tbuckley/cabot-search huggingface dataset:
Minimum Elicitation Dose Determination Using Roasted Peanut-Low Dose Challenges
Authors: J.A. Nordlee, S.L. Hefle, S.L. Taylor, A.C. Knulst, K.A.B.M. Peeters, R.K. Bush, J.O. Hourihane, D.A. Moneret-Vautrin, M. Morisset, P.S. Smailes, C.A. Swenson, J.B.T. Trewin
Journal: Journal of Allergy and Clinical Immunology (2007)
Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine.
Authors: E Estey, P F Thall, S Pierce, H Kantarjian, M Keating
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the effect of omission of cytarabine (ara-C) from treatment of newly diagnosed acute promyelocytic leukemia (APL), which allows administration of more anthracycline. PATIENTS AND METHODS Induction consisted of all-trans retinoic acid (ATRA) 45 mg/m2 daily until complete remission (CR) and idarubicin 12 mg/m2 daily for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2 daily for 3 days and then, until 2 years post-CR date, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2 daily for 2 days. Results in the 43 patients treated (41 with t(15;17) on standard or Southern analysis) were compared with those in 57 historic newly diagnosed APL patients given ara-C with either doxorubicin, amsacrine (AMSA), or daunorubicin without ATRA, using logistic and Cox regression to assess effects of non-treatment-related covariates on patient outcomes. RESULTS The CR rate in the current group was 77% (95% confidence interval [CI], 62% to 88%) and was not significantly different from the historic rate. In contrast, disease-free survival (DFS) in CR is superior in the current group (probability at 1 year 0.87; 95% CI, 0.73 to 1.0). This has translated into superior overall DFS for the current group (P = .03 adjusting for the predictive covariates initial WBC and platelet count; 1-year DFS probability 0.67; 95% CI, 0.52 to 0.82; median follow-up 102 weeks). The current treatment appears better both in patients with and without t(15; 17) on standard cytogenetic analysis. CONCLUSION Given the difficulties inherent in comparing sequential studies and recognizing the multiple differences in treatment between current and historic groups, our results suggest that a large randomized trial incorporating use of ATRA should assess the utility of omitting ara-C from treatment of newly diagnosed APL, thus allowing delivery of more anthracycline.
The Stenting Coronary Arteries in Non-stress/benestent Disease (SCANDSTENT) Trial
Authors: Henning Kelbæk, Leif Thuesen, Steffen Helqvist, Lene Kløvgaard, Erik Jørgensen, Samir Aljabbari, Kari Saunamäki, Lars R. Krusell, Gunnar V.H. Jensen, Hans E. Bøtker, Jens F. Lassen, Henning R. Andersen, Per Thayssen, Anders Galløe, Anton van Weert
Journal: Journal of the American College of Cardiology (2005)
Hsp90 and Caveolin Are Key Targets for the Proangiogenic Nitric Oxide–Mediated Effects of Statins
Authors: Agnès Brouet, Pierre Sonveaux, Chantal Dessy, Stéphane Moniotte, Jean-Luc Balligand, Olivier Feron
Journal: Circulation Research (2001)

3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase inhibitors or statins exert direct beneficial effects on the endothelium in part through an increase in nitric oxide (NO) production. Here, we examined whether posttranslational modifications of the endothelial NO synthase (eNOS) could account for the proangiogenic effects of statins. We used endothelial cells (ECs) isolated from cardiac microvasculature, aorta, and umbilical veins, as well as dissected microvessels and aortic rings, that were cultured on reconstituted basement membrane matrix (Matrigel). Tube or precapillary formation was evaluated after statin treatment, in parallel with immunoblotting and immunoprecipitation experiments. Atorvastatin stimulated NO-dependent angiogenesis from both isolated and outgrowing (vessel-derived) ECs, independently of changes in eNOS expression. We found that in macro- but not microvascular ECs, atorvastatin stabilized tube formation through a decrease in caveolin abundance and its inhibitory interaction with eNOS. We also identified the chaperone protein hsp90 as a key target for the proangiogenic effects of statins. Using geldanamycin, an inhibitor of hsp90 function, and overexpression of recombinant hsp90, we documented that the statin-induced phosphorylation of eNOS on Ser1177 was directly dependent on the ability of hsp90 to recruit Akt in the eNOS complex. Finally, we showed that statin promoted the tyrosine phosphorylation of hsp90 and the direct interaction of hsp90 with Akt, which further potentiated the NO-dependent angiogenic processes. Our study provides new mechanistic insights into the NO-mediated angiogenic effects of statins and underscores the potential of these drugs and other modulators of hsp90 and caveolin abundance to promote neovascularization in disease states associated or not with atherosclerosis.
Event-Related Gamma Activity in Schizophrenia Patients During a Visual Backward-Masking Task
Authors: Jonathan K Wynn, Gregory A Light, Bruno Breitmeyer, Keith H Nuechterlein, Michael F Green
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Schizophrenia patients experience deficits in many aspects of cognition and perception. Abnormalities in gamma activity may underlie some of these deficits, including rapid processing of visual stimuli. This study examined event-related gamma range activity during a visual backward-masking task in schizophrenia patients and normal comparison subjects. METHOD: Event-related gamma activity was recorded in 15 normal comparison subjects and 32 schizophrenia patients. Participants had event-related gamma activity recorded while viewing 60 unmasked visual targets and 240 trials of visual backward masking. Effects of group, accuracy (correct versus incorrect), stimulus-onset asynchrony, and regional activity (left versus right hemisphere, anterior versus posterior regions) were assessed. RESULTS: Schizophrenia patients had significantly reduced gamma activity in relation to comparison subjects during the backward-masking task. Normal comparison subjects showed significantly greater gamma activity in the right hemisphere, whereas schizophrenia patients did not show this pattern of lateralization. For the unmasked target, there was no group effect and no significant interactions in gamma-band responses. CONCLUSIONS: These results extend previous findings of abnormal gamma range activity in schizophrenia patients. Patients showed overall less gamma activity and failed to show lateralization of activity to the right hemisphere during masking, but they showed comparable levels of gamma activity to unmasked stimuli. Schizophrenia patients' poorer performance during a masking task may be partly influenced by this abnormal level and the distribution of gamma activity.
p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis.
Authors: P P Rosen, M L Lesser, C D Arroyo, M Cranor, P Borgen, L Norton
Journal: Journal of Clinical Oncology (1995)

PURPOSE The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression. MATERIALS AND METHODS Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months. RESULTS The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P &lt; .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC). CONCLUSION The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.
Resistance of mitochondrial p53 to dominant inhibition
Authors: Kristina Heyne, Katrin Schmitt, Daniel Mueller, Vivienne Armbruester, Pedro Mestres, Klaus Roemer
Journal: Molecular Cancer (2008)

Abstract Background Mutation of a tumor suppressor allele leaves the second as backup. Not necessarily so with p53. This homo-tetrameric transcription factor can become contaminated with mutant p53 through hetero-tetramerization. In addition, it can be out-competed by the binding to p53 DNA recognition motifs of transactivation-incompetent isoforms (ΔN and ΔTA-isoforms) of the p53/p63/p73 family of proteins. Countermeasures against such dominant-negative or dominant-inhibitory action might include the evolutionary gain of novel, transactivation-independent tumor suppressor functions by the wild-type monomer. Results Here we have studied, mostly in human HCT116 colon adenocarcinoma cells with an intact p53 pathway, the effects of dominant-inhibitory p53 mutants and of Δex2/3p73, a tumor-associated ΔTA-competitor of wild-type p53, on the nuclear transactivation-dependent and extra-nuclear transactivation-independent functions of wild-type p53. We report that mutant p53 and Δex2/3p73, expressed from a single gene copy per cell, interfere with the stress-induced expression of p53-responsive genes but leave the extra-nuclear apoptosis by mitochondrial p53 largely unaffected, although both wild-type and mutant p53 associate with the mitochondria. In accord with these observations, we present evidence that in contrast to nuclear p53 the vast majority of mitochondrial p53, be it wild-type or mutant, is consisting of monomeric protein. Conclusion The extra-nuclear p53-dependent apoptosis may constitute a fail-safe mechanism against dominant inhibition.
Hsp90 inhibition by AT13387 modulates growth factor and cytokine stimulated cell signalling in multiple cell lines.
Authors: Neil Thompson, John Lyons, Giani Chessari, Rachel McMenamin, S Patel, Martin Frederickson, Jon Lewis, Lynsey Fazal, Andrew Woodhead, Brent Graham, Chris Murray
Journal: Cancer Research (2007)

5641  The utility of Hsp90 inhibitors that are currently under clinical investigation is limited by their poor pharmaceutical properties and dose limiting toxicities which may be secondary to off-target effects. The identification of a small molecule inhibitor with improved drug-like properties would be of significant value in clinical development. AT13387 a recently identified clinical candidate is a potent (800pM), novel, small molecule inhibitor of Hsp90 discovered by high-throughput X-ray crystallography and fragment-derived chemistry. The effects of Hsp90 inhibition on tumour related signal transduction pathways in multiple growth factor and cytokine stimulated cell lines have been analyzed. AT13387 downregulated multiple Hsp90 client proteins involved in growth and survival of myeloma and breast cancer cell lines. In order to test if Hsp90 clients were down-regulated sufficiently to affect key cell signalling pathways, cells were stimulated with growth factors such as epidermal growth factor and phorbol ester and cytokines such as interleukin 6 in the presence or absence of AT13387, and the phosphorylation status of specific signalling pathway molecules was assessed. Constitutive, as well as growth factor and cytokine-induced phosphorylation of AKT, ERK and Stat3 were all inhibited by AT13387 in multiple tumour cell lines. There were cell line dependent differences in pathway activation by the various stimuli tested. Cell type-dependent differences in Hsp90 client modulation were also observed. AT13387 also caused a decrease in multiple myeloma cell adhesion to cultured bone marrow stromal cells and resulted in induction of apoptosis. AT13387 treatment resulted in cell cycle arrest of the Her-2 overexpressing breast cancer line Bt474 at an IC50 of 22 nM. AT13387 treatment also induced a cell cycle arrest in multiple tumour cell lines and gave good in vivo efficacy in a Bt474 mouse xenograft model. In conclusion the Hsp90 inhibitor AT13387 negatively regulated multiple signal transduction pathways in growth factor and cytokine stimulated cell lines, an effect which was correlated with inhibition of survival and or growth of these tumor lines.
GENETIC CONTROL OF THE IMMUNE RESPONSE
Authors: Günter J. Hämmerling, Tohru Masuda, Hugh O. McDevitt
Journal: The Journal of Experimental Medicine (1973)

The influence of immunization with (T,G)-A--L on the frequency and characteristics of [(125)I] (T,G)-A--L-binding cells (ABC) was investigated in high and low responder mice, whose ability to respond to (T,G)-A--L is under control of an H-2-linked immune response gene, Ir-1. Unimmunized high and low responder mice have about the same number of ABC in spleen and lymph nodes (6-12 ABC/10(4)). However, after immunization with (T,G)-A--L in aqueous solution, ABC in high responders increase to a much greater extent than they do in low responders. By inhibition of ABC with class-specific anti-Ig sera, it was demonstrated that in nonimmune and primed mice antigen is bound to IgM receptors, which is in agreement with the exclusive production of 19S anti-(T,G)-A--L antibody in primed animals. In contrast, after secondary challenge with antigen, ABC in high and low responder mice have mainly IgG receptors, although under the conditions used for immunization, low responders are not able to produce detectable amounts of 7S anti-(T,G)-A--L antibody. From these results and from the evidence that low responders very probably have a T cell defect, it is suggested that the switchover from IgM to IgG precursor cells can be induced by antigen itself, without the action of specific T cells. Furthermore, the failure of marked proliferation of ABC in low responders after antigenic stimulation is explained by the lack of stimulation by specific T cells. By independent methods it has been shown that all ABC detected in this study are B cells. Preliminary experiments indicate that purified peripheral T cells bind antigen, but much less per cell than do B cells.
Lifetime HIV Antiretroviral Therapy Adherence Intervention: Timing Is Everything
Authors: David R Bangsberg, Jessica E Haberer
Journal: JAMA Internal Medicine (2013)

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Differential effect of global ischemia on the ryanodine-sensitive and ryanodine-insensitive calcium uptake of cardiac sarcoplasmic reticulum.
Authors: J J Feher, W R LeBolt, N H Manson
Journal: Circulation Research (1989)

The effect of ischemia on the function of cardiac sarcoplasmic reticulum (SR) was assessed by the calcium uptake rate of rat whole-heart homogenates in the presence of 10 mM oxalate. Previous studies have shown that this uptake is restricted to the SR. The contribution of the ryanodine-sensitive fractions of the SR to the total homogenate uptake was assessed by using 20 microM ruthenium red and 625 microM ryanodine to close the SR calcium release channel under previously established optimal conditions. Global ischemia of 10, 15, 30, and 60 minutes depressed homogenate calcium uptake rate 19 +/- 2%, 50 +/- 6%, 65 +/- 3%, and 81 +/- 5%, respectively. This decrease was not observed when the uptake rates were measured after closure of the calcium channel with ryanodine or ruthenium red. Similar results were obtained with a Langendorff in vitro perfusion preparation, in which calcium uptake was decreased 35 +/- 5%, 37 +/- 8%, 58 +/- 7%, and 64 +/- 4% after 10, 15, 30, and 60 minutes of ischemia, but no significant decrease was observed when homogenate uptake rates were measured in the presence of ryanodine. Thus, ischemia caused a depression in the calcium uptake rate of cardiac SR only when this activity was measured in the absence of SR calcium channel blockers. Reperfusion of ischemic hearts in a Langendorff preparation resulted in recovery of homogenate calcium uptake activity that correlated well with the return to sinus rhythm of the reperfused hearts. These reperfused hearts showed no change in the calcium uptake rate measured in the presence of ryanodine. These results suggest that the decrease in homogenate calcium uptake caused by ischemia is not due to a defect in calcium pumping capabilities but is due to an increased efflux through the ryanodine-sensitive calcium release channel of cardiac SR.
Pathogenesis of Antineutrophil Cytoplasmic Autoantibody–Associated Small-Vessel Vasculitis
Authors: J. Charles Jennette, Ronald J. Falk, Peiqi Hu, Hong Xiao
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Clinical, in vitro, and experimental animal observations indicate that antineutrophil cytoplasmic autoantibodies (ANCA) are pathogenic. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental adjuvant factors, an initiating antigen, and failure of T cell regulation. ANCA activate primed neutrophils (and monocytes) by binding to certain antigens expressed on the surface of neutrophils in specific inflammatory microenvironments. ANCA-activated neutrophils activate the alternative complement pathway, establishing an inflammatory amplification loop. The acute injury elicits an innate inflammatory response that recruits monocytes and T lymphocytes, which replace the neutrophils that have undergone karyorrhexis during acute inflammation. Extravascular granulomatous inflammation may be initiated by ANCA-induced activation of extravascular neutrophils, causing tissue necrosis and fibrin formation, which would elicit an influx of monocytes that transform into macrophages and multinucleated giant cells. Over time, the neutrophil-rich acute necrotizing lesions cause the accumulation of more lymphocytes, monocytes, and macrophages and produce typical granulomatous inflammation.
An unusual presentation of a common disease
Authors: M von Lilienfeld-Toal
Journal: Annals of the Rheumatic Diseases (2004)

A variety of rheumatic syndromes have been associated with neoplasia. We report a case of occult metastatic breast cancer which presented with symptoms and signs of adult onset Still’s disease (AOSD).

In July 2002, a 52 year old Caucasian woman presented with a 4 week history of high, spiking fevers (up to 40°C) that were accompanied by a transient macular rash, myalgia, and arthralgia affecting most joints. Initially, there had been a sore throat and painful lymphadenopathy in the left supraclavicular fossa. A lymph node was removed for histopathological examination and the lymphadenopathy resolved spontaneously. The past medical history was unremarkable other than a family history of breast cancer which had affected two second degree relatives. The physical and gynaecological examinations were …
Actin Binding GFP Allows 4D In Vivo Imaging of Myofilament Dynamics in the Zebrafish Heart and the Identification of Erbb2 Signaling as a Remodeling Factor of Myofibril Architecture
Authors: Sven Reischauer, Rima Arnaout, Radhan Ramadass, Didier Y.R. Stainier
Journal: Circulation Research (2014)

Dilated cardiomyopathy is a leading cause of congestive heart failure and a debilitating complication of antineoplastic therapies. Despite disparate causes for dilated cardiomyopathy, maladaptive cardiac remodeling and decreased systolic function are common clinical consequences, begging an investigation of in vivo contractile dynamics in development and disease, one that has been impossible to date.To image myocardial contractile filament dynamics in vivo and to assess potential causes of dilated cardiomyopathy in antineoplastic therapies targeting the epidermal growth factor receptor Erbb2.We generated a transgenic zebrafish line expressing an actin-binding green fluorescent protein in cardiomyocytes, allowing an in vivo imaging of myofilaments. Analysis of this line revealed architectural differences in myofibrils of the distinct cardiomyocyte subtypes. We used this model to investigate the effects of Erbb2 signaling on myofibrillar organization because drugs targeting ERBB2 (HER2/NEU) signaling, a mainstay of breast cancer chemotherapy, cause dilated cardiomyopathy in many patients. High-resolution in vivo imaging revealed that Erbb2 signaling regulates a switch between a dense apical network of filamentous myofibrils and the assembly of basally localized myofibrils in ventricular cardiomyocytes.Using this novel line, we compiled a reference for myofibrillar microarchitecture among myocardial subtypes in vivo and at different developmental stages, establishing this model as a tool to analyze in vivo cardiomyocyte contractility and remodeling for a broad range of cardiovascular questions. Furthermore, we applied this model to study Erbb2 signaling in cardiomyopathy. We show a direct link between Erbb2 activity and remodeling of myofibrils, revealing an unexpected mechanism with potentially important implications for prevention and treatment of cardiomyopathy.