tbuckley/cabot-search huggingface dataset:
Single-Cell Pharmacodynamic Monitoring of S6 Ribosomal Protein Phosphorylation in AML Blasts during a Clinical Trial Combining the mTOR Inhibitor Sirolimus and Intensive Chemotherapy
Authors: Alexander E. Perl, Margaret T. Kasner, Doris Shank, Selina M. Luger, Martin Carroll
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Integration of signal transduction inhibitors into chemotherapy regimens generally has generally not led to anticipated increases in response and survival. However, it remains unclear whether this is because of inadequate or inconsistent inhibition of target or other complex biology. The mTOR signaling pathway is frequently activated in acute myelogenous leukemia (AML) and we previously showed the safety of combining the mTOR inhibitor, sirolimus, with mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy. However, we did not reliably determine the extent of mTOR inhibition on that study. Here, we sought to develop an assay that allowed us to serially quantify the activation state of mTOR kinase during therapy. Experimental Design: To provide evidence of mTOR kinase activation and inhibition, we applied a validated whole blood fixation/permeabilization technique for flow cytometry to serially monitor S6 ribosomal protein (S6) phosphorylation in immunophenotypically identified AML blasts. Results: With this approach, we show activation of mTOR signaling in 8 of 10 subjects' samples (80%) and conclusively show inhibition of mTOR in the majority of subjects' tumor cell during therapy. Of note, S6 phosphorylation in AML blasts is heterogeneous and, in some cases, intrinsically resistant to rapamycin at clinically achieved concentrations. Conclusions: The methodology described is rapid and reproducible. We show the feasibility of real-time, direct pharmacodynamic monitoring by flow cytometry during clinical trials combining intensive chemotherapy and signal transduction inhibitors. This approach greatly clarifies pharmacokinetic/pharmacodynamic relationships and has broad application to preclinical and clinical testing of drugs whose direct or downstream effects disrupt PI3K/AKT/mTOR signaling. Clin Cancer Res; 18(6); 1716–25. ©2011 AACR.
Efficacy and safety of insulin degludec three times a week versus insulin glargine once a day in insulin-naive patients with type 2 diabetes: results of two phase 3, 26 week, randomised, open-label, treat-to-target, non-inferiority trials
Authors: Bernard Zinman, J Hans DeVries, Bruce Bode, David Russell-Jones, Lawrence A Leiter, Alan Moses, Thue Johansen, Robert Ratner
Journal: The Lancet Diabetes & Endocrinology (2013)
Optimal Duration and Timing of Adjuvant Chemotherapy After Definitive Surgery for Ductal Adenocarcinoma of the Pancreas: Ongoing Lessons From the ESPAC-3 Study
Authors: Juan W. Valle, Daniel Palmer, Richard Jackson, Trevor Cox, John P. Neoptolemos, Paula Ghaneh, Charlotte L. Rawcliffe, Claudio Bassi, Deborah D. Stocken, David Cunningham, Derek O'Reilly, David Goldstein, Bridget A. Robinson, Christos Karapetis, Andrew Scarfe, Francois Lacaine, Juhani Sand, Jakob R. Izbicki, Julia Mayerle, Christos Dervenis, Attila Oláh, Giovanni Butturini, Pehr A. Lind, Mark R. Middleton, Alan Anthoney, Kate Sumpter, Ross Carter, Markus W. Büchler
Journal: Journal of Clinical Oncology (2014)

Purpose Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. Patients and Methods Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer–3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. Results There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P &lt; .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P &lt; .001). Conclusion Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.
A thermistor probe for measurement of blood temperature and cardiac output in small animals
Authors: D. J. WARREN
Journal: Cardiovascular Research (1974)

This paper describes the construction of a durable, small diameter thermistor catheter suitable for chronic implantation in small animals. It has given reproducible results in studies of cardiac output by the thermodilution technique from day to day for up to three weeks in conscious rabbits. The other possible applications of this detector in cardiovascular studies are discussed.
Dietary Genistein Reduces Metastasis in a Postsurgical Orthotopic Breast Cancer Model
Authors: Sharon A. Vantyghem, Sylvia M. Wilson, Carl O. Postenka, Waleed Al-Katib, Alan B. Tuck, Ann F. Chambers
Journal: Cancer Research (2005)

Abstract Metastatic spread, not primary tumor burden, is the leading cause of breast cancer deaths. For patient prognosis to improve, new systemic adjuvant therapies that are capable of effectively inhibiting the outgrowth of seeded tumor cells after surgical treatment of the primary breast tumor are needed. To facilitate the preclinical development of such therapies, relevant animal models of breast cancer metastasis that can mimic the postsurgical adjuvant setting are required. Here we developed a preclinical xenograft model of breast cancer metastasis where the primary tumor was removed by surgical resection before systemic adjuvant treatment. We used this model to assess the antimetastatic effect of postsurgical dietary intervention with the soy isoflavone genistein. The anticancer activity of genistein has been established in vitro and in vivo, however, few studies have tested the potential of genistein as an antimetastatic therapy. Using our model, we tested the efficacy of adjuvant treatment with genistein to inhibit the outgrowth of metastases postsurgery. To establish primary tumors, human breast carcinoma cells, MDA-MB-435/HAL, were implanted into the mammary fat pad of female nude mice. Primary tumors were left to grow for 5 weeks before being surgically removed. Mice were then randomized into two diet groups: control soy-free diet versus genistein-supplemented diet. Five weeks later, metastatic burden was assessed. Genistein reduced the percent metastatic burden in the lungs by 10-fold. These results indicate that dietary intervention following cancer surgery can affect the outgrowth of seeded tumor cells. The availability of well-characterized, clinically relevant animal models for studying factors that regulate metastatic outgrowth postsurgery will provide an important tool for developing new systemic adjuvant therapies.
Interleukin-5 Expression in the Lung Epithelium of Transgenic Mice Leads to Pulmonary Changes Pathognomonic of Asthma
Authors: James J. Lee, Michael P. McGarry, Steven C. Farmer, Karen L. Denzler, Kirsten A. Larson, Patricia E. Carrigan, Ina E. Brenneise, Margaret A. Horton, Angela Haczku, Erwin W. Gelfand, George D. Leikauf, Nancy A. Lee
Journal: The Journal of Experimental Medicine (1997)

We have generated transgenic mice that constitutively express murine interleukin (IL)-5 in the lung epithelium. Airway expression of this cytokine resulted in a dramatic accumulation of peribronchial eosinophils and striking pathologic changes including the expansion of bronchusassociated lymphoid tissue (BALT), goblet cell hyperplasia, epithelial hypertrophy, and focal collagen deposition. These changes were also accompanied by eosinophil infiltration of the airway lumen. In addition, transgenic animals displayed airway hyperresponsiveness to methacholine in the absence of aerosolized antigen challenge. These findings demonstrate that lung-specific IL-5 expression can induce pathologic changes characteristic of asthma and may provide useful models to evaluate the efficacy of potential respiratory disease therapies or pharmaceuticals.
Effect of exposure to silica on human alveolar macrophages in supporting growth activity in type II epithelial cells.
Authors: B. Melloni, O. Lesur, T. Bouhadiba, A. Cantin, M. Martel, R. Begin
Journal: Thorax (1996)

BACKGROUND: The proliferative response of type II cells is an important event following silica-induced lung injury. Alveolar macrophages, when activated by fibrogenic agents, secrete various biological mediators which affect cell growth. METHODS: Human alveolar macrophages from normal volunteers were incubated in serum-free medium or in the presence of increasing concentrations of silica. Alveolar macrophage conditioned media were diluted and added to type II cell cultures for proliferation studies. Purified type II pneumocytes were isolated from fetal rat lungs for bioassays. Growth factor activities were partially characterised by size exclusion chromatography. Each fractionated mitogenic peak was preincubated with monoclonal antibody against platelet derived growth factor (PDGF) or antisera against insulin-like growth factor 1 (IGF-1) or fibroblast derived growth factor (FGF) in order to study the nature of each activity. RESULTS: Conditioned media from alveolar macrophages exposed to silica induced an increase in type II cell DNA synthesis and cell number over that seen when type II cells were incubated with unstimulated alveolar macrophage supernatants. Size exclusion of alveolar macrophage supernatants exposed to silica showed four peaks of type II cell stimulating activity with apparent molecular weights of 38, 22, 16, and 8 kDa. Anti-PDGF antibody significantly reduced the activity of the first and second peaks, antiserum against IGF-1 partially reduced the activity of the first and fourth peaks, and antiserum against FGF reduced only the third peak of activity. CONCLUSIONS: Human alveolar macrophages exposed to silica in vitro release mitogens for type II pneumocytes including PDGF-like, IGF-1-like, and FGF-like molecules. These agents are likely to be involved in the epithelial repair and type II cell hyperplasia observed in silicosis.
Characterisation of cellular and humoral autoimmune responses to histone H1 and core histones in human systemic lupus erythaematosus
Authors: G H Stummvoll, R D Fritsch, B Meyer, E Hoefler, M Aringer, J S Smolen, G Steiner
Journal: Annals of the Rheumatic Diseases (2008)

To address key aspects of anti-histone autoimmunity in systemic lupus erythaematosus (SLE), we performed a detailed characterisation of cellular and humoral autoreactivity to histone H1 and the four core histones H2A, H2B, H3, H4 in patients with SLE and healthy controls.Peripheral blood mononuclear cells of 41 patients with SLE and 28 healthy controls were exposed to individual histones and proliferation was measured by [(3)H]-thymidine incorporation. H1-reactive T cell clones were obtained by limiting dilution. Cytokines and total IgG in culture supernatants was measured by ELISA, and autoantibodies to histones were determined by ELISA and immunoblotting.Proliferative responses to H1 were more frequent and more pronounced in cell cultures from patients with SLE (p<0.002), while among the core histones only the response to H2A was increased in patient cultures (p<0.01). All histones elicited a Th1-like cytokine response in patients and controls (high interferon (IFN)gamma and tumour necrosis factor (TNF)alpha, no interleukin (IL)4) with H1 inducing the highest levels of TNFalpha. However, H1 stimulated production of IgG and anti-histone antibodies only in cell cultures derived from patients with SLE. H1-specific T cell clones from patients and controls showed a CD4+CD28+ phenotype and a Th1 cytokine profile. Anti-histone antibodies were detected in 51% of patients with SLE, were primarily directed to H1, H3 and H4, and predominantly of the IgG2 subtype.Histone H1 constitutes a major B cell and T cell autoantigen in SLE, triggering a proinflammatory Th1 response and driving autoantibody production. This suggests that histone H1 may be of considerable relevance for the pathogenesis of SLE.
Human intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL-1, its receptor, and its receptor antagonist.
Authors: A Hurwitz, J Loukides, E Ricciarelli, L Botero, E Katz, J M McAllister, J E Garcia, R Rohan, E Y Adashi, E R Hernandez
Journal: Journal of Clinical Investigation (1992)

To delineate the scope of the human intraovarian IL-1 system we used a solution hybridization/RNase protection assay to test for expression of the genes encoding IL-1, its type I receptor (IL-1R), and its receptor antagonist (IL-1RA). IL-1 transcripts were not detected in whole ovarian material from days 4 or 12 of an unstimulated menstrual cycle but transcripts (IL-1 beta much greater than IL-11 alpha) were detected in preovulatory follicular aspirates from gonadotropin-stimulated cycles. Concurrently obtained peripheral monocytes did not contain IL-1 beta transcripts but macrophage-depleted follicular aspirates did, thus implicating the granulosa cells as the site of IL-1 expression. IL-1R transcripts were detected in RNA from whole ovaries and follicular aspirates but not in RNA from peripheral monocytes. IL-1RA transcripts were detected in whole ovarian material as well as in macrophage-free follicular aspirates. Cultured human granulosa and theca cells did not contain mRNA for IL-1 beta or IL-1RA but did contain mRNA for IL-1R. Treatment of cell cultures with forskolin (25 microM) induced IL-1 beta transcripts in granulosa but not theca cells. Forskolin also increased the basal levels of IL-1R transcripts in both granulosa and theca cells but did not induce IL-RA transcripts in either cell type. Taken together, these findings reveal the existence of a complete, highly compartmentalized, hormonally dependent intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist.
Impressions of medicine in India. Provision of medical care: varied and variable.
Authors: T Richards
Journal: BMJ (1985)

Impressions a propos d'une mission de courte duree: premieres impressions, quelques statistiques, ressources, rapports entre nombre de medecins et nombre de malades, programme «reorientation de l'education medicale», les centres de sante vus par un consommateur, les soins medicaux en zone urbaine, la clientele privee; conclusions sur les contrastes
Gene Expression Profile Predicts Patient Survival of Gastric Cancer After Surgical Resection
Authors: Chiung-Nien Chen, Jen-Jen Lin, Jeremy J. W. Chen, Po-Huang Lee, Ching-Yao Yang, Min-Liang Kuo, King-Jen Chang, Fon-Jou Hsieh
Journal: Journal of Clinical Oncology (2005)

Purpose This study was conducted to characterize gene expression profile of survival in patients with surgically curable gastric cancer by using an in-house membrane microarray and developing a survival prediction model. Materials and Methods Data of cDNA microarrays were obtained from 18 pairs of cancerous and noncancerous gastric tissues. Nine patients who survived &gt; 30 months were identified as good survival, and the other nine, who survived &lt; 12 months, were identified as poor survival. Supervised analysis was performed to identify a gene expression profile by good and poor survival. Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to confirm the microarray data in 10 patients with sufficient RNA. Using these 10 patients and another 10 patients selected randomly from 40 newly enrolled patients as the training group, the RT-PCR status of the confirmed genes was used for predicting good versus poor survival. Finally, the prediction model was tested in the remaining 30 newly enrolled gastric cancer patients. Results A survival prediction model consisting of three genes (CD36, SLAM, PIM-1) was developed. This model could correctly predict poor or good survival in 23 (76.7%) of 30 newly enrolled patients, and yielded a specificity of 80% and a sensitivity of 73.3%. The survival rate of the patients predicted to have good survival was significantly higher than that of those predicted to have poor survival in the test group as a whole (N = 30; P = .00531) and in stage III patients (n = 16; P = .04467). Conclusion The semiquantitative RT-PCR gene expression profiling of three genes extracted from microarray study can accurately predict surgery-related outcome in gastric cancer patients.
International Union of Pharmacology. XXXII. The Mammalian Calcitonin Gene-Related Peptides, Adrenomedullin, Amylin, and Calcitonin Receptors
Authors: D. R. Poyner
Journal: Pharmacological Reviews (2002)

The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.
Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitors
Authors: Xin-Yan Pei, Yun Dai, Steven Grant
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to examine interactions between the proteasome inhibitor bortezomib (Velcade) and the histone deacetylase (HDAC) inhibitors sodium butyrate and suberoylanilide hydroxamic acid in human multiple myeloma (MM) cells that are sensitive and resistant to conventional agents. Experimental Design: MM cells were exposed to bortezomib for 6 h before the addition of HDAC inhibitors (total, 26 h), after which reactive oxygen species (ROS), mitochondrial dysfunction, signaling and cell cycle pathways, and apoptosis were monitored. The functional role of ROS generation was assessed using the free radical scavenger N-acetyl-l-cysteine. Results: Preincubation with a subtoxic concentration of bortezomib markedly sensitized U266 and MM.1S cells to sodium butyrate- and suberoylanilide hydroxamic acid-induced mitochondrial dysfunction; caspase 9, 8, and 3 activation; and poly(ADP-ribose) polymerase degradation; resulting in synergistic apoptosis induction. These events were associated with nuclear factor κB inactivation, c-Jun NH2-terminal kinase activation, p53 induction, and caspase-dependent cleavage of p21CIP1, p27KIP1, and Bcl-2, as well as Mcl-1, X-linked inhibitor of apoptosis, and cyclin D1 down-regulation. The bortezomib/HDAC inhibitor regimen markedly induced ROS generation; moreover, apoptosis and c-Jun NH2-terminal kinase activation were attenuated by N-acetyl-l-cysteine. Dexamethasone- or doxorubicin-resistant MM cells failed to exhibit cross-resistance to the bortezomib/HDAC inhibitor regimen, nor did exogenous interleukin 6 or insulin-like growth factor I block apoptosis induced by this drug combination. Finally, bortezomib/HDAC inhibitors induced pronounced lethality in primary CD138+ bone marrow cells from MM patients, but not in the CD138− cell population. Conclusions: Sequential exposure to bortezomib in conjunction with clinically relevant HDAC inhibitors potently induces mitochondrial dysfunction and apoptosis in human MM cells through a ROS-dependent mechanism, suggesting that a strategy combining these agents warrants further investigation in MM.
Usefulness of semiflexble thoracoscopy under local anesthesia for patients with unknown pleural effusion
Authors: Yuichi Yamada, Gen Yamada, Hirotaka Nishikiori, Koji Kuronuma, Mitsuo Otsuka, Hiroki Takahashi
Journal: European Respiratory Journal (2012)

Background:  Pleural effusion may arise from a wide range of diseases. However, it is difficult to make a diagnosis by thoracocentesis or needle biopsy. Recently, semiflexible thoracoscopy has been performed under local anesthesia for diagnosis or treatment of pleural diseases.   Objectives:  To determine the benefit and safety of the thoracoscopy for the diagnosis of unknown pleural effusion or the treatment of pleural diseases.   Method:  Between April 2001 and June 2011, we performed the thoracoscopy in 39 patients (31 men and 8 women) who could not be diagnosed by cytologic and bacteriologic examinations of pleural effusion by thoracocentesis. We used a semiflexible thoracoscope (LFT 240; Olympus Medical Systems Co., Tokyo, Japan) for the observations of pleural cavity, and obtained pleural biopsies from abnormal areas of parietal pleura.   Results:  We underwent semiflexble thoracoscopy in 29 patients for diagnosis of pleural diseases and 22 cases were provided the pathological diagnosis (6 pleuritis carcinomatosa, 2 malignant mesothelioma, 1 synobital sarcoma, 7 empyema, 3 tuberculous pleural effusion, 2 rheumatoid arthritis and 1 sarcoidosis). In addition, semiflexible thoracoscopy was performed for the treatment in 10 cases with acute or chronic empyema for the purpose of detachment of fibrin, destruction and removal of the septum.   Conclusions:  Semiflexible thoracoscopy under local anesthesia can be safely performed by pulmonary physicians. It is considered an easy and useful examination for the diagnosis of pleural diseases.
Sodium Recovery from Normal and Edematous Lungs Studied by Indicator Dilution Curves
Authors: MORTON LEE PEARCE, James Beazell, Joe Yamashita, Sandra Jill Ashcraft
Journal: Circulation Research (1969)

We attempted to measure sodium and water spaces in the lungs before and after pulmonary edema produced in dogs by increasing pulmonary capillary pressure or by alloxan. We employed a technique depending on the difference in transit times through the lungs of tritiated water or 24 Na + , with reference to an intravascular indicator. In the control measurements, there was virtually complete recovery of the sodium indicator, but in pulmonary edema there was a significant loss. It is possible that this represents distribution of some of the 24 Na + into an extravascular volume with an exit other than the pulmonary veins, but we would expect this to be accompanied by an equivalent amount of tritiated water. Since there was complete recovery of tritiated water in pulmonary edema, it seems more likely that the sodium loss represents binding by some extravascular locus and may be related to the extent of alveolar wall injury.