tbuckley/cabot-search huggingface dataset:
Characteristics of De Novo Resistance to Androgen Targeting Therapeutics (Ar Tx) Through Circulating Tumor Cells (Ctcs) Analysis in Metastatic Castration Resistant Prostate Cancer (Mcrpc) Patients
Authors: R.M. Bambury, J. Louw, R. Krupa, D. Danila, Z. Arslan, N.A. Schreiber, A. Jendrisak, D. Marrinucci, R. Dittamore, H.I. Scher
Journal: Annals of Oncology (2014)
Is pulmonary rehabilitation (PR) an effective therapy in lymphangioleiomyomatosis (LAM)
Authors: Bernd Sczepanski, Sandra Winterkamp, Martina Boensch, Inga Heinzelmann, Klaus Kenn
Journal: European Respiratory Journal (2012)

Background:  LAM is an orphan lung disease affecting young women. There is an estimated prevalence of 200 patients in Germany. Beside supportive treatment of respiratory distress there are only few drug therapies (progesterone, sirolimus) of unknown effectiveness. In end-stage LAM lung transplantation (LTx) may be the only remaining therapeutic option. The role of PR is not yet defined.  Methods:  In a prospective open clinical trial data of 22 LAM patients prior to LTx (LAM-P) (45,9±9y., FEV1=31,4±17%pred, diffusion capacity=35,8±13%, paO2=59,1±9 mmHg, LTOT n=19) and 24 LAM patients after LTx (LAM-Tx) (42,8±10y., FEV1=65,7±19%pred) were evaluated. All patients underwent a specialized multidisciplinary inpatient PR for 45±9,6 (LAM-P) and 35,4±18 (LAM-Tx) days.  Results:  We found significant and clinically relevant changes for both PR approaches.  For the LAM-P group we saw a significant improvement in 6-min walking distance (6MWD) 59±50m (p  Thus the benefit of post LTx-PR in LAM-patients is comparable to the results of lung transplant patients with other underlying disease. Health-related quality of life (HRQL) (SF36) improved significantly for the mental summary score in LAM-Tx.  Lung function parameters did not change for LAM-P but FEV1 improved significantly for LAM-Tx patients.  Conclusion:  PR in LAM patients before and after LTx is a safe therapeutic approach that leads to significant increases of exercise capacity and tends to improve HRQL. In view of a progressive disease with only a few therapeutic options rehabilitation should be considered early in the treatment of LAM, especially when LTx is necessary.
Role of occupational exposure on the outcome of sinus surgery: an observational study
Authors: Valérie Hox, Stefan Delrue, Hans Scheers, Els Adams, Stephan Keirsbilck, Mark Jorissen, Peter Hoet, Jeroen Vanoirbeek, Benoît Nemery, Peter Wim Hellings
Journal: European Respiratory Journal (2011)

Background: Functional endoscopic sinus surgery (FESS) is performed in patients with recurrent acute or chronic rhinosinusitis, insufficiently controlled by medical treatment. Several endogenous and exogenous factors may be responsible for failure of FESS with persisting symptoms. The association between occupational exposure and failure of FESS is not known.

Aim: The aim of this study was to evaluate the exposure to occupational agents in patients undergoing FESS and to relate the exposure to the number of FESS procedures needed to control symptoms.

Methods: Questionnaires were sent to 890 patients who had undergone one ore more FESS procedures and to 182 control subjects. Besides general medical health questions, the questionnaire asked about professional and recreational activities and exposure levels to high and low molecular weight (HMW and LMW) occupational agents. Exposure was assessed as a binary variable. A chi-square test was used to investigate the relationship between number of FESS and exposure state. Odds ratios were calculated by a Proportional Odds Model.

Results: Occupational exposure was reported in 11.6% of the controls (n=69) and in 24.6% of FESS patients (n=467). There is a significant relationship between increasing FESS and occupational exposure (chi=12.74, p<0.001). Exposed patients had a higher risk for needing at least 1 (OR=2.45, p<0.05) or at least 2 (OR=1.63, p<0.05) FESS procedures compared to unexposed ones. Mainly LMW agents were reported as occupational substances.

Conclusions: Exposure to occupational agents is associated with higher risk of failure after primary FESS, and hence underlines the importance of occupational exposure in the postoperative healing.
Exposure to cigarette smoke affects the response of dendritic cells to pneumococcus
Authors: Olivier Le Rouzic, Gaëlle Remy, Cyrielle Jardin, Isabelle Tillie-Leblond, Muriel Pichavant, Philippe Gosset
Journal: European Respiratory Journal (2011)

Development of chronic obstructive pulmonary disease (COPD) is linked to tabagism. Acute exacerbation potentially related to infection by streptococcus pneumoniae is responsible for the progression of the disease. Innate immunity associated with dendritic cells (DC) mobilization is involved in the pathophysiology of the disease. We hypothesize that cigarette smoke impairs the response of DC to pathogens, a mechanism that may be involved in COPD progression.  Monocyte-derived DC of healthy donors were exposed to cigarette smoke extract (CSE) and next to pneumococcus (serotype 1). First, endocytosis and bactericidy of S. pneumoniae was analyzed. DC phenotype (costimulatory molecules and endocytosis receptors) and production of immunoregulatory cytokines was measured as well as the capacity of DC to activate autologous T-cells.  Our data showed that CSE exposure inhibited the pneumococcus-dependent expression of CD40, CD80 and CD86 costimulatory molecules. Similarly, proinflammatory cytokine production (IL-12 and TNF-α) was inhibited by CSE exposure. In DC/T coculture, this was associated with a decrease secretion of IL-17 and IFN-γ by T cells. Unexpectedly, this exposure to CSE increased the endocytosis of pneumococcus, whereas CD206 and CD36 expression was affected in an opposite manner. The effect of CSE was mostly related to oxidative stress since it was inhibited by addition of N-acetyl cystein.  In summary, CSE exposure impairs the capacity of DC to activate antigen-specific T-cells against pneumococcus, although it does not alter their endocytosis. These data will be conforted by the ex vivo analysis of DC phenotype in COPD patients with exacerbation.
Erythrocytes prevent inactivation of alpha 1-antitrypsin by cigarette smoke
Authors: S Mangione, F Kueppers, C Puglia, L W Greenspon
Journal: European Respiratory Journal (1991)

Red blood cells (RBC) possess strong antioxidant activity. We tested whether this activity was sufficient to prevent the oxidative inactivation of alpha 1-antitrypsin (alpha 1-AT) by cigarette smoke. We found that RBC in physiological concentrations completely prevented the inactivation of alpha 1-AT. The major erythrocytic antioxidants, catalase, superoxide dismutase and glutathione were then selectively inhibited and the RBC retested. Only the inhibition of catalase significantly impaired the protective ability of added erythrocytes. We suggest that RBC antioxidants may be an important variable in determining the degree of protection of alpha 1-AT against oxidation.
Outcomes of immunotherapy of patients with COPD
Authors: Shamil Farkhutdinov, Usman Farkhutdinov
Journal: European Respiratory Journal (2014)

Disorders in free radical processes and immune system play an important role in latent inflammatory formation in patients with COPD.  The aim was to study the production of active oxygen forms (AOF) and γ-IFN patients with COPD and the efficacy of immunomodulator inferon (IFN) in their treatment.  Methods: The study included 45 patients with moderate to severe COPD. The production of AOF in the blood of patients was studied by registration of spontaneous (SP) and staphylococcus-activated (SA) luminol dependent chemiluminescence (ChL). In addition the level of γ-IFN was determined in the blood of patients. 23 patients with COPD received standard therapy. In 22 patients with COPD IFN was added to conventional treatment.  Results: In patients with COPD SPChL of blood was lower by 2.0 times and SAChL was reduced by 1.8 times. It indicated decreased production of AOF and reduction of microbicidal potential of blood cells. The level of γ-IFN in patients blood has been found to be reduced by 2.0 times. Administration of IFN in patients with COPD increased ChL of blood and the level of γ-IFN by 1.5 times, produced positive effect on the course of the inflammation. In patients who received standard therapy ChL intensity of blood and γ-IFN content remained at a lowered level, the inflammatory process often had a prolonged course.  Conclusion: In patients with COPD IFN administration increased microbicidal potential of blood cells and the level of γ-IFN, improved the results of the treatment.
Inhibition of immunoglobulin gene rearrangement by the expression of a lambda 2 transgene.
Authors: J Hagman, D Lo, L T Doglio, J Hackett, C M Rudin, D Haasch, R Brinster, U Storb
Journal: The Journal of Experimental Medicine (1989)

The rearrangement of Ig genes is known to be regulated by the production of H and kappa L chains. To determine whether lambda L chains have a similar effect, transgenic mice were produced with a lambda 2 gene. It was necessary to include the H chain enhancer, since a lambda gene without the added enhancer did not result in transgene expression. The lambda 2 transgene with the H enhancer was expressed in lymphoid cells only. The majority of the B cells of newborn transgenic mice produced lambda, whereas kappa + cells were reduced. Concomitantly, serum levels of kappa and kappa mRNA were diminished. By 2 wk after birth the proportion of kappa-expressing cells was dramatically increased. Adults had reduced proportions of B cells that produced lambda only, but the levels of lambda were still higher than in normal littermates. Also, kappa + cells were still lower than in normal mice. Analysis of hybridomas revealed that reduction of kappa gene rearrangement was the basis for the decreased frequency of kappa + cells. Furthermore, many cells also contained an unrearranged H chain allele. It was concluded that feedback inhibition by the lambda 2 together with endogenous H protein may have inhibited recombinase activity in early pre-B cells, leading to inhibition of both H chain and kappa gene rearrangement. Thus, lambda 2 can replace kappa in a feedback complex. The levels of serum lambda 1 and, to a lesser degree, of spleen lambda 1 mRNA were reduced in the lambda 2 transgenic mice. However, the proportion of hybridomas with endogenous lambda gene rearrangement was at least as high as in normal mice. It was therefore concluded that the suppression of functional lambda 1 may be a consequence of decreased selection of endogenous lambda-producing cells because of the excess of transgenic lambda. The escape of kappa-producing cells from feedback inhibition may be the result of several mechanisms that operate to varying degrees, among them: (a) kappa rearrangement during a period in which the recombinase is still active after appearance of a lambda 2/mu stop signal; (b) a B cell lineage that is not feedback inhibited at the pre-B cell stage; (c) subthreshold levels of transgenic lambda 2 in some pre-B cells; and (d) loss of the lambda 2 transgenes in rare pre-B cells.
Peritoneal Plasmacytomagenesis in Mice: Comparison of Different Pristane Dose Regimens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M Potter, J S Wax
Journal: JNCI Journal of the National Cancer Institute (1983)

Plasmacytomas were induced in inbred BALB/cπ mice by the ip injection of pristane with 4 different dose schedules. Three 0.5-ml doses (1.5 ml) given at 2-month intervals gave an average yield of 61% plasmacytomas in 6 experimental groups with a range from 51 to 71%; a single 1-ml dose gave an average yield of 42% plasmacytomas in 5 experimental groups with a range from 37 to 45%; and a single 0.5-ml dose gave an average of 22% from 3 experiments involving young mice with a range from 14 to 26%. Two 0.5-ml doses given at various intervals from 14 to 300 days gave yields of plasmacytomas that usually but not always were greater than that obtained with a single 0.5-ml dose of pristane. When the second injection of pristane was delayed as long as 180 days, a strong additive effect over that observed with 0.5 ml alone was obtained. The plasmacytomas developed in mice given the second dose 180 days after the first, with virtually the same latent period as observed with a single 1 -ml dose. No plasmacytomas were found in 200 BALB/cπ mice inoculated with corn oil, aluminum hydroxide, or very small doses of pristane (i.e., 0.05 ml). The minimal latent period for plasmacytoma development is about 120 days. The median latent period ranged from 180 to 250 days in the groups of mice that received 3 0.5-ml injections of pristane. In a single experiment pristane freed of UV-absorbing materials was as potent as commercial grade pristane in inducing plasmacytomas.
Airway Remodeling in Preschool Children with Severe Recurrent Wheeze
Authors: Guillaume Lezmi, Philippe Gosset, Antoine Deschildre, Rola Abou-Taam, Bruno Mahut, Nicole Beydon, Jacques de Blic
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Airway wall structure in preschoolers with severe recurrent wheeze is poorly described.To describe airway wall structure and inflammation in preschoolers with severe recurrent wheeze.Flexible bronchoscopy was performed in two groups of preschoolers with severe recurrent wheeze: group 1, less than or equal to 36 months (n = 20); group 2, 36-59 months (n = 29). We assessed airway inflammation, reticular basement membrane (RBM) thickness, airway smooth muscle (ASM), mucus gland area, vascularity, and epithelial integrity. Comparisons were then made with biopsies from 21 previously described schoolchildren with severe asthma (group 3, 5-11.2 yr).RBM thickness was lower in group 1 than in group 2 (3.3 vs. 3.9 μm; P = 0.02), was correlated with age (P < 0.01; ρ = 0.62), and was higher in schoolchildren than in preschoolers (6.8 vs. 3.8 μm; P < 0.01). ASM area was lower in preschoolers than in schoolchildren (9.8% vs. 16.5%; P < 0.01). Vascularity was higher in group 1 than in group 2 (P = 0.02) and group 3 (P < 0.05). Mucus gland area was higher in preschoolers than in schoolchildren (16.4% vs. 4.6%; P < 0.01). Inflammatory cell counts in biopsies were not correlated with airway wall structure. ASM area was higher in preschoolers with atopy than without atopy (13.1% vs. 7.7%; P = 0.01). Airway morphometrics and inflammation were similar in viral and multiple-trigger wheezers.In preschoolers with severe recurrent wheeze, markers of remodeling and inflammation are unrelated, and atopy is associated with ASM. In the absence of control subjects, we cannot determine whether differences observed in RBM thickness and vascularity result from disease or normal age-related development.
Experimental hypoxia-induced pulmonary hypertension is prevented by moderate exercise training in mice
Authors: Dorothea Peters, Christina Klöpping, Karsten Krüger, Christian Pilat, Sushmita Katta, Michael Seimetz, Hossein Ardeschir Ghofrani, Ralph Schermuly, Werner Seeger, Friedrich Grimminger, Frank Mooren, Norbert Weissmann
Journal: European Respiratory Journal (2011)

Pulmonary hypertension (PH), a progressive disease of multifactorial etiology, has a poor prognosis and results in right heart dysfunction. PH is characterized by pulmonary vasoconstriction and abnormal vascular remodeling processes. Current medication does not cure the disease; at best disease progression can be mitigated. Main symptoms of PH are fatigue and shortness of breath. Thus, exercise training has been considered as counterproductive in the past. In our study, moderate exercise training prevented pulmonary vascular disease in a mouse model of hypoxia-induced pulmonary hypertension. During 21 days of exposure to hypoxia mice were trained on a treadmill, daily, for five days a week. Readouts were maximum walking distance, maximum oxygen uptake (VO2 max), right ventricular systolic pressure (RVSP), measured continuously by telemetry, right ventricular mass in relation to the left ventricle and septum, and small vessel muscularization. Treatment with sildenafil in combination with training improved the maximum walking distance compared to non-trained control mice. Placebo-treated trained mice in hypoxia showed a significant increase of VO2 max, the effect being similar to the effect of sildenafil. RVSP was reduced to a healthy level in placebo-treated trained mice; small vessel muscularization was reduced to a similar degree as with sildenafil-treatment only. Chronic hypoxia induced a significant hypoxia-induced upregulation of PDE5 in whole-lung homogenate, which was absent in trained mice. Overall, our data demonstrate the efficacy of exercise training for prevention of hypoxia-induced pulmonary hypertension, which might be mediated by inhibition of PDE5 upregulation.
Lipid metabolism in human platelets
Authors: Philip W. Majerus, M. B. Smith, G. H. Clamon
Journal: Journal of Clinical Investigation (1969)

Extracts from human platelets contain the enzymes of de novo fatty acid biosynthesis. The pattern of incorporation of acetate-1-14C into fatty acids by intact platelets indicates that these enzymes function in platelets. The level of acetyl-coenzyme A (CoA) carboxylase activity in extracts of platelets from normal subjects is 0.036 ±0.01 mμmole of malonyl-CoA formed per min per mg of protein and that of fatty acid synthetase is 0.075 ±0.016 mμmole of malonyl-CoA utilized per min per mg of protein. Thus, platelets are the only formed elements of the blood capable of de novo fatty acid synthesis. The capacity of platelets to synthesize fatty acids is similar to human liver based on enzyme activity per milligram of soluble protein.
Assessment of diaphragmatic function by ultrasonography (US) and opto-electronic plethysmography (OEP) in patients with Duchenne muscular dystrophy (DMD)
Authors: Marianna Laviola, Rita Priori, Marianna Romei, Maria Grazia D'Angelo, Andrea Aliverti
Journal: European Respiratory Journal (2013)

Variations of diaphragmatic thickness (DT) and excursion (DE) during different respiratory maneuvers can be measured by B- and M-mode US. To verify if and how these parameters provide useful insights for functional assessment in DMD, DT was measured in 44 DMD patients (age 16.3±4.6yrs, FVC 53.4±24.6 %pred) during quiet breathing (QB), inspiratory capacity (IC) and maximal inspiratory pressure (MIP) and DE in 21 DMD (age 14.9±4.6yrs, FVC 55.6±19.9 %pred) during QB and IC. On the same patients, corresponding changes in abdominal volume (Vab) were measured by OEP during QB and IC.  In older DMD patients (>18 yrs) DT variation was higher and MIP lower compared to younger during MIP. Conversely, DE was not influenced by age. Vab variations during QB and IC were also similar between younger and older patients. In all patients a significant linear correlation (r 2 =0.618, p 2 =0.015, p=ns) (see fig.).  In conclusion, DT and DE are estimates of the level of diaphragm contraction and displacement, respectively. In addition, Vab can be considered an optimal index of diaphragm length and changing length. In older DMD patients a dissociation occurs between the drive to the muscle and the development of muscle strength.
Pre-clinical characterization of RP3128, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders
Authors: Swaroop Vakkalanka, Gayatriswaroop Merikapudi, G. Babu, Kasiviswanath Routhu, Sridhar Veeraraghavan, Srikant Viswanadha
Journal: European Respiratory Journal (2013)

Introduction: Calcium release activated calcium channels inhibitors have a potent role in treatment of autoimmune disorders mediated dysregulated T-lymphocyte and mast cell functioning. Herein, we describe the pre-clinical profile of RP3128, a novel and potent CRAC channel inhibitor with scope for development as a clinical candidate for asthma.

Methods: Inhibition of CRAC channel activity in Jurkat cells, cytokine release from human whole blood or PBMC, and mast cell degranulation were estimated. In vivo efficacy of the compound was determined in experimental models of asthma in guinea pigs including PAF or ovalbumin induced eosinophil infiltration into lungs ovalbumin induced histamine release from mast cells, and airway hyper-responsiveness.

Results: RP3128 significantly inhibited ICRAC (103 nM) as well as calcium entry into Jurkat cells (40 nM) besides reducing IL-4 (<400 nM) and IL-5 (<250 nM) release from human whole blood and PBMC and IgE-induced RBL-2H3 cell degranulation (24 nM). Oral administration of RP3128 in guinea pigs resulted in a dramatic reduction in eosinophil infiltration in an acute model of PAF-induced allergic asthma (ED50 = 0.4 mg/kg/p.o) as well as in an experimental model of ovalbumin-induced chronic airway inflammation (ED50 = 0.6 mg/kg/p.o). Consistent with in vitro findings, the compound caused a significant inhibition of mast cell degranulation in Balb/c mice manifested by a reduction in histamine release (ED50 = 0.6 mg/kg/p.o).

Conclusions: Results demonstrate the potential of RP3128 as an anti-asthmatic agent as evidenced from pre-clinical data. Toxicological evaluation of the molecule is currently in progress.
Partially Mismatched Related-Donor Bone Marrow Transplantation for Pediatric Patients With Acute Leukemia: Younger Donors and Absence of Peripheral Blasts Improve Outcome
Authors: K.T. Godder, L.J. Hazlett, S.H. Abhyankar, K.Y. Chiang, N.P. Christiansen, K.D. Bridges, C.G. Lee, S.S. Geier, K.S. Goon-Johnson, A.P. Gee, A.R. Pati, R.S. Parrish, P.J. Henslee-Downey
Journal: Journal of Clinical Oncology (2000)

To extend access to bone marrow transplantation (BMT), we used partially mismatched related donors (PMRD) for pediatric patients with acute leukemia. In this report we sought to determine pretransplantation factors that might predict outcome.Of 67 such patients, 43 had acute lymphocytic leukemia and 24 had acute myelogenous leukemia. At the time of transplantation, 41 patients were in relapse. Donors included 40 parents, 24 siblings, and three cousins. HLA disparity of two to three major antigens was detected in two thirds of the donor-recipient pairs. Conditioning therapy, including total-body irradiation and chemotherapy followed by graft-versus-host disease (GvHD) prophylaxis with partial T-cell depletion of the graft using T10B9 or OKT3, was combined with posttransplantation immunosuppression.Estimated probability (EP) of engraftment was 0.96 and was not affected by donor-antigen mismatch (AgMM; P =.732). EP of grades 2 to 4 acute GvHD was 0.24 and was not affected by recipient AgMM (P =.796). EP of disease-free survival was 0.26 at 3 years but improved to 0.45 when donors were younger than 30 years (P<.001). EP of relapse at 3 years was 0.41 and reduced with younger donors' age. For patients who were in relapse at the time of transplantation, absence of blasts was associated with a lower relapse rate (0.46 v. 0.84; P =. 083), similar to that of patients in remission.PMRD-BMT in pediatric leukemia resulted in high engraftment and low GvHD rates. To improve outcomes, younger donors should be sought, and clinicians should attempt to reduce peripheral blasts in patients who are in relapse.