tbuckley/cabot-search huggingface dataset:
New insights into shear stress-induced endothelial signalling and barrier function: cell-free fluid versus blood flow
Authors: Sulei Xu, Xiang Li, Kyle Brian LaPenna, Stanley David Yokota, Sabine Huke, Pingnian He
Journal: Cardiovascular Research (2017)

Fluid shear stress (SS) is known to regulate endothelial cell (EC) function. Most of the studies, however, focused on the effects of cell-free fluid-generated wall SS on ECs. The objective of this study was to investigate how changes in blood flow altered EC signalling and endothelial function directly through wall SS and indirectly through SS effects on red blood cells (RBCs).Experiments were conducted in individually perfused rat venules. We experimentally induced changes in SS that were quantified by measured flow velocity and fluid viscosity. The concomitant changes in EC [Ca2+]i and nitric oxide (NO) were measured with fluorescent markers, and EC barrier function was assessed by fluorescent microsphere accumulation at EC junctions using confocal imaging. EC eNOS activation was evaluated by immunostaining. In response to changes in SS, increases in EC [Ca2+]i and gap formation occurred only in blood or RBC solution perfused vessels, whereas SS-dependent NO production and eNOS-Ser1177 phosphorylation occurred in both plasma and blood perfused vessels. A bioluminescent assay detected SS-dependent ATP release from RBCs. Pharmacological inhibition and genetic modification of pannexin-1 channels on RBCs abolished SS-dependent ATP release and SS-induced increases in EC [Ca2+]i and gap formation.SS-induced EC NO production occurs in both cell free fluid and blood perfused vessels, whereas SS-induced increases in EC [Ca2+]i and EC gap formation require the presence of RBCs, attributing to SS-induced pannexin-1 channel dependent release of ATP from RBCs. Thus, changes in blood flow alter vascular EC function through both wall SS and SS exerted on RBCs, and RBC released ATP contributes to SS-induced changes in EC barrier function.
Efficient Lysis of Myeloma Cells by CD16 Positive Effector Cells with Recombinant Single Chain Bispecific Antibodies Targeting HM1.24.
Authors: Matthias Peipp, Claudia Ehlert, Matthias Staudinger, Joerg Bruenke, Georg Fey, Martin Gramatzki, Roland Repp
Journal: Blood (2007)
Progressive CD4+ central–memory T cell decline results in CD4+ effector–memory insufficiency and overt disease in chronic SIV infection
Authors: Afam Okoye, Martin Meier-Schellersheim, Jason M. Brenchley, Shoko I. Hagen, Joshua M. Walker, Mukta Rohankhedkar, Richard Lum, John B. Edgar, Shannon L. Planer, Alfred Legasse, Andrew W. Sylwester, Michael Piatak, Jeffrey D. Lifson, Vernon C. Maino, Donald L. Sodora, Daniel C. Douek, Michael K. Axthelm, Zvi Grossman, Louis J. Picker
Journal: The Journal of Experimental Medicine (2007)
Serum hepatitis B core-related antigen is more accurate than hepatitis B surface antigen to identify inactive carriers, regardless of hepatitis B virus genotype
Authors: M. Riveiro-Barciela, M. Bes, F. Rodríguez-Frías, D. Tabernero, A. Ruiz, R. Casillas, J. Vidal-González, M. Homs, L. Nieto, S. Sauleda, R. Esteban, M. Buti
Journal: Clinical Microbiology and Infection (2017)
Post-Babesiosis Warm Autoimmune Hemolytic Anemia
Authors: Ann E. Woolley, Mary W. Montgomery, William J. Savage, Maureen O. Achebe, Kathleen Dunford, Sarah Villeda, James H. Maguire, Francisco M. Marty
Journal: New England Journal of Medicine (2017)

Background Babesiosis, a tickborne zoonotic disease caused by intraerythrocytic protozoa of the genus babesia, is characterized by nonimmune hemolytic anemia that resolves with antimicrobial treatment and clearance of parasitemia. The development of warm-antibody autoimmune hemolytic anemia (also known as warm autoimmune hemolytic anemia [WAHA]) in patients with babesiosis has not previously been well described. Methods After the observation of sporadic cases of WAHA that occurred after treatment of patients for babesiosis, we conducted a retrospective cohort study of all the patients with babesiosis who were cared for at our center from January 2009 through June 2016. Data on covariates of interest were extracted from the medical records, including any hematologic complications that occurred within 3 months after the diagnosis and treatment of babesiosis. Results A total of 86 patients received a diagnosis of babesiosis during the 7.5-year study period; 18 of these patients were asplenic. WAHA developed in 6 patients 2 to 4 weeks after the diagnosis of babesiosis, by which time all the patients had had clinical and laboratory responses to antimicrobial treatment of babesiosis, including clearance of Babesia microti parasitemia. All 6 patients were asplenic (P<0.001) and had positive direct antiglobulin tests for IgG and complement component 3; warm autoantibodies were identified in all these patients. No alternative explanation for clinical hemolysis was found. WAHA required immunosuppressive treatment in 4 of the 6 patients. Conclusions We documented post-babesiosis WAHA in patients who did not have a history of autoimmunity; asplenic patients appeared to be particularly at risk.
Impaired Survival after Unrelated Hematopoietic Stem Cell Transplantation from KIR2DS1 and KIR2DS2 Positive Donors.
Authors: Sebastian Giebel, Tomasz Czerw, Izabela Nowak, Jerzy Wojnar, Tomasz Kruzel, Joanna Dziaczkowska, Miroslaw Markiewicz, Aleksandra Holowiecka-Goral, Agnieszka Karolczyk, Iwona Wylezol, Piotr Kusnierczyk, Jerzy Holowiecki
Journal: Blood (2006)
Profile of axillary nodal disease from the Irish National Breast Cancer Screening Program in the era of sentinel node biopsy
Authors: M. Barry, M. R. Kell
Journal: Journal of Clinical Oncology (2009)

e11629 Introduction: Ireland offers a socialized national breast cancer screening program (Breastcheck) to women between 50 and 65 years of age with the aim of reducing breast cancer mortality. Historical axillary staging for screen detected breast cancer has shown nodal positivity in 25% of cases. This study examines axillary nodal disease from the Irish national breast cancer screening program in the era of sentinel lymph node biopsy (SLNB). Methods: Patients with clinically and radiologically early stage screen detected breast cancer and negative axillae are offered therapeutic surgery with SLNB. We examined prospective Breastcheck data collected from 2006 and 2007. Results: 136,527 women attended for routine screening and from these 574 invasive breast cancers were detected. 55 (9.6%) were clinically/radiologically axillary node positive at diagnosis. 519 clinically node negative patients proceeded to therapeutic surgery with SLNB, 113 (22%) were found to have a positive SLNB. Overall nodal positivity was 29.3% in this asymptomatic population. We examined tumour characteristics, hormone profile and HER-2 status from the SLNB group and tumor size was the only factor significantly associated with a positive SLNB (20.1mm vs. 14.3mm, p, 0.01). Conclusions: SLNB accurately detects axillary nodal disease from a purely screen detected population. Based on historic data, SLNB is superior to axillary sampling in this population. No significant financial relationships to disclose.
Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes
Authors: Jerry R. Mendell, Zarife Sahenk, Samiah Al-Zaidy, Louise R. Rodino-Klapac, Linda P. Lowes, Lindsay N. Alfano, Katherine Berry, Natalie Miller, Mehmet Yalvac, Igor Dvorchik, Melissa Moore-Clingenpeel, Kevin M. Flanigan, Kathleen Church, Kim Shontz, Choumpree Curry, Sarah Lewis, Markus McColly, Mark J. Hogan, Brian K. Kaspar
Journal: Molecular Therapy (2017)

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.
Reply: Better Studies Are Needed to Guide Treatment of Carbon Monoxide Poisoning
Authors: Jason J. Rose, Ling Wang, Qinzi Xu, Charles F. McTiernan, Sruti Shiva, Jesus Tejero, Mark T. Gladwin
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

In their discussion of the treatment of carbon monoxide (CO) poisoning, Rose and colleagues state that ". hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning" (1).In support of this, they cite a randomized trial by Weaver and colleagues (2), which they characterize as the best available evidence because it fulfills all Consolidated Standards of Reporting Trials criteria.This characterization, however, overlooks multiple limitations we and others have detailed previously (3, 4).Arguably the most serious of these is the evolution of the primary outcome from the study's inception to its final publication.As the investigators themselves made clear in early descriptions of the trial (5, 6), the original primary outcome was delayed neurologic sequelae defined by stringent criteria.In contrast, the eventual publication (2) evaluated all neurologic sequelae, using less stringent cutoffs and incorporating nonspecific symptoms in their definition.We subsequently demonstrated that the study by Weaver and colleagues (2) would have found no statistically significant benefit of hyperbaric oxygen had the original primary outcome been retained, and that further assumptions applied during the analysis phase conferred unwarranted statistical significance to outcomes at 6 and 12 months (3, 4).We have raised these concerns previously, including in this Journal (7), only to have leaders in the field of hyperbaric medicine sidestep rather than acknowledge them (8).This is not a pedantic matter.Carbon monoxide poisoning remains a major cause of poisoning-related morbidity and mortality, and the available evidence does not make clear whether hyperbaric oxygen improves clinically meaningful outcomes and, if so, which patients are most likely to benefit.A properly designed randomized trial is needed to answer these questions.Until the limitations of the study by Weaver and colleagues (2) and the resulting clinical equipoise are openly acknowledged, such a trial is unlikely.In the meantime, the treatment of CO poisoning will remain guided by opinion rather than by sound evidence.
Sphingosine 1-Phosphate (S1P) Is a Chemotactic Factor for CD34+ Progenitors and CD34+ Cell Lines Expressing the S1P1 Receptor: Possible Contribution to Progenitor Cell Trafficking.
Authors: Gabriele Seitz, Andreas M. Boehmler, Tina Wiesner, Lothar Kanz, Robert Möhle
Journal: Blood (2004)
Activating Mutations Observed in De Novo Acute Myeloid Leukemia Are Also Present in a Subset of Philadelphia Chromosome (Ph)-Positive Leukemia Patients with BCR-ABL1-Independent Resistance to ABL1 Kinase Inhibitors
Authors: Christopher A. Eide, Samantha L. Savage, Anupriya Agarwal, Daniel Bottomly, Beth Wilmot, Shannon K. McWeeney, Stephen E. Kurtz, Thomas O'Hare, Michael W. Deininger, Marc M. Loriaux, Cristina E. Tognon, Jeffrey W. Tyner, Brian J. Druker
Journal: Blood (2014)
Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study
Authors: Jackie Vandermeer, Allison M Winter, Ajay K. Gopal, Ryan D. Cassaday, Brian T. Hill, Andrei R. Shustov, Andrew J. Cowan, David G. Maloney, Mazyar Shadman, Brian G. Till, Lorinda Soma, Oliver W. Press, Stephen D. Smith
Journal: Blood (2015)
Peripheral Blood Absolute Lymphocyte/Monocyte Ratio Recovery During RCHOP Treatment Cycles Predicts Clinical Outcomes In Diffuse Large B-Cell Lymphoma
Authors: Luis F. Porrata, Kay M. Ristow, Thomas M Habermann, Thomas E Witzig, Joseph P. Colgan, David J. Inwards, Stephen M Ansell, Ivana N. Micallef, Patrick B. Johnston, Grzegorz S. Nowakowski, Carrie A Thompson, Svetomir N. Markovic
Journal: Blood (2013)
Predictors of Nonadherence to NCCN Guideline Recommendations for the Management of Stage I Anal Canal Cancer
Authors: Adam J. Kole, John M. Stahl, Henry S. Park, Sajid A. Khan, Kimberly L. Johung
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Definitive chemoradiotherapy (CRT) is recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma for all patients with stage I anal canal cancer. Because these patients were not well represented in clinical trials establishing CRT as standard therapy, it is unclear whether NCCN recommendations are being closely followed for stage I disease. This study identified factors that predict for NCCN Guideline–concordant versus NCCN Guideline–discordant care. Methods: Using the National Cancer Data Base, we identified patients diagnosed with anal canal carcinoma from 2004 to 2012 who received concurrent CRT (radiotherapy [RT] 45.0–59.4 Gy with multiagent chemotherapy), RT alone (45.0–59.4 Gy), or surgical procedure alone (local tumor destruction, tumor excision, or abdominoperineal resection). Demographic and clinicopathologic factors were analyzed using the chi-square test and logistic regression modeling. Results: A total of 1,082 patients with histologically confirmed stage I anal cancer were identified, among whom 665 (61.5%) received CRT, 52 (4.8%) received RT alone, and 365 (33.7%) received only a surgical procedure. Primary analyses were restricted to patients receiving CRT or excision alone, as these were most common. Multivariable analysis identified factors independently associated with reduced odds of CRT receipt: low versus intermediate/high tumor grade (adjusted odds ratio [AOR], 0.21; 95% CI, 0.14–0.29; P<.001), tumor size <1 cm vs 1 to 2 cm (AOR, 0.24; 95% CI, 0.17–0.35; P<.001), age ≥70 versus 50 to 69 years (AOR, 0.36; 95% CI, 0.24–0.54; P<.001), male sex (AOR, 0.63; 95% CI, 0.45–0.90; P=.009), and treatment at an academic versus a non-academic facility (AOR, 0.58; 95% CI, 0.41–0.81; P=.002). Conclusions: Despite the NCCN recommendation of CRT for stage I anal cancer, at least one-third of patients appear to be receiving guideline-discordant management. Excision alone is more common for patients who are elderly, are male, have small or low-grade tumors, or were evaluated at academic facilities.
Concurrent Treatment with Denileukin Diftitox (DD) To Deplete T-Regulatory Cells Enhances Rebound Lymphocytosis and Eosinophilia in Patients Treated with High-Dose IL-2 (HDIL-2) for Metastatic Renal Cell Cancer (MRCC).
Authors: Adi Gidron, John Eklund, Brenda Martone, Alfred W. Rademaker, Charles Goolsby, Laura Marszalek, Timothy M. Kuzel
Journal: Blood (2006)
Chemoradiotherapy with and without surgery in patients with locally advanced esophageal squamous cell carcinoma.
Authors: Yaping Xu, Qixun Chen, Xinmin Yu, Yuanda Zheng, Qingren Lin, Youhua Jiang, Xinming Zhou, Weimin Mao
Journal: Journal of Clinical Oncology (2014)

e15025 Background: Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. However, the value of adding surgery to chemoradiotherapy is unknown in locally advanced esophageal squamous cell carcinoma (ESCC). The aim of the study was to compare the efficacy and toxicity between chemoradiation with or without surgery in patients with locally advanced ESCC. Methods: All patients with locally advanced resectable (T3-4N0-1M0, T1-2N1M0) ESCC were allocated to either induction chemoradiotherapy weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 6 weeks and concurrent radiotherapy (50.4 Gy in 28 fractions, 5 days per week) followed by surgery (arm A), or chemoradiotherapy alone (the same chemotherapy regimen and concurrent radiotherapy at least 60 Gy) (arm B). The primary endpoint was the 18 months progression free survival time. Results: From April 2011 through December 2013, we enrolled 51 patients: 26 were assigned to arm A, and 25 to arm B. The progression free survival was better in arm A (The 18-month progression free survival was 73.2%.) than in arm B (The18-month progression free survival was 41.4%.). Treatment-related complications and mortality were significantly increased in arm A than in arm B. Cox regression analysis revealed clinical tumor response to chemoradiotherapy to be the single independent prognostic factor for the progression free survival (p=0.047), regardless of the treatment group. Conclusions: Adding surgery to chemoradiotherapy improves the progression free survival of patients with locally advanced ESCC. But the pronounced benefits of surgery need to be weighed against the potential treatment-related toxicity. Tumor response to chemoradiotherapy identifies a favorable prognostic factor within these locally advanced ESCC population,
A Novel, Highly Potent and Selective PDE9 Inhibitor for the Treatment of Sickle Cell Disease
Authors: James G McArthur, Thiago Maciel, Chunsheng Chen, Aurelie Fricot, Dione Kobayashi, Julia Nguyen, Phong Nguyen, Anna Parachova, Fuad Abdulla, Gregory M. Vercellotti, Niels Svenstrup, John D Belcher
Journal: Blood (2016)
Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies
Authors: Peter P. Toth, Olivier Descamps, Jacques Genest, Naveed Sattar, David Preiss, Ricardo Dent, Constantine Djedjos, Yuna Wu, Michelle Geller, Magdalena Uhart, Ransi Somaratne, Scott M. Wasserman
Journal: Circulation (2017)

Evolocumab, a fully human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), markedly reduces low-density lipoprotein cholesterol across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group.This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and, of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in 2 OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs, laboratory assessments, and AEs of interest were evaluated.Overall AE rates were similar between evolocumab and control in the parent trials (51.1% versus 49.6%) and in year 1 of OLE trials (70.0% versus 66.0%), as were those for serious AEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups versus 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing antievolocumab antibodies were detected.Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in OLE trials for 1 year supports a favorable benefit-risk profile for evolocumab.
Monoclonal B-Cell Lymphocytosis (MBL) and CLL Show Intraclonal Variation: Cases Classified as “Unmutated” Have the Greatest Clonal Diversity.
Authors: Andy C. Rawstron, James A.L. Fenton, Marieth Plummer, Harry O. King, Fiona L. Bennett, Andrew S. Jack, Peter Hillmen
Journal: Blood (2006)
Final Results of a Phase 2 Trial of Extended Treatment (tx) with Carfilzomib (CFZ), Lenalidomide (LEN), and Dexamethasone (KRd) Plus Autologous Stem Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (NDMM)
Authors: Todd Zimmerman, Noopur S. Raje, Ravi Vij, Donna Reece, Jesus G. Berdeja, Leonor A Stephens, Kathryn McDonnell, Cara A. Rosenbaum, Jagoda Jasielec, Paul G Richardson, Sandeep Gurbuxani, Jennifer Nam, Erica Severson, Brittany D. Wolfe, Shaun Rosebeck, Andrew Stefka, Dominik Dytfeld, Kent Griffith, Andrzej Jakubowiak
Journal: Blood (2016)
Profiling and Comparing the Immunogenicity of a Novel Single-Chain FVIII Molecule (rVIII-SingleChain) for the Treatment of Hemophilia a
Authors: Eugene Maraskovsky, Anne Verhagen, Huy Huynh, Adriana Baz Morelli, Stefan Schmidbauer, Sabine Zollner, Jerry S. Powell, Katie St Ledger, Alex Veldman, Marco Hofmann
Journal: Blood (2016)
Functional local crosstalk of inositol 1,4,5-trisphosphate receptor- and ryanodine receptor-dependent Ca2+ release in atrial cardiomyocytes
Authors: Marcel Wullschleger, Joaquim Blanch, Marcel Egger
Journal: Cardiovascular Research (2017)

AimsEnhanced inositol 1,4,5-trisphosphate receptor (InsP3R2) expression has been associated with a variety of proarrhythmogenic cardiac disorders. The functional interaction between the two major Ca2+ release mechanisms in cardiomyocytes, Ca2+ release mediated by ryanodine receptors (RyR2s) and InsP3-induced intracellular Ca2+ release (IP3ICR) remains enigmatic. We aimed at identifying characterizing local IP3ICR events, and elucidating functional local crosstalk mechanisms between cardiac InsP3R2s and RyR2s under conditions of enhanced cardiac specific InsP3R2 activity.