tbuckley/cabot-search huggingface dataset:
Efficacy of the TRPV1 antagonist SB-705498 in an MRI guinea pig model of rhinitis
Authors: Kumar Changani, Sarah Hotee, Simon Campbell, Kashmira Pindoria, Paula Saklatvala, Diane Coe, Keith Biggadike, Giovanni Vitulli, Jane Denyer
Journal: European Respiratory Journal (2011)

Rationale: Antagonism of nasal TRPV1 receptors is a potential target for inhibition of symptoms associated with rhinitis. Here, we explore the pharmacology of SB-705498 on the contralateral nasal secretory response to ipsilateral nasal capsaicin challenge in the guinea pig.

Methods: Experiments were conducted on intranasally sensitised guinea pigs. Absolute nasal fluid volumes were measured using MRI techniques that provide images of the total nasal cavity of the guinea pig. Animals were pre-treated with SB-705498 or vehicle (-1, -6 and -24h) and MRI scanned to produce first a baseline measurement and then a further measurement at 10 minutes post capsaicin challenge (0.3mM; 50ul).

Results: 1 hour pre-treatment with SB-705498 resulted in approximately 50% inhibition of the secretory response at 10mg/kg (oral; p<0.05), 1mg/kg (intranasal suspension; p<0.005) and 0.1mg/kg (intranasal particle reduced suspension; p<0.0005). At 12 hour pre-treatment, approximately 60% inhibition (p < 0.0001) was observed with SB-705498 at 1mg/kg (intranasal particle reduced suspension); at 24h this had reduced to ∼50% inhibition (p<0.01).

Conclusion: These studies demonstrate that SB-705498 inhibits capsaicin-induced intranasal parasympathetic responses in guinea pig. Topical application of SB-705498 was associated with a approximately 10-fold reduction in total dose compared with oral administration. In addition, particle reduction of SB-705498 was associated with a further improvement in intranasal potency.
Association of the blood eosinophil count with hematological malignancies and mortality
Authors: Christen L. Andersen, Volkert D. Siersma, Hans C. Hasselbalch, Hanne Vestergaard, Ruben Mesa, Peter Felding, Niels D.F. Olivarius, Ole W. Bjerrum
Journal: American Journal of Hematology (2014)

Blood eosinophilia (≥0.5 × 10(9) /l) may be an early sign of hematological malignancy. We investigated associations between levels of blood eosinophils and risks of hematological malignancies and mortality in order to provide clinically derived cut-offs for referral to specialist hematology care. From the Copenhagen Primary Care Differential Count (CopDiff) Database, we identified 356,196 individuals with at least one differential cell count encompassing the eosinophil count during 2000-2007 and matched these laboratory data with Danish nationwide health registers. We used multivariable logistic regression to calculate odds ratios (ORs) for the 4-year incidences of hematological malignancies and mortality between the eosinophil counts and a reference count of 0.16 × 10(9) /l which was the median eosinophil count in our data. Risks of hematological malignancies and mortality increased above the median eosinophil count. At the 99th percentile, corresponding to an eosinophil count of 0.75 × 10(9) /l, risks of hematological malignancies were increased more than twofold with OR (95% C.I.) of 2.39 (1.91-2.99). Interestingly, risks reached a plateau around an eosinophil count of 1.0 × 10(9) /l. Risks also increased when the eosinophil count approached zero. Here, counts associated relatively more with acute myeloid leukemia and myelodysplastic syndromes whereas counts above 0.16 × 10(9) /l associated more with myeloproliferative neoplasms. Eosinophil counts associate with hematological malignancies and mortality even below the definition of eosinophilia. The observed plateau of risks around 1.0 × 10(9) /l is important for physicians encountering patients with eosinophilia since even mild-to-moderate eosinophilia according to traditional definitions confers maximally increased risks of subsequent/subclinical hematological malignancy.
Risk Factors for Estrogen Receptor-Rich and Estrogen Receptor-Poor Breast Cancers&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Anne McTiernan, David B. Thomas, Lois K. Johnson, Diane Roseman
Journal: JNCI Journal of the National Cancer Institute (1986)

A population-based case-control study was conducted in King County, WA, to investigate whether risk factors for estrogen receptor (ER)-rich and ER-poor breast cancers differ. Responses to interviews with 329 women with breast cancer who were between 25 and 54 years of age at the time of diagnosis were compared to responses of 332 women of similar age who were selected from female residents of King County by random digit dialing. Of the 329 interviewed cases, 143 had ER-rich tumors, 97 had ER-poor tumors, and 89 had tumors that were not assayed for receptors. The relative risks of ER-rich and ER-poor breast cancers were similar with respect to late menarche, single marital status, history of extended lactation, menopause before age 40, history of benign breast disease, positive family history of breast cancer, obesity, and history of oral contraceptive and noncontraceptive estrogen use. Late age at first full-term pregnancy was a risk factor for ER-rich breast cancer but not for ER-poor breast cancer. This finding suggests that different causal mechanisms operate for these two types of breast cancer and supports the hypothesis that an early first birth protects against breast cancer by reducing the level of ERs in the mammary epithelial cells from which carcinomas develop.
Kinins and respiratory tract diseases
Authors: A Trifilieff, A Da Silva, JP Gies
Journal: European Respiratory Journal (1993)

Bradykinin and related kinins are peptidic hormones, formed in tissues and fluids during inflammation. Various functional sites have been proposed as mediators of the biological effects of kinins, including the B1, B2 and B3 receptors. The existence of the B1 and the B2 receptor has largely been confirmed, whilst that of the B3 receptor is controversial and needs further confirmation. The role of bradykinin in the pathophysiology of asthma is not well understood, but bradykinin was proposed as a putative mediator of asthma, since asthmatic subjects are hyperresponsive to bradykinin, and since immunoreactive kinins are increased in the bronchoalveolar lavage fluids of asthmatic patients. Kinins could provoke bronchoconstriction by acting directly on smooth muscle and/or indirectly by their inflammatory properties. They may also contribute to the symptomatology of allergic and viral rhinitis, since they are the only mediators detected to date that are generated in nasal secretion during experimental and natural rhinovirus colds. Moreover, they can induce relevant symptoms when applied to airway mucosa. It has also been proposed that coughing during treatment with angiotensin-converting enzyme (ACE) inhibitors is linked to the action of kinins, since ACE is able to degrade kinins, and since the effects of ACE inhibitors are reduced by kinin antagonists. Due to their mitogenic properties, kinins have been proposed to regulate lung carcinoma growth. Their action remains speculative, but some findings are of great interest in order to define their role in these pathologies. Despite many studies in animals and in humans, the mode of action of kinins in airways is still poorly understood.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute effects of external negative pressure ventilation in chronic obstructive pulmonary disease compared with normal subjects
Authors: C B Cooper, N D Harris, P Howard
Journal: European Respiratory Journal (1991)

This study compares the acute physiological effects of external negative pressure ventilation (ENPV) in normal subjects and patients with chronic obstructive pulmonary disease (COPD). The equipment consisted of an airtight jacket (Pneumosuit) and vacuum pump. Minute ventilation (Ve) was recorded using a light-emitting turbine transducer. Oxygen uptake (VO2) and carbon dioxide output (VCO2) were calculated every 30 s. Measurements were made at rest and during ENPV with pressures of -20 cmH2O and -40 cmH2O. The ventilator rate was fixed at 16.min-1. In 10 normal subjects, Ve increased from 8.6 to 22.9 l.min-1 (p less than 0.01) accompanied by an increase in VCO2 from 0.25 to 0.39 l.min-1 (p less than 0.01). In 10 normocapnic COPD patients (arterial carbon dioxide tension (PaCO2) less than 6.0 kPa) Ve increased from 11.5 to 17.1 l.min-1 (p less than 0.01) whilst in 10 hypercapnic patients (PaCO2 greater than 6.0 kPa) Ve increased from 9.7 to 12.4 l.min-1 (p less than 0.01). A change in VCO2 was not detected in the COPD patients, and VO2 did not change in any group. Arterial blood samples were obtained in eight hypercapnic patients. Baseline mean physiological deadspace ventilation (VD) was calculated to be 4.9 l.min-1 (56% of Ve) whilst Ve was 8.8 l.min-1 in this subgroup. During ENPV, arterial oxygen tension (PaO2) increased from 6.8 to 8.2 kPa (p less than 0.01) whilst PaCO2 decreased from 6.8 to 5.8 kPa (p less than 0.01) suggesting that despite the large physiological deadspace, a significant increase in alveolar ventilation had occurred. In advanced COPD, thoracic compliance falls and limits the ventilatory response to ENPV.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract 9374: High Sensitivity Cardiac Troponin T in Patients with Chronic Heart Failure: Prognostic Value of Changes Over Time and Effects of Randomized Therapy
Authors: Serge Masson, Valentina Milani, Gianfranco Misuraca, Antonio Ciro, Tarcisio Vago, Dietmar Zdunek, Maria Grazia Franzosi, Aldo P Maggioni, Roberto Latini
Journal: Circulation (2010)

Aims: We examined the prognostic value of repeated measurements of cardiac troponin T, assayed with a high sensitivity method, in patients with chronic heart failure (HF), and the effect of randomi...
Phase I trial of murine monoclonal antibody L6 in combination with subcutaneous interleukin-2 in patients with advanced carcinoma of the breast, colorectum, and lung.
Authors: L D Ziegler, P Palazzolo, J Cunningham, M Janus, K Itoh, K Hayakawa, I Hellstrom, K E Hellstrom, C Nicaise, R Dennin
Journal: Journal of Clinical Oncology (1992)

PURPOSE A phase I trial was undertaken to determine the toxicity and biologic effects of a combination of murine monoclonal antibody L6 (MoAb L6) plus subcutaneous (SC) interleukin-2 (IL-2). PATIENTS AND METHODS Fifteen patients with refractory adenocarcinoma (five breast, five lung, five colorectal), received L6 at 200 mg/m2 intravenously (IV) daily on days 1 to 7, followed by a 1-week rest period. IL-2 was given at either 2, 3, or 4.5 x 10(6) U/m2 daily doses times 4 days for a total duration of 3 weeks. RESULTS Side effects of L6 consisted of mild fever and chills along with a rash and serum sickness in one patient. One patient developed dyspnea and urticaria, that resolved with antihistamines. Maximum-tolerated dose (MTD) of SC IL-2 was 3 x 10(6) U/m2, with dose-limiting toxicities that consisted of grade 4 fatigue and dyspnea. Significant decreases in complement levels along with increases in absolute lymphocyte count and eosinophil count were observed. Mean antibody-dependent cellular cytotoxicity from mononuclear cells taken from patients who received IL-2 was elevated significantly compared with baseline in all patients independent of IL-2 dose (P less than .05). Serum IL-2 levels were elevated in 13 of 14 patients (range, 0.9 to 100 U/mL). Human antimouse antibody (HAMA) titers were elevated in nine of 14 (64%) patients who were tested between 3 and 8 weeks after L6 infusion. One patient with breast cancer had a transient mixed response, and one patient with colorectal cancer had a partial response. CONCLUSIONS L6 and SC IL-2 were well tolerated in the majority of patients when given in the outpatient setting. In view of the clinical efficacy of this combination, more phase II trials are warranted.
Comparison of the pharmacokinetic, pharmacodynamic, and safety profiles of three different formulations of intravenous epoprostenol sodium
Authors: Laurent Nicolas, Marcelo Gutierrez, Jasper Dingemanse
Journal: European Respiratory Journal (2012)

A change in excipient of epoprostenol sodium, an i.v. pulmonary arterial hypertension treatment, from glycine-mannitol (epoprostenol GM; Flolan®) to arginine-mannitol (epoprostenol AM; Veletri®) or to undisclosed excipients (epoprostenol XX) has led to improvements in stability of the latter two formulations.  The pharmacokinetic (PK), haemodynamic, safety, and tolerability profiles of these formulations were compared in this 2-part study. 20 healthy males in Part 1 and 20 different subjects in Part 2 received epoprostenol AM and epoprostenol XX, and epoprostenol GM and epoprostenol XX, respectively, in a crossover design, in sequential 2h i.v. infusions of 2, 4, 6 and 8 ng/kg/min.  PK profiles were assessed by analysing plasma concentration-time curves of the primary epoprostenol metabolites 6-keto-prostacyclin F1α (kPF) and 6,15-diketo-13,14-dihydro-prostacyclin F1α (ddPF) obtained after treatment with the different epoprostenol formulations. For Part 1, the ratio of the geometric means (90% CI) of AUC 0–∞  calculated after epoprostenol AM and epoprostenol XX treatment was 0.91 (0.88–0.95) for kPF and 0.88 (0.84–0.92) for ddPF. For Part 2, the ratio of AUC 0–∞  determined after epoprostenol GM and epoprostenol XX treatment was 0.97 (0.91–1.03) for kPF and 1.08 (1.02–1.14) for ddPF. Haemodynamic variables, assessed by echocardiography, showed similar increases in cardiac output, cardiac index, and heart rate for all formulations with maximum values attained after 6–8h. Almost all subjects reported ≤1 adverse event.  These results suggest the 3 formulations of i.v. epoprostenol sodium have the same PK, haemodynamic, safety, and tolerability profiles.
Taxotere inhibition of VEGF- and bFGF-induced endothelial cell migration is a result of Hsp90 degradation
Authors: Janice Murtagh, Haiyan Lu, Edward L. Schwartz
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

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In addition to their effects on tumor cell proliferation and apoptosis, microtubule-binding agents have been shown to be highly potent inhibitors of angiogenesis. We recently determined that taxotere, a microtubule stabilizing drug with significant clinical anti-tumor activity, inhibited endothelial cell migration, a critical step in tumor-associated angiogenesis; this occurred at concentrations significantly lower than those required for the inhibition of human umbilical vein endothelial cell (HUVEC) proliferation. While taxotere had no effect on the extent of VEGF-induced Tyr951 phosphorylation of the VEGF receptor FLK1/KDR (VEGFR-2), it inhibited all subsequent downstream events. In this study, we sought to further define the molecular site of action for the effects of taxotere on VEGF signaling pathways. Heat shock protein 90 (Hsp90) is a chaperone protein implicated in a wide range of receptor-mediated cellular actions based on its ability to maintain the correct folding, function and stability of client signaling molecules. Taxotere (10 pM) caused the rapid and near complete loss of Hsp90 protein in HUVEC, and this could be prevented by the proteasome inhibitor PSI. Decreased expression of Hsp90 by taxotere was the likely cause of the observed decrease in the VEGF-induced association of VEGFR-2 with integrin α5β1 and with FAK (focal adhesion kinase), and in the inhibition of FAK and paxillin tyrosine phosphorylation. This could have prevented signaling from the focal adhesions. Stimulation of endothelial cells with VEGF is known to enhance the recruitment of AKT and eNOS to Hsp90. Treatment of endothelial cells with taxotere inhibited Hsp90-AKT complex formation, resulting in decreased phosphorylation of AKT on Ser473. This impeded the activation of eNOS and prevented subsequent NO generation. FAK and paxillin activation appeared to be less important in bFGF-induced HUVEC migration, compared to migration induced by VEGF. bFGF did stimulate AKT phosphorylation, however, and we showed that taxotere inhibited both bFGF-induced migration and AKT phosphorylation, suggesting that inhibition of AKT signaling, independent of focal adhesion inhibition, can be sufficient to prevent cell migration. While many inhibitors of Hsp90 are currently under clinical investigation as anti-angiogenic agents, this appears to be the first account of a drug that reduces Hsp90 function by enhancing its proteasomal degradation. Further, the depletion of Hsp90 levels is a previously undescribed action of taxotere. This has broader implications for taxotere’s effects on tumor cells, given the role of Hsp90 and chaperone proteins in maintaining the conformation of oncogenic signaling proteins, in guiding the disposition of key regulators of cell growth and differentiation, and in allowing tumor cells to tolerate mutations in signaling molecules that might otherwise be lethal.
Antiemetic effect of oral versus intravenous metoclopramide in patients receiving cisplatin: a randomized, double-blind trial.
Authors: L B Anthony, M G Krozely, N J Woodward, J D Hainsworth, K R Hande, D E Brenner, F A Greco, T G Burish
Journal: Journal of Clinical Oncology (1986)

In a study of the antiemetic effectiveness of high-dose oral metoclopramide, 66 previously untreated patients receiving 60 mg/m2 cisplatin were entered into a double-blind randomized trial. Patients were stratified according to age and tumor type, then randomized to receive either oral or intravenous (IV) high-dose metoclopramide. Patients were evaluated for antiemetic protection, toxicity, affect (anxiety, hostility, and depression), and autonomic arousal (pulse rate and blood pressure) at three-hour intervals on the day of their chemotherapy. Metoclopramide serum levels were measured by high-performance liquid chromatography. Results indicated no significant differences between the oral and IV groups on any measurement of antiemetic protection, affect, or autonomic arousal. There were also no significant differences in side effects except for frequency of stools; patients who received oral metoclopramide had significantly more stools than patients who received IV metoclopramide. The mean (+/- SD) serum metoclopramide level at four hours achieved orally was 1,171 +/- 660 ng/mL; the mean (+/- SD) level achieved IV was 1,030 +/- 392 ng/mL (P = .498). We conclude that high-dose oral and IV regimens of metoclopramide as administered in this study have equivalent antiemetic efficacy in previously untreated patients receiving 60 mg/m2 cisplatin.
BIRC2/cIAP1 Is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency
Authors: Lars Pache, Miriam S. Dutra, Adam M. Spivak, John M. Marlett, Jeffrey P. Murry, Young Hwang, Ana M. Maestre, Lara Manganaro, Mitchell Vamos, Peter Teriete, Laura J. Martins, Renate König, Viviana Simon, Alberto Bosque, Ana Fernandez-Sesma, Nicholas D.P. Cosford, Frederic D. Bushman, John A.T. Young, Vicente Planelles, Sumit K. Chanda
Journal: Cell Host & Microbe (2015)
Combining Composite Endpoints: Counterintuitive or a Mathematical Impossibility?
Authors: Kenneth M. Kessler
Journal: Circulation (2003)

Endpoints: Counterintuitive or a Mathematical Impossibility?To the Editor:In their excellent article, DeMets and Califf 1 discuss composite endpoints.I would appreciate their further thoughts.When the use of a treatment "X" reduces the composite endpoint of death, non-fatal myocardial infarction, and a softer endpoint such as revascularization or hospitalization rates, we are led to the illusion that all 3 endpoints are reduced.Often only the most frequent, ie, the softest endpoint is reduced.Because an increase in mortality would be detected by safety monitoring, isn't the inclusion of death in composite endpoints when the study is underpowered to show a decrease in mortality simply misleading?Aside from perhaps the calculation of event-free survival that uses time as a metric, is the combination of events of different metric "counterintuitive" as suggested in the article, or mathematically impossible?Weighted schemes may or may not be a viable approach to combining endpoints of different metric because, arguably, endpoints may be simply incommensurable.Can anything realistically be compared with death?Is revascularization that causes transient disability and may lead to improved quality, if not quantity, of life comparable to death or myocardial infarction?Until these issues are satisfactorily addressed, is there any mathematical or statistical methodology that validates the current practice of combining endpoints of different metric?
Genetic Epidemiology of Severe, Early-onset Chronic Obstructive Pulmonary Disease
Authors: EDWIN K. SILVERMAN, HAROLD A. CHAPMAN, JEFFREY M. DRAZEN, SCOTT T. WEISS, BERNARD ROSNER, EDWARD J. CAMPBELL, WALTER J. O'DONNELL, JOHN J. REILLY, LEO GINNS, STEVEN MENTZER, JOHN WAIN, FRANK E. SPEIZER
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Severe alpha-1-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assembled a cohort of 44 probands with severe, early-onset COPD, who do not have severe alpha-1-antitrypsin deficiency. A surprisingly high prevalence of females (79.6%) was found. Assessment of the risk to relatives of these early-onset COPD probands for airflow obstruction and chronic bronchitis was performed to determine whether significant familial aggregation for COPD, independent of alpha-1-antitrypsin deficiency, could be demonstrated. First- degree relatives of early-onset COPD probands had significantly lower FEV1 and FEV1/FVC values than control subjects (p < 0.01), despite similar pack-years of smoking. Reduced spirometric values in first-degree relatives of early-onset COPD probands were found only in current or ex-cigarette smokers. The mean FEV1 in current or ex-smoking first-degree relatives was 76.1 ± 20.9% predicted compared to 89.2 ± 14.4% predicted in current or ex-smoking control subjects (p < 0.01); in lifelong nonsmokers, the mean FEV1 was 93.4% predicted for both control subjects and first-degree relatives of early-onset COPD probands. Generalized estimating equations, adjusting for age and pack-years of smoking, demonstrated increased odds of reduced FEV1 and chronic bronchitis in current or ex-smoking first-degree relatives of early-onset COPD probands. Using a new method to estimate relative risk from relative odds, we estimate that the relative risks for FEV1 below 60%, FEV1 below 80%, and chronic bronchitis are each approximately three in current or ex-smoking first-degree relatives of early-onset COPD probands. The increased risk to relatives of early-onset COPD probands for reduced FEV1 and chronic bronchitis, limited to current or ex-smokers, suggests genetic risk factor(s) for COPD that are expressed in response to cigarette smoking.