tbuckley/cabot-search huggingface dataset:
Long-Term Metformin Use Is Associated With Decreased Risk of Breast Cancer
Authors: Michael Bodmer, Christian Meier, Stephan Krähenbühl, Susan S. Jick, Christoph R. Meier
Journal: Diabetes Care (2010)

OBJECTIVE To evaluate whether use of oral hypoglycemic agents is associated with an altered breast cancer risk in women. RESEARCH DESIGN AND METHODS Using the U.K.-based General Practice Research Database, we conducted a nested case-control analysis among 22,621 female users of oral antidiabetes drugs with type 2 diabetes. We evaluated whether they had an altered risk of breast cancer in relation to use of various types of oral hypoglycemic agents. Case and control patients with a recorded diagnosis of type 2 diabetes were matched on age, calendar time, and general practice, and the multivariate conditional logistic regression analyses were further adjusted for use of oral antidiabetes drugs, insulin, estrogens, smoking BMI, diabetes duration, and HbA1c (A1C). RESULTS We identified 305 case patients with a recorded incident diagnosis of breast cancer. The mean ± SD age was 67.5 ± 10.5 years at the time of the cancer diagnosis. Long-term use of ≥40 prescriptions (&amp;gt;5 years) of metformin, based on 17 exposed case patients and 120 exposed control patients, was associated with an adjusted odds ratio of 0.44 (95% CI 0.24–0.82) for developing breast cancer compared with no use of metformin. Neither short-term metformin use nor use of sulfonylureas or other antidiabetes drugs was associated with a materially altered risk for breast cancer. CONCLUSIONS A decreased risk of breast cancer was observed in female patients with type 2 diabetes using metformin on a long-term basis.
Cytidine deaminase activity, C reactive protein, histidine, and erythrocyte sedimentation rate as measures of disease activity in psoriatic arthritis.
Authors: P S Helliwell, A Marchesoni, M Peters, R Platt, V Wright
Journal: Annals of the Rheumatic Diseases (1991)

Cytidine deaminase activity, C reactive protein, histidine, and erythrocyte sedimentation rate were measured in 36 subjects with psoriatic arthritis of varying disease duration and severity. Although cytidine deaminase activity may provide an integrated measure of synovial inflammation in rheumatoid arthritis, neutrophil accumulation in psoriatic plaques compromises this measure in psoriatic arthritis. Low histidine concentrations confirm that this amino acid provides a non-specific index of synovial inflammation. In psoriatic arthritis high C reactive protein concentrations seem to be associated with extensive joint destruction. In this study the erythrocyte sedimentation rate was found to be the best laboratory guide to clinical disease activity in psoriatic arthritis.
Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443--&gt;Val substitution and functional analysis of the recombinant mutant protein.
Authors: R Zahedi, J J Bissler, A E Davis, C Andreadis, J J Wisnieski
Journal: Journal of Clinical Investigation (1995)

We have determined the cause of an unusual C1 inhibitor abnormality in a large kindred. We previously found that half of serum C1 inhibitor molecules in affected kindred members are normal. The other half complexed with C1s but showed little complex formation with C1r. These molecules also appeared to be relatively resistant to digestion by trypsin. Taken together, the findings suggested that members of this kindred are heterozygous for an unusual C1 inhibitor mutation. Sequencing of genomic DNA from the kindred revealed that thymine has replaced cytosine in the codon for Ala443 (P2 residue) in one C1 inhibitor allele, resulting in substitution with a Val residue. To test the effect of this substitution, a mutant C1 inhibitor containing Ala443-->Val was constructed by site-directed mutagenesis and expressed in COS-1 cells. Both the Ala443-->Val mutant and the wild-type C1 inhibitor complexed completely with C1s, kallikrein, and coagulation Factor XIIa after incubation at 37 degrees C for 60 min. In contrast, the mutant inhibitor failed to complex completely with C1r under the same conditions. Time course analysis showed that the ability of the mutant to complex with C1s is also impaired: although it complexed completely in 60 min, the rate of complex formation during a 0-60-min incubation was decreased compared with wild-type C1 inhibitor. The mutant inhibitor also formed a complex with trypsin, a serine protease that cleaves, and is not inhibited by, wild-type C1 inhibitor. The Ala443-->Val mutation therefore converts C1 inhibitor from a substrate to an inhibitor of trypsin. These studies emphasize the role of the P2 residue in the determination of target protease specificity.
CD69 is expressed on platelets and mediates platelet activation and aggregation.
Authors: R Testi, F Pulcinelli, L Frati, P P Gazzaniga, A Santoni
Journal: The Journal of Experimental Medicine (1990)

CD69, a surface dimer so far considered an early activation antigen restricted to lymphocytes, was found constitutively expressed on human platelets. Biochemical analysis revealed that platelet CD69 appears on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a broad 55-65-kD band, in which three 55-, 60-, and 65-kD components were detectable when nonreduced, and as two 28- and 32-kD bands when reduced, corresponding to the two disulfide-linked chains of the dimer. It therefore closely resembles lymphoid CD69, although the resolution of the three bands under nonreducing conditions is not usually seen in lymphoid cells. Moreover, as CD69 expressed on activated lymphocytes and CD3bright thymocytes, both chains are constitutively phosphorylated. CD69 stimulation by anti-Leu-23 monoclonal antibodies induced platelet aggregation in a dose-dependent fashion. This effect was associated with Ca2+ influx and platelet degranulation, as revealed by adenosine triphosphate release. In addition, CD69 stimulation in platelets induced production of thromboxane B2 and PGE2, suggesting activation of arachidonic acid metabolism by cycloxygenase. As observed for CD69-mediated T cell activation, platelet activation through CD69 requires molecular crosslinking. These results suggest that CD69 may function as an activating molecule on platelets, as on lymphocytes, and point toward a more general role of this surface dimer in signal transduction.
Obinutuzumab (GA101) in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Results From the Phase II GAUGUIN Study
Authors: Gilles A. Salles, Franck Morschhauser, Philippe Solal-Céligny, Catherine Thieblemont, Thierry Lamy, Hervé Tilly, Emmanuel Gyan, Guiyuan Lei, Michael Wenger, Elisabeth Wassner-Fritsch, Guillaume Cartron
Journal: Journal of Clinical Oncology (2013)

The phase II part of the phase I/II GAUGUIN study evaluated the efficacy and safety of two different doses of obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, in patients with relapsed/refractory indolent non-Hodgkin lymphoma.Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) as a flat dose of 400 mg on days 1 and 8 of cycle 1 and also on day 1 of cycles 2 to 8 (400/400 mg) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1,600/800 mg).Forty patients were enrolled, including 34 with follicular lymphoma; 38 of 40 patients had previously received rituximab and 22 of 40 were rituximab refractory. The overall response rate at the end of treatment was 55% (95% CI, 32% to 76%) in the 1,600/800-mg group (9% complete responders) and 17% (95% CI, 4% to 41%) in the 400/400-mg group (no complete responders). Five of 10 rituximab-refractory patients had an end-of-treatment response in the 1,600/800-mg group versus one of 12 in the 400/400-mg group. Median progression-free survival was 11.9 months in the 1,600/800-mg group (range, 1.8 to 33.9+ months) and 6.0 months in the 400/400-mg group (range, 1.0 to 33.9+ months). The most common adverse events were infusion-related reactions (IRRs) seen in 73% of patients, but only two patients had grade 3 to 4 IRRs (both in the 1,600/800-mg group). No IRRs were considered serious, and no patients withdrew for IRRs.The 1,600/800-mg dose schedule of obinutuzumab (GA101) has encouraging activity with an acceptable safety profile in relapsed/refractory indolent non-Hodgkin lymphoma.
Determinants of prognosis of COPD in the elderly: mucus hypersecretion, infections, cardiovascular comorbidity
Authors: R. Pistelli, P. Lange, D.L. Miller
Journal: European Respiratory Journal (2003)

In this paper, the authors update the present knowledge about three risk factors for the prognosis of chronic obstructive pulmonary disease (COPD), which may be particularly relevant in elderly people: mucus hypersecretion, respiratory infections, and cardiovascular comorbidity. Chronic mucus hypersecretion (CMH) is a common respiratory symptom in old age, the relevance of which is analysed on the basis of data collected during the first three rounds of the Copenhagen City Heart Study. In subjects aged ≥65 yrs, CMH was a strong predictor of the incidence of respiratory infections in a 10-yr follow-up period and it was also a strong predictor of death from COPD (relative risk=2.5). However, CMH was associated with consistently lower forced expiratory volume in one second (FEV<sub>1</sub>) values, but not with an accelerated decline of FEV<sub>1</sub> in this sample of an elderly population. Acute respiratory infections (ARI) are extremely common at all ages, mostly mild self-limiting illnesses at a young age, but severe often fatal illnesses in elderly people already affected by a chronic disease such as COPD. This paper summarises the present knowledge about aetiology, pathology, prognostic relevance, and prevention of ARI. Furthermore, the areas in which further research is needed are listed. Clinical cohort studies clearly support the relevance of cardiovascular comorbidity for the short- and long-term prognosis of elderly subjects affected by severe COPD. In this paper, the recently demonstrated association between particulate air pollution and cardiovascular events is reported to suggest the presence of an extremely susceptible cluster of elderly subjects in the population identified by the copresence of chronic obstructive pulmonary disease and cardiovascular comorbidity.
Quantitative RT-PCR analysis of activation-induced cytidine deaminase expression in tissue samples from mantle cell lymphoma and B-cell chronic lymphocytic leukemia patients
Authors: Jeroen E. J. Guikema, Stefano Rosati, Karine Akkermans, Richard J. Bende, Carel J. M. van Noesel, Johan H. van Krieken, Martin L. Hansmann, Ed Schuuring, Philip M. Kluin
Journal: Blood (2005)
Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line
Authors: Lars Petter Jordheim, Emeline Cros, Marie-Hélène Gouy, Carlos M. Galmarini, Suzanne Peyrottes, John Mackey, Christian Perigaud, Charles Dumontet
Journal: Clinical Cancer Research (2004)

Abstract Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. Various strategies to overcome resistance have been suggested, but none has yet shown efficacy in vivo. We developed a gemcitabine-resistant cell line (L1210 10K) from the murine leukemic L1210 strain (L1210 wt) by continuous exposure to increasing concentrations of gemcitabine. L1210 10K is highly resistant to gemcitabine (14,833-fold), 1-β-d-arabinofuranosylcytosine (ara-C; 2,100-fold), troxacitabine (&amp;gt;200-fold), and cladribine (160-fold) and slightly resistant to trimidox (7.22-fold), but does not display cross-resistance to fludarabine or nonnucleoside anticancer drugs. Deoxycytidine kinase mRNA was not detected by quantitative real-time reverse transcription-PCR in L1210 10K cells, whereas expression of thymidine kinase 1 and ribonucleotide reductase subunit R2 gene was moderately reduced. L1210 10K cells also demonstrated in vivo resistance to nucleoside analogues: gemcitabine- or ara-C-treated mice carrying L1210 10K had significantly shorter survival than gemcitabine- or ara-C-treated mice carrying L1210 wt (P &amp;lt; 0.05). UA911, a mononucleotide prodrug (pronucleotide) of ara-C was found to significantly sensitize L1210 10K cells in vitro. These results suggest that reduced deoxycytidine kinase expression is a mechanism of resistance to gemcitabine that is relevant in vivo and can be circumvented by a prodrug approach.
Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma
Authors: Adam L. Green, Shakti H. Ramkissoon, Dilara McCauley, Kristen Jones, Jennifer A. Perry, Jessie Hao-Ru Hsu, Lori A. Ramkissoon, Cecile L. Maire, Benjamin Hubbell-Engler, David S. Knoff, Sharon Shacham, Keith L. Ligon, Andrew L. Kung
Journal: Neuro-Oncology (2014)

Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM.Seven patient-derived GBM lines were treated with 3 SINE compounds (KPT-251, KPT-276, and Selinexor) in neurosphere culture conditions. KPT-276 and Selinexor were also evaluated in a murine orthotopic patient-derived xenograft (PDX) model of GBM. Cell cycle effects were assayed by flow cytometry in vitro and immunohistochemistry in vivo. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase 3/7 activity assays.Treatment of GBM neurosphere cultures with KPT-276, Selinexor, and KPT-251 revealed dose-responsive growth inhibition in all 7 GBM lines [range of half-maximal inhibitory concentration (IC50), 6-354 nM]. In an orthotopic PDX model, treatment with KPT-276 and Selinexor demonstrated pharmacodynamic efficacy, significantly suppressed tumor growth, and prolonged animal survival. Cellular proliferation was not altered with SINE treatment. Instead, induction of apoptosis was apparent both in vitro and in vivo with SINE treatment, without overt evidence of neurotoxicity.SINE compounds show preclinical efficacy utilizing in vitro and in vivo models of GBM, with induction of apoptosis as the mechanism of action. Selinexor is now in early clinical trials in solid and hematological malignancies. Based on these preclinical data and excellent brain penetration, we have initiated clinical trials of Selinexor in patients with relapsed GBM.
Multiple dermatomal daughter lesions of postzoster granuloma
Authors: E. Araki, N. Kambe, K. Takahashi, Y. Miyachi, A. Utani
Journal: British Journal of Dermatology (2007)

Conflicts of interest: none declared. Sir, Various cutaneous lesions are known to occur at sites of prior herpes zoster infection. Among such ‘isotopic responses’,1 granulomatous disorders are one of the most frequently reported cutaneous changes. We describe a patient with postzoster granuloma on the abdomen, who later developed additional multiple granulomatous lesions in a dermatomal pattern on the back. An 80‐year‐old woman presented with a persistent, slightly itchy dermatosis on her abdomen and back. Four years previously, she had developed painful eruptions on the right lower abdomen that had been diagnosed as herpes zoster by her physician. The initial lesions healed with no neuralgia. Two years later, slightly itchy reddish skin lesions began to appear at the same site and gradually increased in number. One month prior to her first presentation to our clinic, a similar dermatosis had started to develop at the bilateral sides of the upper back, where no preceding skin changes had ever been noted. The patient's history was negative for diabetes mellitus, malignancies or any immunological disorders.
Does conditioned suppression measure the resistance to change of operant behaviour?
Authors: Julian C. Leslie
Journal: Behavioral and Brain Sciences (2000)

Although conditioned suppression has face validity as a technique for assessing resistance to change of operant behaviour, it is not discussed by Nevin &amp; Grace. However, application of their approach to the results of a conditioned suppression study that varied food deprivation and reinforcement magnitude (Leslie 1977) produces paradoxical results.
Evidence From Human Myectomy Samples That <i>MYBPC3</i> Mutations Cause Hypertrophic Cardiomyopathy Through Haploinsufficiency
Authors: Steven Marston, O‘Neal Copeland, Adam Jacques, Karen Livesey, Victor Tsang, William J. McKenna, Shapour Jalilzadeh, Sebastian Carballo, Charles Redwood, Hugh Watkins
Journal: Circulation Research (2009)

Most sarcomere gene mutations that cause hypertrophic cardiomyopathy are missense alleles that encode dominant negative proteins. The potential exceptions are mutations in the MYBPC3 gene (encoding cardiac myosin-binding protein-C [MyBP-C]), which frequently encode truncated proteins.We sought to determine whether there was evidence of haploinsufficiency in hypertrophic cardiomyopathy caused by MYBPC3 mutations by comparing left ventricular muscle from patients undergoing surgical myectomy with samples from donor hearts.MyBP-C protein and mRNA levels were quantitated using immunoblotting and RT-PCR. Nine of 37 myectomy samples had mutations in MYBPC3: 2 missense alleles (Glu258Lys, Arg502Trp) and 7 premature terminations. No specific truncated MyBP-C peptides were detected in whole muscle homogenates of hypertrophic cardiomyopathy tissue. However, the overall level of MyBP-C in myofibrils was significantly reduced (P<0.0005) in tissue containing either a truncation or missense MYBPC3 mutation: 0.76+/-0.03 compared with 1.00+/-0.05 in donor and 1.01+/-0.06 in non-MYBPC3 mutant myectomies.The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense MYBPC3 mutations argues strongly that haploinsufficiency is sufficient to cause the disease.
Recent trends in COPD prevalence in Spain: a repeated cross-sectional survey 1997-2007
Authors: J.B. Soriano, J. Ancochea, M. Miravitlles, F. García-Río, E. Duran-Tauleria, L. Muñoz, C.A. Jiménez-Ruiz, J.F. Masa, J.L. Viejo, C. Villasante, L. Fernández-Fau, G. Sánchez, V. Sobradillo-Peña
Journal: European Respiratory Journal (2009)

We aimed to describe changes in the prevalence of chronic obstructive pulmonary disease (COPD) in Spain by means of a repeated cross-sectional design comparing two population-based studies conducted 10 yrs apart. We compared participants from IBERPOC ( Estudio epidemiológico de EPOC en España ) (n = 4,030), conducted in 1997, with those of EPI-SCAN (Epidemiologic Study of COPD in Spain) (n = 3,802), conducted in 2007. Poorly reversible airflow obstruction compatible with COPD was defined according to the old European Respiratory Society definitions. COPD prevalence in the population between 40 to 69 yrs of age dropped from 9.1% (95% CI 8.1–10.2%) in 1997 to 4.5% (95% CI 2.4–6.6%), a 50.4% decline. The distribution of COPD prevalence by severity also changed from 38.3% mild, 39.7% moderate and 22.0% severe in 1997, to 85.6% mild, 13.0% moderate and 1.4% severe in 2007, and in the 40–69 yr EPI-SCAN sub-sample to 84.3% mild, 15.0% moderate and 0.7% severe. Overall, underdiagnosis was reduced from 78% to 73% (not a significant difference) and undertreatment from 81% to 54% (p&lt;0.05) within this 10-yr frame. The finding of a substantial reduction in the prevalence of COPD in Spain is unexpected, as were the observed changes in the severity distribution, and highlights the difficulties in comparisons between repeated cross-sectional surveys of spirometry in the population.
Skin bruising in asthmatic subjects treated with high doses of inhaled steroids: frequency and association with adrenal function
Authors: A Roy, C Leblanc, L Paquette, H Ghezzo, J Cote, A Cartier, JL Malo
Journal: European Respiratory Journal (1996)

High doses of inhaled corticosteroids (ICS) (budesonide and beclo-methasone &gt; or = 800 micrograms.day-1) are commonly used in the treatment of asthma. Some investigators have presented evidence for cutaneous effects (bruising), which suggests systemic absorption. This study aimed to assess the prevalence of skin bruising, relate the occurrence of skin bruising to adrenocortical function, and determine the risk factors for skin bruising. One hundred adult asthmatic subjects taking high doses (800-2,000 micrograms.day-1) of ICS for 3 months or more were recruited in an asthma clinic, and 100 control subjects paired for sex and age were recruited from an ophthalmology out-patient clinic. A detailed questionnaire on asthma, general habits and cutaneous lesions was administered. A cutaneous examination was performed. Urine cortisol levels were assessed on two consecutive days. Blood cortisol level and the response to Cortrosyn injection (60 min test) were evaluated. One hundred adult asthmatics (66 females and 34 males), 73 on beclomethasone and 27 on budesonide, were included. The prevalence of skin bruising was 71% based on the questionnaire (32% in controls) and 48% (39 out of 81 subjects) based on direct examination of the skin. We found a satisfactory association between the response to questionnaire and examination of the skin. Adrenocortical function testing showed that a minority of subjects (14 with at least one abnormal test) had lower urinary or blood cortisol levels. These low cortisol levels occurred in subjects who reported skin bruising. By multiple logistic regression, being a female (odds ratio (OR) = 20; 95% confidence interval (95% CI) = 13-33) and taking ICS for asthma (OR = 12; 95% CI = 8-18) were significantly (t = 5.4) related to the likelihood of developing skin bruising. In addition, among the asthmatic subjects, being older (OR = 1.6; 95% CI = 1.1-2.4/10 yrs interval) (t = 2.3) and being a female (OR = 22; 95% CI = 7-75) (t = 5.0) influenced the occurrence of skin bruising as documented by questionnaire. In asthmatic subjects, taking high doses of ICS is associated with: 1) increased occurrence of skin bruising by comparison with controls, particularly in older subjects; and 2) a generally normal adrenocortical function, although this function is significantly lower in subjects reporting skin bruising.