tbuckley/cabot-search huggingface dataset:
A phase II, randomised, placebo controlled trial of 12 weeks treatment with an oral p38 inhibitor in patients with COPD on a background of ICS/LABA
Authors: Robert Fogel, Kathleen Shields, Jared Christensen, Jakob Ribbing, Grant Langdon, Christelle Perros-Huguet, Nicholas Clarke
Journal: European Respiratory Journal (2013)

Despite the recognized role of pulmonary inflammation in the pathogenesis of the disease, anti-inflammatory drugs have demonstrated only limited efficacy in COPD. Inhibitors of the p38 MAP kinase may have an important role in treating inflammation in COPD. Here we extend previous findings (MacNee et. al. Eur Resp J 2010 36Suppl 54 718s) to report the effect of a novel oral p38 inhibitor (PH-797804) on top of a background of salmeterol/fluticasone.

377 subjects with moderate-severe COPD, currently on stable doses of ICS/LABA combination were randomized to receive either 6 mg of oral PH-797804 or placebo once daily orally for 12 weeks. Baseline trough FEV1 was similar in both groups (0.50 -2.92L). Over the 12 week treatment period, trough FEV1 demonstrated an improvement in PH-797804 treated subjects compared with placebo; at 12 weeks, statistically significant effects (mean ± SE) of 27 ± 18 mL was noted. The average difference from placebo over the 12 week treatment period was 31 mL. A statistically significant increase was observed on the Transitional Dyspnea Index at 12 weeks (0.57 ± 0.28 points). hs-C-reactive protein showed a decrease at week 2 that was consistent throughout the dosing period, indicating maintenance of the anti-inflammatory effect.

PH-797804 was generally safe and well tolerated. The rate of discontinuations due to adverse events was somewhat higher in PH-797804 treated patients. Mild-moderate rash was observed in approximately 8% of PH-797804 treated patients.

Our findings suggest that p38 inhibition could represent a potentially useful anti-inflammatory treatment for COPD.Study Sponsored by Pfizer.
Specificity of Human Antibodies to Intracytoplasmic Type-A Particles of the Murine Mammary Tumor Virus
Authors: Martin Müller, Stefan Zotter, Christa Kemmer
Journal: JNCI Journal of the National Cancer Institute (1976)

Large-scale studies showed that antibodies previously detectable in women with proliferating mastopathy or breast cancer were directed to intracytoplasmic type-A particles (iAp) of mouse mammary tumor virus. Immunofluorescence revealed the human antibodies to be bound only by those tumors producing a certain amount of iAp clusters visible by light microscopy. The intensity of the reaction corresponded to the iAp content of every tumor tested as revealed by electron microscopy and rabbit antisera to iAp. The fluorescence patterns obtained with positive human sera were similar to those obtained with rabbit antisera specific for iAp and resembled the tissue distribution patterns of iAp inclusions stained by acid fuchsin. The reaction with human sera was entirely blocked by rabbit antisera to iAp and, less so, by rabbit or mouse antisera to B particles. The human antibody activity was exhaustively absorbed by purified iAp or purified and disrupted B particles, which indicated that the human antibodies were directed to antigenic components shared by iAp and B particles. Preliminary immunoperoxidase studies supported the assumption that the human antibodies were bound to the iAp membrane; technical details might have accounted for the finding that the human antibodies reacted with the iAp but not with B particles in situ.
Treatment of Brain Metastases of Small-Cell Lung Cancer: Comparing Teniposide and Teniposide With Whole-Brain Radiotherapy—A Phase III Study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group
Authors: Pieter E. Postmus, Hanny Haaxma-Reiche, Egbert F. Smit, Harry J. M. Groen, Hanna Karnicka, Tadeusz Lewinski, Jan van Meerbeeck, Mario Clerico, Anna Gregor, Desmond Curran, Tarek Sahmoud, Anne Kirkpatrick, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m 2 was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P &lt; .001). Time to progression in the brain was longer in the combined-modality group (P = .005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P = .087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different.
Corticosteroid-dependent transcription is reduced by inflammatory stimuli in human airway epithelial cells: Rescue by long-acting β2-adrenoceptor agonists
Authors: Christopher Rider, Elizabeth King, Neil Holden, Mark Giemmbycz, Robert Newton
Journal: European Respiratory Journal (2011)

Rationale: Inhaled corticosteroids (glucocorticoids) are the most effective treatment for inflammatory diseases such as asthma. However, in some patients with severe disease, or who smoke, or suffer from COPD, these drugs are less effective. While many investigators focus on the repression of inflammatory gene expression, corticosteroids also induce the expression (transactivation) of numerous genes to elicit anti-inflammatory effects.

Results: Using human bronchial airway epithelial, BEAS-2B, and pulmonary, A549, cells, we show that tumour necrosis factor (TNF) α, interleukin (IL)-1β, fetal calf serum (FCS), phorbol ester, cigarette smoke extract and a Gq-linked G-protein coupled receptor agonist, all attenuate simple glucocorticoid response element (GRE)-dependent transcription. With TNFα and FCS, this was not overcome by increasing concentrations of dexamethasone, budesonide or fluticasone propionate. Thus, maximal GRE-dependent transcription was reduced and this was confirmed for the glucocorticoid-induced gene, p57KIP2. Long-acting β2-adrenoceptor agonists (LABAs), formoterol fumarate and salmeterol xinafoate, enhanced simple GRE-dependent transcription to a level that could not be achieved by glucocorticoid alone. In the presence of TNFα or FCS, which repressed corticosteroid responsiveness, LABAs restored corticosteroid-dependent transcription to that achieved by corticosteroid alone.

Conclusions: The repression of transactivation represents a mechanism to explain corticosteroid resistance and its reversal may explain the clinical benefit of LABAs as an add-on therapy in asthma and COPD.

Funded by AstraZeneca.
The use of forced oscillation technique (FOT) to assess small airways dysfunction
Authors: Andrei Malinovschi, Chiara Veneroni, Alain Michils, Alain Van Muylem, Raffaele Dellacá
Journal: European Respiratory Journal (2013)

BACKGROUND: The slope of third phase (SIII) of single breath nitrogen washout (SBN2) assesses ventilation heterogeneity and indirectly small airway involvement. By performing the SBW maneuver at operating volumes, SIII closer relates to small airways dysfunction (Van Muylem et al. 1992). Recent studies suggest that lung impedance (Zrs) measured by FOT is sensitive to small airways obstruction.

AIM: to study the relationship between SIII and Zrs parameters obtained during spontaneous breathing.

METHODS: Assessment of SIII for SBN2 measurements, both at VC (SIIIN2(VC)) and at operating volume, FRC to FRC+1L (SIIIN2(FRC+1L)), was done in 4 healthy adults and 10 asthmatics. Inspiratory within-breath Zrs at 5, 11 and 19 Hz was measured by FOT and expressed as resistance (R) and reactance (X). All measurements were repeated in asthmatics after methacholine challenge (Mch) at 20% fall in FEV1.

RESULTS: Log-transformed SIIIN2(VC) correlated significantly to X5, X11, X19, R5, and R5-R19 (p<0.05). The correlations between above named FOT parameters and log-transformed SIIIN2(FRC+1L) were slightly stronger: X5 (R2=0.43 vs 0.40 for SIIIN2(VC)), X11(R2=0.43 vs 0.38), X19 (R2=0.55 vs 0.37) and R5-R19 (R2=0.39 vs 0.37).

Significant changes of SIIIN2(VC), SIIIN2(FRC+1L) and all studied FOT parameters were found after Mch (p<0.01). The FOT parameters with largest relative changes (at least 100%) after Mch were: X5, X11, X19 and R5-R19.

CONCLUSIONS: FOT appears to be useful to detect small airways obstruction both at baseline conditions and after bronchial challenge. Reactance at all investigated frequencies and the frequency dependence of resistance might be promising FOT-markers of small airways dysfunction.
Phase I Clinical Trial of Oral COL-3, a Matrix Metalloproteinase Inhibitor, in Patients With Refractory Metastatic Cancer
Authors: Michelle A. Rudek, William D. Figg, Valerie Dyer, William Dahut, Maria L. Turner, Seth M. Steinberg, David J. Liewehr, David R. Kohler, James M. Pluda, Eddie Reed
Journal: Journal of Clinical Oncology (2001)

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m 2 /d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m 2 /d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m 2 /d. The dose of 36 mg/m 2 /d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m 2 /d for phase II trials.
Comparison of Standard and CA-125 Response Criteria in Patients With Epithelial Ovarian Cancer Treated With Platinum or Paclitaxel
Authors: John A. Bridgewater, Ann E. Nelstrop, Gordon J.S. Rustin, Martin E. Gore, William P. McGuire, William J. Hoskins
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To assess CA-125 as a measure of response in patients treated with paclitaxel. PATIENTS AND METHODS: One hundred forty-four patients treated with paclitaxel derived from four different trials and 625 patients treated with platinum from two trials were analyzed using precisely defined 50% and 75% reductions in CA-125. The standard and CA-125 response rates to paclitaxel and platinum were compared. In addition, we analyzed individual patient groups in which there was a difference in response according to the two response criteria. RESULTS: Patients with stable disease as determined by standard criteria who were treated with platinum and responded according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P &lt; .001). Standard and CA-125 response rates for patients treated with platinum (58.93% v 61.31%, respectively) and paclitaxel (30.65% v 31.67%, respectively) were very similar, as were rates of false-positive prediction of response by CA-125 (platinum 2.2% and paclitaxel 2.9%). Responders to paclitaxel had a significantly improved progression-free survival compared with nonresponders by both standard criteria (median progression-free survival, 6.8 v 2.5 months; P &lt; .001) and CA-125 criteria (median progression-free survival, 6.8 v 3.4 months; P &lt; .001). CONCLUSION: For assessing activity of therapy for ovarian cancer, these data show that precise 50% or 75% CA-125 response criteria are as sensitive as standard response criteria. We propose that they may be used as a measure of response in lieu of or in addition to standard response criteria in clinical trials involving epithelial ovarian cancer. Sensitivity is maintained whether patients are treated with platinum or paclitaxel.
Appropriateness of colonoscopy in Europe (EPAGE II) – Iron-deficiency anemia and hematochezia
Authors: I. Peytremann-Bridevaux, C. Arditi, F. Froehlich, J. O’Malley, P. Fairclough, O. Le Moine, R. Dubois, J.-J. Gonvers, S. Schusselé Filliettaz, J.-P. Vader, P. Juillerat, V. Pittet, B. Burnand
Journal: Endoscopy (2009)

See also: Commentaire de "Retour vers le futur: EPAGE II" (6 articles), pp. 200Endoscopy 2009; 41(03): 388-390DOI: 10.1055/s-0032-1306673
Unresolved pneumonia due to endobronchial lipoma and actinomycosis
Authors: N Arber, R Breuer, N Berkman, E Okon, D Ben-Yehuda
Journal: European Respiratory Journal (1989)

We report an unusual case of unresolved pneumonia in a 59 yr old woman due to endobronchial lipoma and actinomycosis, two rare diseases that have never been described before in the same person.
Comparative Effects of Cytotoxic Agents on Transplanted Hematopoietic and Antibody-Producing Cells2
Authors: L. L. Sensenbrenner, A. H. Owens, J. R. Heiby, H. F. Jeejeebhoy
Journal: JNCI Journal of the National Cancer Institute (1973)

The effects of 6 cytotoxic agents were studied on recently transplanted hematopoietic colony-forming units and adoptively transferred antibody-forming cells. Methotrexate, 6-mercaptopurine, and actinomycin D were most effective against both cell lines when given 3 days or longer after cell transplant, which suggests that these compounds profoundly affect actively proliferating cells. Cyclophosphamide exerted a time-dependent effect on antibody production similar to that of methotrexate, but its effect on the colony-forming units was not time related, which suggests that all phases of the hematopoietic cells' proliferative cycle are affected equally. 1,3-Bis(2-chloroethyl)-1-nitrosourea affected both cell lines most markedly when given shortly after marrow transplantation indicating that resting or lag phase cells are most sensitive. Of all agents studied, antilymphocyte serum suppressed antibody production most and affected hematopoietic cells least, especially when given in high doses at the time of or shortly after cell transplantation. Cyclophosphamide and methotrexate achieved more antibody suppression with less hematopoietic cell suppression than the other cytotoxic drugs studied. From these studies one might predict that these latter 3 agents are useful in the treatment of graft-versus-host reactions.
Mechanism of Ovarian Carcinogenesis: Effect of 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene Administration on Intrasplenic Ovarian Grafts in Unilaterally Ovariectomized C3HeB/Fe Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: V Armuth, I Berenblum
Journal: JNCI Journal of the National Cancer Institute (1979)

A single oral administration of 7,12-dimethylbenz[a]anthracene (DMBA) 2 weeks after intrasplenic grafting of ovarian tissue in unilaterally ovariectomized C3HeB/Fe mice resulted in a high tumor incidence (47%) in the grafted tissue, with only 1 tumor (3%) in the orthotopic ovary. No tumors were seen in the control group (unilaterally ovariectomized mice given intrasplenic grafts of ovarian tissue without subsequent DMBA administration), nor did tumors develop in response to DMBA treatment in mice with both ovaries in situ and no grafted tissue in the spleen. The results indicated that some local change caused by the grafting procedure rendered the tissues more sensitive to the action of DMBA and/or more responsive to gonadotropic stimulation.
Bipolar Disorder: Anomalous Brain Asymmetry Associated With Psychosis
Authors: Martin Reite, Peter Teale, Donald C. Rojas, David Arciniegas, Jeanelle Sheeder
Journal: American Journal of Psychiatry (1999)

Anomalous cerebral asymmetry in schizophreniform disorders has been described, but its presence in psychotic mood disorders has not been established. Measures of cerebral asymmetry may distinguish patients with psychotic mood disorders from those with nonpsychotic mood disorders and from comparison subjects. To test this hypothesis, the authors examined functional cerebral asymmetry by using a metric based on magnetic source imaging.A total of 33 subjects participated. Nine were patients with bipolar I disorder and a negative history of psychotic symptoms during mood disorder episodes, 12 were patients with bipolar I disorder and a positive history of psychotic symptoms during mood disorder episodes, and 12 were nonpsychiatric comparison subjects. Equivalent current dipole generators in both hemispheres were estimated for the 20-msec-latency somatosensory evoked field (M20) component produced by stimulation of the contralateral median nerve.The comparison subjects demonstrated asymmetry in anterior-posterior equivalent current dipole locations of the M20 (right anterior to left), and the bipolar subjects with no history of psychosis were similarly asymmetric. The bipolar subjects with a history of psychosis during mood episodes, however, demonstrated a reversal of cerebral asymmetry of the M20 (left anterior to right).Cerebral lateralization of the M20 distinguished bipolar subjects with psychosis from those without psychosis and comparison subjects. The M20 is generated in area 3b of the postcentral gyrus. These findings suggest anatomical displacement of the postcentral gyrus in psychotic disorders and support the hypothesis that anomalous cerebral asymmetry is a feature of psychotic disorders generally, including psychotic mood disorders.
Hypergastrinaemia in patients infected with Helicobacter pylori treated with proton pump inhibitors
Authors: H L Waldum
Journal: Gut (2005)

We read with interest the commentary by McColl on Helicobacter pylori infection and long term proton pump inhibitor (PPI) therapy ( Gut 2004; 53 :5–7).

It is remarkable that he did not mention gastrin although hypergastrinaemia is a result of reduced gastric acidity1 …
Reciprocal imbalance or coexistence? The distribution of Th17 and Treg cells in peripheral blood lymphocytes in patients with non-small-cell lung cancer and its significance
Authors: Haixing Zhu, Guochao Shi, Wei Tang
Journal: European Respiratory Journal (2012)

Objective: To investigate the the distribution of Th17 in relation to Treg in PBMC in patients with non-small cell lung cancer and its significance.  Methods:: We analyzed T cells in the peripheral blood of 22 patients with Stage IV, 18 patients with Stage III, 8 patients with Stage I∼II and 20 healthy volunteers.The proportions of Th17 and Treg cells in peripheral blood were determined by flow cytometry.  The plasma level of IL-17 and TGF-β were measured by ELISA and the mRNA expressions of RORγt and FOXP3 were detected by realtime PCR.Results: The frequency of blood Th17 cells and IL-17A levels in plasma were increased in all patients with non-small cell lung cancer. The ratio of Th17 and Treg cells in patients with Stage IV are much higher than that in early stage. Particulary, we detected a small portion of CD4+IL17+Foxp3+T cells in the peripheral blood. Patients with Stage IV have much this kind of double positive helper T cells than other groups.  Conclusions: Reciprocal imbalance of Th17/Treg were found in patients with early disease. The elevated Th17 cell and Treg cell responses were associated with advanced disease, which indicated coexistence of Th17 cell and Treg cell instead of reciprocal imbalance was the major part in the antitumor immunity with the progression of non-small cell lung cancer.
Evolutionarily conserved Ets family members display distinct DNA binding specificities.
Authors: C Y Wang, B Petryniak, I C Ho, C B Thompson, J M Leiden
Journal: The Journal of Experimental Medicine (1992)

Members of the Ets family of proto-oncogenes encode sequence-specific transcription factors that bind to a purine-rich motif centered around a conserved GGA trinucleotide. Ets binding sites have been identified in the transcriptional regulatory regions of multiple T cell genes including the T cell receptor alpha and beta (TCR-alpha and -beta) enhancers and the IL-2 enhancer, as well as in the enhancers of several T cell-trophic viruses including Maloney sarcoma virus, human leukemia virus type 1, and human immunodeficiency virus-2. T cells express multiple members of the Ets gene family including Ets-1, Ets-2, GABP alpha, Elf-1, and Fli-1. The different patterns of expression and protein-protein interactions of these different Ets family members undoubtedly contribute to their ability to specifically regulate distinct sets of T cell genes. However, previous studies have suggested that different Ets family members might also display distinct DNA binding specificities. In this report, we have examined the DNA binding characteristics of two Ets family members, Ets-1 and Elf-1, that are highly expressed in T cells. The results demonstrate that the minimal DNA binding domain of these proteins consists of adjacent basic and putative alpha-helical regions that are conserved in all of the known Ets family members. Both regions are required for DNA binding activity. In vitro binding studies demonstrated that Ets-1 and Elf-1 display distinct DNA binding specificities, and, thereby interact preferentially with different naturally occurring Ets binding sites. A comparison of known Ets binding sites identified three nucleotides at the 3' end of these sequences that control the differential binding of the Ets-1 and Elf-1 proteins. These results are consistent with a model in which different Ets family members regulate the expression of different T cell genes by binding preferentially to purine-rich sequences that share a GGA core motif, but contain distinct flanking sequences.