tbuckley/cabot-search huggingface dataset:
Inhibition of Dihydroorotase in Pyrimidine Biosynthesis
Authors: Lloyd H. Smith, Margaret Sullivan, Faith A. Baker, Elizabeth Frederick
Journal: Cancer Research (1960)

Summary  Five structural analogs of carbamylaspartic acid—carbamylglutamic acid, carbamylcysteic acid, carbamylcysteinesulfinic acid, carbamylasparagine, and α-ureido-β-methyl-succinic acid—have been studied as inhibitors of dihydroorotase. The inhibitory activities of these analogs varied considerably in the three  in vitro  assay systems utilized— E. coli B  extracts, rat liver homogenates, and human leukocyte sonicates. The inhibition observed was found to be competitive. Some of the biochemical characteristics of the conversion of carbamylaspartic acid to orotic acid in human leukocyte sonicates were studied. In normal circulating leukocytes this two-step conversion was found to be of reproducible activity. The effectiveness of carbamylaspartic acid analogs as  in vivo  inhibitors of nucleic acid synthesis or as carcinostatic agents has yet to be evaluated.
Peripheral blood neutrophil activity during D. pteronyssinus induced late-phase airway inflammation in asthma and rhinitis patients
Authors: Simona Lavinskiene, Jolanta Jeroch, Ieva Bajoriuniene, Kestutis Malakauskas, Edita Gasiuniene, Raimundas Sakalauskas
Journal: European Respiratory Journal (2012)

Background. Recent investigations suggest that neutrophils may play an important role in the late-phase allergen-induced inflammation in allergic airway diseases.  Aim. To evaluate neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) production in patients with allergic asthma and rhinitis challenged with inhaled D. pteronyssinus.  Methods. Twenty eight patients with allergic asthma and 27 with rhinitis, all sensitized to D. pteronyssinus, as well as 10 healthy subjects underwent bronchial challenge with D. pteronyssinus. Neutrophils from peripheral blood were isolated 24 h before as well as 7 h and 24 h after challenge. For chemotaxis analysis neutrophils were stimulated with interleukin-8, and for ROS analysis as well as for phagocytosis cells were stimulated with S. aureus bacteria. Neutrophil functions were analyzed flow cytometrically.  Results. Neutrophils chemotaxis and ROS production were increased, while phagocytosis was decreased 24 h before challenge in patient groups compared with healthy subjects (P  Conclusions. Results show that peripheral blood neutrophil activity is impaired in allergic asthma and rhinitis patients. D. pteronyssinus induced late-phase airway inflammation enhance their chemotaxis, phagocytosis and ROS production.
Hemodynamic effects of different vasodilators in patients with type II pulmonary hypertension (PH)
Authors: Andrei Bautin, Dmitrii Tashkhanov, Sergey Datsenko, Petr Fedotov, Andrei Iakovlev, Olga Moiseeva, Maria Sitnikova
Journal: European Respiratory Journal (2014)

Purpose. To evaluate the hemodynamic effects of nitric oxide(NO) and inhaled iloprost in patients with PH associated with left ventricular (LV) systolic dysfunction.  Materials and Methods. 72 right heart catheterizations and vasoreactivity tests (VRT) were performed in 58 candidates for heart transplantation. All the patients had heart failure (HF) III-IV NYHA and PH associated with LV systolic dysfunction. NO, 60 ppm for 20 min (43 cases, NO gr.), or inhaled Iloprost 5 mcg (29 cases, iloprost gr.) were used for VRT. Hemodynamic effects were estimated at baseline, then after 20 min period of NO inhalation, or 15 min post the completion of iloprost inhalation. T-test for dependent samples and Fisher9s exact test were used for analysis.  Results. There were no differences between the groups in age, HF severity or baseline PAmean and PVR. Both vasodilators significantly decreased PVR. PCWP increased in 20 cases (46,5%) in NO gr. and in 7 cases (24,1%) in iloprost gr. (p  Fall of the afterload resulted in a considerable enhancement in LV performance in iloprost gr., stroke volume index (SVI) significantly increased. There were no changes in LV performance in NO gr.  Conclusions. Inhaled Iloprost causes favorable changes in preload and afterload of the impaired LV and increases its performance in patients with PH associated with LV systolic dysfunction.
LSC 2013 abstract - TLR7 decreases and TLR9 increases the airway responses in mice with established allergic inflammation
Authors: Mikael Adner, Magnus Starkhammar, Susanna Kumlien Georen, Sven-Erik Dahlén, Lars Olaf Cardell
Journal: European Respiratory Journal (2013)

Toll-like receptor (TLR) 7 and TLR9 are localized in the endosomal compartment of the cell sharing the same adaptor protein. Their effect on an established allergic airway inflammation remains to be described. To this end, mice with an established ovalbumin (OVA)-induced allergic airway inflammation were given R848, a TLR7 agonist and CpG, a TLR9 agonist intranasally during four consecutive days. At day five the methacholine induced airway reactivity (AR) and the numbers of inflammatory cells in lung tissue and bronchial lavage fluid as well as presence of various mediators were assessed. OVA treatment enhanced AR. R848 had no effect on airway reactivity among control mice, but decreased the OVA-induced hyperresponsiveness. CpG increased AR in controls but did not affect the increase in airway reactivity caused by OVA treatment. OVA augmented the number of eosinophils and macrophages in bronchial lavage fluid. These increases were reduced by R848 and CpG. CPG enhanced the number of neutrophils and lymphocytes in control pulmonary tissue. The increase of neutrophils was not affected by an established allergic inflammation. In contrast, R848 did not influence pulmonary cell infiltration regardless of treatment. Enhanced pulmonary levels of IL-5 and leukotriene B4 were seen after OVA, an effect reversed by R848-treatment. CpG increased the levels of pro-inflammatory mediators like IL-12, CXCL1 and CXCL9 in both control and OVA-treated mice. The conclusion from this study is that TLR7 activation interact with and decrease the outcome whereas TLR9 activation mainly does not react with and are not affected by an established allergic reaction.
Detection of Combined Hepatocellular and Cholangiocarcinomas: Enhanced Computed Tomography
Authors: Akihiro Nishie, Kengo Yoshimitsu
Journal: Liver Cancer (2009)

Most primary liver cancers are grossly divided into two histologic categories: hepatocellular carcinoma (HCC), derived from hepatocytes, and cholangiocellular carcinoma (CC), arising from the intra-hepatic bile duct epithelium. Combined hepatocellular and cholangiocarcinoma (cHCC-CC) is a rare form of primary liver cancer presenting histologic evidence of both hepatocellular and biliary epithelial differentiation, and is seen in 1.0–3.3% of surgically treated patients with pri mary liver tumors (The liver cancer study group of Japan, 1990; Aoki et al., 1993). Comparing the clinicopathological fea tures of patients with cHCC-CC with those of HCC or CC patients has yielded somewhat conflicting results in several studies. In many studies, cHCC-CC was found to be more prevalent in males (Lee et al., 2002). The incidence of positive hepatitis B or C serological test results in the cHCC-CC group is reported to be intermediate between that in the HCC group and in the CC group (Liu et al., 2003; Koh et al., 2005), or to be similar to that in the HCC group (Yano et al., 2003). Furthermore, the incidence of underlying chronic liver disease in the cHCC-CC group is also intermediate between that in the HCC group and in the CC group (Yano et al., 2003; Liu et al., 2003), or similar to that in the HCC group (The liver cancer study group of Japan, 1990). On the other hand, Jarnagin et al. (2001) reported that the incidence of positive hepatitis B or C serology and liver cirrhosis in patients with cHCC-CC was similar to that in CC patients. The reasons for the difference in this clinicopathological feature may include the difference between Western and Asian societies in the cause of liver cancer or the difference in the selection criteria of patients for hepatic resection (Liu et al., 2003). The survival rate in patients with cHCC-CC has been reported to be worse than that in patients with HCC or CC (Jarnagin et al., 2001; Yano et al., 2003; Liu et al., 2003), while Koh et al. (2005) concluded that the cHCC-CC group had a prognosis that was better than the CC group but worse than the HCC group. We have not come to a conclusion about clinicopathological features of cHCC-CC at the present time, and more cases must be analyzed to elucidate them. In our daily practice we tend to be distressed at the difficulty of making a preoperative diagnosis of this type of tumor because it is rarely encountered. In an examination performed by The liver cancer study group of Japan (1990), the frequency of lymph node metastases in patients with cHCC-CC was 76.2% and was as high as that in patients with CC, while that in patients with HCC is 30.3%. Some of the literature suggests that there was a need for a lymph node resection dur ing a hepatectomy for cHCC-CC (Uenishi et al., 2000; Sasaki et al., 2001; Eguchi et al., 2002). Therefore, it is important to make a diagnosis of cHCC-CC preopera-tively.
Investigation for candidate genes of glucocorticoid resistance by genome-wide gene expression profiling in animal model of asthma
Authors: Zsolt István Komlosi, Ildikό Ungvári, Έva Hadadi, Viktor Virág, Katalin Έder, Gergely Tölgyesi, András Falus, György Losonczy
Journal: European Respiratory Journal (2011)

The prevalence of impaired glucocorticoid (GC) responsiveness or GC resistance (GR) is 5-10% among asthma patients, even so 50% of asthma-related health care costs are spent on these cases. We have developed a murine model of asthma with GR (Clin.Exp.Allergy 2006;36:951). Ovalbumin (Ova) challenge, preceded by intranasal lipopolysaccharide priming, resulted in more severe eosinophil inflammation in Ova sensitized BALB/c mice (LPS/OVA) than Ova provocation alone (OVA). Moreover, the airway inflammation was resistant to dexamethasone (Dex) treatment in LPS/OVA mice. To further investigate the mechanisms of GR in this model, we have performed 20 whole mouse gene expression microarrays (44K; Agilent, St.Clara, USA). Total lung tissue mRNA expression of GC sensitive (OVA) and resistant (LPS/OVA) mice, as well as their Dex-treated counterparts (OVA+Dex and LPS/OVA+Dex) were compared with the gene expression profile of control (C) animals using two sample t test (n=4/group). The obtained gene lists were further dissected by GeneSpring GX (Agilent), considering only the significantly altered genes (p<0.01 vs. C) that show at least 2-fold up or down regulation. From these genes 23 were identified to be GR-related, i.e. were found in the common cluster of uniquely changed genes of LPS/OVA (but not OVA) and LPS/OVA+Dex (but not OVA+Dex) mice. Members of known asthma-related (eg. Serpine1) and GR pathways (eg. transforming growth factor β-2) were found to be involved in our model supporting relevance of this model to human disease. We have also nominated new candidate genes as potential therapeutic targets for GR in asthma. Funded by Hungarian Respiratory Society.
A phase I/II trial of BBR-2778 (pixantrone), methylprednisolone, cisplatin, and cytosine arabinoside (BSHAP) in relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL)
Authors: G. Camboni, L. Fayad, A. Tulpule, M. Modiano, B. M. Espina, F. Cabanillas, A. M. Levine
Journal: Journal of Clinical Oncology (2004)

6590 Background: BBR-2778 (Pixantrone) is a novel aza-anthacenedione DNA intercalator with anti-tumor synergy with cisplatin, no delayed cardiotoxicity in animal models, and evidence of anti-tumor activity in vivo. Pixantrone was substituted for etoposide in the ESHAP regimen to define the safety and efficacy profile in patients(pts) with aggressive relapsed or refractory non-Hodgkin's lymphoma (NHL). Methods: All pts received BBR-2778 (pixantrone) 80 mg/m2, IV day 1; methylprednisolone 500 mg IV days 1–5; cisplatin, 25 mg/m2, IV over 30 minutes, days 1–4; and cytosine arabinoside, 2000 mg/m2 IV, day 5. Treatment was given every 21 days as an outpatient, when possible. Results: 21 patients with a median age of 50 years (range 35–75) were studied. Pathologies included diffuse large B-cell or variants in 19 (90%) and follicular grade 3 in 2. 18 (86%) had stage III or IV disease. All received a prior anthracycline-containing regimen. 14 (67%) were refractory to their immediate prior regimen. Initially, 4 dose levels of pixantrone were planned. However after 2 dose limiting toxicities (grade 3 infection; febrile neutropenia), 80 mg/m2 was defined as the maximum tolerated dose. The most common grade 4 side effects were hematologic: neutropenia in 13 (68%), including febrile neutropenia in 5 (26%); thrombocytopenia in 8 (42%), and anemia in 4 (21%). No clinically significant cardiac events or decreases in LVEF ≥ 20% were noted. Non-hematologic side effects were mostly grade1 or 2 in severity. Of 18 pts evaluable for response, complete remission (CR) was documented in 7 (39%) and partial remissions (PR) in 4 (22%) for a major response rate of 61%. Among the 11 responders, 4 had primary refractory disease. Six pts went on to stem cell transplant after remission to BSHAP. The median duration of CR or PR is 195+ days (range 24+ to 290+). Conclusions: The recommended dose of pixantrone in the BSHAP regimen in 80 mg/m2. The primary toxicity is hematologic. The regimen can be given on an outpatient basis, and is associated with major responses in 61% of relapsed and refractory aggressive NHL patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novuspharma Novuspharma Novuspharma
Axl Tyrosine Kinase Receptor As a Key Regulator of Proliferation and Survival in Colorectal Cancer (Crc)
Authors: G. Martini, T. Troiani, D. Vitagliano, S. Napolitano, F. Morgillo, F. Liotti, R. Melillo, P.P. Vitiello, A. Capasso, V. Gambardella, D. Ciardiello, F. Venturini, C. Cardone, M. Orditura, F. Ciardiello, E. Martinelli
Journal: Annals of Oncology (2014)
MSF hospital is destroyed in Yemen airstrikes
Authors: Owen Dyer
Journal: BMJ (2015)

A hospital in Yemen run by the charity Medecins Sans Frontieres has been completely destroyed by aircraft of the Saudi led coalition fighting the Houthi militia. Staff and patients were able to evacuate without serious casualties.

Saudi forces had been provided with the hospital’s GPS coordinates when they began bombing Yemen in March, and reminders had subsequently been sent every month. The MSF logo was painted clearly on the roof.

The …
Genetic effects on the diameter of thoracic aorta and pulmonary arteries: A twin study
Authors: Adam Domonkos Tarnoki, David Laszlo Tarnoki, Pal Maurovich-Horvat, Adam L. Jermendy, Franciska Somogyi, Bela Merkely, Gyorgy Jermendy
Journal: European Respiratory Journal (2014)

Background and aim:  Thoracic aortic aneurysm and pulmonary hypertension are relatively common diseases but the related geometric mechanism is poorly investigated. Our aim was to assess the heritable affects on the diameter of ascendent aorta (AAd), right and left pulmonary arteries (RPAd, LPAd), and main pulmonary artery (MPAd), and the ratio of the diameter of the pulmonary artery to the diameter of the aorta (PA:A ratio) within a sample of Hungarian twins.   Methods and Materials : 52 Hungarian (26 monozygotic /MZ/ and 26 dizygotic /DZ/) healthy twin pairs (mean age 56±8 years) recruited from the Hungarian Twin Registry underwent computed tomography (Brilliance iCT, Philips Healthcare, Best, The Netherlands) coronarography. Unenhanced and contrast enhanced CT images were analyzed retrospectively to calculate the investigated geometric parameters. All phenotypic variables were screened for outliers and normality. Concordance between MZ and DZ pairs were assessed by Pearson correlations. Rough heritability was calculated according to the Falconer9s formula.   Results : Mean AAd, RPAd, LPAd, MPAd and PA:A ratio indicated 30±4 mm, 18±3 mm, 19±3 mm, 23±3 mm and 0,8±0,1, respectively. A high heritability was found in case of AAd, RPAd, LPAd, MPAd and PA:A ratio (0,62, 0,63, 0,82, 0,81 and 0,75).   Conclusions : This classical twin study has demonstrated that the geometry of ascendent aorta, pulmonary artery and their ratio has a strong heritability. In order to quantify the relative influence of additive genetic, common environmental and unique environmental effects on the twin pairs further investigation is warranted.
Effect of an automatic triggering and cycling system on patient-ventilator synchrony during noninvasive ventilation in a mechanical lung model
Authors: Luíz Melo, Renata Vasconcelos, Raquel Sales, Clarissa Magalhães, Mirizana Almeida, Juliana Silveira, Marcelo Holanda
Journal: European Respiratory Journal (2012)

Evaluate the effect of an automatic triggering and cycling system on patient-ventilator synchrony during NIV in a mechanical lung model. Bench study, one ICU ventilator(Esprit®) and one NIV ventilator(Trilogy®) were tested. The lung simulator ASL 5000(Ingmar) was set with obstructive model:compliance 60mL/cmH2O, resistance 20cmH2O/L/s, and restrictive:compliance 30mL/cmH2O and resistance 8cmH2O/L/s, both with respiratory rate 15 bpm and ventilatory demand of 60 L/min.A facial mask was adapted to a head manikin, with an air leak of 10L/min.The Esprit® was adjusted in the NIV mode and the Trilogy® in the S/T mode:IPAP 10cmH2O and EPAP 4cmH2O, triggering and cycling were set automatically(AutoTrak®) or flow triggering (3L/min) with expiratory cycling 25%(conventional) in both ventilators.Inspiratory and expiratory delay, inspiratory work and patient-ventilator asynchrony were analyzed. Auto-triggering was observed in the restrictive model in the Esprit® with conventional adjustments, but the phenomenon was abolished with the automatic settings. Little difference was observed between the systems, suggesting that both methods were equivalent with respect to inspiratory and expiratory delay and work.  The automatic system showed advantage with respect to synchrony in the restrictive model.
A Randomised Phase Ii Study of Cediranib with or Without Src Inhibition (Saracatinib) in Metastatic Clear Cell Renal Cancer (Rcc) Patients Resistant to Vegf Targeted Therapy
Authors: T. Powles, R. Hawkins, C. Ralph, J. Larkin, R.J. Jones, S. Chowdhury, E. Boleti, K. Fife, A. Bahl, S. Crabb, A. Webb, O.S. Din, J. Dunlop, R. Hill, T. Geldart, D. McLaren, P. Nathan
Journal: Annals of Oncology (2014)
Topotecan Has Substantial Antitumor Activity as First-Line Salvage Therapy in Platinum-Sensitive Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study
Authors: William P. McGuire, John A. Blessing, Michael A. Bookman, Samuel S. Lentz, Charles J. Dunton
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m 2 intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.
Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor.
Authors: J S Lee, A Yoon, S K Kalapurakal, J Y Ro, J J Lee, N Tu, W N Hittelman, W K Hong
Journal: Journal of Clinical Oncology (1995)

Mutation of the p53 gene is one of the most common genetic abnormalities found in lung cancer. The purpose of this study was to evaluate the prognostic value of p53 oncoprotein expression in patients with non-small-cell lung cancer (NSCLC).We studied 156 resected primary NSCLCs by the immunohistochemical staining technique, using the p53 antibody DO7. There were 81 adenocarcinomas, 16 large-cell carcinomas, and 59 squamous cell carcinomas; stages were I in 67, II in 30, and III in 59 cases. For each tumor, the percentage of p53 positivity was calculated by scoring a minimum of 1,000 cells on an arbitrary intensity scale of 0 to 3+.Overall, 103 (66%) tumors expressed p53 in more than 0.1% of cells, and squamous cell carcinomas tended to express more p53 than adenocarcinomas. Since 50% positivity marked the most distinct change in overall survival duration (P = .0008), we divided the cases into three groups, as follows: p53-negative (< or = 0.1%, n = 53), low p53 (0.1% to 50%, n = 54), and high p53 (> 50%, n = 49). Overall, patients in the high-p53 group survived longer than those in the low or negative groups, with respective median survival durations of more than 65, 26, and 33 months (P = .002). The survival difference among the three groups was statistically significant for non-squamous cell (P = .008), but not for squamous cell (P = .17) carcinomas. Among lymph node-negative patients, the survival difference between groups was not statistically significant. However, among lymph node-positive patients (n = 78), more than 65% of the high-p53 group survived for more than 70 months, while the median survival durations for the low and negative groups were 21 and 18 months, respectively (P = .001). A Cox regression analysis with multiple covariates showed that p53 positivity in more than 50% of tumor cells was an independent prognostic factor for better outcome.These results suggest that high expression of the p53 oncoprotein is a favorable prognostic factor in a subset of patients with NSCLC.
Allergic sensitization is associated with increased bronchial responsiveness: a prospective study of allergy to laboratory animals
Authors: A Renstrom, P Malmberg, K Larsson, PH Larsson, BM Sundblad
Journal: European Respiratory Journal (1995)

The purpose of this prospective study was to investigate the extent of change in bronchial responsiveness and the prognostic value of methacholine provocation in early sensitization to laboratory animals. Thirty eight laboratory technicians were studied during training (before first exposure) and after having been exposed to laboratory animals for a median 18 (range 5-33) months. On both occasions they were subjected to spirometry, bronchial methacholine challenge, skin-prick tests and blood sampling, and responded to questionnaires. Nine (24%) developed laboratory animal allergy (LAA), defined as animal work-related symptoms (n = 8), or specific immunoglobulin E (IgE) (n = 7) or both. In the LAA group, bronchial responsiveness was normal before employment, but had increased significantly at follow-up compared to technicians who had not developed LAA. Six of the nine LAA subjects had a more than threefold increase in bronchial responsiveness, and three of these reported chest symptoms. Spirometric values were not different between the groups prior to exposure or at follow-up, and had no prognostic value. However, a pre-employment level of total IgE > 100 kU.L-1 predicted the development of LAA (relative risk 2.8). Thus, early LAA was associated with increased bronchial responsiveness in most subjects. In contrast to total IgE, the level of pre-employment bronchial responsiveness or lung function did not influence the magnitude of change in responsiveness, nor predict sensitization.