tbuckley/cabot-search huggingface dataset:
Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid vs high dose 24h 5-FU infusion/folinic acid (FA) + oxaliplatin(OXA) in metastatic colorectal cancer (MCRC)
Authors: G. Hospers, M. Schaapveld
Journal: Journal of Clinical Oncology (2004)

3539 Background:Oxaliplatin in combination with 5-FU and FA has demonstrated improved outcome as first line and second line treatment in patients (pts) with MCRC. Methods: From July 1999 till August 2002, 302 pts with MCRC were randomized in a phase III study and received as first line treatment bolus 5-FU 425 mg/m2 day 1–5, FA 20 mg/m2 day 1–5, q 4 wk (MA) or OXA 85 mg/m2, 2h-infusion, FA 200 mg/m2, 1h- infusion, 5-FU 2600 mg/m2, 24h-infusion day 1, q 2 wk (OX). The primary endpoints were response rate (RR) and toxicity. Courses were to be continued to progression. Results: 300 pts have been randomized and analyzed for toxicity and efficacy. Treatment arms were balanced for age, sex, PS, tumor sites, prior adjuvant chemotherapy. Number of courses (median) MA vs OX: 6 vs 8. The median follow up is 15.8 month, 70% of the pts have died. An updated analysis will be presented at the meeting. Table 1 shows the grade 3/4 toxicity and efficacy data. In the MA arm there was one TD due to neutropenic septicaemia. Immunological events occurred only in the OX arm; 2 classical anaphylaxis, 5 atypical with; hemolysis, thrombocytopenia, renal and pulmonary dysfunction, with one TD. During treatment with OX, fever (> 38 C) without leucopenia of infection, occurred more often than in the MA arm (odds ratio 3.048). Second line treatment was not specified in the protocol, cross-over of MA to OX occurred in 13%. Conclusions: OX in the first line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhea compared with MA. Immunological side effects deserve attention with OX. Despite a low treatment cross-over rate, OS in both groups was comparable. (Supported by Sanofi-Synthelabo). No significant financial relationships to disclose.
Is obstructive lung disease correlated to age and smoking habit or is there more
Authors: Saeeda Lone, Remco Boksem, Reindert Van Steenwijk
Journal: European Respiratory Journal (2011)

Background:  On World Spirometry Day lung function measurements were done to identify obstructive persons without a previous diagnose of an obstructive lung condition and to rise awareness on lung health and disease.   Aim:  To establish the significance of the degree of obstruction in relation to reported symptoms and other characteristics.   Methods:  783 participants performed lung function and filled a standard questionnaire. The degree of obstruction in relation to smoking, shortness of breath, cough, age and BMI were investigated. Significance in relationships was measured with multivariate analysis with backward elimination.   Results:   In 15.8% an abnormal lungfunction was measured: 124 times obstruction based on FEV 1 /FVC and another 43 cases with a FEV 1  below 80%.  In a linear regression model smoking (β = 0.015 p   Conclusions:  There was a positive correlation between age and smoking but no correlation with other characteristics. Amongst the older obstructive participants there is a large group of non-smokers who need further investigation.   Implications:  In its current form the WSD cannot identify persons at risk for an obstructive lung disease. In case of a low FEV 1  and/or a low FEV 1 /FVC the test should also be repeated after a bronchodilator.There has to be a good description of the target group and a questionnaire adapted to the group.
Stability and microbial properties of reconstituted and diluted epoprostenol with expanded stability
Authors: Olivier Lambert, Dirk Bandilla, Rupa Iyer, Leonore Witchey-Lakshmanan, Nagesh Palepu
Journal: European Respiratory Journal (2011)

Microbial activity and stability of epoprostenol with expanded stability (EPO-ES, Veletri®) were investigated at 5°C and 25°C over a range of concentrations. EPO-ES was reconstituted and immediately diluted with sterile Water for Injection (WFI) or Sodium Chloride 0.9% Injection (NaCl). Stability for up to 72 hours (h) at 25°C was measured immediately following dilution (A), and after 1 (B) or 7 days (C) storage at 5°C. Shelf-life was assessed by determining the time over which potency ≥90% was maintained. For microbiological testing, diluted samples of EPO-ES were inoculated with S. aureus, P. aeruginosa, E. coli, C. albicans, A. niger or C. sporogenes and incubated for up to 14 days at 5°C or 4 days at 25°C. Potency of EPO-ES 6,000 ng/mL at 12h under test condition B was 92% for both diluents.

View this table:

Table 1. Potency of EPO-ES over time (Condition A)





View this table:

Table 2. Shelf-life (hours) of reconstituted and immediately diluted EPO-ES at 25°C based on potency and microbiological testing





Potency of EPO-ES 9,000 ng/mL under test condition C was 91% for WFI and 87% for NaCl at 12h, and ≥90% for both diluents at 12 and 24 h at 12,000 and 30,000 ng/mL. No microbial proliferation occurred in any diluted solution of EPO-ES.
Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells
Authors: Abdullah Alsuliman, Dilek Colak, Olfat Al-Harazi, Hanaa Fitwi, Asma Tulbah, Taher Al-Tweigeri, Monther Al-Alwan, Hazem Ghebeh
Journal: Molecular Cancer (2015)

The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified. We have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections. Induction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation. We have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment.
Abstract 1008: Inflammatory Cytokines Mobilize Bone Marrow Cells to Vascular Wall, Resulting in Neointimal Formation through Their Inflammatory Effects
Authors: Makoto Shoji, Hiroshi Suzuki, Taro Kusuyama, Yasutoshi Omori, Teruko Soda, Fumiyoshi Tsunoda, Takatoshi Sato, Shinji Koba, Eiichi Geshi
Journal: Circulation (2006)
Abstract 269: Cardiac Aging in Rats: Do Female and Male Hearts Age Differently?
Authors: Eduard I Dedkov, Alessandro Pingitore
Journal: Circulation Research (2012)

Background: In recent years, the use of middle-aged and old animals of both sexes has become preferential in experimental studies involving the models of cardiovascular diseases to better reflect a human population. However, the evidence showing the extent of sex-related differences in cardiac aging of laboratory animals remains obscure. Accordingly, we designed our study to determine whether the male and female rats differ during aging with regard to left ventricular (LV) geometry and systolic function. Methods: We performed transthoracic echocardiographic examinations in 12-month-old (12mo) and 24 month-old (24mo) male and female Sprague-Dawley rats (Charles River, Wilmington, MA) under 1.5% isoflurane anesthesia using a linear (Matrix) array transducer probe GE M12L (5.5-14.0 MHz) and a GE Vivid 7 Dimension ultrasound system. Two-dimensional short-axis views and M-mode tracings of the LV at the papillary muscle level were recorded and used to estimate various LV parameters. Results: We found that 24mo-Female rats had a significant increase in LV chamber dimensions associated with a reduction in its systolic performance as compared to 12mo-Female rats (Table 1). In contrast, LV parameters remained similar between 12mo- and 24mo-Male rats. Table 1. Echocardiographic parameters of LV chamber geometry and systolic performance Values are means ± SE. Arrow indicates a significant difference between age groups ( P ≤ 0.05). Conclusion: Our data demonstrate that during cardiac aging female rats have a different pattern of LV changes compared to males that must be considered in the design of future experimental studies.
Exposure to aminoglycosides should be monitored during treatment
Authors: E. J Begg, S. B Duffull, C. M Kirlpatrick
Journal: BMJ (1996)

EDITOR,—In her commentary on Michael Barza and colleagues' meta-analysis of whether aminoglycosides should be given in single or multiple daily doses, Fiona Smaill advocates once daily dosing.1 We agree with her but believe that her recommendation not to monitor aminoglycoside concentrations routinely is ill conceived. Opinion on this …
LSC 2014 abstract - Matriptase is an important player in fibroproliferative disorders
Authors: Olivier Bardou, Charlene Francois, Nicolas Carlier, Herve Mal, Bruno Crestani, Keren Borensztajn
Journal: European Respiratory Journal (2014)

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder which remains refractory to therapies. Recently, type II transmembrane serine proteases have emerged as key actors in pathophysiology, by proteolysis of cell surface receptors and/or cell environment, thereby orchestrating cell crosstalks. Among them, deregulation of the matriptase contributes to various proliferative disorders. These observations lead us to investigate the role of matriptase in pulmonary fibrosis.  Matriptase expression and activity were analyzed in human lung material from controls and IPF patients. Human fibroblasts were stimulated with recombinant matriptase and the activation of key signaling pathways involved in IPF was analyzed. Impact of matriptase on human lung fibroblast proliferation and migration was then evaluated. Using the murine model of bleomycin-induced pulmonary fibrosis, mice were administrated for 14 days with 0 or 0.5mg of camostat mesilate (CM), a matriptase inhibitor. The markers of tissue fibrosis in lung homogenate were measured; cytokines and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) of the animals were assessed.  We show that matriptase is upregulated in the lung and BALF of IPF patients compared to controls. In fibroblasts, matriptase induced the activation of p42/44, Akt, EGFR and Smad2/3 pathways. Finally, CM administration in bleomycin-treated mice led to a significant decrease of fibronectin and collagen expression. Cytokines and inflammatory cell influx in BALF were diminished in bleomycin+CM group compared to bleomycine-treated animals. Matriptase seems instrumental in pulmonary fibrosis, and targeting matriptase with CM could be a promising therapeutic way for IPF.
Incident pulmonary arterial hypertension in a Brazilian reference center: Results of a four-year registry
Authors: Jose Leonidas Alves-Jr., Francisca Gavilanes, Carlos Jardim, Caio Fernandes, Luciana Kato, Susana Hoette, Bruno Dias, Andre Hovnanian, Rogerio Souza
Journal: European Respiratory Journal (2013)

Background: There is an increasing interest in the worldwide characteristics of pulmonary arterial hypertension (PAH) patients although data from the southern hemisphere are still scarce.  Objective: To describe baseline characteristics of incident PAH cases from a large Brazilian reference center.  Methods: All consecutive patients diagnosed as PAH between 2008 and 2012 were included in the study. Baseline clinical, functional and hemodynamic data were collected for all patients.  Results: A total of 171 patients were enrolled in the study (mean age of 46.8 ± 14.6 yo, female/male ratio of 3.3:1 and 45.9% in functional class III or IV). Connective tissue disease (CTD), idiopathic (IPAH), schistosomiasis and porto-pulmonary hypertension (PoPAH) accounted for 29, 25, 17 and 10% of all cases, respectively. Mean pulmonary artery pressure and cardiac output were 50.8 ± 19.2 mmHg and 4.6 ± 1.7 l/min, respectively, with mean six-minute walk distance of 420 ± 111 m and mean BNP levels of 212 ± 300 pg/ml. Female predominance was more evident in CTD and higher cardiac output was found in PoPAH. Furthermore, IPAH patients were younger than the other groups (mean age 40.7 ± 15.5 yo). The higher prevalence of CTD, as compared to previous registries, might be explained by the existence of a large rheumatology reference center in our University.  Conclusions: Our results highlight the importance of regional registries in rare diseases for reflecting the existence of specific clinical conditions and health policies, such as schistosomiasis and the interaction with the rheumatology department, in order to appropriately design regional strategies for management of PAH.
Bone marrow-derived MSCs from patients with COPD have abnormal functional capacity
Authors: Andreas Jahn, Carlos Rio, Orlando Gigirey, Laura Fueyo, Catalina Balaguer, Aina Noguera, Juan Antonio Torrecilla, María Antonia Duran, Severiano Dosanjos, Ramon Llull, Luis A. Ortiz, Ernest Sala-Llinas
Journal: European Respiratory Journal (2013)

Introduction : Chronic Obstructive Pulmonary Disease (COPD) is a major health problem. Bone marrow (BM)-derived MSCs have been shown to contribute to pulmonary repair and regeneration in experimental models. However, their role in COPD is unclear. Since COPD is also characterized by systemic inflammation, we hypothesize that BM-MSCs functional capacity and/or regenerative capability can be altered in these patients.   Aims : To study the functional capacity of BM-MSCs from COPD patients (BM-COPD) compared to BM-MSCs from controls (BM-C). We have evaluated: 1) the cellular response of MSCs to both tobacco smoke (TS) and VEGF; and, 2) their differentiation capacity.   Methods : MSCs were isolated from BM of sternum from subjects who underwent thoracic surgery. After treatments, MSCs were monitored with the xCELLigence system. This system measures real time changes in cellular impedance providing a value named cell index (CI). The differentiation protocol and cellular staining was carried out following RD 2) Both COPD and C cells react to VEGF also in a dose/time dependent manner, but at the higher doses and the longer times, BM-COPD are 4 times less sensitive than BM-C; and, 3) There is also a clear differentiation deficiency in BM-COPD, at least to adipocytes.   Conclusions : BM-COPD have abnormal functional capacity compared with BM-C. However, whether BM-MSCs can be involved in the pathogenesis of COPD should be evaluated in further studies. Supported by FIS 10/00983 and SEPAR 2011.
The Volume of Cell Nuclei in Amputation Neuromas and in Neurofibromas
Authors: Rudolf Altschul, Aganeta M. Friesen
Journal: Cancer Research (1949)

The enlargement of nuclei in damaged skeletal muscle and in severed tendons and nerves is reviewed. It is believed that a common factor in these different tissues is a decrease of extranuclear pressue leading to a secondary nuclear enlargement which in turn may result in nuclear division.

Sheath nuclei in twelve amputation neuromas and in three neurofibromas were measured. They were distinctly larger than the nuclei in the adjacent normal nerve segments. Some relations between amputation neuromas and neurofibromas are discussed. It is believed that in the former the nuclear increase is caused by a loss of pressure equilibrium, due to the severing of the connective tissue sheaths. It is possible that in neurofibromas some obscure weakness of the perineurium may be responsible for a similar loss of intraneurial but extranuclear pressure and thus for the ensuing nuclear enlargement and proliferation.
Abstract #5440: Pharmacokinetics of ABI-007, cremophor-free nanoparticle formulation of paclitaxel, in Japanese and Chinese patients with malignancies
Authors: Koji Furushiro, Tomohide Tamura, Hironobu Minami, Toru Mukohara, Yasuhiro Fujiwara, Noboru Yamamoto, Kazuhiko Yamada, Yasuhide Yamada, Hikaru Nakajima, Shunji Nagai, Masashi Ando, Kan Yonemori, Eriko Nakano, Mayu Yunokawa, Tsutomu Kouno, Chikako Shimizu, Kenji Tamura, Noriyuki Katsumata, Guan Zhongzhen, Hidetoshi Yamaya, Neil Desai, Vuong Trieu
Journal: Cancer Research (2009)

Background:  ABI-007 is a novel cremophor-free nanoparticle formulation of paclitaxel. The elimination of cremophor allows for a higher dosage of paclitaxel in shorter infusion period without premedication. Recently, pharmacokinetic studies of ABI-007 were conducted in Japan and China to assess the PK of ABI-007 as well as the tolerability and safety. This analysis was conducted to evaluate the ethnic differences in PK and tolerability between Asian and Caucasian population.  Method:  In two Phase I trials of Japanese patients with advanced solid tumor, fifteen patients received weekly regimen at doses of 80, 100, 125 mg/m 2 , and twelve patients received every three weeks regimen at doses of 200, 260, 300 mg/m 2  via intravenous infusion for 30 minutes. The concentration data of total 27 patients was analyzed both in whole blood and plasma. Subsequently, Chinese Phase III study evaluating ABI-007 at 260 mg/m 2  in patients with breast cancer and its companion PK analysis of twelve patients were referenced to compare PK, tolerability and safety profiles of Asian population with those of Caucasian in retrospective manner.  Results:  ABI-007 was well tolerated up to 100 mg/m 2  with weekly schedule, and up to 300 mg/m 2  with once every three weeks schedule in  two Japanese studies, and a combination analysis of both studies successfully demonstrated the dose-proportional exposure of ABI-007 as having been observed in Caucasian. Moreover, the time-concentration profiles and PK parameters in both Japanese and Chinese patients at the dose of 260mg/m 2  were similar to those reported in the West. [Table] There were no significant differences in the tolerability and safety profiles between both ethnic groups.  Conclusion:  Both pharmacokinetics and tolerability of ABI-007 were similar among Japanese, Chinese and Western population. The common dosage and regimen of ABI-007 may be applicable to these populations.$$table_{D4521BAC-7173-473C-812E-3F93BCD5FB42}$$   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5440.
Hyperventilation in Patients Who Have Sustained Myocardial Infarction after a Work Injury
Authors: Stuart D Rosen, Jenny C King, Peter G F Nixon
Journal: Journal of the Royal Society of Medicine (1994)

Patients who present with acute myocardial infarction after a work injury (AMI-WI) often report symptoms consistent with chronic hyperventilation which date back as far as the work injury itself, rather than to the AMI. The aim of the study was to test the hypothesis that hyperventilation significantly contributes to the symptoms of AMI-WI patients. The prevalence of hyperventilation was assessed by clinical capnography in 12 AMI-WI patients, 20 normal controls, 15 AMI patients whose AMI was conventional and not subsequent to a work injury (AMI-C) and 14 patients with post-traumatic stress disorder (PTSD). End-tidal carbon dioxide partial pressure (P(et)CO2) was measured at rest, after 1 min hyperventilation (FHPT), after recall of the relevant stressor (Think) and when the breathing was felt to be normal (MBIN). P(et)CO2 levels after FHPT were: 29.0 +/- 1.5 (mean +/- SD) mmHg for AMI-WI; 26.7 +/- 1.9 mmHg for PTSD; 32.1 +/- 4.1 mmHg for AMI-C and 33.7 +/- 1.4 mmHg for the controls (P < 0.05 and P < 0.01 for AMI-WI and PTSD, respectively, versus controls). After Think, the levels were 25.8 +/- 1.6 mmHg for AMI-WI, 24.6 +/- 1.4 mmHg for PTSD, 31.2 +/- 4.1 mmHg for AMI-C and 31.2 +/- 1.5 mmHg for normals (P < 0.05 and P < 0.01 for AMI-WI and PTSD, respectively, versus controls). For MBIN, values of P(et)CO2 were 26.8 +/- 1.7 mmHg and 26.7 +/- 1.5 mmHg for AMI-WI and PTSD versus 33.8 +/- 1.2 mmHg for normals, (P < 0.01 for both versus controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Detection of the t(2; 5)(p23; q35) and NPM-ALK Fusion in Non-Hodgkin's Lymphoma by Two-Color Fluorescence In Situ Hybridization
Authors: Prasad Mathew, Warren G. Sanger, Dennis D. Weisenburger, Marcus Valentine, Virginia Valentine, Diane Pickering, Chris Higgins, Michelle Hess, Xiaoli Cui, Deo Kumar Srivastava, Stephan W. Morris
Journal: Blood (1997)
Airway Wall Thickness in Asthma Assessed by Computed Tomography
Authors: AKIO NIIMI, HISAKO MATSUMOTO, RYOICHI AMITANI, YASUTAKA NAKANO, MICHIAKI MISHIMA, MASAYOSHI MINAKUCHI, KOICHI NISHIMURA, HARUMI ITOH, TAKATERU IZUMI
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Postmortem studies have shown that airway wall thickening is present in asthmatic patients and may play a pathophysiologic role. We investigated the presence and characteristics of airway wall thickening in patients with asthma, using helical computed tomography. Eighty-one asthmatic patients and 28 healthy control subjects were studied cross-sectionally. Airway wall thickness was assessed by a validated method on the basis of wall area (WA), WA corrected by body surface area (WA/BSA), and WA%, defined as (WA/total area) x 100 at the apical bronchus of the right upper lobe. Airway luminal area (Ai) and Ai/BSA were also examined. Asthma duration and severity, pulmonary function, and serum eosinophil cationic protein levels were evaluated. Intraobserver and interobserver reproducibility of WA, WA%, and Ai measurements were good. As compared with control, WA, WA/BSA, and WA% were significantly increased in patients with mild (n = 13), moderate (39), and severe persistent (22) asthma but not in patients with intermittent asthma (7). Comparison of the four asthmatic subgroups demonstrated thicker airways in more severe disease, but no difference in Ai or Ai/BSA. When all asthmatic patients were analyzed together, WA and WA/BSA correlated with the duration, although weakly, and severity of asthma. WA and WA/BSA negatively correlated with FEV(1) (percentage of predicted), FEV(1)/FVC (%), and FEF(25-75%) (percentage of predicted), whereas WA% negatively correlated with only FEV(1). We conclude that airway wall thickening occurs in patients with asthma and is not limited to those with severe disease. The degree of airway wall thickening may relate to the duration and severity of disease and the degree of airflow obstruction.
Practical, regulatory and clinical considerations for development of inhalation drug products
Authors: Shuguang Hou, Jiangyue Wu, Xu Li, Hong Shu
Journal: Asian Journal of Pharmaceutical Sciences (2015)

The formulation and device collectively constitute an inhalation drug product. Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction. From the points of formulation, device and patient use, this article summarizes the inhalation drugs, including pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), and nebulizer that are currently available in the US and UK markets. It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency).