tbuckley/cabot-search huggingface dataset:
Outcome in Elderly Patients Undergoing Primary Coronary Intervention for Acute Myocardial Infarction
Authors: Giulio Guagliumi, Gregg W. Stone, David A. Cox, Thomas Stuckey, James E. Tcheng, Mark Turco, Giuseppe Musumeci, John J. Griffin, Alexandra J. Lansky, Roxana Mehran, Cindy L. Grines, Eulogio Garcia
Journal: Circulation (2004)

Background— Biological age is a strong determinant of prognosis in patients with acute myocardial infarction (AMI). We sought to examine the impact of age after primary percutaneous coronary intervention in AMI and to determine whether routine coronary stent implantation and/or platelet glycoprotein IIb/IIIa inhibitors improve clinical outcomes in elderly patients after primary angioplasty. Methods and Results— In the CADILLAC trial, 2082 patients with AMI were randomized to balloon angioplasty, angioplasty plus abciximab, stenting alone, or stenting plus abciximab. No patient was excluded on the basis of advanced age; patients ranging from 21 to 95 years of age were enrolled. One-year mortality increased for each decile of age, exponentially after 65 years of age (1.6% for patients &lt;55 years, 2.1% for 55 to 65 years, 7.1% for 65 to 75 years, 11.1% for patients &gt;75 years; P &lt;0.0001). Elderly patients also had increased rates of stroke and major bleeding compared with their younger counterparts. Among elderly patients (≥65 years), 1-year rates of ischemic target revascularization (7.0% versus 17.6%; P &lt;0.0001) and subacute or late thrombosis (0% versus 2.2%; P =0.005) were reduced with stenting compared with balloon angioplasty. Routine abciximab administration, although safe, was not of definite benefit in elderly patients. Rates of mortality, reinfarction, disabling stroke, and major bleeding in the elderly were independent of reperfusion modality. Conclusions— Despite contemporary mechanical reperfusion strategies, mortality, major bleeding, and stroke rates remain high in elderly patients undergoing primary percutaneous coronary intervention, outcomes that are not affected by stents or glycoprotein IIb/IIIa inhibitors. By reducing restenosis, however, stent implantation improves clinical outcomes in elderly patients with AMI.
Stimulation of glycosaminoglycan production and lysosomal activity of human synovial cells in culture by low environmental pH.
Authors: B J Clarris, J R Fraser, K D Muirden, L P Malcolm, M W Holmes, K Rogers
Journal: Annals of the Rheumatic Diseases (1984)

Glycosaminoglycan production, acid hydrolase activity, proliferation, and morphology were examined in human synovial cells subjected to low environmental pH. The amount and the molecular size of newly synthesised glycosaminoglycan (GAG) were increased without significant change in the rate of cell proliferation. Lowered pH produced an increase in the size of cytoplasmic organelles. Some of these possessed ultrastructural features of lysosomes, but others were clearly nonlysosomal and were of uncertain identity. Intracellular activity of the lysosomal acid hydrolase N-acetyl-beta-glucosaminidase (NAG) was not altered by low pH, but a marked increase occurred in extracellular NAG activity, indicating enhanced release.
Efficacy of Photodynamic Therapy vs Other Interventions in Randomized Clinical Trials for the Treatment of Actinic Keratoses
Authors: Gayatri Patel, April W. Armstrong, Daniel B. Eisen
Journal: JAMA Dermatology (2014)

IMPORTANCE Photodynamic therapy (PDT) is used extensively to treat actinic keratoses (AKs).An analysis of the effectiveness of PDT compared with other treatments may help physicians decide what role it should play in their own clinical practices.OBJECTIVE To determine the effectiveness of PDT for the treatment of AKs relative to other methods.DATA SOURCES MEDLINE, EMBASE, Web of Knowledge, and Cochrane Central Register.No restrictions on years were placed, and all searches extended to the year of each database inception.Our search was conducted on March 20, 2013, and included the search terms solar keratosis, actinic keratosis, photodynamic therapy, and photochemotherapy.No restrictions were used for the search string.STUDY SELECTION Only randomized PDT trials that used aminolevulinic acid hydrochloride or methyl aminolevulinate hydrochloride as stabilizers with 10 or more participants were considered.Two of the authors undertook the search independently.DATA EXTRACTION AND SYNTHESIS Data were extracted independently by the 2 authors.We assessed data quality using the Jadad scoring system and used a random-effects model for pooled data analysis. MAIN OUTCOMES AND MEASURESPrimary outcome measures specified a priori were lesion response, cosmetic results, and patient satisfaction after the intervention. RESULTSOur search identified 875 journal articles and meeting abstracts.We excluded 862 owing to lack of adherence to our inclusion criteria or lack of author response to our queries for further information.We assessed 13 studies for inclusion in our final synthesis, of which 4 were eligible for final meta-analysis.The only comparator for which meta-analysis was performed was cryotherapy.The meta-analysis consisted of 641 participants, with a total of 2174 AKs treated with cryotherapy and 2170 AKs treated with PDT.Compared with cryotherapy, the pooled relative risk for the meta-analysis for complete response (lesion clearance) was 1.14 (95% CI, 1.11-1.18)at 3 months after treatment.Visual inspection of a funnel plot revealed no publication bias, which was confirmed by the Begg test (P = .80).CONCLUSIONS AND RELEVANCE Photodynamic therapy has a 14% better chance of complete lesion clearance at 3 months after treatment than cryotherapy for thin AKs on the face and scalp.
A case of Churg-Strauss syndrome: tissue diagnosis established by sigmoidoscopic rectal biopsy.
Authors: E J Leen, P J Rees, J D Sanderson, M L Wilkinson, M I Filipe
Journal: Gut (1996)

A case is presented of Churg-Strauss syndrome in a young man in whom the definitive diagnostic procedure was a full thickness sigmoidoscopic rectal biopsy, with submucosal sampling. Gastrointestinal changes in Churg-Strauss syndrome, a rare systemic illness characterised by asthma, blood and tissue eosinophilia, vasculitis, and granulomatous inflammation are common but poorly reported. The endoscopic and histopathological features of a case are described and emphasise the potential value of a limited sigmoidoscopy in establishing the diagnosis, when lower gastrointestinal symptoms are present.
Contact sport and osteoarthritis
Authors: Michael G Molloy, Catherine B Molloy
Journal: British Journal of Sports Medicine (2011)

Osteoarthritis (OA) is the most common joint disease in the world and the single largest cause of disability for those over 18 years. It affects more than twice as many people as does cardiac disease, and increases in incidence and prevalence with age. Animal and human studies have shown no evidence of increased risk of hip or knee OA with moderate exercise and in the absence of traumatic injury, sporting activity has a protective effect. One age-matched case control study found recreational runners who ran 12-14 miles per week for up to 40 years had no increase in radiological or symptomatic hip or knee OA. However, higher rates of hip OA occur in contact sports than in age-matched controls, with the highest rate in professional players. Soccer players with torn anterior cruciate ligaments (ACL) are more likely to develop knee OA than those with intact ACL. Early ACL repair reduces the risk of knee OA, but does not prevent it. Established injury prevention programmes have been refined to prevent injuries such as ACL rupture.
Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma
Authors: Nienke van Rooij, Marit M. van Buuren, Daisy Philips, Arno Velds, Mireille Toebes, Bianca Heemskerk, Laura J.A. van Dijk, Sam Behjati, Henk Hilkmann, Dris el Atmioui, Marja Nieuwland, Michael R. Stratton, Ron M. Kerkhoven, Can Keşmir, John B. Haanen, Pia Kvistborg, Ton N. Schumacher
Journal: Journal of Clinical Oncology (2013)

The evidence for T-cell–mediated regression of human cancers such as non–small-cell lung carcinoma, renal cell carcinoma, and—in particular—melanoma after immunotherapy is strong. Anti-CTLA4 (ipilimumab) treatment has been approved for treatment of meta-static melanoma,1 and antibody-mediated blockade of PD-1, a second inhibitory receptor on T cells, has shown highly encouraging results in early clinical trials.2,3 Although the clinical activity of these treatments is apparent, it is still unknown which T-cell reactivities are involved in immunotherapy-induced cancer regression.4 T-cell reactivity against nonmutated tumor-associated self-antigens has been analyzed in patients treated with ipilimumab or with autologous tumor-infiltrating T cells, but the magnitude of the T-cell responses observed has been relatively modest.5,6 In part on the basis of such data, recognition of patient-specific mutant epitopes (hereafter referred to as neoantigens) has been suggested to be a potentially important component.7 A potential involvement of mutated epitopes in T-cell control would also fit well with the observation that the mutation load in sun-exposed melanomas is particularly high.8-10

Intriguingly, on the basis of animal model data, it has recently been suggested that (therapy-induced) analysis of T-cell reactivity against patient-specific neoantigens may be feasible through exploitation of cancer genome data.11,12 However, human data have thus far been lacking. Here we report a case of a patient with stage IV melanoma who exhibited a clinical response to ipilimumab treatment. Cancer exome–guided analysis of T-cell reactivity in this patient revealed reactivity against two neoantigens, including a dominant T-cell response against a mutant epitope of the ATR (ataxia telangiectasia and Rad3 related) gene product that increased strongly after ipilimumab treatment. These data provide the first demonstration (to our knowledge) of cancer exome–guided analysis to dissect the effects of melanoma immunotherapy.
Detecting Selective Sweeps from Pooled Next-Generation Sequencing Samples
Authors: S. Boitard, C. Schlotterer, V. Nolte, R. V. Pandey, A. Futschik
Journal: Molecular Biology and Evolution (2012)

Due to its cost effectiveness, next-generation sequencing of pools of individuals (Pool-Seq) is becoming a popular strategy for characterizing variation in population samples. Because Pool-Seq provides genome-wide SNP frequency data, it is possible to use them for demographic inference and/or the identification of selective sweeps. Here, we introduce a statistical method that is designed to detect selective sweeps from pooled data by accounting for statistical challenges associated with Pool-Seq, namely sequencing errors and random sampling among chromosomes. This allows for an efficient use of the information: all base calls are included in the analysis, but the higher credibility of regions with higher coverage and base calls with better quality scores is accounted for. Computer simulations show that our method efficiently detects sweeps even at very low coverage (0.5× per chromosome). Indeed, the power of detecting sweeps is similar to what we could expect from sequences of individual chromosomes. Since the inference of selective sweeps is based on the allele frequency spectrum (AFS), we also provide a method to accurately estimate the AFS provided that the quality scores for the sequence reads are reliable. Applying our approach to Pool-Seq data from Drosophila melanogaster, we identify several selective sweep signatures on chromosome X that include some previously well-characterized sweeps like the wapl region.
P203 Development Of An Optimal F/hn Pseudotyped Siv Vector For Cf Gene Therapy
Authors: S. Hyde, E. Alton, A. Boyd, M. Connolly, M. Chan, J. Davies, L. Davies, S. Gea-Sorli, U. Griesenbach, M. Hasegawa, J. Innes, M. Inoue, G. McLachlan, C. Meng, I. Pringle, S. Sumner-Jones, S. Tsugumine, D. Gill
Journal: Thorax (2014)

<h3></h3> We are developing lung gene transfer vectors to treat acquired and inherited lung disorders such as cystic fibrosis, and have identified two platforms for efficient respiratory gene delivery: one non-viral system based on CpG-free plasmid DNA combined with cationic lipids (pDNA/GL67A), which has recently completed evaluation in a Phase IIb clinical study; and one novel viral system based on a recombinant simian immunodeficiency virus pseudotyped with the F/HN proteins of Sendai virus (rSIV. F/HN) to promote airway cell uptake. Here we report on the development of a “third generation” rSIV. F/HN vector suitable for use in the clinic. The vector is manufactured by transient transfection of cultured human cells using five producer plasmids, all of which have been engineered to be pharmacopoeia compliant. A variety of vector configurations, including a range of enhancers/promoters and transgenes, were evaluated in a panel of airway models. rSIV. F/HN vectors directed high-level, robust gene expression in fully differentiated human airway cells, human nasal brushings and human and sheep lung slices. In the mouse nose and lung, the preferred configuration directed up to x500-fold higher transgene expression than the non-viral platform, for the lifetime of the animal. Transgene expression was observed in 14.1% of lung epithelial cells (p &lt; 0.0001 compared to controls). Repeated monthly administration (3X) was possible without loss of expression or significant histological inflammatory reactivity. Reassuringly, insertion site profiling from transduced cell lines and mouse nose/lung samples reveals a pattern of integration comparable to those reported for other lentiviral vectors in clinical development, with no evidence for enrichment of insertion at undesirable loci. The stability of rSIV. F/HN vectors was evaluated in two bronchoscope catheters and two aerosol generation devices. Encouragingly for clinical translation, no significant loss of transduction activity was noted with any of these clinically relevant delivery devices (p = 0.64). Delivery of rSIV. F/HN expressing CFTR to sheep lung resulted in CFTR mRNA at ∼30% the levels of endogenous ovine CFTR (p &lt; 0.0001 compared to non-treated lobes), exceeding presumed therapeutic levels. With the majority of translational hurdles addressed, we are now entering toxicology studies and the final stages of pharmaceutical development prior to entering clinical trials.
Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis
Authors: Ana Lleo, Christopher L. Bowlus, Guo-Xiang Yang, Pietro Invernizzi, Mauro Podda, Judy Van de Water, Aftab A. Ansari, Ross L. Coppel, Howard J. Worman, Gregory J. Gores, Eric M. Gershwin
Journal: Hepatology (2010)

Abstract Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage T and B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). PDC-E2 is a ubiquitous protein present in mitochondria of nucleated cells. However, the damage of PBC is confined to small biliary epithelial cells (BECs). We have previously demonstrated that BECs translocate immunologically intact PDC-E2 to apoptotic bodies and create an apotope. To define the significance of this observation, we have studied the ability of biliary or control epithelial apotopes to induce cytokine secretion from mature monocyte-derived macrophages (MDMΦs) from either patients with PBC or controls in the presence or absence of anti-mitochondrial antibodies (AMAs). We demonstrate that there is intense inflammatory cytokine production in the presence of the unique triad of BEC apotopes, macrophages from patients with PBC, and AMAs. The cytokine secretion is inhibited by anti-CD16 and is not due to differences in apotope uptake. Moreover, MDMΦs from PBC patients cultured with BEC apoptotic bodies in the presence of AMAs markedly increase tumor necrosis factor–related apoptosis-inducing ligand expression. Conclusion: These results provide a mechanism for the biliary specificity of PBC, the recurrence of disease after liver transplantation, and the success of ursodiol in treatment. They further emphasize the critical role of the innate immune system in the perpetuation of this autoimmune disease.
Breast Cancer With Synchronous Metastases: Survival Impact of Exclusive Locoregional Radiotherapy
Authors: Romuald Le Scodan, Denise Stevens, Etienne Brain, Jean Louis Floiras, Christine Cohen-Solal, Brigitte De La Lande, Michelle Tubiana-Hulin, Sameh Yacoub, Maya Gutierrez, David Ali, Miriam Gardner, Patricia Moisson, Sylviane Villette, Florence Lerebours, Jean Nicolas Munck, Alain Labib
Journal: Journal of Clinical Oncology (2009)

Several studies suggest that surgical excision of the primary tumor improves survival among patients with stage IV breast cancer at diagnosis. Exclusive locoregional radiotherapy (LRR) is an alternative form of locoregional treatment (LRT) in this setting. We retrospectively studied the impact of LRT on the survival of breast cancer patients with synchronous metastases.Among 18,753 breast cancer patients treated in our institution between 1980 and 2004, 598 patients (3.2%) had synchronous metastasis at diagnosis. Demographic data, tumor characteristics, metastatic sites, and treatments were prospectively recorded. The impact of LRT on overall survival (OS) was evaluated by multivariate analysis including known prognostic factors.Among 581 eligible patients, 320 received LRT (group A), and 261 received no LRT (group B). LRT consisted of exclusive LRR in 249 patients (78%), surgery of the primary tumor with adjuvant LRR in 41 patients (13%), and surgery alone in 30 patients (9%). With a median follow-up time of 39 months, the 3-year OS rates were 43.4% and 26.7% in group A and group B (P =.00002), respectively. The association between LRT and improved survival was particularly marked in women with visceral metastases. LRT was an independent prognostic factor in multivariate analysis (hazard ratio [HR] = 0.70; 95% CI, 0.58 to 0.85; P = .0002). The adjusted HR for late death (>or= 1 year) was 0.76 (95% CI, 0.61 to 0.96; P = .02).In our experience, LRT, consisting mainly of exclusive LRR, was associated with improved survival in breast cancer patients with synchronous metastases. Exclusive LRR may thus represent an active alternative to surgery.
CC Chemokine Ligand-5 (CCL5/RANTES) and CC Chemokine Ligand-18 (CCL18/PARC) Are Specific Markers of Refractory Unstable Angina Pectoris and Are Transiently Raised During Severe Ischemic Symptoms
Authors: A.O. Kraaijeveld, S.C.A. de Jager, W.J. de Jager, B.J. Prakken, S.R. McColl, I. Haspels, H. Putter, T.J.C. van Berkel, L. Nagelkerken, J.W. Jukema, E.A.L. Biessen
Journal: Circulation (2007)

Chemokines play an important role in atherogenesis and in ischemic injury and repair; however, prospective data on individual chemokines in unstable angina pectoris (UAP) are scarce. Therefore, we assessed chemokine patterns in a prospective cohort of patients with UAP.Plasma samples of 54 patients with Braunwald class IIIB UAP were examined at baseline for 11 chemokines and 5 inflammatory mediators via multiplex analysis. Levels of CC chemokine ligand (CCL)-5 (also known as RANTES [regulated on activation, normally T-cell expressed, and secreted]; 32.7 versus 23.1 ng/mL, P=0.018) and CCL18 (also known as PARC [pulmonary and activation-regulated chemokine]; 104.4 versus 53.7 ng/mL, P=0.011) were significantly elevated in patients with refractory ischemic symptoms versus stabilized patients. Temporal monitoring by ELISA of CCL5, CCL18, and soluble CD40 ligand (sCD40) levels revealed a drop in CCL5 and sCD40L levels in all UAP patients from day 2 onward (CCL5 12.1 ng/mL, P<0.001; sCD40L 1.35 ng/mL, P<0.05), whereas elevated CCL18 levels were sustained for at least 2 days, then were decreased at 180 days after inclusion (34.5 ng/mL, P<0.001). Peripheral blood mononuclear cells showed increased protein expression of chemokine receptors CCR3 and CCR5 in CD3+ and CD14+ cells at baseline compared with 180 days after inclusion, whereas mRNA levels were downregulated, which was attributable in part to a postischemic release of human neutrophil peptide-3-positive neutrophils and in part to negative feedback. Finally, elevated CCL5 and CCL18 levels predicted future cardiovascular adverse events, whereas C-reactive protein and sCD40L levels did not.We are the first to report that CCL18 and CCL5 are transiently raised during episodes of UAP, and peak levels of both chemokines are indicative of refractory symptoms. Because levels of both chemokines, as well as of cognate receptor expression by circulating peripheral blood mononuclear cells, are increased during cardiac ischemia, this may point to an involvement of CCL5/CCL18 in the pathophysiology of UAP and/or post-UAP responses.
FKBP12.6-Mediated Stabilization of Calcium-Release Channel (Ryanodine Receptor) as a Novel Therapeutic Strategy Against Heart Failure
Authors: Masafumi Yano, Shigeki Kobayashi, Masateru Kohno, Masahiro Doi, Takahiro Tokuhisa, Shinichi Okuda, Masae Suetsugu, Takayuki Hisaoka, Masakazu Obayashi, Tomoko Ohkusa, Michihiro Kohno, Masunori Matsuzaki
Journal: Circulation (2003)

The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury.Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts.During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.