tbuckley/cabot-search huggingface dataset:
Brief Report: Carboxypeptidase B Serves as a Protective Mediator in Osteoarthritis
Authors: Christin M. Lepus, Jason J. Song, Qian Wang, Catriona A. Wagner, Tamsin M. Lindstrom, Constance R. Chu, Jeremy Sokolove, Lawrence L. Leung, William H. Robinson
Journal: Arthritis & Rheumatology (2013)

We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA.We compared the development of OA in CPB-deficient (Cpb2(-/-) ) mice and wild-type mice by subjecting them to medial meniscectomy and histologically assessing cartilage damage, osteophyte formation, and synovitis in the stifle joints 4 months later. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used enzyme-linked immunosorbent assay, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)-a complement effector critical to OA pathogenesis.Cpb2(-/-) mice developed dramatically greater cartilage damage than did wild-type mice (P < 0.01) and had a greater number of osteophytes (P < 0.05) and a greater degree of synovitis (P < 0.05). In synovial fluid samples from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis.Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.
Baseline characteristics of patients with frequent exacerbations in the POET-COPD™ trial
Authors: Leonardo M. Fabbri, Claus Vogelmeier, Maureen P.M.H. Rutten-van Mölken, Klaus F. Rabe, Thomas Glaab, Fee Rühmkorf, Hendrik Schmidt, Kai M. Beeh
Journal: European Respiratory Journal (2011)

Background:  The randomized, double-blind, double-dummy, 1-year POET-COPD™ trial showed that tiotropium (18 μg qd) was superior to salmeterol (50 μg bid) in preventing moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations.   Aims and objectives:  An exploratory post-hoc subgroup analysis to compare baseline characteristics of frequent and infrequent exacerbators (patients experiencing ≥2 and ≤1 exacerbations during the trial, respectively).   Methods:  Important inclusion criteria were age ≥40 years, postbronchodilator forced expiratory volume in 1 s (FEV 1 ) ≤70% predicted and ≥1 exacerbation in previous year.   Results:  Baseline characteristics of the 7376 patients who were randomized and treated are shown in the table.   Conclusion:  Compared with infrequent exacerbators, frequent exacerbators in POET-COPD™ were characterized at baseline by: more severe COPD; longer disease duration; increased LABA and ICS use; and more frequent antibiotic or systemic steroid courses in the past year.  Funded by Boehringer Ingelheim/Pfizer
A phase I dose-finding study of sunitinib (SU) in combination with gemcitabine (G) in patients (pts) with advanced solid tumors
Authors: M. D. Michaelson, A. Schwarzberg, D. P. Ryan, D. F. McDermott, G. I. Shapiro, L. Tye, I. Chen, P. Selaru, E. Wang, A. Zhu
Journal: Journal of Clinical Oncology (2008)

14522 Background: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor that shows significant antitumor activity in renal cell carcinoma (RCC) and other cancers. This study assessed the maximum tolerated dose (MTD), safety and pharmacokinetic (PK) profile of SU in combination with G in advanced solid tumor pts. Methods: Pts received escalating oral doses of SU (25–50 mg/day) on a 6-week (wk) cycle (4 wks on, 2 wks off treatment; 4/2 schedule) with G (750–1250 mg/m2) IV over 30 min on Days 1, 8, 22, and 29. Subsequently, patients received SU on a 3-wk cycle (2 wks on, 1 wk off; 2/1 schedule) with G on Days 1 and 8. Safety was evaluated using adverse event (AE) reports and laboratory analyses. Objective responses were assessed by RECIST; PK data were analyzed at each dose level. Results: 34 pts (most common tumor types: RCC, n=19; pancreatic, n=11) received SU+G, including 8 pts on Schedule 4/2 and 26 pts on Schedule 2/1. Schedule 4/2 was not pursued beyond the initial dose level. On schedule 2/1, MTD has not yet been reached, and enrollment continues at the highest dose level (SU 50 mg/day + G 1250 mg/m2). On Schedule 2/1, grade (Gr) 4 non-hematologic AEs included myocardial infarction (n=1) and pulmonary embolism (n=1), neither considered related to study treatment. Gr 4 laboratory abnormalities included thrombocytopenia (n=1) and neutropenia (n=6), with no instances of febrile neutropenia. Evidence of antitumor efficacy has been observed on both schedules, in pts with pancreatic or renal cancer. Among 9 pts with poor-risk or sarcomatoid RCC, 5 pts exhibited partial responses and 3 had stable disease, across different dose levels. At all dose levels analyzed to date, the Cmax and AUC of the drugs and their metabolites following combination therapy were similar to those following single-agent SU or G dosing; these data indicate that there are no clinically significant drug-drug interactions during co-administration. Conclusions: Combination therapy with SU and G in pts with advanced solid tumors is well tolerated, does not result in significant drug-drug interactions, and is associated with notable antitumor activity. The efficacy and safety of this combination will be studied further in disease-specific clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Bayer, Genentech, Pfizer, Wyeth Pfizer Pfizer, Wyeth Pfizer
One-year adherence to CPAP treatment in cardiac patients with non-sleepy sleep apnoea in the RICCADSA trial
Authors: Yüksel Peker, Yelda Turgut Celen, Anna Stålkrantz, Helena Glantz, Özlem Sengören Dikis, Björn Cederin, Selda Korkmaz, Erik Thunström
Journal: European Respiratory Journal (2012)

The RICCADSA study is an on-going randomized controlled trial started in December 2005 addressing the impact of continuous positive airway pressure (CPAP) in revascularized coronary artery disease (CAD) patients with Obstructive Sleep Apnoea (OSA) without significant daytime sleepiness (Epworth Sleepiness Scale [ESS] <10). The primary end-point is the combined rate of new revascularization, myocardial infarction, stroke and cardiovascular mortality over a period of 2 to 7 years by December 2012. Sleepy OSA patients (ESS≥10) treated with CPAP as well as patients without OSA are also included in the study. In the current report, we aimed to address 1-yr adherence to CPAP treatment.

Among 662 patients undergoing sleep study, 511 were included in the trial, and 277 (122 non-sleepy OSA vs 155 sleepy OSA) started auto-CPAP (S8®or S9® ResMed) at baseline. In non-sleepy OSA randomized to CPAP, 77 (63.1%) were still using the device compared to 117 (75.5%) sleepy OSA patients at 1-yr follow-up (p=0.026). Average daily CPAP use was 5.8 h in the non-sleepy group (average 271 days) vs 5.7 h (average 281 days) in the sleepy OSA patients, respectively (n.s).

We conclude that 1-yr adherence to auto-CPAP in a revascularized cardiac clinic population with non-sleepy OSA was slightly lower than that in the sleepy OSA patients, which in turn was not much different from the adherence ratios generally reported from the sleep clinic cohorts.

Supported by the Swedish Research Council, the Swedish Heart-Lung-Foundation, Research Fund at Skaraborg Hospital, ResMed Foundation and ResMed Ltd. YTC is the recipient of a European Respiratory Society / European Lung Foundation Fellowship (Nr 156).
Intrapatient emergence of OXA-247: a novel carbapenemase found in a patient previously infected with OXA-163-producing Klebsiella pneumoniae
Authors: S. Gomez, F. Pasteran, D. Faccone, M. Bettiol, O. Veliz, D. De Belder, M. Rapoport, B. Gatti, A. Petroni, A. Corso
Journal: Clinical Microbiology and Infection (2013)
Tumor Angiogenesis: A Quantitative Method for Histologic Grading&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Steven Brem, Ramzi Cotran, Judah Folkman
 4
Journal: JNCI Journal of the National Cancer Institute (1972)

A quantitative technique for measuring the degree of angiogenesis in tumors is described. The microscopic angiogenesis grading system was based on 3 parameters of endothelial regeneration: vasopro-liferation, endothelial cell hyperplasia, and endothelial cytology, providing a composite rating of 0–100. The method was tested in grading the degree of neovascularization in cerebral neoplasms and vascular tissues induced by tumors and tumor extracts; it appeared to give quantitatively reproducible and biologically reasonable results. Preliminary observations on a variety of other tumors suggest that solid neoplasms can be classified according to the extent of angiogenesis along a spectrum ranging from the "endothelial-poor" tumors, such as the chondrosarcomas, to the "endothelial-rich" tumors, such as glioblastomas.
The Medical Management of Traumatic Hyphaema: A Survey of Opinion among Ophthalmologists in the UK
Authors: B C Little, G W Aylward
Journal: Journal of the Royal Society of Medicine (1993)

Current attitudes to the medical management of traumatic hyphaema were investigated by means of a postal survey. A single page questionnaire was sent to all consultant ophthalmologists in the UK who were members of the college of ophthalmologists. The response rate was 50%. Opinion was sharply divided on the use of bed rest, padding and topical therapy. However, there was almost universal agreement that systemic therapy, either steroids or antifibrinolytics, were not indicated.
Synthesis of 1-(2-Hydroxyethyl)-1-nitrosourea and Comparison of Its Carcinogenicity With That of 1-Ethyl-1-nitrosourea&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: D H Swenson, J V Frei, P D Lawley
Journal: JNCI Journal of the National Cancer Institute (1979)

1-(2-Hydroxyethyl)-1-nitrosourea (HNU) was prepared by the action of nitrosyl chloride on (2-hydroxyethyl)urea. Attempts to synthesize HNU by an earlier described method were unsuccessful and led to the formation of the cyclized derivative 1-nitroso-2-oxazolidone. In addition, the spectral data that we obtained for HNU differed from those reported earlier. Female C57BL/Cbl mice were treated with single ip doses of HNU to determine its median lethal dose (LD50) and its ability to induce lymphocytic thymic lymphomas in these mice. The results showed that the LD50 was the same as that for 1-ethyl-1-nitrosourea (ENU) and that its was slightly more potent than ENU as a carcinogen in this system.
Prevalence of comorbidities in patients with COPD: Data from the TOPDOCS cohort
Authors: Christian F. Clarenbach, Noriane A. Sievi, Thomas Brack, Martin Brutsche, Martin Frey, Sarosh Irani, Jörg Leuppi, Jochen Ruediger, Oliver Senn, Robert Thurnheer, Malcolm Kohler
Journal: European Respiratory Journal (2013)

Introduction: The management of chronic diseases such as COPD is complicated by the presence of comorbidities. Comorbidities in patients with COPD impair quality of life, contribute to hospitalizations and mortality. The knowledge on the prevalence and type of comorbidities in patients with COPD is still limited. The objective of this cross-sectional analysis was to evaluate the prevalence of comorbid conditions in The Obstructive Pulmonary Disease Outcomes Cohort of Switzerland (TOPDOCS). Methods: In 203 patients with COPD (67% men; mean (SD) age: 63 (7) years; FEV1: 46 (21) % predicted) comorbidities were assessed by medical history, clinical interview, clinical examination and blood analysis. Results: 72% of the COPD patients had at least one additional chronic comorbidity, 42% had 2 or more comorbidities and 21% had 3 or more comorbidities. The prevalence of comorbidities among patients with COPD was: arterial hypertension (43%), obesity (21%), coronary artery disease (19%), peripheral artery disease (12%), diabetes (11%), osteoporosis (11%), depression (8%) and cerebrovascular accident (4%). Polypharmacy, defined as ≥4 prescribed medications, was observed in 64% of patients with a median (quartiles) number of prescribed drugs of 6 (5,8). Conclusions: The majority of patients with COPD in this Swiss cohort had at least one comorbid condition and the prevalence of multi-morbidity was high. Thus future COPD trials evaluating therapeutic effects need to include typical COPD patients with comorbidities and practice guidelines need to address COPD in the context of comorbidity.
Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy
Authors: Michele Maio, Alessia Covre, Elisabetta Fratta, Anna Maria Di Giacomo, Pietro Taverna, Pier Giorgio Natali, Sandra Coral, Luca Sigalotti
Journal: Clinical Cancer Research (2015)

Abstract Epigenetic regulation allows heritably modulating gene expression profiles without modifying the primary sequence of gDNA. Under physiologic conditions, epigenetic patterns determine tissue-specific gene expression landscapes, gene imprinting, inactivation of chromosome X, and preservation of genomic stability. The most characterized mediators of epigenetic inheritance are gDNA methylation and histone posttranslational modifications that cooperate to alter chromatin state and genome transcription. According to these notions, it is not surprising that cancer cells invariantly deploy epigenetic alterations to achieve gene expression patterns required for neoplastic transformation and tumor progression. In this context, the recently uncovered use of epigenetic alterations by cancer cells to become stealth from the host's immune recognition has significant immunobiologic relevance in tumor progression, and it appears to have potential clinical usefulness. Indeed, immune evasion is among the major obstacles to further improve the efficacy of cancer immunotherapies and to increase long-lasting disease control. Luckily, different “epigenetic drugs” able to revert these “epimutations” are available, some of which have already been approved for clinical use. Here, we summarize the immunomodulatory activities of epigenetic drugs that lead to improved immune recognition of cancer cells and focus on the potential of this class of agents in improving the anticancer activity of novel immunotherapies through combinatorial epigenetic immunotherapy approaches. Clin Cancer Res; 21(18); 4040–7. ©2015 AACR.
Abstract 174: Role of Cardiomyocyte-Localized Nuclear Factor (NF)-κB in Diet-Induced Diabetic Cardiomyopathy
Authors: Mehak Goel, Mohamed A Ismahil, Tariq Hamid, Sumanth D Prabhu
Journal: Circulation Research (2014)

Role of Inflammatory signaling in the development of obesity- and type 2 diabetes (T2D)-associated cardiomyopathy remains unclear. We hypothesized that cardiomyocyte-specific inflammatory activation, independent of systemic inflammation, is sufficient for the genesis of diabetic cardiomyopathy. Wild-type (WT) and transgenic (Tg) C57BL/6 mice with myocyte-restricted overexpression of phosphorylation-resistant IκBα (IκBαS32A,S36A) were fed a high fat (HFD, 45% kcal fat) or control diet (CD, 10% kcal fat) for 28 weeks to induce obesity and T2D. These Tg mice exhibit attenuated NF-kB activation, a central regulator of inflammation. After 28 weeks of feeding, WT HFD mice exhibited increased body weight, hyperglycemia, hyperinsulinemia, insulin resistance, and glucose intolerance. In contrast, although HFD-fed Tg mice exhibited significantly (p &lt; 0.05) increased body weight, the mice still maintained normal fasting blood glucose, insulin levels, and insulin sensitivity compared to CD Tg mice, indicating absence of overt T2D. Echocardiography revealed that both HFD-fed WT and Tg mice developed concentric left ventricular (LV) hypertrophy with increased septal and posterior wall thickness, decreased LV end-diastolic diameter and had unchanged LV ejection fraction suggesting development of LV hypertrophy in both strains regardless of the severity of the metabolic disorder. Analysis of mononuclear phagocyte cell profiles revealed similar trends in WT and IκB Tg mice. HFD fed mice had higher levels of pro-inflammatory (CD11b+Ly6chi) and anti-inflammatory (CD11b+Ly6clo) monocytes in the blood, heart, spleen and adipose tissue compared to CD fed mice. Analysis of antigen presenting cells indicated that HFD fed mice in both genotypes had significantly increased levels of both classical (CD11c+CD45R–) and plasmacytoid (CD11cintCD45R+) dendritic cells in blood, heart, spleen and adipose tissues compared to respective CD fed mice. Thus, we conclude that cardiomyocyte inflammation is central to the development of metabolic abnormalities related to obesity, whereas neither cardiomyocyte-specific nor systemic insulin resistance is required for the development of the hypertrophic cardiomyopathic phenotype.
Improvement of left ventricular function by intensified exercise training in COPD patients
Authors: Peter Alter, Daniel Haid, Lea Luetteken, Christoph Nell, Katharina Kehr, Timm Greulich, Sandra Apelt, Carsten Hohmann, Claus Franz Vogelmeier, Andreas Rembert Koczulla
Journal: European Respiratory Journal (2014)

Background  COPD is associated with increased pulmonary vascular resistance, leading to increased right heart load, decreased filling pressure and stroke volume of the left ventricle (LV). Exercise training (ET) is assumed to increase exercise capacity and quality of live. It is hypothesized that exercise training exhibits beneficial effects on LV function in COPD.   Methods  10 COPD patients(GOLD I/II/III/IV = 4/4/1/1) were prospectively examined at enrolment and after 6 month ET (twice weekly, 1.5 hr). The ET contained group training (warming), followed by individual strength and endurance components. LV enddiastolic volume (LVEDV), endsystolic volume (LVESV), stroke volume (LVSV) and ejection fraction (LVEF) were assessed by transthoracic echocardiography. LV mass (LVM) was obtained based on the Penn-cube convention. LV enddiastolic and endsystolic wall stress was calculated using the wall stress index as previously reported.   Results  Echocardiographic results are displayed in table 1. Furthermore pCO 2  values in capillary blood gases decreased from 40.5 ± 6.8 to 38.2 ± 6.7 (p=0.015).   Conclusions  Improved cardiac function based on increased LV stroke volume and mass was observed after 6 months of ET. The increase of LV volume and mass was not associated with increased ventricular wall stress. It is concluded that moderate exercise training leads to improved LV function and stroke volume in COPD.
Cerebrospinal Fluid Rhinorrhoea in Pituitary Tumours
Authors: I E Cole, Malcolm Keene
Journal: Journal of the Royal Society of Medicine (1980)

Three cases of CSF rhinorrhoea due to pituitary tumours are reported and the literature reviewed. The treatment of choice appears to be trans-sphenoidal exploration of the pituitary fossa with insertion of a free muscle graft followed by radiotherapy. The probability of the tumour being a prolactin-secreting adenoma is discussed.
Alteration of Macrophage Function in AKR Leukemia&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;,&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: S J Normann, M Schardt, E Sorkin
Journal: JNCI Journal of the National Cancer Institute (1981)

A virally induced T-cell leukemia-lymphoma developed spontaneously in 80% of inbred AKR mice between the ages of 6 and 12 months. Advanced cancer inhibited macrophage accumulation at inflammatory sites, with the degree of inhibition being directly related to the elevation in peripheral white blood cell (WBC) count and inversely correlated with the weight of the tumorous lymph nodes and thymus. Sixty AKR mice were examined biweekly between the ages of 5 1/2 and 10 months; macrophage inflammatory responses were compared with peripheral WBC counts. Depressed macrophage responses were not observed before onset of leukemia but did occur coincidently with or within 2 weeks of each episode of leukemia. The conclusion was reached that an inhibition of macrophage function typically occurred with the onset of spontaneous leukemia and during the terminal phase of illness, but this inhibition did not precede leukemia, was probably not related to lymph node or thymus enlargement, and was not always present despite persistent tumor growth.
Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia.
Authors: S Sacchi, H Kantarjian, S O'Brien, P R Cohen, S Pierce, M Talpaz
Journal: Journal of Clinical Oncology (1995)

PURPOSE Long-term treatment with interferon alfa (IFN alpha) can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC and unusual complications in patients with chronic myelogenous leukemia (CML) undergoing IFN alpha treatment. PATIENTS AND METHODS The occurrence of IMC and unusual complications was evaluated in patients with Philadelphia chromosome (Ph)-positive CML. RESULTS Well-documented and clinically evident complications developed in 35 patients after a median of 14 months of IFN alpha treatment. These included 28 (5%) of 581 patients with Ph-positive CML treated with IFN alpha-containing regimens at M.D. Anderson Cancer Center (MDACC) and seven patients referred for opinion or problems who were on other studies. Hypothyroidism occurred in 11 patients (2%), immune-mediated hemolysis in seven (1%), and connective tissue diseases in 11 (2%). Other unusual occurrences included congestive heart failure (CHF; n = 4), porphyria cutanea tarda (PCT; n = 3), membranous glomerulonephritis (MGN; n = 1), and vitiligo (n = 1). IFN treatment was discontinued in 19 patients and the dose was reduced in five. Ten of 11 patients (91%) with immune-mediated hypothyroidism and eight of 11 (73%) with connective tissue diseases had some degree of cytogenetic response at the time of the event. CONCLUSION Although the frequency of IMC is low, patients treated with IFN alpha should be monitored for signs and symptoms of autoimmunity.
Is there a delay in diagnosis of post infectious obliterative bronchiolitis (PBO)
Authors: Sonal Kansra, Harish Vyas, Alan Smyth, John Somers, Jayesh Bhatt
Journal: European Respiratory Journal (2012)

Background: PBO, an orphan lung disease results following an antecedent severe viral lower respiratory tract infection (LRTI),commonly due to adenovirus.The clinical symptoms of PBO are non-specific.This may result in a significant delay in diagnosis.  Methods: We retrospectively examined the medical records of children with PBO to determine the time from initial illness to diagnosis based on clinical and radiological criteria as follows:  1. History of antecedent viral LRTI  2. Evidence of airway obstruction (clinical or spirometry)  3. Radiological investigations consistent with PBO  Results: Of the nine cases identified over last 17 years,adenovirus(n=7)was the main organism implicated in the initial infection in keeping with description in literature.Common referrals were for difficult or severe wheeze, exercise limitation, recurrent respiratory infections or bronchiectasis.The diagnosis was made earlier in children who had a persistent oxygen requirement or were admitted under the care of respiratory paediatricians.  Conclusions: There is a significant delay in diagnosis of PBO in our experience. Severe LRTI especially with adenovirus and a prolonged oxygen requirement at initial presentation followed by persistent respiratory symptoms should prompt further investigations.Confirmation of the diagnosis leads to better understanding of the disease for the child with the opportunity to network with other children with rare diseases, could lead to potentially disease modifying treatment like Azithromycin and avoid unnecessary treatment for asthma.