tbuckley/cabot-search huggingface dataset:
Phase I Study of ON 01910.Na, a Novel Modulator of the Polo-Like Kinase 1 Pathway, in Adult Patients With Solid Tumors
Authors: Antonio Jimeno, Jing Li, Wells A. Messersmith, Daniel Laheru, Michelle A. Rudek, Manoj Maniar, Manuel Hidalgo, Sharyn D. Baker, Ross C. Donehower
Journal: Journal of Clinical Oncology (2008)

We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G(2)/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1.Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months.ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.
Dysfunctional Renal Nitric Oxide Synthase as a Determinant of Salt-Sensitive Hypertension
Authors: MATTHIAS BARTON, INGRID VOS, SIDNEY SHAW, PETER BOER, LIVIUS V. D'USCIO, HERMANN-JOSEF GRO[Combining Diaeresis]NE, TON J. RABELINK, THOMAS LATTMANN, PIERRE MOREAU, THOMAS F. LU[Combining Diaeresis]SCHER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. This study investigated the role of renal nitric oxide synthase (NOS), endothelin, and possible mechanisms of renovascular dysfunction in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated for 8 wk with high salt diet (4% NaCl) alone or in combination with the ET A receptor antagonist LU135252 (60 mg/kg per d). Salt loading markedly increased NOS activity (pmol citrulline/mg protein per min) in renal cortex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hypertension in DS rats was associated with renal artery hypertrophy, increased vascular and renal endothelin-1 (ET-1) protein content, and glomerulosclerosis. In the renal artery but not in the aorta of hypertensive DS rats, endothelium-dependent relaxation to acetylcholine was unchanged; however, endothelial dysfunction due to enhanced prostanoid-mediated, endothelium-dependent contractions and attenuation of basal nitric oxide release was present. Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels. This was associated with a slight increase of renal NOS activity, normalization of endothelial dysfunction and renal artery hypertrophy, and marked attenuation of glomerulosclerosis. Thus, DS rats fail to increase NOS activity in response to salt loading. This abnormality may predispose to activation of the tissue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chronic ET A receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET antagonists in salt-sensitive forms of hypertension.
Antigen receptors on murine T lymphocytes in contact sensitivity. III. Mechanism of negative feedback regulation by auto-anti-idiotypic antibody.
Authors: J W Moorhead
Journal: The Journal of Experimental Medicine (1982)

Contact sensitivity (CS) to 2,4-dinitrofluorobenzene (DNFB) is maximal 6 d after sensitization but declines rapidly. Previous studies have shown that this rapid decline is due to auto-anti-idiotypic (anti-Id) antibodies produced by the host. The present study was done to investigate the mechanism(s) involved in his down-regulation of the effector phase of the CS reaction. Using transfer of CS to mimic the natural effector phase, we found that the inhibition of transfer by treating DNFB-sensitized lymph node (LN) cells with either auto-anti-Id or syngeneic anti-Id serum is complement (C) independent. This inhibition requires Ia+ T cells in the immune population. Depleting immune LN cells of Ia+ T cells rendered them insensitive to inhibition by anti-Id alone, although the same population is inhibited by anti-Id plus C. This cell population is rendered sensitive to inhibited by anti-Id alone by addition of untreated DNFB-sensitized LN cells, but not by addition of normal LN cells. Further studies showed that the suppression of immunity by anti-Id-activated Ia+ T cells is not systemic, but rather occurs locally at the skin test site and is antigen nonspecific. We interpret these data to indicate that the natural regulation of CS to DNFB by auto-anti-Id antibodies is an active process that involves a negative feedback regulatory loop.
Functional Dichotomy in Natural Killer Cell Signaling
Authors: Francesco Colucci, Eleftheria Rosmaraki, Søren Bregenholt, Sandrine I. Samson, Vincenzo Di Bartolo, Martin Turner, Lesley Vanes, Victor Tybulewicz, James P. Di Santo
Journal: The Journal of Experimental Medicine (2001)

The product of the protooncogene Vav1 participates in multiple signaling pathways and is a critical regulator of antigen–receptor signaling in B and T lymphocytes, but its role during in vivo natural killer (NK) cell differentiation is not known. Here we have studied NK cell development in Vav1−/− mice and found that, in contrast to T and NK-T cells, the absolute numbers of phenotypically mature NK cells were not reduced. Vav1−/− mice produced normal amounts of interferon (IFN)-γ in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo. In vitro stimulation of surface receptors in Vav1−/− NK cells resulted in normal IFN-γ production but reduced tumor cell lysis. Vav1 was found to control activation of extracellular signal-regulated kinases and exocytosis of cytotoxic granules. In contrast, conjugate formation appeared to be only mildly affected, and calcium mobilization was normal in Vav1−/− NK cells. These results highlight fundamental differences between proximal signaling events in T and NK cells and suggest a functional dichotomy for Vav1 in NK cells: a role in cytotoxicity but not for IFN-γ production.
Future of oral iron chelator deferiprone (L1)
Authors: GeorgeJ. Kontoghiorghes, M.B. Agarwal Petrign Tondury, M.J. Kersten Michael Jaeger, G. Vreugdenhil A, Y.E. Rahman, None for the ICOC committee, Friedlieb Pfannkuch, Phil Bentley, Hans Peter Schnebli, Jayesh Mehta, Seema Singhal, B.C. Mehta
Journal: The Lancet (1993)
Brain tuned to music
Authors: P. E. Andrade, J. Bhattacharya
Journal: Journal of the Royal Society of Medicine (2003)

Music is the art of thinking in sounds.1 With its power to evoke and communicate emotions it has long intrigued philosophers, but only recently has it claimed the attention of neuroscientists. Even today, there are some who see it as a mere epiphenomenon.2 Many others, however, are exploring the neurological foundations of music perception. In this review article we focus on mechanisms by which music is processed by the brain.
High-Throughput Screening in Drug Metabolism and Pharmacokinetic Support of Drug Discovery
Authors: Ronald E. White
Journal: The Annual Review of Pharmacology and Toxicology (2000)

The application of rapid methods currently used for screening discovery drug candidates for metabolism and pharmacokinetic characteristics is discussed. General considerations are given for screening in this context, including the criteria for good screens, the use of counterscreens, the proper sequencing of screens, ambiguity in the interpretation of results, strategies for false positives and negatives, and the special difficulties encountered in drug metabolism and pharmacokinetic screening. Detailed descriptions of the present status of screening are provided for absorption potential, blood-brain barrier penetration, inhibition and induction of cytochrome P450, pharmacokinetics, biotransformation, and computer modeling. Although none of the systems currently employed for drug metabolism and pharmacokinetic screening can be considered truly high-throughput, several of them are rapid enough to be a practical part of the screening paradigm for modern, fast-moving discovery programs.
Analysis of interectopic activation patterns during sustained ventricular tachycardia.
Authors: J Brachmann, G Kabell, B Scherlag, L Harrison, R Lazarra
Journal: Circulation (1983)

We analyzed the patterns of interectopic continuous electrical activity recorded within interectopic intervals of sustained ventricular tachycardias. These arrhythmias were induced in dogs that were studied 4 days after left anterior descending coronary artery occlusion. Standard ECG leads and electrograms from the His bundle and left ventricular epicardium, both infarct and normal zone, were recorded. In 19 of 24 dogs with transmural myocardial infarction, one to three ventricular paced beats induced sustained ventricular tachycardia, characterized by continuous electrical activity between the initiating and spontaneous ectopic beat and between successive ectopic beats recorded from the epicardium over the infarct zone but not from the normal epicardium. Continuous activity consisted of discrete potentials that were reproduced in each cardiac cycle, suggesting slow conduction within a reentrant circuit. The interectopic activity was divided into three distinct temporal periods, delineated by potentials occurring at the initial portion, the mid-interectopic portion and terminal portion or exit of the slow conduction segment of the presumed reentrant circuit. In some cases, sustained ventricular tachycardia was induced only if an appropriate initial potential was engaged. Spontaneous termination of the sustained ventricular tachycardia was associated with Wenckebach-like block of conduction in the initial or exit potential. Ventricular pacing caused alteration of the interectopic patterns and resulted in cessation of the arrhythmia. Procainamide produced dose-dependent slowing of the ectopic rate due to depression of conduction in the mid-interectopic portion of the continuous electric activity. Inducibility of the sustained ventricular tachycardia was inhibited by decremental conduction in this compartment of the presumed reentry circuit. The present study uses a preparation showing sustained ventricular tachycardia that is stable and regular. Functional analysis of the various portions of the continuous electrical activity during sustained tachycardias allows further insight into the mechanisms of initiation and termination of sustained ventricular tachycardias. The ability to localize the effect of antiarrhythmic drugs on specific portions of a possible reentrant circuit may provide important correlative data for the analysis and interpretation of detailed epicardial mapping studies.
The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization
Authors: Wenjiao Zeng, Annette S.H. Gouw, Marius C. van den Heuvel, Peter J. Zwiers, Pieter E. Zondervan, Sibrand Poppema, Nong Zhang, Inge Platteel, Koert P. de Jong, Grietje Molema
Journal: Hepatology (2008)

Abstract Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein expression of members of the vascular endothelial growth factor (VEGF) and angiopoietin systems and studied localization of VEGF, its receptors VEGFR-1 and VEGFR-2, Angiopoietin (Ang)-1 and Ang-2, and their receptor, in HCC in noncirrhotic and cirrhotic livers. We employed real-time reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistology, and compared the outcome with highly angiogenic human renal cell carcinoma (RCC). HCC in noncirrhotic and cirrhotic livers expressed VEGF and its receptors to a similar extent as normal liver, although in cirrhotic background, VEGFR-2 levels in both tumor and adjacent tissue were decreased. Ang-1 expression was slightly increased compared with normal liver, whereas Tie-2 was strongly down-regulated in the tumor vasculature. Ang-2 messenger RNA (mRNA) levels were also low in HCCs of both noncirrhotic and cirrhotic livers, implying that VEGF-driven angiogenic sprouting accompanied by angiopoietin-driven vascular destabilization is not pronounced. In RCC, VEGF-A levels were one order of magnitude higher. At the same time, endothelially expressed Ang-2 was over 30-fold increased compared with expression in normal kidney, whereas Ang-1 expression was decreased. Conclusion: In hepatocellular carcinoma, tumor vascularization is not per se VEGF/angiopoietin driven. However, increased CD31 expression and morphological changes representative of sinusoidal capillarization in tumor vasculature indicate that vascular remodeling is taking place. This portends that therapeutic intervention of HCC at the level of the vasculature is optional, and that further studies into the molecular control thereof are warranted. (Hepatology 2008.)
A Quantification of the Lung Surface Area in Emphysema Using Computed Tomography
Authors: HARVEY O. COXSON, ROBERT M. ROGERS, KENNETH P. WHITTALL, YULIA D'YACHKOVA, PETER D. PARÉ, FRANK C. SCIURBA, JAMES C. HOGG
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Quantitative analysis of computed tomography (CT) has been combined with a stereologically based histologic analysis of lung structure to assess regional lung inflation and the structural features of the lung parenchyma. In this study, CT measurements of lung inflation were compared with histologic estimates of surface area in order to develop prediction equations that allow lung surface to volume ratio and surface area to be predicted from an analysis of the CT scan. The results show that mild emphysema is associated with an increase in lung volume and a reduction in surface to volume ratio, whereas surface area and tissue weight were only decreased in severe disease. The CT predicted surface to volume ratio correlated with histology, and both predicted and measured surface areas correlated with the diffusing capacity. We conclude that this CT analysis can be used to monitor the progression of emphysematous lung destruction in individual patients, and to assess the impact of both surgical and medical treatments for emphysema.
FcγRIIb Balances Efficient Pathogen Clearance and the Cytokine-mediated Consequences of Sepsis
Authors: Menna R. Clatworthy, Kenneth G.C. Smith
Journal: The Journal of Experimental Medicine (2004)

The immune response to infection must be controlled to ensure it is optimal for defense while avoiding the consequences of excessive inflammation, which include fatal septic shock. Mice deficient in FcγRIIb, an inhibitory immunoglobulin G Fc receptor, have enhanced immune responses. Therefore, we examined whether FcγRIIb controls the response to Streptococcus pneumoniae. Macrophages from FcγRIIb-deficient mice showed increased antibody-dependent phagocytosis of pneumococci in vitro, and consistent with this infected FcγRIIb-deficient mice demonstrated increased bacterial clearance and survival. In contrast, previously immunized FcγRIIb-deficient mice challenged with large inocula showed reduced survival. This correlated with increased production of the sepsis-associated cytokines tumor necrosis factor α and interleukin 6. We propose that FcγRIIb controls the balance between efficient pathogen clearance and the cytokine-mediated consequences of sepsis, with potential therapeutic implications.
Inhibition of tumor cell glutamine uptake by isolated neutrophils.
Authors: D B Learn, E L Thomas
Journal: Journal of Clinical Investigation (1988)

Antitumor activity of phorbol myristate acetate-(PMA) stimulated neutrophils was measured against CCRF-CEM cells. Neutrophils and tumor cells were incubated (a) as a suspension with continuous mixing to maximize the availability of oxygen or (b) after centrifugation as a pellet to maximize cell-cell contact. The cells were then incubated briefly as a suspension with [14C]glutamine under conditions that blocked further damage to the tumor cells. When cells were incubated as a suspension, inhibition of tumor-cell glutamine uptake was mediated by the myeloperoxidase/hydrogen peroxide/chloride system of stimulated neutrophils. Inhibition was blocked by adding catalase, an inhibitor of myeloperoxidase, or compounds that scavenge hypochlorous acid or chloramines. When cells were incubated as a pellet, a portion of the inhibition could not be blocked in this way, indicating that a nonoxidative mechanism contributed to inhibition. In both systems, inhibition of glutamine uptake was rapid and was obtained at effector-cell/target-cell ratios as low as 0.5:1. This inhibition was obtained under conditions that did not result in 51Cr release from cells labeled with [51Cr]-chromate, indicating that inhibition of glutamine uptake measured cytotoxicity rather than cytolysis. 51Cr release was observed only when cells were incubated together for an hour or more as a pellet at high E/T ratios. This cytolysis was mediated by the myeloperoxidase system, and a nonoxidative contribution to cytolysis was not observed. The results indicate that stimulated neutrophils are potent antitumor effectors cells when cytotoxicity rather than cytolysis is the measure of activity. Because glutamine is required for growth of many tumor cells, inhibition of glutamine uptake may represent a significant tumoristatic or tumoricidal effect.
Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet
Authors: Hartmut Döhner, Elihu H. Estey, Sergio Amadori, Frederick R. Appelbaum, Thomas Büchner, Alan K. Burnett, Hervé Dombret, Pierre Fenaux, David Grimwade, Richard A. Larson, Francesco Lo-Coco, Tomoki Naoe, Dietger Niederwieser, Gert J. Ossenkoppele, Miguel A. Sanz, Jorge Sierra, Martin S. Tallman, Bob Löwenberg, Clara D. Bloomfield
Journal: Blood (2009)
Association Between Hemochromatosis (HFE) Gene Mutation Carrier Status and the Risk of Colon Cancer
Authors: N. J. Shaheen, L. M. Silverman, T. Keku, L. B. Lawrence, E. M. Rohlfs, C. F. Martin, J. Galanko, R. S. Sandler
Journal: JNCI Journal of the National Cancer Institute (2003)

Iron is a pro-oxidant that may promote carcinogenesis. Mutations in the hemochromatosis (HFE) gene are associated with increased total body iron stores in some individuals. We assessed the risk of colon cancer among individuals with and without HFE gene mutations.We performed a population-based, case-control study in North Carolina. Case patients with colon cancer and control subjects provided information on multiple environmental exposures, including total iron intake and nonsteroidal anti-inflammatory drug (NSAID) use. They also provided a venous blood sample, from which DNA was extracted, amplified, and subjected to diagnostic restriction enzyme mapping to detect two major HFE gene mutations, C282Y and H63D. Data were analyzed with Fisher's exact test and logistic regression. All statistical tests were two-sided.Thirteen hundred and eight subjects participated (475 case patients, 833 control subjects). The allele frequencies of the H63D and C282Y mutations were greater among case patients (0.11 and 0.046, respectively) than among control subjects (0.09 and 0.044, respectively; P =.14 and P =.85, respectively). When we controlled for age, race, sex, red meat consumption, NSAID use, and total iron intake, subjects with any HFE gene mutation were more likely to have colon cancer than subjects with no HFE gene mutations (adjusted odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.07 to 1.87). The magnitude of the effect was similar for both the H63D (adjusted OR = 1.44, 95% CI = 1.04 to 1.98) and C282Y mutations (adjusted OR = 1.39, 95% CI = 0.88 to 2.19). The risk of colon cancer associated with an HFE gene mutation was similar for those who did and did not have a family history of colon cancer. Among those with HFE mutations, cancer risk increased with increasing age and total iron intake.HFE gene mutations are associated with an increased risk of colon cancer. Cancer risk is greatest in mutation carriers who are older or consume high quantities of iron.
Acute Tissue Injury Activates Satellite Cells and Promotes Sarcoma Formation via the HGF/c-MET Signaling Pathway
Authors: David Van Mater, Leonor Añó, Jordan M. Blum, Micah T. Webster, WeiQiao Huang, Nerissa Williams, Yan Ma, Diana M. Cardona, Chen-Ming Fan, David G. Kirsch
Journal: Cancer Research (2014)

Some patients with soft-tissue sarcoma (STS) report a history of injury at the site of their tumor. Although this phenomenon is widely reported, there are relatively few experimental systems that have directly assessed the role of injury in sarcoma formation. We recently described a mouse model of STS whereby p53 is deleted and oncogenic Kras is activated in muscle satellite cells via a Pax7(CreER) driver following intraperitoneal injection with tamoxifen. Here, we report that after systemic injection of tamoxifen, the vast majority of Pax7-expressing cells remain quiescent despite mutation of p53 and Kras. The fate of these muscle progenitors is dramatically altered by tissue injury, which leads to faster kinetics of sarcoma formation. In adult muscle, quiescent satellite cells will transition into an active state in response to hepatocyte growth factor (HGF). We show that modulating satellite cell quiescence via intramuscular injection of HGF increases the penetrance of sarcoma formation at the site of injection, which is dependent on its cognate receptor c-MET. Unexpectedly, the tumor-promoting effect of tissue injury also requires c-Met. These results reveal a mechanism by which HGF/c-MET signaling promotes tumor formation after tissue injury in a mouse model of primary STS, and they may explain why some patients develop a STS at the site of injury.
Response to autoimmune enteropathy to cyclosporin A therapy.
Authors: I R Sanderson, A D Phillips, J Spencer, J A Walker-Smith
Journal: Gut (1991)

Small bowel enteropathies that are associated with an autoimmune process are often resistant to treatment. Two children with autoimmune enteropathy were treated with cyclosporin A for eight months. Both improved, as assessed by growth, small intestinal mucosal morphology, and carbohydrate absorption. Cyclosporin A is useful in the treatment of autoimmune enteropathy. This report also suggests that T cell activation (which is suppressed by cyclosporin A) is important in the pathogenesis of this condition.