tbuckley/cabot-search huggingface dataset:
Anti-PD1 therapy increases peripheral blood NKT cells and chemokines in metastatic melanoma patients
Authors: H. Hakanen, M. Hernberg, S. Mäkelä, B. Yadav, O. Brück, S. Juteau, L. Kohtamäki, M. Ilander, S. Mustjoki, A. Kreutzman
Journal: Annals of Oncology (2018)

Background: Anti-PD1 therapy has proven to be effective in various cancer types, but the overall impact of the treatment on the immune system is not yet fully understood. Therefore, we aimed in this study to discover the effects of anti-PD1 therapy on the immune system, especially on NK and NKT cells, which are less studied, but known to be involved in antitumor immune events. Methods: Peripheral blood from immuno-oncology naive metastatic melanoma patients (n = 19) were obtained before the first infusion of anti-PD1, then 1 and 3 months later. From each time-point, complete blood counts (CBC) were obtained, and comprehensive immunophenotyping of NK, NKT, and T cells was performed. Also, 92 serum cytokines were measured using the Olink inflammation panel. Results: Patients were categorized into two cohorts: responders (R, n = 6, PFS=17.0 months) and progressive disease (PD, n = 9, PFS=5.0 months). 4 patients were excluded due to challenging clinical evaluation of response. CBC indicated a significant decrease in the mean frequency of lymphocytes in PD but not in the R cohort. The responders had also higher frequency of lymphocytes at 1- and 3-month time points and lower frequency of neutrophils before initiation and after 1 and 3 months of treatment. The CBC absolute counts revealed that the responders had less neutrophils and monocytes after 3 months of treatment when compared to PD. Immunophenotyping revealed no changes in the frequency of T and NK cells during treatment, however the frequency of NKTbrightcells increased significantly. Moreover, R had more NKTdimcells before and after 3 months of therapy. Also, cytotoxic CD56dimNK cells expressed increased CD25 and CD45RO after 1 month of therapy. The cytokine assay indicated that anti-PD1 significantly increased the levels of CXC-family cytokines in the serum; CXCL9, CXCL11, CXCL10. Also, IL-12B and TNFRSF9 levels were increased. Further comparison of the two cohorts showed that CXCL9 was only increased in R cohort. Conclusions: Anti-PD1 therapy increases the levels of NKT cells, inflammation related chemokines in blood and the expression of markers linked to enhanced cytotoxicity of NK cells. Therefore, further studies to investigate the role of NK and NKT cells in anti-PD1 induced responses are warranted. Legal entity responsible for the study: Anna Kreutzman. Funding: Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation. Disclosure: M. Hernberg, S. Mäkelä, L. Kohtamäki: Trial funding: MSD, BMS, Amgen. S. Mustjoki: Honoraria, research funding: Novartis, Bristol-Myers Squibb, Ariad, Pfizer. All other authors have declared no conflicts of interest.
SP0013 S100-alarmins: potential therapeutic targets for arthritis
Authors: J. Roth
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Innate immunity is a pivotal factor in the pathogenesis of rheumatic diseases During the last years there is growing evidence that pro-inflammatory alarmins of the family of calcium-binding S100-proteins promote inflammation in rheumatic, auto-inflammatory and auto-immune diseases. Serum concentrations of S100A8/S100A9 correlate with disease activity in several rheumatic diseases and are useful surrogate markers for monitoring disease activity predicting response to treatment, systemic organ involvement, or relapses in several autoimmune diseases. We have now identified a novel mechanism of auto-inhibition in mice and man restricting S100-alarmin activity to local sites of inflammation. We identified specific peptide sequences within the second calcium-binding EF-hands of S100A8 and S100A9 binding to TLR4/MD2 and triggering inflammation. However, biological activity of S100A8/S100A9 is locally restricted by calcium-induced (S100A8/S100A9)<sub>2</sub>-tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase. This auto-inhibitory mechanism is essential to prevent fatal inflammation in mice <i>in vivo</i>. Since S100A8/S100A9 complexes are the most abundant alarmins in arthritis, blocking of active S100A8/S100A9-dimers may represent an innovative approach for local inhibition of inflammatory processes in rheumatic diseases. <h3>Disclosure of Interest</h3> None declared
Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures
Authors: Raquel Guimarães-Costa, Thomas Similowski, Isabelle Rivals, Capucine Morélot-Panzini, Marie-Cécile Nierat, Mai Thao Bui, David Akbar, Christian Straus, Norma Beatriz Romero, Patrick Pierre Michel, Fabrice Menegaux, François Salachas, Jésus Gonzalez-Bermejo, Gaëlle Bruneteau
Journal: European Respiratory Journal (2018)

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov; NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity (IC) correlated modestly with slow-twitch myofibre atrophy. Supine fall in VC correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that IC, SNIP and functional residual capacity were independent predictors of slow-twitch diaphragmatic atrophy, but not fast-twitch atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function.
Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis
Authors: Paul A. Reyfman, James M. Walter, Nikita Joshi, Kishore R. Anekalla, Alexandra C. McQuattie-Pimentel, Stephen Chiu, Ramiro Fernandez, Mahzad Akbarpour, Ching-I Chen, Ziyou Ren, Rohan Verma, Hiam Abdala-Valencia, Kiwon Nam, Monica Chi, SeungHye Han, Francisco J. Gonzalez-Gonzalez, Saul Soberanes, Satoshi Watanabe, Kinola J. N. Williams, Annette S. Flozak, Trevor T. Nicholson, Vince K. Morgan, Deborah R. Winter, Monique Hinchcliff, Cara L. Hrusch, Robert D. Guzy, Catherine A. Bonham, Anne I. Sperling, Remzi Bag, Robert B. Hamanaka, Gökhan M. Mutlu, Anjana V. Yeldandi, Stacy A. Marshall, Ali Shilatifard, Luis A. N. Amaral, Harris Perlman, Jacob I. Sznajder, A. Christine Argento, Colin T. Gillespie, Jane Dematte, Manu Jain, Benjamin D. Singer, Karen M. Ridge, Anna P. Lam, Ankit Bharat, Sangeeta M. Bhorade, Cara J. Gottardi, G. R. Scott Budinger, Alexander V. Misharin
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis.
New Prognosis Score Including Absolute Lymphocytes/Monocytes Ratio and Beta2microglobulin in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Treated with R-CHOP: Spanish Lymphoma Group Experience (GELTAMO)
Authors: Leyre Bento, Antonio Diaz-Lopez, Gilberto Israel Barranco, Ana Maria Martin Moreno, Monica Baile, Alejandro Martín, Juan Manuel Sancho, Olga Garcia, Mario Rodríguez, José María Sánchez-Pina, Silvana Novelli, Antonio Salar, Mariana Bastos, Maria J. Rodriguez-Salazar, Sonia González de Villambrosia, Raul Cordoba, Marta Garcia Recio, Jordi Martínez-Serra, Raquel Del Campo, Hugo Daniel Luzardo Henriquez, Daniel García, Azueg Hong, Pau Abrisqueta, Jose Rodriguez, Antonio Gutiérrez
Journal: Blood (2018)
AB0396 Relationship between patient global assessment and pain assessment in the disease activity indexes in rheumatoid arthritis, and its correspondence with sonographic alterations
Authors: R. Menor Almagro, R.M. Martínez, E.M. Rubio, M.M. Fernández
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Disease activity indexes in rheumatoid arthritis (RA) provide information of different parameters in a single value. It is very useful in the evaluation of the disease activity and its progression. The subjective component of these indexes can modify the index final value. <h3>Objectives</h3> The aim of our study was to describe the relation between the patient global assessment (PGA) and pain assessment (PA) with the sonographic alterations in AR. <h3>Methods</h3> Transversal study describing the ultrasonographic changes and disease activity indexes in AR. We included patients with RA according to ACR/EULAR classification criteria. They were sent by their usual clinician, in random selection. They were reviewed in the same day by a rheumatologist and blind sonographer. PGA, PA, HAQ, tender and swollen joint count, CDAI, SDAI and DAS28 were evaluated. The ultrasound were realyzed by grey scale and doppler in 12 joints (wrists, second to fifth MCF and fifth bilateral MTF). <h3>Results</h3> A total of 48 patients had PGA &lt;50 and 37 PGA ≥50. The mean age was 53.2±11.7 for group 1 and 56.5±10.2 for group 2, women 64.6% and 83.8% respectively. The positive rheumatoid factor resulted in 72.9% vs 73%. The evolution of the disease in months presented a median of 96 (47.2–132.7) vs 108 [48–138], p=0.564. The Body Mass Index in the groups was 26.6 (23.5–29.7) and 26.0 (22.8–30.0), p=0.647, and the tobacco consumption of 11 patients group 1 and 12 in group 2 (p=0.397). No significant difference was found in the treatment at the time of the evaluation with methotrexate, median of 10 (0–15) vs 7.5 (0–15), p=0.350, or corticosteroids 1.4 (0–2,3) vs 2.5 (0–4.5), p=0.05. 23 patients in the group 1 and 19 in the group 2 were in biological therapy. The results referring to the patient's assessment of their disease, acute-phase reactants, clinical examination, ultrasound and disease activity indexes are presented in table 1. <h3>Conclusions</h3> Disease activity indexes in AR have been established as a very useful measure, both in the homogenization of the results obtained in the research and in the daily clinical practice. In our study, we observed the modification in the values of disease activity indexes due to PGA and PA, even those in which its contribution is less decisive than other parameters, as it happens in the DAS 28. Those variables no relationated in their value with the patient assessment of his disease status did not show statistical significance between the groups. The patients' valuation about activity of their AR and the modification of the indexes in which it participates in our study were not concordant with the echographic alterations found in grey scale and doppler echo. <h3>Disclosure of Interest</h3> None declared
Assessment of metagenomic Nanopore and Illumina sequencing for recovering whole genome sequences of chikungunya and dengue viruses directly from clinical samples
Authors: Liana E. Kafetzopoulou, Kyriakos Efthymiadis, Kuiama Lewandowski, Ant Crook, Dan Carter, Jane Osborne, Emma Aarons, Roger Hewson, Julian A. Hiscox, Miles W. Carroll, Richard Vipond, Steven T. Pullan
Journal: Eurosurveillance (2018)

BackgroundThe recent global emergence and re-emergence of arboviruses has caused significant human disease. Common vectors, symptoms and geographical distribution make differential diagnosis both important and challenging. AimTo investigate the feasibility of metagenomic sequencing for recovering whole genome sequences of chikungunya and dengue viruses from clinical samples.MethodsWe performed metagenomic sequencing using both the Illumina MiSeq and the portable Oxford Nanopore MinION on clinical samples which were real-time reverse transcription-PCR (qRT-PCR) positive for chikungunya (CHIKV) or dengue virus (DENV), two of the most important arboviruses. A total of 26 samples with a range of representative clinical Ct values were included in the study.ResultsDirect metagenomic sequencing of nucleic acid extracts from serum or plasma without viral enrichment allowed for virus identification, subtype determination and elucidated complete or near-complete genomes adequate for phylogenetic analysis. One PCR-positive CHIKV sample was also found to be coinfected with DENV. ConclusionsThis work demonstrates that metagenomic whole genome sequencing is feasible for the majority of CHIKV and DENV PCR-positive patient serum or plasma samples. Additionally, it explores the use of Nanopore metagenomic sequencing for DENV and CHIKV, which can likely be applied to other RNA viruses, highlighting the applicability of this approach to front-line public health and potential portable applications using the MinION.
Evaluation of anti-cancer effect of Daucus carota on the human promyelocytic leukemia HL-60 cells
Authors: Mona Diab-Assaf, Samir El-Sharif, Mohamad Mroueh
Journal: Clinical Cancer Research (2007)

B56  Introduction: Daucus carota, Apiaceae, commonly used in Lebanese folklore medicine for the treatment of leukemia. The anti-cancer aqueous extract of DC was examined by evaluating its effect on the induction of differentiation and inhibition of proliferation of the human promyelocytic leukemia HL-60 cells.  Materials and Methods: The effects of non-cytotoxic concentrations of DC were evaluated against HL-60 cells. The effect of DC on the proliferation was evaluated by MTT assay and TGF mRNA protein expression using RT-PCR. The anti-proliferative effects were tested by determining the changes in the expression of transforming growth factors (TGF-alpha, TGF-beta1 and TGF-beta2). In parallel, the differentiation effect was measured by NBT reduction assay. The degree of differentiation was assayed by the ability of Results: DC was found to reduce cell proliferation and induced cell differentiation. Conclusion: The results of this study show DC extract possesses anti-proliferative effects and stimulates of differentiation of HL-60 cells.
Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients
Authors: Barbara Testoni, Fanny Lebossé, Caroline Scholtes, Françoise Berby, Clothilde Miaglia, Miroslava Subic, Alessandro Loglio, Floriana Facchetti, Pietro Lampertico, Massimo Levrero, Fabien Zoulim
Journal: Journal of Hepatology (2018)
Survival among Veterans Obtaining Dialysis in VA and Non-VA Settings
Authors: Virginia Wang, Cynthia J. Coffman, Karen M. Stechuchak, Theodore S.Z. Berkowitz, Paul L. Hebert, David Edelman, Ann M. O’Hare, Susan T. Crowley, Hollis J. Weidenbacher, Matthew L. Maciejewski
Journal: Journal of the American Society of Nephrology (2018)

Background Outcomes of veterans with ESRD may differ depending on where they receive dialysis and who finances this care, but little is known about variation in outcomes across different dialysis settings and financial arrangements. Methods We examined survival among 27,241 Veterans Affairs (VA)–enrolled veterans who initiated chronic dialysis in 2008–2011 at ( 1 ) VA-based units, ( 2 ) community-based clinics through the Veterans Affairs Purchased Care program (VA-PC), ( 3 ) community-based clinics under Medicare, or ( 4 ) more than one of these settings (“dual” care). Using a Cox proportional hazards model, we compared all-cause mortality across dialysis settings during the 2-year period after dialysis initiation, adjusting for demographic and clinical characteristics. Results Overall, 4% of patients received dialysis in VA, 11% under VA-PC, 67% under Medicare, and 18% in dual settings (nearly half receiving dual VA and VA-PC dialysis). Crude 2-year mortality was 25% for veterans receiving dialysis in the VA, 30% under VA-PC, 42% under Medicare, and 23% in dual settings. After adjustment, dialysis patients in VA or in dual settings had significantly lower 2-year mortality than those under Medicare; mortality did not differ in VA-PC and Medicare dialysis settings. Conclusions Mortality rates were highest for veterans receiving dialysis in Medicare or VA-PC settings and lowest for veterans receiving dialysis in the VA or dual settings. These findings inform institutional decisions about provision of dialysis for veterans. Further research identifying processes associated with improved survival for patients receiving VA-based dialysis may be useful in establishing best practices for outsourced veteran care.
Mindfulness Meditation and Psychopathology
Authors: Joseph Wielgosz, Simon B. Goldberg, Tammi R.A. Kral, John D. Dunne, Richard J. Davidson
Journal: Annual Review of Clinical Psychology (2018)

Mindfulness meditation is increasingly incorporated into mental health interventions, and theoretical concepts associated with it have influenced basic research on psychopathology. Here, we review the current understanding of mindfulness meditation through the lens of clinical neuroscience, outlining the core capacities targeted by mindfulness meditation and mapping them onto cognitive and affective constructs of the Research Domain Criteria matrix proposed by the National Institute of Mental Health. We review efficacious applications of mindfulness meditation to specific domains of psychopathology including depression, anxiety, chronic pain, and substance abuse, as well as emerging efforts related to attention disorders, traumatic stress, dysregulated eating, and serious mental illness. Priorities for future research include pinpointing mechanisms, refining methodology, and improving implementation. Mindfulness meditation is a promising basis for interventions, with particular potential relevance to psychiatric comorbidity. The successes and challenges of mindfulness meditation research are instructive for broader interactions between contemplative traditions and clinical psychological science.
A novel recombinant human anti-PD-1 monoclonal antibody GLS-010 in patients with advanced cancer: Result of a phase Ia clinical trial
Authors: L. Shen, J. Gong, Y. Xu, X. Zhang, Z. Peng, C. Qi, G. Li, H. Meng, Z. Liu, H. Wang, C. Chen, J. Li, Y. Zheng, J. Lee, Y. Zhang, Q. Zhang
Journal: Annals of Oncology (2018)

Background: GLS-010 is a novel recombinant fully human anti-programmed cell death protein 1 (PD-1) monoclonal antibody. This phase Ia study was to primarily evaluate the safety and tolerance profile of GLS-010 and to identify a proper dose. Methods: A 3 + 3 dose escalation design was applied. GLS-010 was given at 1mg/kg, 4mg/kg and 10mg/kg respectively once every 2 weeks. An exploratory cohort with 240mg fixed dosage was also conducted along with the 10mg/kg cohort. Results: Until August 2018, 18 subjects were enrolled, including 5 gastric cancer, 4 esophageal cancer, 2 Hodgkin's lymphoma, 2 cervical cancer, and 1 each for rectum cancer, endometrial cancer, penile cancer, leiomyosarcoma and fibrosarcoma patients. The median dosing number was 5 (range: 1-12). No DLT was observed[JK1], and MTD was not reached. Related treatment emergent adverse event (TEAE)s included haemoglobin decreased (61.1%), blood bilirubin increased (22.2%), fatigue (16.7%), diarrhea (11.1%), decreased appetite (11.1%), neutropenia (11.1%), protein urine present (11.1%), blood creatine kinase increased (11.1%), leukopenia (11.1%) and blood TSH increased (11.1%). Possibly related Grade 3-4 TEAEs was observed in 2 subjects, one subject with haemoglobin decreased, leucopenia and thrombocytopenia, and the other one with haemoglobin decreased only. Pharmacokinetic analysis indicated the drug exposure was increased dose-dependently, with a half-life of 8.2 to 10.1 days. The T cell PD-1 receptor occupancy (RO) rate was over 80% and no anti-drug antibody (ADA) was detected for all subjects. Partial response (PR) was observed in 5 subjects (2 Hodgkin's lymphoma, 1 gastric cancer, 1 cervical cancer and 1 penile cancer patients). Stable disease (SD) was observed with 1 subject (endometrial cancer). The objective response rate (ORR) was assessed to be 27.8%, and the disease control rate (DCR) was 33.3%. Conclusions: GLS-010 demonstrated acceptable safety and tolerance, and preliminary efficacy in patients with advanced cancer. A 240mg fixed dosing regimen is currently recommended for further clinical study. Legal entity responsible for the study: Guangzhou Gloria Biosciences Co., Ltd. Funding: Guangzhou Gloria Biosciences Co., Ltd. Disclosure: All authors have declared no conflicts of interest.
Abstract 16464: Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies (pcsk9-i) Treatment of Cardiovascular High Risk Patients in Clinical Practice - New Data Regarding Safety and Effectivity
Authors: Tim Hollstein, Thomas Grenkowitz, Dominik Spira, Hubert Scharnagl, Winfried März, Elisabeth Steinhagen-Thiessen, Ursula Kassner
Journal: Circulation (2017)

Introduction: Only recently, PCSK9-I became available to treat therapy-refractory hypercholesterolemia. The aim of this study is to provide new safety and efficacy data of PCSK9-I collected in clin...
An innovative “unlocked mechanism” by a double key avenue for one-pot detection of microRNA-21 and microRNA-141
Authors: Weipan Peng, Qian Zhao, Minghui Chen, Jiafang Piao, Weichen Gao, Xiaoqun Gong, Jin Chang
Journal: Theranostics (2018)

The accurate and quantitative detection of microRNAs (miRNAs) as next-generation, reliable biomarkers will provide vital information for cancer research and treatment.However, their unique, intrinsic features pose quite a challenge for miRNA profiling, especially for multiplexed detection.Thus, there is a strong and an ever-growing need to develop an accurate, simple, sensitive and specific miRNA sensing method.Methods: In this study, a simple and novel sensor is presented that uses a flow cytometry (FCM) method based on the double key "unlocked mechanism" and a fluorescence enrichment signal amplification strategy.The "unlocked mechanism" was cleverly designed via using hairpin DNA probes (HDs) labeled by fluorescent particles (FS) as the lock to block part of them, which can specifically hybridize with the probe on polystyrene microparticles (PS).The target miRNA and duplex-specific nuclease (DSN) forming the double key can specifically open the HDs and cleave a single-stranded DNA (ssDNA) into DNA/RNA dimers circularly in order to unlock the special part of the HDs to be specially enriched further on the PS.Results: The designed sensor with a hairpin structure and DSN special performance was found to have a high specificity.The circularly unlocking fluorescent probes and fluorescent signal enrichment can be beneficial for achieving a high sensitivity with a detection limit of 3.39 fM for miRNA-21.Meanwhile, the performance of multiplexing was estimated by simultaneous detection of miR-21 and miR-141, and the method also allowed for miR-21 detection in breast cancer blood samples. Conclusion:The designed sensor based on an "unlocked mechanism" and a signal enrichment strategy resulted in a one-pot, highly specific and sensitive detection of multiplex miRNAs.The whole detection without the need for a complex purification process is based on a FCM and is expected to have a great value in cancer diagnosis and biomedical research.