tbuckley/cabot-search huggingface dataset:
Phase I Study of MGCD0103 Given As a Three-Times-Per-Week Oral Dose in Patients With Advanced Solid Tumors
Authors: Lillian L. Siu, Roberto Pili, Ignacio Duran, Wells A. Messersmith, Eric X. Chen, Rana Sullivan, Martha MacLean, Serina King, Shirley Brown, Gregory K. Reid, Zuomei Li, Ann M. Kalita, Eric J. Laille, Jeffrey M. Besterman, Robert E. Martell, Michael A. Carducci
Journal: Journal of Clinical Oncology (2008)

Purpose MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies. Patients and Methods A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs. Results Six dose levels ranging from 12.5 to 56 mg/m 2 /d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m 2 /d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m 2 /d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103. Conclusion At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.
A randomized trial of intravenous and intracoronary streptokinase in patients with acute myocardial infarction.
Authors: J L Anderson, H W Marshall, J C Askins, J R Lutz, S G Sorensen, R L Menlove, F G Yanowitz, A D Hagan
Journal: Circulation (1984)

The clinical effects of intravenous streptokinase in patients with acute myocardial infarction were compared with those of intracoronary streptokinase in a randomized, prospective study. Comparisons were also made with a historical control group. Fifty patients were entered into the study at 2.4 +/- 1.2 hr after onset of pain, and 27 were assigned to intravenous and 23 to intracoronary therapy. The doses of streptokinase averaged 212,000 U ic and 845,000 U iv (0.75 X 10(6) U/5 hr, n = 14 or 10(6) U/1 hr, n = 13). Results of studies of the two intravenous dosage schedules were similar and so were combined. Streptokinase was administered at 2.8 +/- 1.0 hr after onset of pain in the intravenous and at 4.3 +/- 1.4 hr in the intracoronary drug group (p less than .001). Convalescent (day 10) radionuclide ejection fractions were 54 +/- 14% for the intravenous and 50 +/- 16% for the intracoronary drug group. Change in ejection fraction from day 1 to 10 tended to be greater after intravenous drug: 5.1% (p less than .08) vs 1.2% (NS). Semiquantitative regional wall motion indexes in the infarct zone showed significant and similar modest improvement from admission to day 10 in both groups (p less than .02). Accelerated enzyme-release kinetics were noted after both therapies. Times of peak enzyme levels for patients on intravenous and intracoronary drug were, respectively, 12.5 +/- 5.0 and 11.5 +/- 4.3 hr for creatine kinase MB isoenzyme and 31.7 +/- 11.8 and 28.1 +/- 12.7 hr for lactic dehydrogenase (LDH). Peak LDH-1 level was lower in patients receiving intravenous drug than in the historical control group (p less than .05). Electrocardiographically summed ST segments diminished rapidly after therapy in both groups; Q wave development was similar and overall R wave loss was equivalent and less extensive compared with in historical control subjects. Infarct pain requiring morphine was diminished similarly in both treatment groups. Incidence of early arrhythmias and heart failure also did not differ. Posttherapy ischemic events and early surgery tended to be more common in the intracoronary group and bleeding was more common in the intravenous group. Intravenous drug did not decrease early hospital mortality (intravenous drug = 5, historical control = 4, intracoronary drug = 1); the differences in this parameter among groups were not significant. At convalescent angiographic evaluation, anterograde perfusion was present in 73% of those receiving intravenous and 76% of those receiving intracoronary drug.(ABSTRACT TRUNCATED AT 400 WORDS)
Detection of Isolated Tumor Cells in Bone Marrow Is an Independent Prognostic Factor in Breast Cancer
Authors: G. Wiedswang, E. Borgen, R. Kåresen, G. Kvalheim, J.M. Nesland, H. Qvist, E. Schlichting, T. Sauer, J. Janbu, T. Harbitz, B. Naume
Journal: Journal of Clinical Oncology (2003)

Purpose: This study was performed to disclose the clinical impact of isolated tumor cell (ITC) detection in bone marrow (BM) in breast cancer. Patients and Methods: BM aspirates were collected from 817 patients at primary surgery. Tumor cells in BM were detected by immunocytochemistry using anticytokeratin antibodies (AE1/AE3). Analyses of the primary tumor included histologic grading, vascular invasion, and immunohistochemical detection of c-erbB-2, cathepsin D, p53, and estrogen receptor (ER)/progesterone receptor (PgR) expression. These analyses were compared with clinical outcome. The median follow-up was 49 months. Results: ITC were detected in 13.2% of the patients. The detection rate rose with increasing tumor size (P = .011) and lymph node involvement (P &lt; .001). Systemic relapse and death from breast cancer occurred in 31.7% and 26.9% of the BM-positive patients versus 13.7% and 10.9% of BM-negative patients, respectively (P &lt; .001). Analyzing node-positive and node-negative patients separately, ITC positivity was associated with poor prognosis in the node-positive group and in node-negative patients not receiving adjuvant therapy (T1N0). In multivariate analysis, ITC in BM was an independent prognostic factor together with node, tumor, and ER/PgR status, histologic grade, and vascular invasion. In separate analysis of the T1N0 patients, histologic grade was independently associated with both distant disease-free survival (DDFS) and breast cancer–specific survival (BCSS), ITC detection was associated with BCSS, and vascular invasion was associated with DDFS. Conclusion: ITC in BM is an independent predictor of DDFS and BCSS. An unfavorable prognosis was observed for node-positive patients and for node-negative patients not receiving systemic therapy. A combination of several independent prognostic factors can classify subgroups of patients into excellent and high-risk prognosis groups.
Polymerase Chain Reaction-Based Detection of Circulating Melanoma Cells as an Effective Marker of Tumor Progression
Authors: Giuseppe Palmieri, Maria Strazzullo, Paolo A. Ascierto, Sabrina M.R. Satriano, Antonio Daponte, Giuseppe Castello for the Melanoma Cooperative Group
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Reverse transcriptase (RT) polymerase chain reaction (PCR) with multiple markers has been demonstrated to be highly sensitive in detecting circulating cells from patients with malignant melanoma (MM). We evaluated the clinical significance of the presence in peripheral blood of specific PCR-positive mRNA markers as an expression of circulating melanoma cells. PATIENTS AND METHODS: Total cellular RNA was obtained from the peripheral blood of 235 patients with either localized (n = 154) or metastatic (n = 81) melanoma. We performed RT-PCR using tyrosinase, p97, MUC18, and MelanA/MART1 as gene markers. The PCR products were analyzed by gel electrophoresis and Southern blot hybridization. In addition, 20 healthy subjects and 21 patients with nonmelanoma cancer were used as negative controls. RESULTS: Although detected at various levels among assessable patients, each mRNA marker was significantly correlated with disease stage. A significant correlation with disease stage was demonstrated for patients who were positive to all four markers (P &lt; .0001) or to at least three markers (P &lt; .001). Univariate analysis showed a significant correlation between risk of recurrence (evaluated in stage I, II, and III patients) and increasing number of PCR-positive markers (P = .0002). Logistic regression multivariate analysis indicated that each single marker (except tyrosinase) and, more especially, the presence of four PCR-positive markers remained statistically independent prognostic factors for tumor progression. CONCLUSION: Our data establish the existence of a significant correlation among clinical stages, tumor progression, and presence of circulating melanoma-associated antigens in peripheral blood of MM patients. Preliminary assessment of a subset of patients with a higher risk of recurrence needs longer follow-up and further studies to define the role of RT-PCR in monitoring MM patients.
Non-invasive measurement of cardiac output by a single breath constant expiratory technique.
Authors: U Elkayam, A F Wilson, J Morrison, P Meltzer, J Davis, P Klosterman, J Louvier, W L Henry
Journal: Thorax (1984)

A new single breath test has been developed that measures pulmonary blood flow (Qc) and pulmonary tissue volume by using the fact that Qc is proportional to the relationship between the absorption rate of acetylene (C2H2) from the alveolar gas and the rate of change of lung volume during constant expiratory flow. To make these measurements a bag in bottle system with a rolling seal spirometer, a mass spectrometer, and a minicomputer with analogue to digital conversion have been used. Qc was compared with cardiac output measured by the thermodilution technique in 20 patients with cardiac disease; some also had mild chronic obstructive pulmonary disease. The mean (SD) resting Qc for the group was 5.27 (1.22) l/min and the cardiac output measured by thermodilution was 5.30 (1.31) l/min. The mean difference between the two estimations of cardiac output was 0.03 l and the standard deviation of this difference was 0.76 l. The Qc technique was not successful in patients with an FEV1/FVC less than 60%, but seemed to be accurate in those with higher FEV1/FVC values. Correction of Qc for the effect of venous admixture in 14 patients resulted in an average 19% overestimation of cardiac output (6.01 (2.52) l/min v 5.05 (1.64) l/min). It is concluded that cardiac output can be accurately measured in patients with cardiac or mild pulmonary disease. No correction for venous admixture due to ventilation-perfusion mismatch was necessary in these patients, presumably because the large breath used by the technique overcomes most mild ventilation-perfusion maldistribution. These findings, in addition to the non-invasive nature of the technique, suggest potential value for the measurement of cardiac output in various clinical conditions.
Pten regulates homeostasis and inflammation-induced migration of myelocytes in zebrafish
Authors: Zhi-Wei Dong, Chun-Guang Ren, Yu Xia, Dan Su, Ting-Ting Du, Hong-Bo Fan, Hao Yuan, Lei Wang, Mei Dong, Wei-Chun Li, Yi Jin, Yi Chen, Min Deng, Ting-Xi Liu, Ai-Hua Gu, Yong Zhou
Journal: Journal of Hematology & Oncology (2014)

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is frequently observed in hematopoietic malignancies. Although PTEN has been implicated in maintaining the quiescence of hematopoietic stem cells (HSCs), its role in hematopoiesis during ontogeny remains largely unexplored. The expression of hematopoietic marker genes was analyzed via whole mount in situ hybridization assay in ptena and ptenb double mutant zebrafish. The embryonic myelopoiesis was characterized by living imaging and whole mount in situ immunofluorescence with confocal microscopy, as well as cell-specific chemical staining for neutrophils and macrophages. Analyses of the involved signaling pathway were carried out by inhibitor treatment and mRNA injection. Pten-deficient zebrafish embryos exhibited a strikingly increased number of myeloid cells, which were further characterized as being immune deficient. In accordance with this finding, the inhibition of phosphoinositide 3-kinase (PI3K) or the mechanistic target of rapamycin (mTOR) corrected the expansive myelopoiesis in the pten-deficient embryos. Further mechanistic studies revealed that the expression of cebpa, a critical transcription factor in myeloid precursor cells, was downregulated in the pten-deficient myeloid cells, whereas the injection of cebpa mRNA markedly ameliorated the dysmyelopoiesis induced by the loss of pten. Our data provide in vivo evidence that definitive myelopoiesis in zebrafish is critically regulated by pten via the elevation of cebpa expression.
The power of song
Authors: Ian Nesbitt
Journal: BMJ (2004)

Like most doctors, I have seen a great many deaths. Those in intensive care epitomise the undignified nature of death in modern Western society, but one becomes used to, inured to, fully monitored deaths, where coloured lines chart final dysfunction.

While working in Samoa, I helped to treat a middle aged patient. Two days after his admission to hospital with back pain, a diagnosis of dissecting thoracic aortic aneurysm was made, and he underwent surgery. The procedure was difficult and prolonged, with a large false lumen, no identifiable re-entry site, and probable carotid artery damage.

Within hours of arriving on the intensive care unit, he required an emergency thoracotomy for cardiac …
Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway
Authors: Robbert van der Voort, Taher E.I. Taher, Robert M.J. Keehnen, Lia Smit, Martijn Groenink, Steven T. Pals
Journal: The Journal of Experimental Medicine (1997)

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.
The Predisposition to Inspiratory Upper Airway Collapse during Partial Neuromuscular Blockade
Authors: Matthias Eikermann, Florian M. Vogt, Frank Herbstreit, Mehdi Vahid-Dastgerdi, Michael O. Zenge, Christof Ochterbeck, Armin de Greiff, Jürgen Peters
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Partial neuromuscular transmission failure by acetylcholine receptor blockade (neuromuscular blockade) or antibody-mediated functional loss (myasthenia gravis), even with a magnitude of muscle weakness that does not evoke respiratory symptoms, can evoke dysphagia and decreased inspiratory airflow, and increases the risk of susceptible patients to develop severe pulmonary complications.Objectives: To assess whether impaired neuromuscular transmission predisposes individuals to inspiratory upper airway collapse, we assessed supraglottic airway diameter and volume by respiratory-gated magnetic resonance imaging, upper airway dilator muscle function (genioglossus force and EMG), and changes in lung volume, respiratory timing, and peripheral muscle function before, during, and after partial neuromuscular blockade in healthy, awake volunteers.Measurements and Main Results: Partial neuromuscular blockade (train-of-four [TOF] ratio: 0.5 and 0.8) was associated with the following: (1) a decrease of inspiratory retropalatal and retroglossal upper airway volume to 66 ± 22 and 82 ± 12% of baseline, which was significantly more intense in the retropalatal area; (2) an attenuation of the normal increase in anteroposterior upper airway diameter during forced inspiration to 74 ± 18% of baseline; (3) a decrease in genioglossus activity during maximum voluntary tongue protrusion to 39 ± 19% (TOF, 0.5) and 73 ± 29% (TOF, 0.8) of baseline; and (4) no effects on upper airway size during expiration, lung volume, and respiratory timing.Conclusions: Thus, impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function. This may be explained by an impairment of the balance between upper airway dilating forces and negative intraluminal pressure generated during inspiration by respiratory “pump” muscles.
Mouse Models of Brain Tumors and Their Applications in Preclinical Trials
Authors: Elena I. Fomchenko, Eric C. Holland
Journal: Clinical Cancer Research (2006)

Abstract Primary brain tumors, including gliomas and medulloblastomas, often represent the most devastating and difficult-to-treat tumors, and are thought to arise from glial cells and/or their precursors or the external granule cell layer, respectively. The majority of genetic alterations characteristic of the human brain tumors are thought to occur in genes encoding proteins involved in signal transduction or cell cycle regulation. Accurate recapitulation of these genetic alterations using genetically engineered mouse models allows for in vivo modeling of brain tumors with similar histopathology, etiology, and biology. These mouse models, in turn, increase our understanding of brain tumor initiation, formation, progression, and metastasis, providing an experimental system to discover novel therapeutic targets and test various therapeutic agents.
Enoxaparin vs. unfractionated heparin for anticoagulation during continuous veno-venous hemofiltration: a randomized controlled crossover study
Authors: Michael Joannidis, Jordan Kountchev, Markus Rauchenzauner, Nicola Schusterschitz, Hanno Ulmer, Andreas Mayr, Romuald Bellmann
Journal: Intensive Care Medicine (2007)
Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L)
Authors: G. S Alarcon, G. McGwin, A. M Bertoli, B. J Fessler, J. Calvo-Alen, H. M Bastian, L. M Vila, J. D Reveille
Journal: Annals of the Rheumatic Diseases (2007)

In patients with systemic lupus erythematosus (SLE), hydroxychloroquine prevents disease flares and damage accrual and facilitates the response to mycophenolate mofetil in those with renal involvement. A study was undertaken to determine whether hydroxychloroquine also exerts a protective effect on survival.Patients with SLE from the multiethnic LUMINA (LUpus in MInorities: NAture vs nurture) cohort were studied. A case-control study was performed within the context of this cohort in which deceased patients (cases) were matched for disease duration (within 6 months) with alive patients (controls) in a proportion of 3:1. Survival was the outcome of interest. Propensity scores were derived by logistic regression to adjust for confounding by indication as patients with SLE with milder disease manifestations are more likely to be prescribed hydroxychloroquine. A conditional logistic regression model was used to estimate the risk of death and hydroxychloroquine use with and without the propensity score as the adjustment variable.There were 608 patients, of whom 61 had died (cases). Hydroxychloroquine had a protective effect on survival (OR 0.128 (95% CI 0.054 to 0.301 for hydroxychloroquine alone and OR 0.319 (95% CI 0.118 to 0.864) after adding the propensity score). As expected, the propensity score itself was also protective.Hydroxychloroquine, which overall is well tolerated by patients with SLE, has a protective effect on survival which is evident even after taking into consideration the factors associated with treatment decisions. This information is of importance to all clinicians involved in the care of patients with SLE.
Eating Fish and Risk of Type 2 Diabetes
Authors: Geertruida J. van Woudenbergh, Adriana J. van Ballegooijen, Anneleen Kuijsten, Eric J.G. Sijbrands, Frank J.A. van Rooij, Johanna M. Geleijnse, Albert Hofman, Jacqueline C.M. Witteman, Edith J.M. Feskens
Journal: Diabetes Care (2009)

To investigate the relation between total fish, type of fish (lean and fatty), and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake and risk of type 2 diabetes in a population-based cohort.The analysis included 4,472 Dutch participants aged >or=55 years without diabetes at baseline. Dietary intake was assessed with a semiquantitative food frequency questionnaire. Hazard ratios (relative risk [RR]) with 95% CIs were used to examine risk associations adjusted for age, sex, lifestyle, and nutritional factors.After 15 years of follow-up, 463 participants developed type 2 diabetes. Median fish intake, mainly lean fish (81%), was 10 g/day. Total fish intake was associated positively with risk of type 2 diabetes; the RR was 1.32 (95% CI 1.02-1.70) in the highest total fish group (>or=28 g/day) compared with that for non-fish eaters (P(trend) = 0.04). Correspondingly, lean fish intake tended to be associated positively with type 2 diabetes (RR highest group [>or=23 g/day] 1.30 [95% CI 1.01-1.68]; P(trend) = 0.06), but fatty fish was not. No association was observed between EPA and DHA intake and type 2 diabetes (RR highest group [>or=149.4 mg/day] 1.22 [0.97-1.53]). With additional adjustment for intake of selenium, cholesterol, and vitamin D, this RR decreased to 1.05 (0.80-1.38; P(trend) = 0.77).The findings do not support a beneficial effect of total fish, type of fish, or EPA and DHA intake on the risk of type 2 diabetes. Alternatively, other dietary components, such as selenium, and unmeasured contaminants present in fish might explain our results.