tbuckley/cabot-search huggingface dataset:
Final Results of Sequential Doxorubicin Plus Gemcitabine and Ifosfamide, Paclitaxel, and Cisplatin Chemotherapy in Patients With Metastatic or Locally Advanced Transitional Cell Carcinoma of the Urothelium
Authors: Matthew I. Milowsky, David M. Nanus, Fernando C. Maluf, Svetlana Mironov, Weiji Shi, Alexia Iasonos, Jamie Riches, Ashley Regazzi, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2009)

Purpose Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity. Patients and Methods Sixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles. Results Myelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to ≥ 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free. Conclusion AG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens.
Randomized Phase III Trial of Platinum-Doublet Chemotherapy Followed by Gefitinib Compared With Continued Platinum-Doublet Chemotherapy in Japanese Patients With Advanced Non–Small-Cell Lung Cancer: Results of a West Japan Thoracic Oncology Group Trial (WJTOG0203)
Authors: Koji Takeda, Toyoaki Hida, Tosiya Sato, Masahiko Ando, Takashi Seto, Miyako Satouchi, Yukito Ichinose, Nobuyuki Katakami, Nobuyuki Yamamoto, Shinzoh Kudoh, Jiichiro Sasaki, Kaoru Matsui, Koichi Takayama, Tatsuhiko Kashii, Yasuo Iwamoto, Toshiyuki Sawa, Isamu Okamoto, Takayasu Kurata, Kazuhiko Nakagawa, Masahiro Fukuoka
Journal: Journal of Clinical Oncology (2009)

Purpose Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life. Results Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P &lt; .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). Conclusion This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.
Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension
Authors: M. M. Hoeper, H. Leuchte, M. Halank, H. Wilkens, F. J. Meyer, H. J. Seyfarth, R. Wensel, F. Ripken, H. Bremer, S. Kluge, G. Hoeffken, J. Behr
Journal: European Respiratory Journal (2006)

Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan. The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period. The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups. The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.
Pharmacokinetics (PK), safety and tolerability of abediterol and mometasone furoate fixed- and free-dose combinations in healthy subjects
Authors: Eulalia Jimenez, Emanuel DeNoia, Sandrine Ruiz, Beatriz Seoane, Eric Massana, Gonzalo De Miquel, Carol Astbury
Journal: European Respiratory Journal (2014)

Background 

Abediterol (LAS100977) is a novel, once-daily, LABA in development for the treatment of asthma and COPD. We investigated the PK and pharmaceutical interaction of mometasone furoate (inhaled corticosteroid) in combination with abediterol in healthy subjects.

Methods 

In this Phase I, 4-way crossover study, healthy subjects were randomised to single doses of: fixed-dose combination (FDC) abediterol/mometasone 0.625/340 µg and 2.5/340 µg; free-dose combination abediterol+mometasone 2.5/340 µg; or mometasone 340 µg alone, via Genuair®/Pressair™, with ≥10-days washout. Endpoints included 36-hour PK parameters and safety and tolerability.

Results 

24/28 subjects completed the study (N=22 male, mean age 33.0 years [SD±7.0]). Mometasone disposition kinetics were similar across all treatments; tmax: 1.7 – 2.3 hours; t½: 8.5 – 9.4 hours. Abediterol tmax was achieved within 30 minutes (all treatments). Estimated t½ for abediterol 2.5 µg: 23.8 hours (FDC); 24.3 hours (free-dose). See table for PK parameter comparisons. All treatments were safe and well tolerated; the most common treatment-emergent adverse events were headache (14%), myalgia (11%), diarrhoea, nausea, vomiting and anxiety (each 7%).

Conclusion 

Abediterol and mometasone co-administration (FDC or free-dose) has minimal impact on PK parameters of either drug within predicted therapeutic dose ranges.

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Predictive value of bronchoscopy after infant cardiac surgery: a prospective study
Authors: P. P. Nayak, J. Sheth, P. N. Cox, L. Davidson, V. Forte, C. Manlhiot, B. W. McCrindle, S. M. Schwartz, M. Solomon, G. S. Van Arsdell, V. B. Sivarajan
Journal: Intensive Care Medicine (2012)
Extracellular acidosis suppresses endothelial function by inhibiting store-operated Ca2+ entry via non-selective cation channels
Authors: Masayoshi Asai, Kazuhiko Takeuchi, Masao Saotome, Tsuyoshi Urushida, Hideki Katoh, Hiroshi Satoh, Hideharu Hayashi, Hiroshi Watanabe
Journal: Cardiovascular Research (2009)

AimsHypoxia, ischaemia, and exogenous chemicals can induce extracellular and intracellular acidosis, but it is not clear which of these types of acidosis affects endothelial cell function. The synthesis and release of endothelium-derived relaxing factors (EDRFs) are linked to an increase in cytosolic Ca2+ concentration, and we therefore examined the effects of extracellular and intracellular acidosis on Ca2+ responses and EDRF production in cultured porcine aortic endothelial cells.
Acute asthma epidemics, weather and pollen in England, 1987-1994
Authors: R Newson, D Strachan, E Archibald, J Emberlin, P Hardaker, C Collier
Journal: European Respiratory Journal (1998)

Recent epidemics of acute asthma have caused speculation that, if their causes were known, early warnings might be feasible. In particular, some epidemics seemed to be associated with thunderstorms. We wondered what risk factors predicting epidemics could be identified. Daily asthma admissions counts during 1987-1994, for two age groups (0-14 yrs and > or = 15 yrs), were measured using the Hospital Episodes System (HES). Epidemics were defined as combinations of date, age group and English Regional Health Authority (RHA) with exceptionally high asthma admission counts compared to the predictions of a log-linear autoregression model. They were compared with control days 1 week before and afterwards, regarding seven meteorological variables and 5 day average pollen counts for four species. Fifty six asthma epidemics were identified. The mean density of sferics (lightning flashes), temperature and rainfall on epidemic days were greater than those on control days. High sferics densities were overrepresented in epidemics. Simultaneously high sferics and grass pollen further increased the probability of an epidemic, but only to 15% (95% confidence interval 2-45%). Two thirds of epidemics were not preceded by thunderstorms. Thunderstorms and high grass pollen levels precede asthma epidemics more often than expected by chance. However, most epidemics are not associated with thunderstorms or unusual weather conditions, and most thunderstorms, even following high grass pollen levels, do not precede epidemics. An early warning system based on the indicators examined here would, therefore, detect few epidemics and generate an unacceptably high rate of false alarms.
Clinical evaluation of a screen pneumotachograph as an in-line filter
Authors: H. Normand, F. Normand, X. Le Coutour, M-A. Metges, A. Mouadil
Journal: European Respiratory Journal (2006)

The American Thoracic Society/European Respiratory Society Task Force underlined that the use of in-line filters during respiratory function tests "is an area of controversy". The aim of the present study was to measure the contamination occurring during forced expiration downstream from a screen pneumotachograph (SP) with and without an in-line filter (Pall PF30S). A total of 40 healthy subjects performed eight consecutive maximal expiratory manoeuvres into four sterile apparatuses (A1: no filter, no SP; A2: filter-only; A3: SP-only; A4: filter and SP) in random order. A blood agar plate was fixed downstream from the apparatus. Colony-forming units (CFUs) were counted after 24 h incubation at 37 degrees C. Of the 40 plates obtained with each apparatus, 13 were sterile with A1 (range 0-679 CFUs), 25 with A2 (0-49 CFUs), 30 with A3 (0-35 CFUs) and 39 with A4 (one CFU in the only positive plate). A1 versus A2 and also A3 versus A4 gave different values for the CFU number, but A2 and A3 showed similar contamination levels. The authors conclude that: 1) the in-line filter does not perform better than a screen pneumotachograph; 2) it does not eliminate the need to decontaminate the pneumotachograph; and 3) equipment placed downstream from an in-line filter and a screen pneumotachograph is almost protected from contamination.
Gemcitabine and Docetaxel in Patients With Unresectable Leiomyosarcoma: Results of a Phase II Trial
Authors: Martee L. Hensley, Robert Maki, E. Venkatraman, Gennifer Geller, Meghan Lovegren, Carol Aghajanian, Paul Sabbatini, William Tong, Richard Barakat, David R. Spriggs
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Few chemotherapy agents are active in leiomyosarcoma (LMS), particularly LMS that has progressed after doxorubicin treatment. We sought to determine the response to gemcitabine plus docetaxel among patients with LMS. PATIENTS AND METHODS: Patients with unresectable LMS of uterine (n = 29) or other (n = 5) primary sites who did not respond to zero to two prior chemotherapy regimens were enrolled onto a phase II study of gemcitabine 900 mg/m 2 intravenously (IV) on days 1 and 8 plus docetaxel 100 mg/m 2 IV on day 8 with granulocyte colony-stimulating factor given subcutaneously on days 9 to 15, delivered every 21 days. Patients with prior pelvic radiation received 25% lower doses of both agents. Gemcitabine was delivered over 30 or 90 minutes in cycles 1 and 2 and by 90-minute infusion in all subsequent cycles. Pharmacokinetic studies assessed in vivo differences in gemcitabine concentrations with different rates of infusion. RESULTS: Thirty-four patients (median age, 55 years; range, 32 to 74 years) have enrolled. Fourteen had received prior pelvic radiation. Sixteen of 34 patients had progressed after doxorubicin-based therapy; 18 had no prior chemotherapy. Among 34 patients, complete response was observed in three patients and partial response in 15, for an overall response rate of 53% (95% confidence interval, 35% to 70%). Seven patients had stable disease. Fifty percent of patients previously treated with doxorubicin responded. Hematologic toxicity was common (neutropenia: grade 3, 15%; grade 4, 6%; thrombocytopenia: grade 3, 26%; grade 4, 3%), but neutropenic fever (6%) and bleeding events (0%) were rare. The median time to progression was 5.6 months (range, 4 to 10 months). CONCLUSION: Gemcitabine plus docetaxel is tolerable and highly active in treated and untreated patients with LMS.
Uromodulin Triggers IL-1β–Dependent Innate Immunity via the NLRP3 Inflammasome
Authors: Murthy Narayana Darisipudi, Dana Thomasova, Shrikant R. Mulay, Dorothee Brech, Elfriede Noessner, Helen Liapis, Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2012)

Uromodulin/Tamm-Horsfall protein is not immunostimulatory in the tubular lumen, but through unknown mechanisms it can activate dendritic cells and promote inflammation in the renal interstitium. Here, we noted that uromodulin isolated from human urine aggregates to large, irregular clumps with a crystal-like ultrastructure. These uromodulin nanoparticles activated isolated human monocytes to express costimulatory molecules and to secrete the mature proinflammatory cytokines, including IL-1β. Full release of IL-1β in response to uromodulin depended on priming of pro-IL-1β expression by Toll-like receptors, TNF-α, or IL-1α. In addition, uromodulin-induced secretion of mature IL-1β depended on the NLRP3 inflammasome, its linker molecule ASC, and pro-IL-1β cleavage by caspase-1. Activation of NLRP3 required phagocytosis of uromodulin particles into lysosomes, cathepsin leakage, oxidative stress, and potassium efflux from the cell. Taken together, these data suggest that uromodulin is a NLRP3 agonist handled by antigen-presenting cells as an immunostimulatory nanoparticle. Thus, in the presence of tubular damage that exposes the renal interstitium, uromodulin becomes an endogenous danger signal. The inability of renal parenchymal cells to secrete IL-1β may explain why uromodulin remains immunologically inert inside the luminal compartment of the urinary tract.
Transplantation of β-Endorphin Neurons into the Hypothalamus Promotes Immune Function and Restricts the Growth and Metastasis of Mammary Carcinoma
Authors: Dipak K. Sarkar, Changqing Zhang, Sengottuvelan Murugan, Madhavi Dokur, Nadka I. Boyadjieva, Maria Ortigüela, Kenneth R. Reuhl, Sepide Mojtehedzadeh
Journal: Cancer Research (2011)

Neurobehavioral stress has been shown to promote tumor growth and progression and dampen the immune system. In this study, we investigated whether inhibiting stress hormone production could inhibit the development of mammary carcinoma and metastasis in a rat model of breast carcinogenesis. To enhance β-endorphin (BEP), the endogenous opioid polypeptide that boosts immune activity and decreases stress, we generated BEP neurons by in vitro differentiation from fetal neuronal stem cells and transplanted them into the hypothalami of rats subjected to breast carcinogenesis. BEP-transplanted rats displayed a reduction in mammary tumor incidence, growth, malignancy rate, and metastasis compared with cortical cells-transplanted rats. BEP neuron transplants also reduced inflammation and epithelial to mesenchymal transition in the tumor tissues. In addition, BEP neuron transplants increased peripheral natural killer (NK) cell and macrophage activities, elevated plasma levels of antiinflammatory cytokines, and reduced plasma levels of inflammatory cytokines. Antimetastatic effects along with stimulation of NK cells and macrophages could be reversed by treatment with the opiate antagonist naloxone, the β-receptor agonist metaproterenol, or the nicotine acetylcholine receptor antagonist methyllycaconitine. Together, our findings establish a protective role for BEP against the growth and metastasis of mammary tumor cells by altering autonomic nervous system activities that enhance innate immune function.
Role of acute diverticulitis in the development of complicated colonic diverticular disease and 1-year mortality after diagnosis in the UK: population-based cohort study
Authors: David J Humes, Joe West
Journal: Gut (2011)

<h3>Objective</h3> To determine the risk of developing complicated colonic diverticular disease (CCDD) with prior episodes of acute diverticulitis and determine the mortality of the spectrum of CCDD. <h3>Design</h3> Population-based cohort study. <h3>Setting</h3> Computerised records from the General Practice Research Database linked to Hospital Episode Statistics data from the UK. <h3>Participants</h3> Patients and controls registered in the General Practice Research Database from 1990 to 2007. <h3>Main outcome measures</h3> Mortality was calculated and Cox regression modelling used to provide adjusted HRs and 95% CI. Logistic regression was used to model the effect of prior acute diverticulitis on the development of complications. <h3>Results</h3> 2950 patients (1872 (63.5%) female) had a diagnosis of CCDD (8739 controls). A total of 1042 (35.3%) patients died compared with 2062 (23.6%) controls. Most excess deaths occurred in the first year after the complication. Patients with a perforation/abscess had a 4.5-fold increase in 1-year mortality (HR 4.55, 95% CI 3.74 to 5.52) compared with the general population, whereas those with a fistula or stricture had a 2.5-fold increase in mortality (fistula HR 2.60, 95% CI 1.47 to 4.62; stricture HR 2.41, 95% CI 1.86 to 3.11). Although most patients (2133 (72.3%)) had suffered no prior episodes of acute diverticulitis, increasing episodes of acute diverticulitis were associated with an increased risk of developing a fistula (two or more prior episodes, OR 1.54 95%, CI 1.08 to 2.19), but there was no clear relationship with stricture or perforation/abscess. <h3>Conclusions</h3> Although most patients have experienced no prior episodes of acute diverticulitis, fistula formation is preceded by bouts of inflammation. Excess 1-year mortality across the spectrum of CCDD compared with the general population is substantial.
Molecular and particulate depositions for regional myocardial flows in sheep.
Authors: J B Bassingthwaighte, M A Malone, T C Moffett, R B King, I S Chan, J M Link, K A Krohn
Journal: Circulation Research (1990)

The deposition of microspheres in small tissue regions is not strictly flow dependent. In comparison with the soluble flow marker 2-iododesmethylimipramine (IDMI), deposition of 16.5-microns microspheres was mildly but systematically biased into high flow regions of rabbit hearts (Bassingthwaighte JB, Malone MA, Moffett T-C, King RB, Little SE, Link JM, Krohn KA. Am J Physiol 1987;253 (Heart Circ Physiol 22):H184-H193). To examine the possibility of bias in larger hearts, a similar study was undertaken in sheep. 141Ce- and 103Ru-labeled 16.5-microns microspheres in one syringe and 125I- and 131I-DMI in another syringe were injected simultaneously into the left atrium of five open-chest sheep while obtaining reference blood samples from the femoral artery. In six other sheep, one microsphere type and one IDMI were used. Hearts were removed 1 minute after injection, cut into approximately 254 pieces averaging 217 mg, and regional deposition densities calculated for each tracer from the isotopic counts. Correlations in the five animals between the two differently labeled IDMIs and between the two microspheres were both greater than or equal to 0.98. In all 11 sheep, scatter plots of microsphere deposition densities versus IDMI densities showed that differences between microspheres and IDMI had substantially more scatter (0.84 less than r less than 0.98) but were not random. Microsphere depositions tended to be lower than IDMI depositions in low flow regions and higher in high flow regions, in accord with the expected bias that at a bifurcation a microsphere is most likely to enter the branch with higher flow. There was less bias ascribable to endomyocardial/epicardial maldistribution. Thus, while microsphere depositions appear to err systematically with respect to flow when the regions of interest are small enough that the diameters of their arterioles are only a few times those of the microspheres, microspheres are, in sheep as in rabbits, adequate for estimating regional flows.