tbuckley/cabot-search huggingface dataset:
Expression of the Bcl-2 binding protein beclin 1 in human idiopathic pulmonary fibrosis
Authors: Davide Scozzi, Salvatore Mariotta, Emanuela Cherubini, Vittorio Pietrangeli, Manuela Del Forno, Luca Tabbì, Lara Pisani, Pierdonato Bruno, Alberto Ricci
Journal: European Respiratory Journal (2011)

Autophagy is the main cellular route for degradation of long-lived proteins and cytoplasmic organelles and its dysregulation contributes to the pathogenesis of different disease. In some settings it seems to be interconnected with apoptosis. In this regard the binding of the anti-apoptotic protein Bcl-2 with a key regulator of autophagy as Beclin 1 seems to down-regulate both apoptosis and autophagy. It is known that fibroblasts in idiopathic pulmonary fibrosis (IPF) acquire resistance to apoptosis but no data are available about the regulation of autophagy in IPF. Here we examined the expression of Beclin 1 and Bcl-2 in human IPF fibroblasts before and after cisplatin exposure.  We performed immunohistochemistry for Beclin 1 on sections of lung biopsies obtained from patients affected with IPF (n=25) histologically normal (n=5) or with emphysema (n=5). In 4 IPF, 2 normal and 2 emphysema the tissue was used to isolate lung fibroblasts. We performed Western Blot analysis and co-immunoprecipitation for Bcl2 and Beclin 1 on cultured fibroblasts before and after cisplatin exposure.  Expression of Beclin 1 in fibroblasts from IPF was down-regulated in comparison with normal and emphysema while the anti-apoptotic protein Bcl-2 was over-expressed. Treatment of fibroblast cell cultures with cisplatin induced a significant increase in Beclin 1 but a reduction in Bcl-2 expression in IPF fibroblasts. The immunoprecipitation of Bcl-2 and the following immunodetection of Beclin 1 indicate that Bcl-2 is mainly bound to Beclin 1.  The modified expression of Beclin 1 and Bcl-2 in human IPF fibroblasts in comparison with normal ones seems to suggest the possibility of an autophagic/apoptosis system dysfunction.
Translating clinical activity and gene expression signatures of etanercept and ciclosporin to the psoriasis xenograft SCID mouse model
Authors: H. Norsgaard, L. Svensson, P.H. Hagedorn, K. Moller, G.M. Olsen, T. Labuda
Journal: British Journal of Dermatology (2011)

The psoriasis xenograft severe combined immunodeficiency (SCID) mouse model is used in drug discovery to obtain preclinical proof-of-principle of new antipsoriatic drug candidates. Validation of this model by antipsoriatic therapeutic agents in clinical use is important to understand its utility as well as its limitations. The effects of the clinically efficacious antitumour necrosis factor-α biologics have not yet been demonstrated in the psoriasis xenograft SCID mouse model.To investigate the effect of etanercept and to explore the time-dependent changes induced by ciclosporin on psoriatic biomarkers at the gene expression level in the psoriasis xenograft SCID mouse model.Xenografted SCID mice were treated either with etanercept and vehicle for 2 weeks or with ciclosporin and vehicle for 2 and 4 weeks, respectively. Treatment-induced changes in the psoriatic grafts were assessed by gene expression analysis and compared with published clinical microarray data. The grafts were further evaluated by histology and immunohistochemistry.Etanercept induced normalization of gene expression, which correlated with a significant reduction in epidermal thickness as well as a decrease in the number of proliferative cells. Anti-inflammatory activity induced by ciclosporin preceded the reduction in epidermal hyperplasia. Comparison of the etanercept- and ciclosporin-induced gene expression signatures with clinical microarray data showed significant correlations.Efficacy of etanercept and ciclosporin could be translated to the psoriasis xenograft SCID mouse model.
Stability and achievement of asthma control with higher doses of inhaled conticosteroids regular treatment
Authors: Shih-Lung Cheng
Journal: European Respiratory Journal (2011)

Background/purpose:  Uncontrolled asthma is characterized by variability. Previous GOAL study demonstrated that once asthma is achieved, the future risk of instability is greatly reduced. Higher stability (lower variability) in asthma control is also associated with a lower future possibility of unscheduled healthcare resource use. In the study, we attempted to increase inhaled combined agent doses initially and hypothesized that stability was positively associated with the level of control achieved.   Methods:  This was a prospective study and new diagnosed asthma patients were included and randomized into two groups. One group was treated with higher doses (HD) one month then shifted to guideline-practice (GP) treatment and another was treated with GP therapy model. Peak expiratory flow (PEF), asthma control test (ACT) and exacerbation times were measured. The follow-up time was 1/2 year.   Results:  39 patients were treated with HD and 40 patients were GP therapy policy. PEF change were significantly improved in HD group compared with GP (56±17 vs. 45±19, p=0.04). The obvious improvement especially in initial 2 months (77±39 vs. 52±23, p=0.01). There were significantly differences in ACT change and exacerbation frequency in patients with mild and moderate persistent asthma using HD therapy.   Conclusion:  Our findings demonstrated that patients with HD treatment were more improved and stabilized than patients with previous conventional therapy policy. Further evaluation should be performed more patients and long term follow-up to confirm the higher doses9 efficiency.
Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease
Authors: Rafael León, Antonio G. Garcia, José Marco‐Contelles
Journal: Medicinal Research Reviews (2011)

With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one‐compound‐one‐target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium‐permeable channels such as voltage‐dependent calcium channels, N ‐methyl‐ D ‐aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one‐compound‐various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD. © 2011 Wiley Periodicals, Inc. Med Res Rev
A dose intensity study of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy and Escherichia coli-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) in advanced breast cancer patients
Authors: J.A. O’Shaughnessy, A.M. Denicoff, D.J. Venzon, D. Danforth, L.J. Pierce, J.N. Frame, A. Bastian, B. Ghosh, B. Goldspiel, L. Miller, F.A. Dorr, P. Keegan, N. Ben-Bamch, H. Mrose, M. Noone, K.H. Cowan
Journal: Annals of Oncology (1994)

It has been demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) can ameliorate chemotherapy-induced neutropenia. The extent to which GM-CSF can increase the actual delivered dose intensity of combination chemotherapy over multiple cycles of therapy to patients with advanced breast cancer has not been well defined. We conducted a phase I/II study of dose-intensive FLAC chemotherapy (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) in combination with GM-CSF in patients with locally advanced and metastatic breast cancer to study the acute and cumulative toxicities, anti-tumor activity and dose-intensity achievable with this regimen.Eighty-one patients with newly diagnosed stages IIB, III and IV breast cancer who were previously untreated with chemotherapy and who had measurable disease received multiple cycles of FLAC chemotherapy plus E. coli-derived GM-CSF administered every three weeks.FLAC plus GM-CSF as associated with significant cumulative hematologic toxicity. Ninety-eight percent of patients developed grade 4 neutropenia; 29% of all cycles administered required hospitalization for fever and neutropenia; 41% and 22% of cycles required red blood cell and platelet transfusions, respectively. Other significant toxicities with E. coli-derived GM-CSF included mild to moderate first dose effects (hypotension, dyspnea, abdominal cramping) in 30% of patients; late occurring anaphylactoid reactions in 11% of patients; and vascular thromboses. The average delivered dose intensities over all cycles were cyclophosphamide, 210 mg/m2/week; doxorubicin, 14.8 mg/m2/week and 5-fluorouracil, 342 mg/m2/week. The overall clinical response rates were 100% and 83% for LABC and metastatic patients, respectively. There were 23% (6/26) pathologic CR's in the LABC patients given neoadjuvant FLAC and 22% (12/54) clinical CR's in the stage IV patients. The median survival of the LABC patients has not been reached (> 26 months) and is 30 months for the stage IV patients.The administration of multiple cycles of FLAC plus E. coli-derived GM-CSF therapy is associated with cumulative, dose-limiting myelosuppression, especially thrombocytopenia, as well as significant clinical toxicity. A modest increase in FLAC dose intensity over the starting doses was achievable with the addition of GM-CSF. FLAC chemotherapy has substantial antitumor activity in the treatment of advanced breast cancer. The potential usefulness of FLAC plus GM-CSF must be balanced by its considerable cost and alteration in patients' quality of life due to toxicity. Combination hematopoietic growth factor strategies may be able to reduce the toxicity of FLAC and to allow further increase dose intensity.
The relationship between testosterone, obesity and depressive mood in obstructive sleep apnea (OSA) postmenopausal women
Authors: Raluca Mihaela Bercea, Elena Cojocaru, Traian Mihaescu
Journal: European Respiratory Journal (2011)

Background:  The relationship between respiratory sleep disorders and menopausal state in women is not well supported; only known that obese female have higher androgen levels then non-obese females.   Aim:  The aim of our study was to illustrate the link between OSA severity, serum total testosterone level and depressive mood in obese postmenopausal women.   Material and method:  The present study included 13 severe OSA female patients (apnea hypopnea index (AHI) >30 events/h) with obesity (body mass index (BMI) >30 kg/m 2 ), ages between 53 and 60 years, for least two years of amenorrhea. All patients fulfilled Beck Depression Inventory (BDI). Serum total testosterone level (T) was performed from blood samples collected in the morning after wake up. Control group selected consisted in 10 non-OSA females with same characteristic with study group.   Results:  We found significant correlations between T level and BMI (r=0.636, p=0.019), without correlation between T level and AHI or BDI (p>0.05). It was remarked a strong positive correlation between BDI score and AHI (r=0.720, p=0.006). T-test shows no differences between two groups in testosterone level (OSA group 0.757±0.28 ng/dl vs. non-OSA group 0.625±0.19 ng/dl, p=0.226), but significant differences for BDI score (OSA 9.69±5.15 vs. non-OSA 4.3±2.16, p=0.005).   Conclusion:  Our study reveals no effect relationship between OSA severity and serum testosterone level. Testosterone level is positive correlated with obesity. Depressive mood is induced by OSA severity, without relation with testosterone level. More approaches are needed to elucidate androgens involvement in severe OSA postmenopausal women.
Abstract 15352: ELABELA/Toddler, a Critical Regulator of Cardiac Development, is Expressed in the Human Cardiovascular System and Binds the Apelin Receptor
Authors: Peiran Yang, Janet J Maguire, Rhoda E Kuc, Keith Siew, Lalarukh Haris Shaikh, Rubben Torella, Robert C Glen, Anthony P Davenport
Journal: Circulation (2014)

Introduction: ELABELA/Toddler (ELA) (a.k.a. Ende/APELA), a recently identified peptide from a previously designated non-coding region, is expressed in human stem cells and is reported to regulate zebrafish cardiac development. Hearts fail to develop after ELA gene deletion, phenocopying apelin receptor knock-outs. Dibasic cleavage sites predict the expression of 3 isoforms; ELA-32, ELA-21 and ELA-11. Binding of ELA to the human apelin receptor, expression of ELA in the human cardiovascular system, and the functional role of ELA in vivo have not been determined. Hypothesis: We hypothesised ELA is a ligand for the apelin receptor, endogenously expressed in adult human heart and vessels, and attenuates AngII induced pressor responses. Methods: Peptides were tested in [125I]apelin-13 competition assays. RT-qPCR and immunocytochemistry with selective antisera were performed in adult human normal cardiovascular tissues (IRB approval). The attenuation of AngII (1μg/kg iv)-induced rise in blood pressure by ELA-32...
Characterization of Three Human Cell Lines by Chromosomal Complement and by Certain Biochemical Parameters. Reversible Alteration of Isozyme Patterns by Different Media&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: James L. German, Virginia J. Evans, Jean A. Cortner, Benton B. Westfall
Journal: JNCI Journal of the National Cancer Institute (1964)

Three aneuploid epithelium-like cell lines, maintained in vitro for 7 to 12 years and under identical cultural conditions in chemically defined medium for 20 to 60 months, have been characterized by multiple parameters. The lines were: (a) NCTC 3075 (from human skin), (b) NCTC 3354 (from human bone), and (c) NCTC 3952 (from human uterine cervical carcinoma, the S3 clone of HeLa). The parameters were: (a) growth characteristics, (b) nutritional requirements, (c) chromosomal complement, (d) glycogen production, (e) phosphatase activity, (f) arginase activity, (g) lactate dehydrogenase (LDH) isozyme pattern, and (h) response of LDH isozyme pattern to alteration of the environment in vitro. Each line differs from the other two in at least three ways. Nutritional requirements differentiate the HeLa line from the other two. The skin line differs from the bone and HeLa by having the highest alkaline phosphatase activity and the highest glycogen content. The isozyme pattern of HeLa shows a prominent LDH 1 and a very faint LDH 5; when serum is added to the growth medium the pattern changes, LDH 1 almost disappearing and LDH 5 increasing in intensity. Removal of serum from the growth medium occasions a return to the original pattern. The isozyme patterns of skin and bone growing in serum-free medium resemble each other but are clearly different from HeLa. In comparison to HeLa, skin and bone show a distinct but less striking change of pattern when transferred to the serum-containing medium. Finally, the chromosomal complement of each of the three lines is characteristic with its own modal number (skin 72, bone 66, HeLa 70) and certain structurally distinctive chromosomes.
Fine Structure of Bowen's Disease in Chronic Arsenicalism2
Authors: Shu Yeh, H.C. Chen, S.W. How, C.S. Deng
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Fine Structure of Bowen's Disease in Chronic Arsenicalism Get access Shu Yeh, M.D., Shu Yeh, M.D. 3Department of Pathology, National Taiwan University, Taipei, Taiwan, Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar H.C. Chen, M.D., H.C. Chen, M.D. 3Department of Pathology, National Taiwan University, Taipei, Taiwan, Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar S.W. How, M.D., S.W. How, M.D. 3Department of Pathology, National Taiwan University, Taipei, Taiwan, Republic of China Search for other works by this author on: Oxford Academic PubMed Google Scholar C.S. Deng C.S. Deng 4Department of Dermatology, National Taiwan University Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 53, Issue 1, July 1974, Pages 31–44, https://doi.org/10.1093/jnci/53.1.31 Published: 01 July 1974 Article history Received: 07 December 1973 Accepted: 25 March 1974 Published: 01 July 1974
Moloney Murine Sarcoma Virus Oncogenesis in T-Lymphocyte-Deprived Mice: Biologic and Immunologic Studies&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Dino Collavo, Paola Zanovello, Elisabeth Leuchars, Antony J. S. Davies, Luigi Chieco-Bianchi, Giovanni Biasi
Journal: JNCI Journal of the National Cancer Institute (1980)

CBA mice, selectively deprived of T-lymphocytes by adult thymectomy, X-irradiation, and syngeneic bone marrow injection, have a high susceptibility to Moloney murine sarcoma virus (M-MuSV) oncogenesis. These mice developed nonregressing tumors after they had received injections of the virus either im or intradermally (id) and in various concentrations. The time to tumor induction was inversely proportional to the amount of virus injected. After iv inoculation of the virus, deprived mice usually developed sarcomas in various soft tissues of the body. The importance of the T-cells in affording protection was further confirmed by the observation that lymph node cells depleted of T-cells were unable to prevent tumor development in the deprived inoculated mice. A protective effect of T-cells could be provided by transfer of as few as 0.25×106 lymphoid cells. The effect was long-lasting because comparable results were obtained when deprived mice were given injections of graded numbers of cells immediately or 60 days before M-MuSV inoculation. When spleen cells from M-MuSV immune donors (i.e., deprived mice protected with lymph node cells before M-MuSV inoculation) were transferred into deprived mice 10 days before the M-MuSV injection, the protective effect depended on the presence of T-cells within the cell inoculum; B-cells apparently were unable to prevent tumor development. In addition, when normal and deprived mice were given id injections of M-MuSV and their tumors were excised, normal mice were resistant to a second M-MuSV challenge, whereas deprived mice developed tumors. Tumor-bearing deprived mice could be cured by transfer of immune lymph node cells from M-MuSV tumor regressor mice.
Vitamin B or L-arginine supplementation in hyperhomocysteinaemia: think twice!: EXPERT'S PERSPECTIVE
Authors: J.-L. Balligand
Journal: Cardiovascular Research (2012)

This editorial refers to an article by K. Sydow et al.3 published in Cardiovascular Research in 2003. It is accompanied by a retrospective editorial by two of the authors of that original article, K. Sydow and R.H. Bo¨ ger, pp. 167–171, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research.
Invasion and Metastasis of a Xenogeneic Tumor in Nude Mice2
Authors: Henry Maguire, Henry C. Outzen, R. Philip Custer, Richmond T. Prehn
Journal: JNCI Journal of the National Cancer Institute (1976)

When aliquots of a malignant hamster tumor were transplanted to nude mice and to hamsters, the tumor showed 1) more rapid growth in the hamster, 2) local invasion and metastasis in both species, and 3) occasional spontaneous regression in the nude mouse.
What determines the quality of spirometry in primary care
Authors: Michal Bednarek, Dariusz Kaminski, Teresa Rayska, Witold Pobozy, Barbara Gebala-Jarocka, Marzena Zaluska, Mariola Kumanska, Grzegorz Augustyniak, Dorota Gorecka
Journal: European Respiratory Journal (2013)

Aim: To assess the determinants of good quality spirometry in primary care.

Methods: In 6 primary care centers spirometric tests performed during 1 year were assessed in relation to quality by reference respiratory clinic. Spirometry was assumed good quality when all ATS criteria were met.

Results: A total number of 3.074 spirometric tests were analyzed. ATS quality criteria were met in 62.1% of examinations. Subjects who met ATS criteria had longer education history (11.0±3.4 vs 10.4±3.7 yr, p<0.001). ATS quality criteria were met in 45.6%, 58.6%, 64.2% and 67.7% in subjects with none, primary, secondary and higher education level, respectively (p<0.001). Effects of gender, reversibility testing and previous experience with spirometry are shown in table. There was also a bias between centers in fulfilling ATS quality criteria in a range from 53.8 to 72.9% (p<0.001).

View this table:



Conclusions: Females, subjects better educated and previously experienced with spirometry achieved significantly better quality of spirometry. Repeating the spirometric examination together with staff training is essential to perform a good quality spirometry in primary care.

Supported by: National Science Centre grant #N N404 0818343.
Can quantitative computed tomography (QCT) differentiate between asthma & COPD in patients with similar degrees of airflow limitation?
Authors: Ruth Hartley, Bethan Barker, Mini Pakkal, Chris Newby, Salman Siddiqui, Chris Brightling, Sumit Gupta
Journal: European Respiratory Journal (2014)

Background: Airflow limitation is seen in COPD & asthma.

Aim: Using QCT we sought to determine differences between asthma and COPD subjects grouped by airflow limitation.

Material & Methods: COPD (n=81), asthma (n=171) & healthy (n=49) subjects had clinical & physiological characterization. COPD & Asthma subjects were split based on FEV1% predicted; Group 0>80%, Group 1 50-80% and Group 2<50%. QCT included average lumen area of segmental bronchi corrected for body surface area (LA/BSA), mean lung density expiratory/inspiratory ratio (MLDE/I), 15th percentile point (Perc15) & fractal dimension of low attenuation clusters in inspiration (LAC-D-950).

Results: Asthmatics with moderate airflow limitation have smaller median (IQR) LA/BSA (mm2/m2) when compared to asthmatics with no airflow limitation & COPD with moderate airflow limitation; 9.28[8.28-10.83] v11.15[9.56-13.04]; 11.32[9.63-13.33],p<0.05 respectively. Perc15 is not significantly different between asthmatics with severe airflow limitation & COPD with moderate airflow limitation;-955[-966 to -949] v-958[-971 to -947]HU respectively, but is significantly different (p<0.05) between asthmatics with no airflow limitation & healthy controls. However LAC-D-950 is significantly different between asthmatics with severe airflow limitation & COPD groups 1 & 2; 1.91[1.87-1.96] v1.85[1.78-1.92]; 1.81[1.72-1.89],p<0.05 respectively.

Conclusion: Asthmatics with moderate airflow limitation show LA/BSA narrowing compared to spirometrically similar COPD. QCT measured Emphysema may be overestimated in asthmatics with severe airflow limitation as LAC-D-950 remains different between them and COPD.

Funded by AirPROM.