tbuckley/cabot-search huggingface dataset:
Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study
Authors: Maria Antonietta D'Agostino, Richard J. Wakefield, Hilde Berner-Hammer, Olivier Vittecoq, Georgios Filippou, Peter Balint, Ingrid Möller, Annamaria Iagnocco, Esperanza Naredo, Mikkel Østergaard, Maarten Boers, Corine Gaillez, Karina Van Holder, Manuela Le Bars
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). <h3>Methods</h3> In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. <h3>Results</h3> Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. <h3>Conclusions</h3> In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. <h3>Trial registration number</h3> NCT00767325.
Abstract 3242: The Geoform Annuloplasty Ring for the Surgical Treatment of Functional Mitral Regurgitation in Advanced Dilated Cardiomyopathy
Authors: Michele De Bonis, Antonio Grimaldi, Francesco Maisano, Maurizio Taramasso, Elisabetta Lapenna, Giovanni La Canna, Andrea Galanti, Ottavio Alfieri
Journal: Circulation (2009)
Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells
Authors: Thamotharampillai Dileepan, Erica D. Smith, Daniel Knowland, Martin Hsu, Maryann Platt, Peter Bittner-Eddy, Brenda Cohen, Peter Southern, Elizabeth Latimer, Earl Harley, Dritan Agalliu, P. Patrick Cleary
Journal: Journal of Clinical Investigation (2015)

Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.
Invasive micropapillary carcinoma of the breast
Authors: F. G. Gercovich, H. Japaze, N. Gercovich, J. Emina, C. Diaz, J. Novelli, C. García Gerardi, E. Morgenfeld, E. Rivarola, E. Gil Deza
Journal: Journal of Clinical Oncology (2005)

769 Background: Invasive micropapillary carcinoma (IMC) of the breast is a poor prognosis subtype. The aim of this study is to evaluate a series of pts with IMC treated at our institution. Methods: From 1998 to 2003, 35 consecutive pts (F:34,M:1, mean age: 54 years) were treated at the IOHM. Three independent pathologists confirmed the diagnosis. Prognostic factors: T: T1: 8 pt, T2: 21 pt, T3: 3 pt, T4: 3 pt; tumor size (mean, range) 3.04 cm (1–8 cm). N: N0: 10 pt, N1: 24 pt, N2: 1 pt; axilary lymph node involvement (mean, range): 6,6 (2–16). M0: 35 pt. Disease stage: I: 7pt, II:22 pt, III:6 pt. Histological grade: 3 (all pts). Nuclear grade (NG): NG2:18 pt, NG3:17 pt. Mitotic index (MI):MI1: 18 pt, MI2: 17 pt. Standardized tumoral grade (STG) STG#6: 12 pt, STG#7: 12 pt, STG#8: 11 pt. Estrogen and progestin receptors: Both positive 26, both negative 5, estrogen+progestin-: 3, unknown: 1. Treatment: Surgery (mastectomy/tumorectomy) 15/20, postoperative radiotherapy 25, adyuvant chemotherapy: 30 (including anthracyclines 21/30), adyuvant tamoxifen 28. Results: After a mean follow up of 37.4 months, 24 pts (68.5%) remained free from progression. Ten pts had metastatic recurrence stage (II:6, III:3, I:1) and one local progression. Two pts had secondary malignancies. Four pts died from the disease. Mean disease-free survival was 33 months (range 13 to 59) and median survival has not been reached yet. Conclusions: IMC is probably a poor prognosis variant of breast carcinoma and 20% of them are stage III. About two thirds have lymph node involvement. Despite the high frequency of both hormone receptor positives and the intense treatment received, 28% of the pts relapsed and 11% died. Future genetic studies may allow us for further investigation of the mechanisms of aggressiveness of this tumor No significant financial relationships to disclose.
Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings
Authors: Xiyuan Lu, Jennifer Q. Kwong, Jeffery D. Molkentin, Donald M. Bers
Journal: Circulation Research (2015)

Mitochondria produce ATP, especially critical for survival of highly aerobic cells, such as cardiac myocytes. Conversely, opening of mitochondrial high-conductance and long-lasting permeability transition pores (mPTP) causes respiratory uncoupling, mitochondrial injury, and cell death. However, low conductance and transient mPTP openings (tPTP) might limit mitochondrial Ca(2+) load and be cardioprotective, but direct evidence for tPTP in cells is limited.To directly characterize tPTP occurrence during sarcoplasmic reticulum Ca(2+) release in adult cardiac myocytes.Here, we measured tPTP directly as transient drops in mitochondrial [Ca(2+)] ([Ca(2+)]mito) and membrane potential (ΔΨm) in adult cardiac myocytes during cyclic sarcoplasmic reticulum Ca release, by simultaneous live imaging of 500 to 1000 individual mitochondria. The frequency of tPTPs rose at higher [Ca(2+)]mito, [Ca(2+)]i, with 1 μmol/L peroxide exposure and in myocyte from failing hearts. The tPTPs were suppressed by preventing mitochondrial Ca(2+) influx, by mPTP inhibitor cyclosporine A, sanglifehrin, and in cyclophilin D knockout mice. These tPTP events were 57±5 s in duration, but were rare (occurring in <0.1% of myocyte mitochondria at any moment) such that the overall energetic cost to the cell is minimal. The tPTP pore size is much smaller than for permanent mPTP, as neither Rhod-2 nor calcein (600 Da) were lost. Thus, proteins and even molecules the size of NADH (663 Da) will be retained during these tPTP.We conclude that tPTP openings (MitoWinks) may be molecularly related to pathological mPTP, but are likely to be normal physiological manifestation that benefits mitochondrial (and cell) survival by allowing individual mitochondria to reset themselves with little overall energetic cost.
Abstract 1415: Sustained Reductions in C-reactive Protein, Retinol Binding Protein-4 and Leptin: One-Year Randomized Controlled Family Based Lifestyle Intervention in Obese Children
Authors: Prabhakaran Balagopal, Amanda Lochrie, Jason Lang, Shawn Sweeten, Karl Mann, Astride Altomare, Atilio Canas, Timothy Wysocki
Journal: Circulation (2009)

Elevated circulating levels of CRP, leptin and RBP4 confer increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Alterations in these potential etiological r...
Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials
Authors: Paul W. Noble, Carlo Albera, Williamson Z. Bradford, Ulrich Costabel, Roland M. du Bois, Elizabeth A. Fagan, Robert S. Fishman, Ian Glaspole, Marilyn K. Glassberg, Lisa Lancaster, David J. Lederer, Jonathan A. Leff, Steven D. Nathan, Carlos A. Pereira, Jeffrey J. Swigris, Dominique Valeyre, Talmadge E. King
Journal: European Respiratory Journal (2015)

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day −1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.
Low dose interferon-α2b (IFN) + thalidomide (T) in patients (pts) with previously untreated renal cell cancer (RCC). Improvement in progression-free survival (PFS) but not quality of life (QoL) or overall survival (OS). A phase III study of the Eastern Cooperative Oncology Group (E2898)
Authors: M. S. Gordon, J. Manola, D. Fairclough, D. Cella, R. Richardson, J. Sosman, B. Kasimis, J. P. Dutcher, G. Wilding
Journal: Journal of Clinical Oncology (2004)

4516 Background: Both low dose IFN and T have anti-angiogenic properties (PNAS U S A. 1995 92:4562 & PNAS U S A. 1994 91:4082). We performed a randomized trial to assess the value of combining these two agents compared to low-dose IFN alone in RCC. Methods: Eligibility included no prior therapy, ECOG PS 0–2 and normal organ function. Treatment consisted of IFN 1 MIU SC BID alone or in combination with T (intra-pt dose escalation from 200 mg/day to 1,000 mg/day maximum). Patients were stratified according to prior nephrectomy, disease-free interval and ECOG performance status (PS). The study was designed to detect an improvement in PFS at 6 months of 35% compared to 20% in the std arm and was re-sized to detect a 50% improvement in median OS from 12 to 18 mos. Results: We enrolled 353 pts of whom 342 were eligible with a median age of 59 years (range 24–84) including 227M:115F with a median ECOG PS 1. 254 pts had undergone a prior nephrectomy and 236 had a disease-free interval of ≤1yr. Fatigue, myelosuppression and thrombotic events (12 vs 4) were greater in I+T arm. There was no difference in response rates or overall survival though progression-free survival was statistically significantly longer in the IFN+T arm (see table). QoL and fatigue scores were worse on the IFN+T arm. Conclusions: The addition of T to this IFN regimen modestly improves PFS but not OS and worsens QoL in RCC patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Schering
Drug-Eluting Stents for Acute Myocardial Infarction⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: H. Vernon Anderson, Richard W. Smalling, Timothy D. Henry
Journal: Journal of the American College of Cardiology (2007)
Esophagogastric junction morphology assessment by high resolution manometry in obese patients candidate to bariatric surgery
Authors: Salvatore Tolone, Edoardo Savarino, Nicola de Bortoli, Marzio Frazzoni, Manuele Furnari, Antonio d’Alessandro, Roberto Ruggiero, Giovanni Docimo, Luigi Brusciano, Simona Gili, Raffaele Pirozzi, Simona Parisi, Carmine Colella, Mariachiara Bondanese, Beniamino Pascotto, NunzioMattia Buonomo, Vincenzo Savarino, Ludovico Docimo
Journal: International Journal of Surgery (2015)
Abstract 226: Relation Between Glasgow Coma Scale Motor Score Immediately After ROSC and Neurologic Outcomes in Patients Treated With Hypothermia After Out-of-Hospital Cardiac Arrest: J-PULSE-Hypo Registry
Authors: Yasuhiro Kuroda, Kenya Kawakita, Ken Nagao, Naohiro Yonemoto, Hiroyuki Yokoyama, Hiroshi Nonogi
Journal: Circulation (2013)

Background: The 2010 American Heart Association Guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) recommend that comatose adult patients with return of spontaneous circulation (ROSC) after out-of-hospital ventricular fibrillation (VF) cardiac arrest should receive therapeutic hypothermia (Class I). However, it remains unclear whether Glasgow Coma Scale (GCS) immediately after ROSC predicts neurologic outcome in patients treated with hypothermia after out-of-hospital cardiac arrest. Methods: We conducted a multicenter retrospective study at 14 institutions to evaluate the effect of therapeutic hypothermia on out-of-hospital cardiac arrest between January 2005 and March 2011 (505 patients). The study committee entrusted each hospital with the timing of cooling, cooling methods, target temperature, duration, and rewarming rate. In the patients with ROSC at hospital arrivals, the relationship between GCS score at hospital arrivals and neurological outcomes were analyzed. Neurologic outcomes at 90 days after cardiac arrest were examined. A favorable outcome was defined as a Cerebral Performance Category (CPC) of 1-2. Results: A total of 100 patients were studied. GCS score at hospital arrivals was distributed from 3 to 10. GCS motor scale at hospital arrivals was distributed from M1 (n=64), M2 (n=9), M3 (n=10), M4 (n=15), to M5 (n=2). Time interval between ROSC and hospital arrivals was distributed from 0 to 51 min (median 10 min, IQR: 5 - 17). A favorable outcome at 90 days after cardiac arrest was observed in 89 patients (89 %). All patients with GCS M4 and M5 (n=17) in which examined within 22 min after ROSC predict favorable outcome. Among the patients with GCS M1-3 (n=83) in which examined within 51 min after ROSC, favorable outcome was observed in 87 % (n=72) patients. Conclusions: Our results suggest that GCS motor scale at hospital arrivals after ROSC before induction of therapeutic hypothermia predict favorable outcomes.
Variable incidence of candidemia in patients admitted to ICUs or medical wards of large tertiary-care Italian hospitals
Authors: C. Tascini, F. Menichetti, M. Merelli, A. Farese, E. Sozio, C. Scarparo, B. Viaggi, G.M. Rossolini, M. Bassetti
Journal: Clinical Microbiology and Infection (2015)
Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer.
Authors: K. A. Gelmon, H. W. Hirte, A. Robidoux, K. S. Tonkin, M. Tischkowitz, K. Swenerton, D. Huntsman, J. Carmichael, E. Macpherson, A. M. Oza
Journal: Journal of Clinical Oncology (2010)

3002 Background: Olaparib is a PARP inhibitor (PARPi) which has reported encouraging response data in BRCA mutation carriers. We have completed a phase II translational study evaluating tumor response with serial tumor biopsies to determine markers of response. Methods: Eligible women with advanced breast (BC) or ovarian cancer (OC) were enrolled in 4 cohorts. A Simon 2 stage design was used for 2 cohorts of BRCA mutation negative or unknown patients (pts) with either high grade serous OC (Arm A) or triple negative BC (Arm B). Two other cohorts are reference groups with recurrent OC (Arm C) or BC (Arm D) with identified BRCA mutations. All (pts) had tumor biopsies prior to treatment, after 2 cycles and at progression to assess PARPi activity, loss of heterozygosity (LOH), mutational changes, BRCA1/2 expression, and markers of response including deep sequencing. CT/MRI assessments were done prior to treatment and every 2 cycles. Selected pts had PET scans. Pts were treated with single agent olaparib 400 mg bid on a continuous basis in 4 week cycles. Results: 91 evaluable pts were enrolled. Arm A enrolled 55 pts after evidence of response(s) in the first 15 pts. Arm B did not meet continuation criteria and closed at 15 pts. Arms C and D enrolled predetermined numbers of 10 and 11 pts. Preliminary results show 3 partial responses in Arm C with 6 pts in Arms C and D continuing on treatment at this time. In arm A, 20 of 55 measurable pts remain on treatment with 22+ pts receiving ≥6 cycles of olaparib. Confirmed radiological PRs have been observed in 8 pts with GCIG CA125 response criteria in 14 pts and 142 biopsies collected overall. Conclusions: This is the first trial demonstrating significant evidence of single agent activity of olaparib in women with high grade serous OC. Updated translational study data and response data in BRCA+ and BRCA− tumors will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca
Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy
Authors: Stefania Catalano, Antonella Campana, Cinzia Giordano, Balázs Győrffy, Roberta Tarallo, Antonio Rinaldi, Giuseppina Bruno, Aurora Ferraro, Francesco Romeo, Marilena Lanzino, Fabio Naro, Daniela Bonofiglio, Sebastiano Andò, Ines Barone
Journal: Clinical Cancer Research (2015)

Abstract Purpose: By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and effects in different (patho)physiologic processes, including cancers. As PDE5 is a known druggable target, we investigated the clinical significance of its expression in breast cancer and the underlying mechanisms by which it may contribute to tumor progression. Experimental Design: PDE5 expression was evaluated in seven breast cancer cell lines by RT-PCR and immunoblotting. To examine the impact of PDE5 on cancer phenotype, MCF-7 cells expressing lower levels of the enzyme were engineered to stably overexpress PDE5. Proliferation was evaluated by MTT assays, motility and invasion by wound-healing/transmigration/invasion assays, transcriptome-profiling by RNA-sequencing, and Rho GTPase signaling activation by GST-pulldown assays and immunoblotting. Clinical relevance was investigated by IHC on tissues and retrospective studies from METABRIC cohort. Results: PDE5 is differentially expressed in each molecular subtype of both breast cancer cell lines and tissues, with higher levels representing a startling feature of HER2-positive and triple-negative breast cancers. A positive correlation was established between elevated PDE5 levels and cancers of high histologic grade. Higher PDE5 expression correlated with shorter patient survival in retrospective analyses. On molecular level, stable PDE5 overexpression in Luminal-A–like MCF-7 cells resulted in enhanced motility and invasion through Rho GTPase signaling activation. Treatment of PDE5-stable clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control vector cells. Conclusions: PDE5 expression enhances breast cancer cell invasive potential, highlighting this enzyme as a novel prognostic candidate and an attractive target for future therapy in breast cancers. Clin Cancer Res; 22(9); 2271–82. ©2015 AACR.
Establishment and Characterization of an <i>In Vitro</i> Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity
Authors: Tatsuya Ishiguro, Ai Sato, Hirokazu Ohata, Yoshinori Ikarashi, Ryou-u Takahashi, Takahiro Ochiya, Masayuki Yoshida, Hitoshi Tsuda, Takashi Onda, Tomoyasu Kato, Takahiro Kasamatsu, Takayuki Enomoto, Kenichi Tanaka, Hitoshi Nakagama, Koji Okamoto
Journal: Cancer Research (2015)

The establishment of cancer stem-like cell (CSC) culture systems may be instrumental in devising strategies to fight refractory cancers. Inhibition of the Rho kinase ROCK has been shown to favorably affect CSC spheroid cultures. In this study, we show how ROCK inhibition in human serous ovarian cancer (SOC) cells can help establish a CSC system, which illuminates cancer pathophysiology and its treatment in this setting. In the presence of a ROCK kinase inhibitor, spheroid cultures of SOC cells expressed characteristic CSC markers including ALDH1A1, CD133, and SOX2, along with differentiation and tumorigenic capabilities in mouse xenograft models of human SOC. High expression levels of ALDH, but not CD133, correlated with spheroid formation CSC marker expression and tumor forming capability. In clinical specimens of SOC, high levels of ALDH1A1 correlated with advanced stage and poor prognosis. Pharmacologic or genetic blockade of ALDH blocked cell proliferation and reduced expression of SOX2, the genetic ablation of which abolished spheroid formation, whereas SOX2 overexpression inhibited ALDH1A1 expression and blocked spheroid proliferation. Taken together, our findings illustrated a new method to culture human ovarian CSC, and they defined a reciprocal regulatory relationship between ALDH1A1 and SOX2, which impacts ovarian CSC proliferation and malignant progression.
Androgen deprivation therapy should be used with caution in some prostate cancer cases, study warns
Authors: Jacqui Wise
Journal: BMJ (2015)

Combining androgen deprivation and radiotherapy is known to improve outcomes in aggressive prostate cancer, but research published in JAMA shows that it should be used with caution in men with coexisting illness.1

Six months of androgen deprivation therapy and radiation therapy is the standard treatment for unfavourable risk prostate cancer. But a post-randomisation analysis found that men with moderate or severe comorbidity showed no survival benefit from combined therapy. …
The sibling relationship as a context for the development of social understanding
Authors: Nina Howe
Journal: Behavioral and Brain Sciences (2004)

Carpendale & Lewis (C&L) provide a convincing argument for how children construct social understanding through social interaction. Certainly mothers are important in family interaction; however, sibling interaction may also be key in the process of developing social understanding. In particular, the highly affective and reciprocal dynamics of the sibling relationship in both positive and conflictual interaction may be critical.