tbuckley/cabot-search huggingface dataset:
Abstract 17896: Azithromycin Therapy Reduces Cardiac Inflammation and Mitigates Adverse Cardiac Remodeling After Myocardial Infarction: Potential Therapeutic Strategy in Ischemic Heart Disease
Authors: Ahmed Al-Darraji, Dalia Haydar, Lakshman Chelvarajan, Himi Tripathi, Bryana Levitan, Ahmed E Ahmed, Shaojing Ye, David Feola, Ahmed Abdel-Latif
Journal: Circulation (2017)

Introduction and Hypothesis:  Acute myocardial infarction (AMI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-AMI inflammation. Pro-inflammatory macrophages (M1-like) can lead to adverse cardiac remodeling and heart failure while anti-inflammatory macrophages (M2-like) enhance tissue healing. Shifting the balance between M1 and M2 macrophages post-AMI is a novel therapeutic strategy. Azithromycin (AZM) polarizes macrophages towards M2-like phenotype in animal and human studies. We hypothesized that using AZM can decrease adverse cardiac remodeling and improve heart function following AMI.   Methods and results:  Male mice (C57BL/6, 6-8 weeks old) were treated with AZM orally (160 mg/kg/day) or vehicle starting 3 days prior to MI and continued to day 7 post-AMI. We observed significant reduction in mortality with AZM therapy. AZM-treated mice showed reduction in M1-like (CD45+/Ly6G-/F4-80+/CD86+) and increase in M2-like (CD45+/Ly6G-/F4-80+/CD206+) macrophages leading to significant reduction in the M1/M2 ratio in the heart and peripheral blood (Fig 1A) as assessed by flow cytometry. Macrophage changes were associated with significant reduction in pro-inflammatory and increase in anti-inflammatory cytokine production as assessed by real-time PCR (Fig 1B and 1C). Mechanistically, AZM treatment was associated with increased neutrophil apoptosis, a known signal for shifting macrophages towards an M2-like phenotype. AZM treatment was associated with enhanced cardiac recovery, higher global ejection fraction, lower systolic diameter and smaller scar size at 30 days post-AMI (Fig 1D).   Conclusion:  Azithromycin plays a cardioprotective role post-AMI through attenuating inflammation and enhancing cardiac recovery. Long term and human translational studies are planned to examine the therapeutic applications of AZM.
BEVATEM: Phase II study of bevacizumab (B) in combination with temozolomide (T) in patients (pts) with first-line metastatic uveal melanoma (MUM): Final results.
Authors: Sophie Piperno-Neumann, Vincent Servois, Francois-Clement Bidard, Pascale Mariani, Corine Plancher, Alhassane Diallo, Nora Vago-Ady, Laurence Desjardins
Journal: Journal of Clinical Oncology (2013)

9057 Background: Overall survival (OS) of MUM pts remains poor (median 12 months), stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma (UM). Antiangiogenic agents are used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. B suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental UM. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and B. Methods: Two-stage phase II trial; expected 6-month progression-free rate (PFR) of 40% with BEVATEM versus 15% with chemotherapy (power 94%, α risk 3%). Primary endpoint: 6-month PFR according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on B pharmacodynamics. Treatment schedule: T 150mg/m2 d1-d7 and d15-d21 oral route, B 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then B maintenance until toxicity or progression. Results: 35 evaluable pts have been enrolled from May 2010 to May 2012. First step analysis showed 3/17 first patients with disease control at 6 months and good tolerance. The final population consisted of 19 men and 16 women, median age 55 (29-72). PS was 0 in 28 and 1 in 7 pts, and the median time to metastasis was 38 months (17-62). Liver was the sole metastatic site in 29 pts.With an administered dose-intensity similar to the planned schedule, 7 and 9 pts experienced grade 3 (neutropenia 4, thrombocytopenia 1, constipation 1, pruritis 1) or grade 4 toxicities (neutropenia 3, thrombocytopenia 4, thrombosis 1) respectively. Despite no objective response, 9/35 pts showed stable disease, and the 6-month PFR was 26% [95%CI 13-41]. With a median follow-up of 18 months, 5 pts (14%) had long lasting non progressive disease with B maintenance (10+ to 29+ months). Finally, the median PFS and OS were 3 and 12 months respectively. Conclusions: BEVATEM regimen in first line MUM patients showed safety and 6-month PFR of 26% including 14% of pts with durable clinical benefit. Clinical trial information: 2009-011751-46.
Bimodal Evolutionary Developmental miRNA Program in Animal Embryogenesis
Authors: Gal Avital, Gustavo S França, Itai Yanai
Journal: Molecular Biology and Evolution (2017)

miRNAs play essential roles in the mechanics of gene regulation, however, on an organismal-scale, the processes in which they are deployed are not well understood. Here, we adopt an evolutionary developmental approach to study miRNA function by examining their expression throughout embryogenesis in both Caenorhabditis elegans and Drosophila melanogaster. We find that, in both species, miRNA transcriptomic shifts in a punctuated fashion during the mid-developmental transition, specifying two dominant modes of early and late expression profiles. Strikingly, late-expressed miRNAs are enriched for phylogenetic conservation and function by fine-tuning the expression of their targets, implicating a role in the canalization of cell types during differentiation. In contrast, early expressed miRNAs are inversely expressed with their targets suggesting strong target-inhibition. Taken together, our work exposes a bimodal role for miRNA function during animal development, involving late-expressed physiological roles and early expressed repressive roles.
Outcomes in coronary artery disease patients with sleepy obstructive sleep apnoea on CPAP
Authors: Yüksel Peker, Erik Thunström, Helena Glantz, Karl Wegscheider, Christine Eulenburg
Journal: European Respiratory Journal (2017)

Coronary artery disease (CAD) patients with obstructive sleep apnoea (OSA) have increased risk for major adverse cardiovascular and cerebrovascular events (MACCEs) compared with CAD patients without OSA. We aimed to address if the risk is similar in both groups when OSA patients are treated. This study was a parallel observational arm of the RICCADSA randomised controlled trial, conducted in Sweden between 2005 and 2013. Patients with revascularised CAD and OSA (apnoea–hypopnoea index (AHI) ≥15 events·h −1 ) with daytime sleepiness (Epworth Sleepiness Scale score ≥10) were offered continuous positive airway pressure (CPAP) (n=155); CAD patients with no OSA (AHI &lt;5 events·h −1 ) acted as controls (n=112), as a randomisation of sleepy OSA patients to no treatment would not be ethically feasible. The primary end-point was the first event of MACCEs. Median follow-up was 57 months. The incidence of MACCEs was 23.2% in OSA patients versus 16.1% in those with no OSA (adjusted hazard ratio 0.96, 95% CI 0.40–2.31; p=0.923). Age and previous revascularisation were associated with increased risk for MACCEs, whereas coronary artery bypass grafting at baseline was associated with reduced risk. We conclude that the risk for MACCEs was not increased in CAD patients with sleepy OSA on CPAP compared with patients without OSA.
Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase
Authors: Francesco Puzzo, Pasqualina Colella, Maria G. Biferi, Deeksha Bali, Nicole K. Paulk, Patrice Vidal, Fanny Collaud, Marcelo Simon-Sola, Severine Charles, Romain Hardet, Christian Leborgne, Amine Meliani, Mathilde Cohen-Tannoudji, Stephanie Astord, Bernard Gjata, Pauline Sellier, Laetitia van Wittenberghe, Alban Vignaud, Florence Boisgerault, Martine Barkats, Pascal Laforet, Mark A. Kay, Dwight D. Koeberl, Giuseppe Ronzitti, Federico Mingozzi
Journal: Science Translational Medicine (2017)

Liver delivery of engineered GAA transgenes to mice with Pompe disease rescued glycogen accumulation in multiple tissues.
Presence of naturally occurring anti-telomerase CD4 Th1 immunity in glioblastoma
Authors: G. Meynard, L. Boullerot, S. Belmiloudi, M. Dosset, C. Laheurte, D. Guenat, L. Rangan, E. Lauret Marie Joseph, C. Verlut, Y. Godet, S. Valmary-Degano, I. Mihai, X. Pivot, E. Curtit, O. Adotevi
Journal: Annals of Oncology (2017)
The neonatal window of opportunity—early priming for life
Authors: Harald Renz, Becky D. Adkins, Sina Bartfeld, Richard S. Blumberg, Donna L. Farber, Johan Garssen, Peter Ghazal, David J. Hackam, Benjamin J. Marsland, Kathy D. McCoy, John Penders, Immo Prinz, Valerie Verhasselt, Erika von Mutius, Jeffrey N. Weiser, Duane R. Wesemann, Mathias W. Hornef
Journal: Journal of Allergy and Clinical Immunology (2017)
BP in Dialysis: Results of a Pilot Study
Authors: Dana C. Miskulin, Jennifer Gassman, Ronald Schrader, Ambreen Gul, Manisha Jhamb, David W. Ploth, Lavinia Negrea, Raymond Y. Kwong, Andrew S. Levey, Ajay K. Singh, Antonia Harford, Susan Paine, Cynthia Kendrick, Mahboob Rahman, Philip Zager
Journal: Journal of the American Society of Nephrology (2017)

The optimal BP target for patients receiving hemodialysis is unknown. We randomized 126 hypertensive patients on hemodialysis to a standardized predialysis systolic BP of 110–140 mmHg (intensive arm) or 155–165 mmHg (standard arm). The primary objectives were to assess feasibility and safety and inform the design of a full-scale trial. A secondary objective was to assess changes in left ventricular mass. Median follow-up was 365 days. In the standard arm, the 2-week moving average systolic BP did not change significantly during the intervention period, but in the intensive arm, systolic BP decreased from 160 mmHg at baseline to 143 mmHg at 4.5 months. From months 4–12, the mean separation in systolic BP between arms was 12.9 mmHg. Four deaths occurred in the intensive arm and one death occurred in the standard arm. The incidence rate ratios for the intensive compared with the standard arm (95% confidence intervals) were 1.18 (0.40 to 3.33), 1.61 (0.87 to 2.97), and 3.09 (0.96 to 8.78) for major adverse cardiovascular events, hospitalizations, and vascular access thrombosis, respectively. The intensive and standard arms had similar median changes (95% confidence intervals) in left ventricular mass of −0.84 (−17.1 to 10.0) g and 1.4 (−11.6 to 10.4) g, respectively. Although we identified a possible safety signal, the small size and short duration of the trial prevent definitive conclusions. Considering the high risk for major adverse cardiovascular events in patients receiving hemodialysis, a full-scale trial is needed to assess potential benefits of intensive hypertension control in this population.
Detection of lymph nodes micrometastases and its clinical significance in patients with PN0 gastric cardia adenocarcinoma
Authors: Xiaoshan Feng, Luo Zhang, Gongping Wang, Zhaoxuan Luo, Jianqiang Mi, Luqi Xing, Jiangtao Sun, Shegan Gao, Zhifeng Qu, Jing Han, Tanyou Shan, Na Qian, Zhikun Ma
Journal: Cancer Research (2008)

900   Background: It is difficult to identify micrometastases in lymph nodes with fewer cancer cells using conventional hematoxylin and eosin (HE) stains. Immunohistochemical (IHC) techniques have been applied to identify lymph node micrometastases that are missed by routine pathological examination. In recent years, micrometastases have been correlated with a poorer prognosis in some studies. However, to date, it is still controversial over the importance of micrometastases in patients with gastric carcinoma. The aim of this study was to investigate the micrometastases characteristics in the gastric cardia adenocarcinoma (GCA) patients with negative lymph node by routine pathological examination and evaluate relationships between micrometastases and clinical pathological features.  Methods: 349 lymph nodes from 45 GCA patients who underwent gastrectomy with negative lymph node by routine pathological examination were examined immunohistochemical for the lymph nodes micrometastases. The anti-CK19 and anti-CD44v6 monoclonal antibody were used in this assay. Micrometastases was defined as a single tumor cell or clusters of tumor cells that missed on conventional examination with HE stains but were detected by immunostaining with anti-CK19 or anti-CD44v6. Clinicopathological data were analyzed by statistical method.  Results: Micrometastases were found in 33 lymph nodes (9.46%) from 15 cases (33.33%). 33 lymph nodes (9.46%) were positive for CK19, 27 lymph nodes (7.74%) were positive for CD44v6. The micrometastases in lymph node was correlated with the depth of invasion and Lauren classification (P  0.05). In 42 patients followed up, a higher incidence of micrometastases was found in recurrent patients (7/8) compared with result from recurrent-free patients (8/34).  Conclusions: It is necessary to detect the micrometastases in GCA with negative lymph node by routine examination. CK19 and CD44v6 can be a guide line for detection of micrometastases. Micrometastases might correlate with worse prognosis for patients with histologic node negative GCA.
Vonoprazan, aspirin and NSAIDs: new era in acid inhibition and gastroprotection
Authors: Ali S Taha
Journal: Gut (2017)

The ‘ No acid, no ulcer ’ dictum has dominated the pathogenesis and treatment of peptic ulcer disease for more than 100 years, and since it was proposed in 1910 by Dragutin (Carl) Schwarz (1868–1917).1 The dream of having a relatively potent and safe acid inhibitor was only realised in the mid-1970s with the marketing of cimetidine, later followed by other histamine-2 receptor antagonists (H2RA). The real breakthrough only came by the late 1980s with the introduction of proton pump inhibitors (PPI). The use of these products, particularly the PPIs, continues to increase making them some of the most commonly prescribed or bought over-the-counter agents in the world.2–4 This has added to the credibility of Schwarz’s dictum, as it is exceptional to come across a peptic ulcer that does not respond fully or partially to acid inhibition. The process of healing seems to be triggered or enhanced by the presence of a relatively acid-free medium regardless of aetiological factors: Helicobacter pylori , alcohol, aspirin, non-steroidal anti-inflammatory drugs (NSAID), or even in the case of some atypical ulcers such as those related to Crohn’s disease or malignancy.1–6

Of particular interest is the success of acid inhibitors in the healing or …
Rituximab in Combination with Cyclophosphamide, Mitoxantrone, Vincristine and Prednisone (R-CNOP) As First Line Regimen in Elderly Patients with Diffuse Large B-Cell Lymphoma
Authors: Alma Aslan, Alev Turker, Ayse Kars, Ibrahim Barista, Evren Ozdemir
Journal: Blood (2016)
Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC).
Authors: Ravindra Uppaluri, Paul Zolkind, Tianxiang Lin, Brian Nussenbaum, Ryan S Jackson, Jason Rich, Patrik Pipkorn, Randal Paniello, Wade Thorstad, Loren Michel, Tenny Mudianto, Peter John Oppelt, Tanya Marya Wildes, Gavin P Dunn, Jay F Piccirillo, Dorina Kallogjeri, Scott Rodig, Ian S. Hagemann, Rebecca Chernock, Douglas Adkins
Journal: Journal of Clinical Oncology (2017)

6012 Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with &gt; 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in &gt; 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( &gt; 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.
Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis
Authors: Christopher P. Denton, Éric Hachulla, Gabriela Riemekasten, Andreas Schwarting, Jean‐Marie Frenoux, Aline Frey, Franck‐Olivier Le Brun, Ariane L. Herrick
Journal: Arthritis & Rheumatology (2017)

Objective To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon ( RP ) in patients with systemic sclerosis ( SS c). Methods Patients with SS c‐related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 μg twice daily) during a 3‐week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score ( RCS ), RP attack duration, and treatment‐emergent adverse events ( AE s). Results Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 μg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary ( eD iary)–recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double‐blind period, 86.8% of placebo‐treated patients and 100% of selexipag‐treated patients reported ≥1 AE ; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin‐associated AE . Conclusion Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eD iary reporting of RP attacks in clinical trials.
RCGP bans Babylon from sponsoring annual conference
Authors: Abi Rimmer
Journal: BMJ (2017)

The private healthcare company Babylon will no longer be a sponsor of the Royal College of General Practitioners’ (RCGP) annual conference, the college has said.

Kamila Hawthorne, RCGP vice chair, said that the decision followed complaints that Babylon held a recruitment event at this year’s conference in Liverpool in October.

Earlier this year Babylon launched the GP at Hand service, a pilot scheme offering NHS patients in west London …
MicroRNA-145 Antagonism Reverses TGF-β Inhibition of F508del CFTR Correction in Airway Epithelia
Authors: Farruk Lutful Kabir, Namasivayam Ambalavanan, Gang Liu, Peng Li, George M. Solomon, Charitharth V. Lal, Marina Mazur, Brian Halloran, Tomasz Szul, William T. Gerthoffer, Steven M. Rowe, William T. Harris
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3'-untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-β.
Treating Specific Variants Causing Cystic Fibrosis
Authors: Garry R. Cutting
Journal: JAMA (2017)

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Cost Offsets in the Treatment Journeys of Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Sikander Ailawadhi, Maral DerSarkissian, Mei Sheng Duh, Marie-Hélène Lafeuille, George Posner, Stephen Ralston, Erin Zagadailov, Abbie Ba-Mancini, Robert M Rifkin
Journal: Blood (2017)
Abstract 20708: Secular Trends in Reported Success Rates of Catheter Ablation for Paroxysmal Atrial Fibrillation: Findings From the SMASH-AF Meta-Analysis Study Cohort
Authors: Alexander C Perino, George C Leef, Andrew Cluckey, Fahd N Yunus, Mariam Askari, Paul A Heidenreich, Mintu Turakhia
Journal: Circulation (2016)

Introduction: Approaches, tools, and technologies for catheter ablation for paroxysmal atrial fibrillation (PAF) have evolved significantly since its inception. We sought to characterize secular tr...
Relationship of Aging and Incident Comorbidities to Stroke Risk in Patients With Atrial Fibrillation
Authors: Tze-Fan Chao, Gregory Y.H. Lip, Chia-Jen Liu, Yenn-Jiang Lin, Shih-Lin Chang, Li-Wei Lo, Yu-Feng Hu, Ta-Chuan Tuan, Jo-Nan Liao, Fa-Po Chung, Tzeng-Ji Chen, Shih-Ann Chen
Journal: Journal of the American College of Cardiology (2018)
Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma
Authors: Anne S. Tsao, Heather Lin, Brett W. Carter, J. Jack Lee, David Rice, Ara Vaporcyan, Steven Swisher, Reza Mehran, John Heymach, Monique Nilsson, Youhong Fan, Maria Nunez, Lixia Diao, Jing Wang, Junya Fujimoto, Ignacio I. Wistuba, Waun Ki Hong
Journal: Journal of Thoracic Oncology (2017)