tbuckley/cabot-search huggingface dataset:
Sex-associated differences in presentation and survival in patients with lung cancer.
Authors: M K Ferguson, C Skosey, P C Hoffman, H M Golomb
Journal: Journal of Clinical Oncology (1990)

A retrospective study of 478 men and 294 women with primary lung cancer was conducted to characterize sex-associated differences in their presentation and survival. At the time of diagnosis, women were younger than men (mean age, 57.4 +/- 10.4 v 60.2 +/- 9.9 years, respective; P = .0007). Men were more likely to be current or previous smokers (94% v 84%; P less than .005), and in patients with a positive smoking history, cigarette consumption was greater in men (52.2 v 40.2 pack years; P = .0001). The proportion of adenocarcinomas compared with squamous cancers was high in women (45% v 23%), while these cell types were equally represented in men. The majority of patients in both sex groups had regionally advanced or metastatic disease at diagnosis. Survival was related to age, stage at presentation and cell type. In addition, sex was found to be an independent prognostic factor for survival. Women with tumors of all cell types lived longer than their male counterparts (P less than .0001), and survival by stage in patients with nonsmall-cell cancers was greater for women than it was for men. These data demonstrate that important sex-associated differences exist in presentation and survival from lung cancer. Such differences should be considered when planning and analyzing clinical trials.
On the PAM matrix model of protein evolution.
Authors: W J Wilbur
Journal: Molecular Biology and Evolution (1985)

The internal consistency of the PAM matrix model of protein evolution is here investigated. The 1 PAM matrix has been constructed from amino acid replacements observed in closely related sequences. Such replacements are of two types, those that do not require an intermediate amino acid replacement and those that do. The second type of replacement must generally be produced by a repetition of the first. This allows data on the first type to be used in predicting data on the second type so that some elements of the 1 PAM matrix may be used to predict others. A discrepancy of more than two orders of magnitude is found between the predictions and the data when this is carried out. This is partly accounted for by an error in constructing the matrix. However, it also seems necessary that the basic model be modified. Several possibilities are considered. One of these is to incorporate a site-dependent spectrum of mutabilities associated with each amino acid.
Auditing patterns of azithromycin use in respiratory disease
Authors: David Hodgson, Robert Hurford, Tim Harrison, Dominick Shaw
Journal: European Respiratory Journal (2011)

Introduction: In response to increasing use of Azithromycin in respiratory disease we set out to audit local prescribing and clinical outcome.

Methods: Data on all Azithromycin prescriptions from a Respiratory Consultant in a large UK teaching hospital between 1st September 2009 and 31st March 2010 were collected. There were 192 prescriptions corresponding to 123 patients. After excluding patients with cystic fibrosis (CF) and Pseudomonas aeruginosa colonisation, 62 sets of notes were reviewed. The subjective clinical benefit of Azithromycin and objective improvement in terms of exacerbations or lung function was assessed.

Results: Despite the large variation in phenotypic disease (Figure 1), there was an overall reduction of 0.36 exacerbations per month (P<0.0001, 95% CI 0.27–0.46). On further analysis we found that those with evidence of bronchiectasis were significantly more likely to improve after Azithromycin therapy than those without; 88% and 39% respectively (P<0.0001).

![Figure][1] 



Conclusions: Azithromycin is used in a variety of respiratory conditions and we found variable recording of its benefit. A more formal assessment of benefit is required, especially in light of its side effect risk and potential for microbial resistance. Additional randomised controlled trials to further guide treatment are recommended.

 [1]: pending:yes
The effect of CTP-347 on CYP2D6-mediated tamoxifen metabolism
Authors: D. S. Wells, A. Morales, R. Gallegos, V. Uttamsingh, G. Bridson, C. Cheng, C. Masse, S. Harbeson, R. Zelle, R. Tung
Journal: Journal of Clinical Oncology (2008)

11552 Background: The activity of tamoxifen is primarily mediated through its 4-hydroxy metabolites which are potent antagonists of the estrogen receptor in breast tissue. The 4-hydroxylation reaction is mediated through the cytochrome P450 isozyme CYP2D6. Unfortunately, high concentrations of endoxifen, the major 4-hydroxy metabolite, have also been implicated in the occurrence of hot flashes. Although paroxetine has been demonstrated to reduce the frequency of hot flashes in investigator trials of patients with breast cancer, co- administration would reduce the effectiveness of tamoxifen since paroxetine has been shown to be a mechanism-based inactivator of CYP2D6. CTP-347 is a new chemical entity in which key hydrogen atoms of paroxetine are replaced with deuterium atoms. CTP-347 is being developed for the treatment of post-menopausal and tamoxifen-induced hot flashes and will enter clinical trials in mid-2008. Methods: Serotonin and norepinephrine reuptake inhibition was measured in rat synaptosomes using radiolabeled neurotransmitters. Time- dependent inactivation of CYP2D6 was determined by pre-incubating CTP-347 or paroxetine with human liver microsomes and measuring the extent of dextromethorphan metabolism, a CYP2D6-specific substrate. The effect on tamoxifen active metabolite formation was determined by pre-incubating CTP-347 or paroxetine with expressed human CYP2D6 in the presence of N-desmethyl tamoxifen and measuring endoxifen concentrations. All drug concentrations were measured by LC/MS-MS. Results: There was no difference in binding between CTP-347 and paroxetine at the serotonin (IC50s: 2.1 vs. 1.7 nM) or norepinephrine (IC50s: 28 vs. 38 nM) binding sites. Paroxetine caused time-dependent inhibition of CYP2D6 (Kinact = 0.08 min-1) at a level similar to that reported previously, while the Kinact of CTP-347 could not be determined due to insignificant inactivation. Endoxifen formation was up to 12-fold higher in the presence of CTP-347 than paroxetine. Conclusions: CTP-347 does not cause mechanism-based inactivation of CYP2D6 at clinically relevant concentrations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Concert Pharmaceuticals Concert Pharmaceuticals Concert Pharmaceuticals
Revisiting the Cochrane Collaboration
Authors: M. Clarke, P. Langhorne
Journal: BMJ (2001)

See also Papers p 829 

> It is surely a great criticism of our profession that we have not organised a critical summary, by specialty or subspecialty, updated periodically, of all relevant randomised controlled trials.
> 
> Archie Cochrane, 19791

In 1992, Iain Chalmers and colleagues wrote an editorial in the BMJ that began with the above quotation and set out challenges foreseen at the time of the opening of what became the first Cochrane Centre, in Oxford.2 Some of these challenges have been met, some remain, and new ones have arisen as the centre which is now the Cochrane Collaboration strives to prepare and keep up to date systematic reviews of the effects of healthcare interventions.

At the time, the major hurdle facing reviewers was identifying relevant randomised trials, and the editorial described efforts to make the task easier. Nine years on, these efforts have contributed to the Cochrane controlled trials …
GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells
Authors: Styliani Karanika, Theodoros Karantanos, Shinji Kurosaka, Jianxiang Wang, Takahiro Hirayama, Guang Yang, Sanghee Park, Alexei A. Golstov, Ryuta Tanimoto, Likun Li, Timothy C. Thompson
Journal: Molecular Cancer (2015)

Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells. The synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model. We found that GLIPR1-ΔΤΜ synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔΤΜ to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did. Our data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.
Silicosis caused by sandblasting in teflon coated pan manufacturing
Authors: Nurhan Köksal, Hasan Kahraman, Nurhan Atilla
Journal: European Respiratory Journal (2012)

Silicosis is an occupational disease of the lungs caused by inhalation of crystalline silica and is marked by fibrotic pulmonary reaction. Sandblasting has been commonly used during abrading of jeans, glass, and metal. We presented 17 silicosis cases occurring in teflon coated pan manufacturing. Symptoms questionnaire, pulmonary function tests, carbon monoxide diffusion test, and thorax HRCT were done. All of employees are male and mean age was 28.8±5.2 (18-41). The mean duration of working period for this job was 24.8±15.4 (9-60) months.  Clinically total 17 cases was evaluated, 7 cases as acute silicosis(AS), 6 cases as classic silicosis, 3 cases as accelerated silicosis (ACS) and one case as silicotuberculosis (ST). Four cases of AS and one ST case were died during follow-up. Acute respiratory failure was present in one AS case and one ACS case. Clinical follow-up of other patients has been continued.  In view of thie report, sandblasting of teflon pan manufacturing cause silicosis. These clinical type commanly acute form and mortaly was high.
Depressive Disorder Due to Craniopharyngioma
Authors: Sean A Spence, David G Taylor, Steven R Hirsch
Journal: Journal of the Royal Society of Medicine (1995)

Secondary causes of depression are legion, and must always be considered in patients presenting with features atypical of primary idiopathic depressive disorder. The case described is that of a middle-aged woman presenting initially with a major depressive disorder who was subsequently found to have a craniopharyngioma, leading to a revised diagnosis of mood disorder due to the tumour. Some features of the presentation might have led to earlier diagnosis had their localizing significance been recognized. Diencephalic lesions should always be considered in patients presenting with the hypersomnic-hyperphagic variant of depressive disorder.
Influence of the duration of inhalation of cold dry air on the resulting bronchoconstriction in asthmatic subjects
Authors: N Caire, A Cartier, H Ghezzo, J L Malo
Journal: European Respiratory Journal (1989)

Hyperventilation of cold dry air causes bronchoconstriction in asthmatic subjects and has been proposed as a test for assessing bronchial hyperresponsiveness. The influence of the duration of inhalation of unconditioned cold air has not been studied. We have investigated the question in 12 asthmatic subjects in a clinically stable state. Each subject underwent three inhalation tests at a maximum interval of two weeks. On each day, the duration of inhalation was different, being randomly 2, 3 or 4 min depending on the subject. Doubling doses of cold air produced by a freon conditioner were administered, increasing ventilation from 7.5 to 15, 30, 60 l.min-1 and maximum voluntary ventilation (MVV). Forced expiratory volume in one second (FEV1) was assessed after each period of cold air inhalation. The test was stopped when the FEV1 had decreased by 20% or more, or when MVV had been achieved. The dose of cold air expressed as the level of ventilation causing a 20% change in FEV1 (PD20) was interpolated from individual dose-response curves. Dose-response curves shifted to the left when the duration of ventilation was increased. PD20 was significantly lower after 3 min of ventilation than after 2 min (mean +/- SD PD20 of 41.7 +/- 1.4 l.min-1 compared with 53.3 +/- 1.2 l.min-1; p = 0.002). There was a further fall in PD20 after 4 min of ventilation (PD20 = 36.1 +/- 1.5 l.min-1) but the difference compared with the values obtained after 3 min was not significant (p = 0.09), thus suggesting a plateau.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiovascular and Inflammatory Biomarkers to Predict Short- and Long-Term Survival in Community-acquired Pneumonia
Authors: Stefan Krüger, Santiago Ewig, Sven Giersdorf, Oliver Hartmann, Norbert Suttorp, Tobias Welte
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Several new biomarkers are related to mortality in community-acquired pneumonia (CAP).Aim of this study was to compare new biomarkers for the prediction of short- and long-term all-cause mortality in CAP.We enrolled 728 patients (59.0 ± 18.2 yr) with CAP. Midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), proarginin-vasopressin (copeptin), proendothelin-1 (CT-proET-1), procalcitonin (PCT), C-reactive protein, white blood cell (WBC) count, and clinical confusion, respiratory rate, blood pressure, and age over 65 years (CRB-65) score were determined on admission. Patients were followed up for 180 days.In patients who died of any cause within 28 and 180 days (2.5 and 5.1%, respectively), MR-proADM, MR-proANP, copeptin, CT-proET-1 and PCT as well as CRB-65 were significantly higher compared with survivors. MR-proADM had the best performance for 28 days (HR 3.67) and 180 days (HR 2.84) survival. The C index of MR-proADM for 28-day survival (0.85) was superior to MR-proANP (0.81), copeptin (0.78), CT-proET-1 (0.79), and CRB-65 (0.72) for the prediction of mortality. For prediction of mortality at 180 days, the C index of MR-proADM (0.78) was higher than that for MR-proANP (0.74), copeptin (0.73), CT-proET-1 (0.76), PCT, C-reactive protein, and white blood cells. MR-proADM was independent of CRB-65, and added prognostic information for short- and long-term mortality. MR-proADM was an independent and strong predictor of short- and long-term mortality.All new biomarkers were good predictors of short- and long-term all-cause mortality, superior to inflammatory markers, and at least comparable to CRB-65 score. MR-proADM showed the best performance. A combination of CRB-65 with MR-proADM might be the best predictor for mortality.
Visualising regional ventilation heterogeneity by linking multiple breath washout to 3He MRI imaging
Authors: Felix Horn, Alex Horsley, Laurie Smith, Christopher Tayler, Helen Marshall, Juan Parra-Robles, Jim Wild
Journal: European Respiratory Journal (2014)

Introduction: Fractional ventilation imaging with 3He MRI can be used to visualise the processes underlying inert gas multiple breath washout measurement (MBW) from a regional perspective [1].

Objectives: This proof-of-principle study compares MBW-imaging to clinical MBW measurements.

Methods: Both methods were performed in 5 healthy volunteers (22±10years; 3 females) and 7 patients with mild-CF (age 12.7±2.6years, 2 males, FEV1>80%)

1) 0.2% SF6 MBW was performed supine to mimic posture in MRI.

2) MBW-imaging was performed with sequential 3He MRI [1]. Washout time-constants were calculated for each individual voxel (∼1cm3) and integrated to produce a predicted washout curve from the whole lungs.

The total normalized tracer gas volume expired at each breath was plotted for both SF6 and 3He against lung turn over.

![Figure][1] 



Results: There was good agreement between methods (see Figure ).

Spatial heterogeneity of ventilation was observed in both curves for this CF patient with a deviation from mono exponential decay, and was clearly seen in the MBW fractional ventilation images.

Conclusions: This preliminary study shows that simulated washout from imaging predicts that from MBW. MBW-imaging gives novel spatial insight into washout time constants within the lung, and will play an important role in understanding ventilation heterogeneity in the context of MBW indices (e.g. LCI).

References:[1]Horn et al., JAP;[116]129-39.

 [1]: pending:yes
Pulmonary function tests after whole-lung irradiation and doxorubicin in patients with osteogenic sarcoma.
Authors: E R Ellis, R B Marcus, M J Cicale, D S Springfield, F J Bova, J Graham-Pole, W F Enneking, S S Spanier, R R Million
Journal: Journal of Clinical Oncology (1992)

Because of the scarcity of information regarding long-term follow-up of pulmonary function after whole-lung irradiation, a prospective study was started at the University of Florida in 1979 to evaluate pulmonary function after treatment with whole-lung irradiation and doxorubicin in patients with osteogenic sarcoma.Between 1979 and 1984, 57 osteogenic sarcoma patients with no evidence of metastatic disease at diagnosis received adjuvant therapy consisting of whole-lung irradiation (with the heart shielded) followed by Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). The whole-lung irradiation schema was 1,600 cGy in 10 fractions with 8-MV x-rays via anterior and posterior fields. This was followed by five cycles of Adriamycin for a total dose of 450 mg/m2. Pulmonary function tests (PFTs) consisting of spirometry, lung volumes, and diffusing capacity were obtained before the whole-lung irradiation, at 6 and 12 months after irradiation, and at yearly intervals thereafter.At the time of analysis, 28 of the 57 patients were available for study, with a mean follow-up of 42 months (range, 6 to 77 months). Follow-up pulmonary function testing revealed decreased forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1) during the first 6 to 12 months after whole-lung irradiation. These values returned to baseline during the second-year posttherapy and remained at baseline throughout the remainder of the follow-up period. Changes in lung volumes demonstrated a similar early trend, with significant decreases in total lung capacity (TLC) and functional residual capacity (FRC) at 6 to 12 months. These changes, however, did not improve significantly during the remainder of the follow-up period. Diffusing capacity of the lungs for carbon monoxide (DLCO) also reached a nadir at 6 to 12 months after whole-lung irradiation, with resolution by 2 years and maintenance of at least baseline values for the remainder of the follow-up period.Treatment with whole-lung irradiation and Adriamycin, as given in this study, caused no significant sequelae, as demonstrated by pulmonary function testing during the mean follow-up period of 42 months, although a mild, transient restrictive ventilatory defect occurred at 6 to 12 months after treatment.
Phase Ib Trial of Intravenous Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor in Combination With Chemotherapy in Patients With Advanced Cancer: Pharmacologic and Long-Term Safety Data
Authors: K. Margolin, M. S. Gordon, E. Holmgren, J. Gaudreault, W. Novotny, G. Fyfe, D. Adelman, S. Stalter, J. Breed
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens. PATIENTS AND METHODS: Twelve adult patients were enrolled four on each combination. rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with (1) doxorubicin 50 mg/m 2 every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m 2 every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m 2 with leucovorin 20 mg/m 2 weekly, weeks 1 to 6 every 8 weeks. RESULTS: The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea (one 5-FU patient), thrombocytopenia (two patients on carboplatin plus paclitaxel), and leukopenia (one patient on carboplatin plus paclitaxel). These toxicities were likely attributable to the chemotherapy component of the regimen. The mean (± SD) peak serum level of rhuMAbVEGF was 167 ± 46 μg/mL, and the mean terminal half-life was 13 days. Total (free plus bound) serum VEGF levels increased from 51 ± 39 pg/mL (day 0) to 211 ± 112 (day 49) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy, receiving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumulative or late toxicities. CONCLUSION: rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials.
Detection of Cancer in Patients by Reduced Lymphocytic Cortisol Metabolism-Enhancing Effect<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref><xref ref-type="fn" rid="FN4">4</xref>
Authors: Ami Klein, Haiuta Kaufman, Raphael Arie, Henriette Hoogervorst-Spalter, Ephraim Semach, Ariel Barkan, Josef Martfel, Ciro Servadio
Journal: JNCI Journal of the National Cancer Institute (1980)

A double-blind study was done on the plasma from 59 hospitalized patients to determine whether a diminished lymphocytic cortisol metabolism-enhancing effect among cancer patients could be used to distinguish them from persons with noncancerous diseases. Known concentrations of human lymphocytes from healthy donors were incubated with cortisol in media containing 50% phosphate-buffered saline (PBS) and 50% of one of the following additives: 1) homologous plasma (HP), 2) plasma from the patient being tested, or 3) additional PBS. Plasma in which the metabolism-enhancing effect was less than 70% of that obtained with HP was considered to be that of a cancer patient. Among the 19 patients known to have cancer, there were only two false-negative results, whereas among the 40 patients diagnosed as having noncancerous diseases, there were six false-positive results. Thus the test findings and the pathologic diagnosis were obviously correlated in approximately 90% of the patients.