tbuckley/cabot-search huggingface dataset:
Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency
Authors: Gregory D. Lewis, Rajeev Malhotra, Adrian F. Hernandez, Steven E. McNulty, Andrew Smith, G. Michael Felker, W. H. Wilson Tang, Shane J. LaRue, Margaret M. Redfield, Marc J. Semigran, Michael M. Givertz, Peter Van Buren, David Whellan, Kevin J. Anstrom, Monica R. Shah, Patrice Desvigne-Nickens, Javed Butler, Eugene Braunwald
Journal: JAMA (2017)

<h3>Importance</h3> Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. <h3>Objective</h3> To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. <h3>Design, Setting, and Participants</h3> Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (&lt;40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites. <h3>Interventions</h3> Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. <h3>Main Outcomes and Measures</h3> The primary end point was a change in peak oxygen uptake (V̇o<sub>2</sub>) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). <h3>Results</h3> Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o<sub>2</sub>was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o<sub>2</sub>at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs −2 mL/min; difference, 21 mL/min [95% CI, −34 to +76 mL/min];<i>P</i> = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), NT-proBNP levels (159; 95% CI, −280 to 599 pg/mL), or KCCQ score (1; 95% CI, −2.4 to 4.4), all<i>P</i> &gt; .05. <h3>Conclusions and Relevance</h3> Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. <h3>Trial Registration</h3> clinicaltrials.govIdentifier:NCT02188784
Guidelines for cardiopulmonary resuscitation and emergency cardiac care. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Part V. Pediatric basic life support
Journal: JAMA (1992)

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Must Good HMOs Go Bad? — The Search for Checks and Balances
Authors: Robert Kuttner
Journal: New England Journal of Medicine (1998)

Part 1 of this article suggested that without countervailing forces, market pressures to reduce costs in managed care may compel all health maintenance organizations (HMOs) to adopt practices that compromise medical ethics and patient care. Theoretically, there are two types of counterweights: those that rely on market discipline and those external to the market. How effective are they?Market Discipline: The Discerning ConsumerAdvocates of market discipline in health care, such as Alain Enthoven and Regina Herzlinger, propose systems in which consumers discipline health plans and providers by choosing among competing plans.21,22 Ironically, the late Clinton health care proposal, . . .
Relative contribution should be given after each author's name
Authors: W. Foulkes, N. Neylon
Journal: BMJ (1996)

EDITOR,—Richard Horton and Richard Smith's editorial addresses the continuing problem of authorship.1 The authors suggest that a “film credit” style of authorship might be possible. This would be unwieldy. An even less plausible alternative is the use of font size to indicate relative contribution to a scientific paper.2 This would result in visually interesting title pages …
Predictive markers in metastatic transitional cell carcinoma (mTCC) patients treated with carboplatin plus pemetrexed regimen.
Authors: Guadalupe Aparicio, Vanessa Medina Villaamil, Miquel Taron, Rafael Rosell, Luis M. Antón Aparicio
Journal: Journal of Clinical Oncology (2013)

e15558 Background: Treatment with platinum derivatives plus pemetrexed has shown a benefit in metastatic transitional cell bladder carcinoma (mTCC); however, the subset of patients most likely to benefit has not yet been identified. Predictive markers of pemetrexed response can be inferred from its mechanism of action in inhibiting nucleotide synthesis. In the present study we evaluated the predictive role of BRCA1, RAP80, TS, REV3 and AEG1 mRNA levels in a series of mTCC samples from patients treated with carboplatin plus pemetrexed (CP) and correlated with pathological response to chemotherapy and median survival. Methods: We retrospectively analyzed 18 patients with mTCC. Eligible patients received pemetrexed 500 mg/m 2 in combination with carboplatin at an area under the concentration curve of 5. Total treatment dose was given on day 1 of each cycle and repeated every 21 days for 6 cycles. Gene expression levels were quantified by real-time quantitative PCR from paraffin-embedded pre-treatment tumor samples obtained by transurethral resection. Results: Patients were male, mean age 71 years (range 51-83). Median overall survival was 3.5 years (95% CI, 0.377-3.623). Non-responders had average survival of 2.2 years (SE=0.436) compared to an average of 5.5 years for responders (SE=0.661) (Pearson X 2 =4.667, p=0.031). We found an association between non-responders and elevated RAP80 expression (paired t (df)=-2.69, p=0.028) (paired t (df)=2.372, p=0.039). In the multivariate analysis elevated TS level was the variable most predictive of shorter survival (OR=1.158, p=0.047). Conclusions: CP regimen demonstrated moderate activity in patients with mTCC. Our data indicates that RAP80 and TS could be predictors of poor outcome. Also, RAP80 expression may predict efficacy of CP as first-line treatment and could be a useful tool to customize therapy in bladder cancer patients. A prospective study is warranted to validate these observations.
Abstract 19957: Angiotensin II Type 2 Receptor Potentiates Skeletal Muscle Stem Cell Differentiation via GSK-3β/β-catenin Signaling Pathway: Implications for Treatment of Cachexia and Skeletal Muscle Wasting
Authors: Tadashi Yoshida, Patrice Delafontaine
Journal: Circulation (2016)

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II infusion in rodents causes skeletal muscle wasting and decreases muscle regenerative potential via Ang II type 1 receptor (AT1R) signaling, likely contributing to cachexia in CHF and CKD. We also found that Ang II type 2 receptor (AT2R) potentiates skeletal muscle stem cell (MuSC) differentiation and muscle regenerative capacity. However, mechanisms whereby AT2R regulates MuSC differentiation and its potential involvement in cachexia development remain unknown. To understand the signaling pathways downstream of AT2R in MuSC, we screened for phosphoprotein changes using microarray, on which 1318 unique antibodies against various phosphoproteins are spotted. We found that 20 phosphoproteins were upregulated (>1.4 fold change) and 28 were downregulated ( in vitro  and  in vivo . The increase in GSK-3β activity after AT2R knockdown was associated with inhibition of downstream β-catenin activity, measured by TCF/LEF reporter assay both  in vitro  and  in vivo . Treatment with GSK-3β inhibitor BIO and Wnt3A inhibited GSK-3β activity after AT2R knockdown and restored MuSC differentiation  in vitro  and skeletal muscle regeneration  in vivo . Importatnly, we found that skeletal muscle regeneration was reduced (decreased regenerating myofiber size and myogenin/desmin expression) in a mouse myocardial infarction model of CHF, concomitantly with markedly blunted AT2R expression and with an increase of GSK-3β activity. In these mice, hindlimb injection of BIO inhibited GSK-3β activity and restored muscle regenerative capacity. These data indicate that AT2R/GSK-3β/β-catenin pathway plays a critical role in regulating MuSC differentiation and muscle regeneration, and could be a novel therapeutic target in wasting disorders such as CHF and CKD.
Open-Label, Multicenter, Phase II Study of Ceritinib in Patients With Non–Small-Cell Lung Cancer Harboring <i>ROS1</i> Rearrangement
Authors: Sun Min Lim, Hye Ryun Kim, Jong-Seok Lee, Ki Hyeong Lee, Yun-Gyoo Lee, Young Joo Min, Eun Kyung Cho, Sung Sook Lee, Bong-Seog Kim, Moon Young Choi, Hyo Sup Shim, Jin-Haeng Chung, Yoon La Choi, Min Jeong Lee, Maria Kim, Joo-Hang Kim, Siraj M. Ali, Myung-Ju Ahn, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2017)

Purpose ROS1 rearrangement is a distinct molecular subset of non–small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.
Anti-Inflammatory Effects of OxPAPC Involve Endothelial Cell–Mediated Generation of LXA4
Authors: Yunbo Ke, Noureddine Zebda, Olga Oskolkova, Taras Afonyushkin, Evgeny Berdyshev, Yufeng Tian, Fanyong Meng, Nicolene Sarich, Valery N. Bochkov, Ji Ming Wang, Anna A. Birukova, Konstantin G. Birukov
Journal: Circulation Research (2017)

Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid products with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells are critical for prevention of acute lung injury caused by bacterial pathogens or excessive mechanical ventilation. Anti-inflammatory properties of OxPAPC are associated with its antagonistic effects on Toll-like receptors and suppression of RhoA GTPase signaling.Because OxPAPC exhibits long-lasting anti-inflammatory and lung-protective effects even after single administration in vivo, we tested the hypothesis that these effects may be mediated by additional mechanisms, such as OxPAPC-dependent production of anti-inflammatory and proresolving lipid mediator, lipoxin A4 (LXA4).Mass spectrometry and ELISA assays detected significant accumulation of LXA4 in the lungs of OxPAPC-treated mice and in conditioned medium of OxPAPC-exposed pulmonary endothelial cells. Administration of LXA4 reproduced anti-inflammatory effect of OxPAPC against tumor necrosis factor-α in vitro and in the animal model of lipopolysaccharide-induced lung injury. The potent barrier-protective and anti-inflammatory effects of OxPAPC against tumor necrosis factor-α and lipopolysaccharide challenge were suppressed in human pulmonary endothelial cells with small interfering RNA-induced knockdown of LXA4 formyl peptide receptor-2 (FPR2/ALX) and in mFPR2-/- (mouse formyl peptide receptor 2) mice lacking the mouse homolog of human FPR2/ALX.This is the first demonstration that inflammation- and injury-associated phospholipid oxidation triggers production of anti-inflammatory and proresolution molecules, such as LXA4. This lipid mediator switch represents a novel mechanism of OxPAPC-assisted recovery of inflamed lung endothelium.
Anti–Interleukin‐6 Receptor Tocilizumab for Severe Juvenile Idiopathic Arthritis–Associated Uveitis Refractory to Anti–Tumor Necrosis Factor Therapy: A Multicenter Study of Twenty‐Five Patients
Authors: Vanesa Calvo‐Río, Montserrat Santos‐Gómez, Inmaculada Calvo, M. Isabel González‐Fernández, Berta López‐Montesinos, Marina Mesquida, Alfredo Adán, María Victoria Hernández, Olga Maíz, Antonio Atanes, Beatriz Bravo, Consuelo Modesto, Gisela Díaz‐Cordovés, Natalia Palmou‐Fontana, Javier Loricera, M. C. González‐Vela, Rosalía Demetrio‐Pablo, J. L. Hernández, Miguel A. González‐Gay, Ricardo Blanco
Journal: Arthritis & Rheumatology (2016)

To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis.We conducted a multicenter study of patients with JIA-associated uveitis that was refractory to conventional immunosuppressive drugs and anti-tumor necrosis factor (anti-TNF) agents.We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 [range 1-5]), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 μm to 259.1 ± 39.5 μm after 6 months of TCZ (P = 0.012). The best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow-up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient.TCZ appears to be a useful therapy for severe refractory JIA-associated uveitis.
Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice
Authors: Monique E. Verhaegen, Doris Mangelberger, Paul W. Harms, Markus Eberl, Dawn M. Wilbert, Julia Meireles, Christopher K. Bichakjian, Thomas L. Saunders, Sunny Y. Wong, Andrzej A. Dlugosz
Journal: Cancer Research (2017)

Abstract Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151–7. ©2017 AACR.
Incorporating tissue architecture into cellular assays using existing HTS infrastructure
Authors: Steven Hayes, Allyson Skoien, Ivar Meyvantsson, Dave Beebe
Journal: Clinical Cancer Research (2007)

A34  The advantages of microfluidics have been difficult to fully realize in drug discovery because highly parallel operation requires complex networks of tubing and pumps. We present here a tubeless microfluidics platform that can be operated by standard automated liquid handlers. The ability of microfluidics to deliver high resolution cell patterning enables cell-based assays with more realistic tissue architecture. The deposition of adjacent cell compartments by laminar flow can be used to create co-culture assays consisting of adjacent epithelial and stromal compartments. Cells can be readily embedded in 3D matrices, providing more representative biological responses. This approach has significant advantages over conventional approaches: no physical interventions by the user are required, both cellular compartments are fully assayable, and dilution of paracrine effectors is minimized. Using laminin-rich 3D extracellular matrix, we demonstrate that mammary epithelial cells undergo normal differentiation in these devices, and phenotypic reversion can be induced in tumor cells. Deposition of an adjacent stromal compartment containing fibroblasts allows complex paracrine interactions to be studied. These devices make complex cellular assays much more accessible to drug discovery and biomedical research in general.
Intrathymic injection of hematopoietic progenitor cells establishes functional T cell development in a mouse model of severe combined immunodeficiency
Authors: Andrea Z. Tuckett, Raymond H. Thornton, Richard J. O’Reilly, Marcel R. M. van den Brink, Johannes L. Zakrzewski
Journal: Journal of Hematology & Oncology (2017)

Even though hematopoietic stem cell transplantation can be curative in patients with severe combined immunodeficiency, there is a need for additional strategies boosting T cell immunity in individuals suffering from genetic disorders of lymphoid development. Here we show that image-guided intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice is feasible and facilitates the generation of functional T cells conferring protective immunity. Hematopoietic stem and progenitor cells were isolated from the bone marrow of healthy C57BL/6 mice (wild-type, Luciferase+, CD45.1+) and injected intravenously or intrathymically into both male and female, young or aged NOD-scid IL2rγnull recipients. The in vivo fate of injected cells was analyzed by bioluminescence imaging and flow cytometry of thymus- and spleen-derived T cell populations. In addition to T cell reconstitution, we evaluated mice for evidence of immune dysregulation based on diabetes development and graft-versus-host disease. T cell immunity following intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice was assessed in a B cell lymphoma model. Despite the small size of the thymic remnant in NOD-scid IL2rγnull mice, we were able to accomplish precise intrathymic delivery of hematopoietic stem and progenitor cells by ultrasound-guided injection. Thymic reconstitution following intrathymic injection of healthy allogeneic hematopoietic cells was most effective in young male recipients, indicating that even in the setting of severe immunodeficiency, sex and age are important variables for thymic function. Allogeneic T cells generated in intrathymically injected NOD-scid IL2rγnull mice displayed anti-lymphoma activity in vivo, but we found no evidence for severe auto/alloreactivity in T cell-producing NOD-scid IL2rγnull mice, suggesting that immune dysregulation is not a major concern. Our findings suggest that intrathymic injection of donor hematopoietic stem and progenitor cells is a safe and effective strategy to establish protective T cell immunity in a mouse model of severe combined immunodeficiency.