tbuckley/cabot-search huggingface dataset:
Combination Chemotherapy in Patients With Advanced Pancreatic Cancer With an Eastern Cooperative Oncology Group Performance Status of 2: Lights and Shadows of a Frail Route
Authors: Irene Pecora, Lorenzo Fornaro, Enrico Vasile, Silvia Catanese, Francesca Salani, Caterina Vivaldi
Journal: Journal of Clinical Oncology (2019)

Macarulla et al 1 have recently reported the results of a phase I/II trial (NAB-Paclitaxel in Combination With Gemcitabine in Fragile Patients With Advanced Pancreatic Cancer [FRAGANCE]) that explored the safest and most effective dose and schedule of gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (Gem-NAB) in patients with previously untreated, locally advanced and metastatic pancreatic cancer and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. The authors identified two well-tolerated schedules (NAB-paclitaxel administered at 100 or 125 mg/m 2 in combination with gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days) and randomly assigned patients to two parallel phase II studies.They found that these two schedules achieved similar safety and efficacy results compared with the pivotal Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT).We sincerely recognize the clinical relevance of this issue in real life and congratulate the authors for successfully completing this important trial.Patients with a PS of 2 are commonly encountered in everyday clinical practice and have been under-represented or excluded in the major first-line phase III studies conducted so far for combination regimens in pancreatic cancer. 2,3However, we feel there are a number of key points that need further discussion.
Abstract 14280: Impact of Change in Red Cell Distribution Width on Long-term Outcomes in Patients With Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Hidefumi Nakahashi, Masami Kosuge, Masayoshi Kiyokuni, Toshiaki Ebina, Kiyoshi Hibi, Noriaki Iwahashi, Nobuhiko Maejima, Yasushi Matsuzawa, Yuichiro Kimura, Kazuo Kimura
Journal: Circulation (2016)

Introduction: High red cell distribution width (RDW) on admission has been shown to be associated with poor outcomes after acute myocardial infarction (AMI). However, the prognostic value of the ch...
AB0832 VERTEBRAL PAIN AND PHYSICAL PERFORMANCE INDICES IN POSTMENOPAUSAL WOMEN WITH VERTEBRAL FRACTURES DEPENDING ON PRESENCE OF OBESITY
Authors: Nataliia Grygorieva, Vladyslav Povoroznyuk
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Vertebral fractures (VFs) are important osteoporotic fractures which manifest increased morbidity and mortality; however, their clinical features usually differ. Obesity is one of the important parameters of risk of osteoporotic fractures and vertebral pain syndrome. <h3>Objectives</h3> The aim of the research was to study the indices of vertebral pain (VP) and physical performance (PP) in postmenopausal women with VFs depending on presence of obesity. <h3>Methods</h3> We examined 87 females aged 50-89 years old with VFs in thoracic and/or lumbar spine which were divided into 3 groups: I – patients with normal weight (NW), according to WHO criteria, n=32; II – women with overweight (OW), n=37; III – females with obesity (OB), n=18. The parameters of VP in thoracic and/or lumbar spine were measured by 11-component visual analog scale (VAS), the indices of PP using static and dynamic functional tests (Thomayer, Schober tests, chest excursion, lateral trunk lean, 3-, 4-, 15-meter tests, "stand up from the chair", static balancing). Bone mineral density (BMD) was measured by DXA (Lunar, Prodigy). <h3>Results</h3> We have found the significantly higher parameters of BMD of femoral neck and lumbar spine in women with VFs and OB compared to females with NW. However, we did not establish any reliable differences of VP neither in thoracic nor in lumbar spine depending on obesity presence. Also, we did not reveal the significant differences of most parameters of PP, except for the indices of chest excursion (mean parameter, of the inhalation and exhalation) which were reliably higher in patients with OB. <h3>Conclusion</h3> In conclusion, the indices of VP and PP do not differ in postmenopausal women depending on obesity presence, except for chest excursion that should be taken into account in rehabilitation programs for females with VFs. <h3>Disclosure of Interests</h3> None declared
Abstract 15831: A Flattening Oxygen Consumption Trajectory Reflects Higher Disease Severity and Poor Prognosis in Patients With Heart Failure
Authors: Cemal Ozemek, Dejana Popovic, Ross Arena, Marco Guazzi
Journal: Circulation (2017)

Introduction: A flattening oxygen consumption (VO2) trajectory during a progressive exercise test is linked to a real-time decrease in cardiac output and is an effective diagnostic marker of myocar...
Midlife cardiorespiratory fitness and the long-term risk of chronic obstructive pulmonary disease
Authors: Gorm Mørk Hansen, Jacob Louis Marott, Andreas Holtermann, Finn Gyntelberg, Peter Lange, Magnus T Jensen
Journal: Thorax (2019)

Background Good midlife cardiorespiratory fitness (CRF) may reduce the risk of chronic obstructive pulmonary disease (COPD). Reverse causation may play a role if follow-up time is short. We examined the association between CRF and both incident COPD and COPD mortality in employed men with up to 46 years follow-up, which allowed us to account for reverse causality. Methods Middle-aged men (n=4730) were recruited in 1970–1971. CRF was determined as VO 2 max by ergometer test. Categories of CRF (low, normal, high) were defined as ± 1 Z-score (± 1 SD) above or below the age-adjusted mean. Endpoints were identified through national registers and defined as incident COPD, and death from COPD. Multi-adjusted Cox models and restricted mean survival times (RMST) were performed. Results Compared with low CRF, the estimated risk of incident COPD was 21% lower in participants with normal CRF (HR 0.79, 95% CI 0.63 to 0.99) and 31 % lower with high CRF (HR 0.69, 95% CI 0.52 to 0.91). Compared with low CRF, the risk of death from COPD was 35% lower in participants with normal CRF (HR 0.65, 95% CI 0.46 to 0.91) and 62% lower in participants with high CRF (HR 0.38, 95% CI 0.23 to 0.61). RMST showed a delay to incident COPD and death from COPD in the magnitude of 1.3–1.8 years in normal and high CRF vs low CRF. Test for reverse causation did not alter the results. Conclusion In a population of healthy, middle-aged men, higher levels of CRF were associated with a lower long-term risk of incident COPD and death from COPD.
Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals
Authors: Neelakshi R Jog, Kendra A Young, Melissa E Munroe, Michael T Harmon, Joel M Guthridge, Jennifer A Kelly, Diane L Kamen, Gary S Gilkeson, Michael H Weisman, David R Karp, Patrick M Gaffney, John B Harley, Daniel J Wallace, Jill M Norris, Judith A James
Journal: Annals of the Rheumatic Diseases (2019)

Objective Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. Methods SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10 , CR2 , TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. Results Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. Conclusion Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.
NHS negligence pay-out to boy with brain damage could reach £26m
Authors: Clare Dyer
Journal: BMJ (2019)

The NHS has agreed to a clinical negligence pay-out that could total £26m (€29.2m; $33m) for failings at the birth of a boy who will “forever remain a child.”

That total, one of the highest NHS settlements, will be reached if the 8 year old boy lives to his late 70s, as experts predict.

Chelsea and Westminster Hospital NHS Foundation Trust has admitted liability for errors at his birth in March 2011, and the settlement has been approved by the High Court.

The …
Current progress of mitochondrial transplantation that promotes neuronal regeneration
Authors: Chu-Yuan Chang, Min-Zong Liang, Linyi Chen
Journal: Translational Neurodegeneration (2019)

Mitochondria are the major source of intracellular adenosine triphosphate (ATP) and play an essential role in a plethora of physiological functions, including the regulation of metabolism and the maintenance of cellular homeostasis. Mutations of mitochondrial DNA, proteins and impaired mitochondrial function have been implicated in the neurodegenerative diseases, stroke and injury of the central nervous system (CNS). The dynamic feature of mitochondrial fusion, fission, trafficking and turnover have also been documented in these diseases.A major bottleneck of traditional approach to correct mitochondria-related disorders is the difficulty of drugs or gene targeting agents to arrive at specific sub-compartments of mitochondria. Moreover, the diverse nature of mitochondrial mutations among patients makes it impossible to develop one drug for one disease. To this end, mitochondrial transplantation presents a new paradigm of therapeutic intervention that benefits neuronal survival and regeneration for neurodegenerative diseases, stroke, and CNS injury. Supplement of healthy mitochondria to damaged neurons has been reported to promote neuronal viability, activity and neurite re-growth. In this review, we provide an overview of the recent advance and development on mitochondrial therapy.Key parameters for the success of mitochondrial transplantation depend on the source and quality of isolated mitochondria, delivery protocol, and cellular uptake of supplemented mitochondria. To expedite clinical application of the mitochondrial transplantation, current isolation protocol needs optimization to obtain high percentage of functional mitochondria, isolated mitochondria may be packaged by biomaterials for successful delivery to brain allowing for efficient neuronal uptake.
PB1790 DURABILITY OF COMPLETE RESPONSE AFTER BLINATUMOMAB THERAPY FOR REFRACTORY/RELAPSED AGGRESSIVE B-CELL NON-HODGKIN LYMPHOMA
Authors: A. Viardot, G. Hess, R. Bargou, N.J. Morley, G. Gritti, K. Iskander, D. Cohan, A. Zhang, J. Franklin, L. Coyle
Journal: HemaSphere (2019)

Background: Achieving durable response in patients (pts) with relapsed/refractory (R/R) aggressive B-cell lymphoma (B-NHL) is challenging. Blinatumomab, a bispecific T-cell engager (BiTE®) immunotherapy targeting CD19-expressing cancer cells, has shown promising efficacy in pts with R/R aggressive B-NHL. Aims: We report the durability of complete response (DOCR) in pts treated with blinatumomab. Methods: The DOCR in pts with R/R aggressive B-NHL responding to blinatumomab was assessed using data from two phase 2 studies (study 1 [N = 25], NCT01741792; study 2 [N = 41], NCT02910063) in pts with R/R aggressive B-NHL. Complete response (CR) was assessed using Cheson (study 1) and Lugano (study 2) criteria. Time-to-event variables were analyzed using the Kaplan-Meier (KM) method. Results: Baseline pt characteristics in the pooled analysis were: median age 59 years (range, 41–77); 54% men; 54% treatment refractory; median 2 lines of prior therapy (range, 1–7); and 15% with prior autologous hematopoietic stem cell transplant. Of 25 pts treated with blinatumomab in study 1, 4 (16%) evaluable pts achieved CR. Of 41 pts treated with blinatumomab in study 2, 9 (22%) achieved CR. Median DOCR was not reached (Table). At a median follow-up of 9.1 months in the pooled analysis, 3 pts (23%) had relapsed (study 1, n = 2 [50%]; study 2, n = 1 [11%]). At 12 and 18 months, the KM probability of maintaining CR in the pooled analysis was 53.0% (95% confidence interval [CI], 8.5, 85.0).Summary/Conclusion: For pts with R/R aggressive B-NHL who received blinatumomab, a durable response is possible. Longer-term follow up is needed to fully characterize the DOCR to blinatumomab.
Author Correction: Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch
Authors: Jarkko Salojärvi, Olli-Pekka Smolander, Kaisa Nieminen, Sitaram Rajaraman, Omid Safronov, Pezhman Safdari, Airi Lamminmäki, Juha Immanen, Tianying Lan, Jaakko Tanskanen, Pasi Rastas, Ali Amiryousefi, Balamuralikrishna Jayaprakash, Juhana I Kammonen, Risto Hagqvist, Gugan Eswaran, Viivi Helena Ahonen, Juan Alonso Serra, Fred O Asiegbu, Juan de Dios Barajas-Lopez, Daniel Blande, Olga Blokhina, Tiina Blomster, Suvi Broholm, Mikael Brosché, Fuqiang Cui, Chris Dardick, Sanna E Ehonen, Paula Elomaa, Sacha Escamez, Kurt V Fagerstedt, Hiroaki Fujii, Adrien Gauthier, Peter J Gollan, Pauliina Halimaa, Pekka I Heino, Kristiina Himanen, Courtney Hollender, Saijaliisa Kangasjärvi, Leila Kauppinen, Colin T Kelleher, Sari Kontunen-Soppela, J Patrik Koskinen, Andriy Kovalchuk, Sirpa O Kärenlampi, Anna K Kärkönen, Kean-Jin Lim, Johanna Leppälä, Lee Macpherson, Juha Mikola, Katriina Mouhu, Ari Pekka Mähönen, Ülo Niinemets, Elina Oksanen, Kirk Overmyer, E Tapio Palva, Leila Pazouki, Ville Pennanen, Tuula Puhakainen, Péter Poczai, Boy J H M Possen, Matleena Punkkinen, Moona M Rahikainen, Matti Rousi, Raili Ruonala, Christiaan van der Schoot, Alexey Shapiguzov, Maija Sierla, Timo P Sipilä, Suvi Sutela, Teemu H Teeri, Arja I Tervahauta, Aleksia Vaattovaara, Jorma Vahala, Lidia Vetchinnikova, Annikki Welling, Michael Wrzaczek, Enjun Xu, Lars G Paulin, Alan H Schulman, Martin Lascoux, Victor A Albert, Petri Auvinen, Ykä Helariutta, Jaakko Kangasjärvi
Journal: Nature Genetics (2019)

In the version of this article initially published, there was a mistake in the calculation of the nucleotide mutation rate per site per generation: 1 × 10−9 mutations per site per generation was used, whereas 9.5 × 10−9 was correct. This error affects the interpretation of population-size changes over time and their possible correspondence with known geological events, as shown in the original Fig. 4 and supporting discussion in the text, as well as details in the Supplementary Note. Neither the data themselves nor any other results are affected. Figure 4 has been revised accordingly. Images of the original and corrected figure panels are shown in the correction notice.
SP0144 CASE 2: SOLITARY ENTHESITIS AS A THERAPEUTIC CHALLENGE
Authors: Philippe Carron
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> The enthesis is a site crucial for mobility of the musculoskeletal system yet it is also commonly a target of inflammation, especially in spondyloarthritis. Because the enthesis is prone to high biomechanical forces, it has been hypothesized that biomechanical forces may be implicated in the onset of the enthesitis and spondyloarthritis in general. However, treatment recommendations involve exercise therapy which at first glance appears to pose a paradox. Using a case, we will discuss the current knowledge on enthesitis, the link with mechanical stress and the implications thereof in diagnosis and management of spondyloarthritis. <h3>Disclosure of Interests:</h3> None declared
Combination Therapy of TGF-β Blockade and Commensal-derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression
Authors: Linlin Shi, Jianyong Sheng, Mengli Wang, Han Luo, Jun Zhu, Bixiang Zhang, Zhi Liu, Xiangliang Yang
Journal: Theranostics (2019)

Galunisertib (Gal) is a transforming growth factor (TGF-β) blockade which is being investigated as a potential tumor immunotherapy candidate drug in clinical trials. However, primary or acquired resistance is often found in the recruited cancer patients, which limits its clinical application. Tumor immune microenvironment can be regulated by intestinal microbiota, leading to different therapeutic outcomes. It is hypothesized that manipulation of cancer patients' intestinal microbiome in the early stage of therapy may be a promising strategy to improve the therapeutic efficacy of Gal.
Blocking histone deacetylase activity as a novel target for epithelial barrier defects in patients with allergic rhinitis
Authors: Brecht Steelant, Paulina Wawrzyniak, Katleen Martens, Anne-Charlotte Jonckheere, Benoit Pugin, Rik Schrijvers, Dominique M. Bullens, Jeroen A. Vanoirbeek, Krzysztof Krawczyk, Anita Dreher, Cezmi A. Akdis, Peter W. Hellings
Journal: Journal of Allergy and Clinical Immunology (2019)
Functional Properties of <i>KIT</i> Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia
Authors: Katherine Tarlock, Todd A. Alonzo, Yi-Cheng Wang, Robert B. Gerbing, Rhonda Ries, Michael R. Loken, Laura Pardo, Tiffany Hylkema, Jason Joaquin, Leela Sarukkai, Susana C. Raimondi, Betsy Hirsch, Lillian Sung, Richard Aplenc, Irwin Bernstein, Alan S. Gamis, Soheil Meshinchi, Jessica A. Pollard
Journal: Clinical Cancer Research (2019)

KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML.Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [KIT+ vs. wild-type KIT (KIT-)] and mutation location (E8 vs. E17).KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT+ CBF AML had overall survival similar to those with KIT- (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT+ outcomes were inferior to KIT- patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ patients.
Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
Authors: Mike Becker, Nicole Graf, Rafael Sauter, Yannick Allanore, John Curram, Christopher P Denton, Dinesh Khanna, Marco Matucci-Cerinic, Janethe de Oliveira Pena, Janet E Pope, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.
Combination prevention and HIV: a cross-sectional community survey of gay and bisexual men in London, October to December 2016
Authors: Louise Logan, Ibidun Fakoya, Alison Howarth, Gary Murphy, Anne M Johnson, Alison J Rodger, Fiona Burns, Anthony Nardone
Journal: Eurosurveillance (2019)

BackgroundMen who have sex with men (MSM) are at risk of HIV and are an important population to monitor and ameliorate combination prevention efforts.AimTo estimate HIV prevalence and identify factors associated with frequent HIV testing (≥ 2 HIV tests in the last year) and pre-exposure prophylaxis (PrEP) use among MSM in London.MethodsFor this cross-sectional study, MSM recruited from 22 social venues provided oral-fluid samples for anonymous HIV antibody (Ab) testing and completed a questionnaire. Factors associated with frequent HIV testing and PrEP use were identified through logistic regression.ResultsOf 767 men recruited, 545 provided an eligible oral specimen. Among these, 38 MSM (7.0%) were anti-HIV positive including five (13.2%; 5/38) who reported their status as negative. Condomless anal sex within the previous 3 months was reported by 60.1% (412/685) men. Frequent HIV testing was associated with, in the past year, a reported sexually transmitted infection (adjusted odds ratio (AOR): 5.05; 95% confidence interval (CI): 2.66-9.58) or ≥ 2 casual condomless partners (AOR 2-4 partners: 3.65 (95% CI: 1.87-7.10); AOR 5-10 partners: 3.34(95% CI: 1.32-8.49). Age ≥ 35 years was related to less frequent HIV testing (AOR 35-44 years: 0.34 (95% CI: 0.16-0.72); AOR ≥ 45 years: 0.29 (95% CI: 0.12-0.69). PrEP use in the past year was reported by 6.2% (46/744) of MSM and associated with ≥ 2 casual condomless sex partners (AOR: 2.86; 95% CI: 1.17-6.98) or chemsex (AOR: 2.31; 95% CI: 1.09-4.91).ConclusionThis bio-behavioural study of MSM found high rates of behaviours associated with increased risk of HIV transmission. Combination prevention, including frequent HIV testing and use of PrEP, remains crucial in London.