress toward eliminating disparities in cancer and achieving health equity.
Persistent Dengue Infection in an Immunosuppressed Patient Reveals the Roles of Humoral and Cellular Immune Responses in Virus Clearance
Authors: Kar-Hui Ng, Summer Lixin Zhang, Hwee Cheng Tan, Swee Sen Kwek, October Michael Sessions, Chang-Yien Chan, Isaac Desheng Liu, Chun Kiat Lee, Paul Ananth Tambyah, Eng Eong Ooi, Hui-Kim Yap
Journal: Cell Host & Microbe (2019)
OA03.01 Biomarkers of Autoimmune Toxicity in Metastatic SCLC Patients Receiving PD-1/PDL-1 Targeted Therapy
Authors: I. Tarhoni, A. Tangri, B. Gilmore, M. Fidler, M. Batus, P. Bonomi, J. Borgia
Journal: Journal of Thoracic Oncology (2019)
Concurrent chemoradiotherapy with weekly docetaxel and cisplatin for locally advanced head and neck cancer: Phase I study
Authors: H. S. Kim, K. Park, M. J. Ahn, Y. Park, S. Lee, C. Baek, Y. Son, H. Jeong, Y. Ahn, B. Park
Journal: Journal of Clinical Oncology (2009)

e17026 Background: This phase I study was performed to determine maximum tolerated dose of docetaxel when administered concomitantly with radiotherapy and cisplatin in patients with locally advanced head and neck cancer. Methods: Fifteen patients were treated at varying levels of docetaxel (level 1: 0 mg/m 2 , level 2: 10 mg/m 2 , level 3: 15 mg/m 2 , and level 4: 20 mg/m 2 , once per week for a total 6 weeks) with a fixed dose of 20 mg/m 2 cisplatin weekly on an outpatient basis. Radiotherapy was delivered as a standard regimen (1.8–2.0 Gy/day, 5 fraction/week) to a total dose of 66–72 Gy. Results: One out of six patients presented with dose-limiting toxicity at the 10 mg/m 2 /week dose of docetaxel (grade 4 febrile neutropenia which results in treatment-related death). No DLTs was noticed at the 15 mg/m 2 , and 20 mg/m 2 dose level. Thus, the weekly docetaxel dose of 20 mg/m 2 was considered as the maximum tolerated dose. Radiotherapy was completed in all patients except one, and more than 95% of the scheduled cisplatin and docetaxel were given in 93% of patients. Acute grade 3–4 toxicities were dominated by anorexia (26.7%), xerostomia (13.3%), and febrile neutropenia (6.6%). Eight (57.1%) and six (42.9%) patients had complete response and partial response. The 2-year actuarial overall survival rate and local control rate were 93.3%, and 87.5%, respectively. With a median 17.5 months (1.25–23.6) of follow-up, 13 out of 14 patients are still alive without evidence of diseases, and only one is alive with evidence of diseases. Conclusions: We determined the MTD of docetaxel to be 20 mg/m 2 administered once weekly concurrently with combined with conventionally fractionated RT and weekly 10 mg/m 2 CDDP. This chemoradiotherapeutic regimen serves as a promising treatment modality, in which level 3 is the recommended dose for a phase II study. No significant financial relationships to disclose.
Moonshot or groundshot: addressing Europe's cancer challenge through a patient-focused, data-enabled lens
Authors: Mark Lawler, Peter Naredi, Tanja Cufer, Ian Banks, Yolande Lievens, Giles Vassal, Matti Aapro, Maja Južnič Sotlar, Thierry Philip, Jacek Jassem, Jana Pelouchova, Françoise Meunier, Richard Sullivan
Journal: The Lancet Oncology (2019)
OA01.02 Prognostic Value of Baseline Autoantibodies in Metastatic NSCLC Patients Receiving PD-/PDL-1 Targeted Immunotherapy
Authors: I. Tarhoni, R. Kollipara, W.-R. Li, H. Moudgalya, M. Fidler, M. Batus, P. Bonomi, J. Borgia
Journal: Journal of Thoracic Oncology (2019)
The effect of alcohol consumption in the treatment of nontuberculous mycobacteria
Authors: Maria Jacob, Ricardo Silva, Rita Gaio, Raquel Duarte
Journal: Pulmonology (2019)

Background: the incidence of nontuberculous mycobacteria (NTM) disease is increasing and its presentation and severity can vary. Treatment of NTM disease is long, requires multiple drugs and the overall outcome can be related to host factors.  Aim: to identify the effect of the alcohol consumption on the treatment outcome, crude and adjusted for other host variables.  Methods: a retrospective analysis of patients with NTM disease between 2003-2016 (data from the Portuguese National Epidemiological Surveillance Commission for TB). Logistic regression models assessed odds ratios (OR) with 95% confidence interval (CI) for an unsuccessful treatment outcome.  Results: 610 patients were included, 540 (89%) had lung NTM disease. The average age was 58±18.2 years and 369 were male patients. Five hundred and seventeen (84.8%) patients finished treatment successfully (good outcome) and 93 (15.2%) died while in treatment (bad outcome). The crude OR for alcohol consumption was 3.48 (95% CI1.91-6.21 p  Conclusion: after adjustment for potential risk factors, alcohol consumption was estimated to double the odds for an unsuccessful outcome. This underlines the need of close monitoring among patients with alcohol dependencies to improve treatment outcomes.
The Rho GTPase RND3 regulates adipocyte lipolysis
Authors: Simon N. Dankel, Therese H. Røst, Agné Kulyté, Zina Fandalyuk, Thomas Skurk, Hans Hauner, Jørn V. Sagen, Mikael Rydén, Peter Arner, Gunnar Mellgren
Journal: Metabolism (2019)

BackgroundAdipose tissue plays a crucial role in diet- and obesity-related insulin resistance, with implications for several metabolic diseases. Identification of novel target genes and mechanisms that regulate adipocyte function could lead to improved treatment strategies. RND3 (RhoE/Rho8), a Rho-related GTP-binding protein that inhibits Rho kinase (ROCK) signaling, has been linked to diverse diseases such as apoptotic cardiomyopathy, heart failure, cancer and type 2 diabetes, in part by regulating cytoskeleton dynamics and insulin-mediated glucose uptake.ResultsWe here investigated the expression of RND3 in adipose tissue in human obesity, and discovered a role for RND3 in regulating adipocyte metabolism. In cross-sectional and prospective studies, we observed 5-fold increased adipocyte levels of RND3 mRNA in obesity, reduced levels after surgery-induced weight loss, and positive correlations of RND3 mRNA with adipocyte size and surrogate measures of insulin resistance (HOMA2-IR and circulating triglyceride/high-density lipoprotein cholesterol (TAG/HDL-C) ratio). By screening for RND3-dependent gene expression following siRNA-mediated RND3 knockdown in differentiating human adipocytes, we found downregulation of inflammatory genes and upregulation of genes related to adipocyte ipolysis and insulin signaling. Treatment of adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), hypoxia or cAMP analogs increased RND3 mRNA levels 1.5–2-fold. Functional assays in primary human adipocytes confirmed that RND3 knockdown reduces cAMP- and isoproterenol-induced lipolysis, which were mimicked by treating cells with ROCK inhibitor. This effect could partly be explained by reduced protein expression of adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase (HSL).ConclusionWe here uncovered a novel differential expression of adipose RND3 in obesity and insulin resistance, which may at least partly depend on a causal effect of RND3 on adipocyte lipolysis.
Metastatic Conditioning of Myeloid Cells at a Subcutaneous Synthetic Niche Reflects Disease Progression and Predicts Therapeutic Outcomes
Authors: Robert S. Oakes, Grace G. Bushnell, Sophia M. Orbach, Pridvi Kandagatla, Yining Zhang, Aaron H. Morris, Matthew S. Hall, Petrina LaFaire, Joseph T. Decker, Rachel M. Hartfield, Michael D. Brooks, Max S. Wicha, Jacqueline S. Jeruss, Lonnie D. Shea
Journal: Cancer Research (2019)

Abstract Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. Significance: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression.
p300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization
Authors: Jinjin Peng, Jiacheng Li, Jing Huang, Pan Xu, Heming Huang, Yanjun Liu, Liang Yu, Yaxi Yang, Bing Zhou, Hualiang Jiang, Kaixian Chen, Yongjun Dang, Yuanyuan Zhang, Cheng Luo, Guangming Li
Journal: Theranostics (2019)

High morbidity and mortality are associated with acute liver injury (ALI) for which no effective targeted drugs or pharmacotherapies are available.Discovery of potential therapeutic targets as well as inhibitors that can alleviate ALI is imperative.As excessive inflammatory cytokines released by macrophages are a critical cause of liver injury, we aimed to find novel compounds that could inhibit macrophage expression of inflammatory cytokines and alleviate liver injury.Methods: A high throughput assay was established to screen a small molecule inhibitor library of epigenetic targets.A highly selective catalytic p300/CBP inhibitor A-485 was identified as a potent hit in vitro and administrated to the lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced mice in vivo.For in vitro analysis, RAW264.7 cells and primary BMDM cells exposed to LPS were co-incubated with A-485.A model of acute liver injury induced by LPS and GalN was used for evaluation of in vivo treatment efficacy.Results: A-485 inhibited LPS-induced inflammatory cytokine expression in a concentration-dependent manner in vitro.Significantly, A-485 administration alleviated histopathological abnormalities, lowered plasma aminotransferases, and improved the survival rate in the LPS/GalN-stimulated mice.Integrative ChIP-Seq and transcriptome analysis in the ALI animal model and macrophages revealed that A-485 preferentially blocked transcriptional activation of a broad set of pathologic genes enriched in inflammation-related signaling networks.Significant inhibition of H3K27ac/H3K18ac at promoter regions of these pivotal inflammatory genes was observed, in line with their suppressed transcription after A-485 treatment.Reduced expression of these pathological pro-inflammatory genes resulted in a decrease in inflammatory pathway activation, M1 polarization as well as reduced leukocyte infiltration in ALI mouse model, which accounted for the protective effects of A-485 on liver injury.Conclusion: Using a novel strategy targeting macrophage inflammatory activation and cytokine expression, we established a high-throughput screening assay to discover potential candidates for ALI treatment.We demonstrated that A-485, which targeted pathological inflammatory signaling networks at the level of chromatin, was pharmacologically effective in vivo and in vitro.Our study thus provided a novel target as well as a potential drug candidate for the treatment of liver injury and possibly for other acute inflammatory diseases.