tbuckley/cabot-search huggingface dataset:
Abstract 996: SFRP1 reduction results in an increased sensitivity to TGF-β signaling
Authors: Kelly Gauger, Sallie Smith Schneider, Kerry Chenausky, Molly Murray
Journal: Cancer Research (2011)

Abstract Metastasis remains the most deadly aspect of breast cancer. We previously published that when the Wnt/β-catenin signaling antagonist, secreted frizzled-related protein-1 (SFRP1), is knocked down in immortalized non-malignant mammary epithelial cells, the cells (TERT-siSFRP1) exhibit a malignant phenotype which resembles the characteristics observed in metastatic breast cancer. Interestingly, the observed phenotypic and genotypic changes that occur in response to loss of SFRP1 define the EMT process. Among the genes analyzed, the drastic increase in ZEB2 expression was of particular interest to us. This protein is a zinc-finger transcription factor that represses the expression of E-cadherin, which is the mechanism by which ZEB2 is thought to contribute to EMT. Additionally, ZEB2 has been shown to interact with downstream mediators of Transforming Growth Factor (TGF)-β signaling (SMADs). TGF-β signaling is known to actively contribute to the acquisition and development of metastatic phenotypes in part through its ability to stimulate EMT and we wondered whether this cytokine plays a role in the EMT observed in response to SFRP1 loss. Therefore, we tested the hypothesis that TGF-β signaling is augmented due to SFRP1 reduction. First, we used luciferase assays and real-time PCR analysis to show that in response to TGF-β treatment, the expression of TGF-β responsive genes are elevated in TERT-siSFRP1 cells. These downstream targets were also measured after cells were treated with a TGF-βR antagonist (LY364947) to ensure these effects were specifically due to the TGF-β signaling pathway. TGF-β signaling has also been shown to increases the phosphorylation of ERK1/2 which in turn enhances cellular migration. We found that the migratory TERT-siSFRP1 cells exhibit a marked increase in ERK1/2 phosphorylation that is readily blocked by the addition of LY364947. Furthermore, transwell assays revealed that LY364947 blocks cellular migration and this phenomenon is likely due to the inhibition of ERK1/2 because the ERK1/2 inhibitor (U0126) similarly blocks cellular migration. To investigate the contribution of ZEB2, we used siZEB2 oligonucleotides to knock down the expression of this protein. Reduced levels of ZEB2 lowered the expression of exogenous and endogenous TGF-β transcriptional targets and hindered cellular migration. We can conclude from these data that the TGF-β signaling pathway is aberrantly activated in TERT-siSFRP1 cells due to the significant up-regulation of the SMAD-interacting protein, ZEB2. This work has been supported in part by the Rays of Hope Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 996. doi:10.1158/1538-7445.AM2011-996
Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload.
Authors: H Ito, M Hiroe, Y Hirata, H Fujisaki, S Adachi, H Akimoto, Y Ohta, F Marumo
Journal: Circulation (1994)

BACKGROUND We have recently shown that angiotensin II-induced hypertrophy of cultured rat cardiomyocytes was partially blocked by an endothelin (ET) receptor antagonist (BQ123) selective for the ETA subtype, suggesting the possible involvement of endogenous ET-1 in the mechanism of cardiac hypertrophy in vitro. In the present study, we studied the in vivo blockade effects of BQ123 on cardiac hypertrophy provoked by left ventricular overload with aortic banding in adult rats. METHODS AND RESULTS Forty rats were divided into four groups: (1) sham-operated rats without BQ123 administration, (2) rats with aortic banding without BQ123 administration, (3) sham-operated rats with BQ123 administration, and (4) rats with aortic banding with BQ123 administration. BQ123 (250 micrograms/h) was administered continuously by an osmotic pump starting 24 hours before operation. BQ123 blocked increases in the ratio of left ventricular weight to body weight and in the diameter of cardiomyocytes provoked by aortic banding at 1 week, but those blockade actions were no longer observed at 2 weeks. Skeletal alpha-actin and atrial natriuretic peptide (ANP) mRNA in the left ventricle, transcriptional markers for cardiac hypertrophy, significantly increased in the rats with aortic banding at 1 week and 2 weeks. In the rats with BQ123 administration, despite the hemodynamic overload, skeletal alpha-actin and ANP mRNA in the left ventricle remained at the control levels at 1 week; however, those blockade actions were abolished at 2 weeks. Plasma ET-1 levels increased after aortic banding, peaking at 24 hours, then returned to the basal level at 4 days. Prepro-ET-1 mRNA levels in the left ventricle also increased 24 hours after aortic banding, then declined to the basal level at 4 days. CONCLUSIONS These data suggest that endogenous ET-1 synthesized in the cardiovascular system plays a role in the mechanism of cardiac hypertrophy during the early phase of pressure overload in vivo.
Long‐term ultra‐low‐dose acyclovir against varicella‐zoster virus reactivation after allogeneic hematopoietic stem cell transplantation
Authors: Yuki Asano‐Mori, Yoshinobu Kanda, Kumi Oshima, Shinichi Kako, Akihito Shinohara, Hideki Nakasone, Hiroyuki Sato, Takuro Watanabe, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
Journal: American Journal of Hematology (2008)

Abstract To evaluate the efficacy of long‐term prophylaxis with ultra‐low‐dose acyclovir against varicella‐zoster virus (VZV) reactivation, we analyzed the records of 242 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2006 at our hospital. We started long‐term oral acyclovir at 200 mg/day in July 2001. Acyclovir was continued until the end of immunosuppressive therapy and at least 1 year after transplantation. Sixty‐six patients developed VZV reactivation at a median of 248 days after HSCT, with a cumulative incidence of 34.7%. Only one breakthrough reactivation occurred during long‐term acyclovir, which responded well to therapeutic dose of valacyclovir. The use of long‐term acyclovir was the only independent determinant that significantly decreased the overall incidence of VZV reactivation (20% vs. 50%, P &lt; 0.0001). With this prophylaxis, visceral dissemination and serious complications other than post‐herpetic neuralgia was completely eliminated, and thereby need for hospitalization was significantly reduced (21% vs. 71%, P = 0.0034). Fifteen of the 57 patients who discontinued acyclovir developed VZV reactivation, with a cumulative incidence of 32.1%. VZV reactivation following discontinuation tended to occur in patients who were receiving immunosuppressive therapy at the cessation of acyclovir. These findings suggested that long‐term prophylaxis of ultra‐low‐dose acyclovir resulted in a successful prevention of severe VZV‐related symptoms and death, with a significantly decreased overall incidence of VZV reactivation. Prolongation of prophylactic acyclovir on profound immunosuppression might be important for thorough suppression of VZV reactivation. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
1021-100 Metabolic syndrome: An underecognized risk factor for myocardial infarction in the young
Authors: Patrick J Curran, Eugene H Chung, Manish S Chauhan, Christopher T Pyne, Thomas C Piemonte, David E Gossman, James Waters, Seth Bilazarian, Khether Raby, Nabila Riskala, Richard W Nesto
Journal: Journal of the American College of Cardiology (2004)
Physicians Find That Medicine in Museums Mixes Equal Parts of Knowledge and Fun
Authors: Chris Anne Raymond
Journal: JAMA (1987)

FOUR MILLION PEOPLE each year surge through its art deco doors and enter a realm of near chaos. Teenagers roam the exhibit halls, sniggering when the reproductive system of the female anatomical mannequin lights up. Over the din of bells and buzzers, a father patiently tries to explain to his little girl the meaning of those squishy-looking things in the glass cubes (they're fetal specimens from conception through birth). Dozens of visitors queue up to walk through a bigger-than-life-size model of the human heart. Welcome to the world of the contemporary science museum. Physicians who think it hard to explain hypertension or diabetes to a patient at least have the advantage of a captive audience. On the other hand, it's unlikely they have an interactive computer game at their fingertips to demonstrate renal hemodynamics or the action of insulin. For that, they might refer their patients to the local science
Individual Variation of Somatic Gene Mutability in Relation to Cancer Susceptibility: Prospective Study on Erythrocyte Glycophorin A Gene Mutations of Atomic Bomb Survivors
Authors: Seishi Kyoizumi, Yoichiro Kusunoki, Tomonori Hayashi, Masayuki Hakoda, John B. Cologne, Kei Nakachi
Journal: Cancer Research (2005)

Abstract It has previously been reported that hemizygous mutant fraction (Mf) at the glycophorin A (GPA) locus in erythrocytes increased with radiation dose in heterozygotes among Hiroshima and Nagasaki atomic bomb survivors. In the present study, we analyzed the relationship between GPA Mf and cancer risk using newly developed cancers among previously cancer-free subjects whose GPA Mf had been measured between 1988 and 1996. Among 1,723 survivors (1,117 in Hiroshima and 606 in Nagasaki), we identified 186 subjects who developed a first cancer by the end of 2000. We compared the radiation dose responses of GPA Mf between cancer and cancer-free groups using a linear-quadratic model fit by multiple regression analysis in combination with age, sex, and city. The slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancer-free group among Hiroshima subjects. Moreover, no significant difference of GPA Mf between cancer and cancer-free groups was found in unexposed controls in the two cities. The same conclusions were obtained using a linear dose-response model and by further analysis using Cox regression of cancer incidence. These findings suggest that there might be interindividual variation in mutability of somatic genes and that Hiroshima survivors who have higher mutability in response to radiation exposure would be expected to have a higher probability of suffering radiation-related cancer.
The Pharmaceutic Exhibit at the Association Meetings.
Authors: R. W. Gardner
Journal: JAMA (1902)

New York City, July 22, 1902. <h3>To the Editor:</h3> —The exhibit at the meetings of the American Medical Association is intended to show progress in pharmacy, pharmacology, medical and surgical instruments and appliances, all electrical and mechanical devices and other matters directly allied to, or of special application in, the practice of medicine. In no other way can such information be so effectively imparted as by a personal inspection of the exhibits, and the scientific explanation of these subjects afforded by the trained experts who are sent by exhibitors expressly for this purpose. The value of such an exhibit to the busy practitioner can hardly be overestimated. The exhibit is, or ought to be, in view of its importance, as interesting and valuable a part of the meeting as any other feature. A lack of interest by many members has been observed for several years past. Many do not visit
DOSE REDUCTION OF NEUROHORMONAL ANTAGONISTS DURING HEART FAILURE HOSPITALIZATION MARKS PATIENTS AS HIGH RISK FOR READMISSION AT BOTH TERTIARY AND COMMUNITY HOSPITALS
Authors: Lauren Gray Gilstrap, Akshay Desai, Mandeep Mehra, Roy Small, Rose Hamershock, Ron Parambi, Roya Ghazinouri, Christina Carr, Lynne Stevenson
Journal: Journal of the American College of Cardiology (2015)
Racial Disparities in Medical Care
Authors: Arnold M. Epstein, John Z. Ayanian
Journal: New England Journal of Medicine (2001)

Many studies have shown that black Americans are less likely than whites to receive a wide range of medical services, including potentially lifesaving surgical procedures.1,2 Despite these data, which span two decades, there is little evidence that racial disparities in medical care or in measures of health have substantially diminished. Black Americans have an average life expectancy that is 6 years shorter than that of white Americans, and there has been little change in this disparity during the past 30 years.3 Why has the evidence on racial disparities failed to galvanize a response within the medical community? Four factors . . .
Mycobacterial catalase–peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis
Authors: Zhimin Song, Lisa Marzilli, Brian M. Greenlee, Edward S. Chen, Richard F. Silver, Frederic B. Askin, Alvin S. Teirstein, Ying Zhang, Robert J. Cotter, David R. Moller
Journal: The Journal of Experimental Medicine (2005)

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4+ T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab′)2 fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150–160, 80, or 60–64 kD) but only 3 of 22 (14%) control tissues (all 62–64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase–peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)− (P = 0.0059) and 4 of 10 (40%) PPD+ (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase–peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.
P3-101: The potential role of PDGFR inhibition using Imatinib (I) with Docetaxel (D) in the treatment of Recurrent Non:Small Cell Lung Cancer (NSCLC)
Authors: Chao H. Huang, Stephen K. Williamson, Peter J. Van Veldhuizen, Chung T. Hsueh, Ace Allen, Holly Smith, Mathew Mayo, Karen Kelly
Journal: Journal of Thoracic Oncology (2007)
Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia
Authors: Andromachi Scaradavou, Claudio G. Brunstein, Mary Eapen, Jennifer Le-Rademacher, Juliet N. Barker, Nelson Chao, Corey Cutler, Colleen Delaney, Fangyu Kan, Luis Isola, Chatchada Karanes, Mary J. Laughlin, John E. Wagner, Elizabeth J. Shpall
Journal: Blood (2012)
GPs must not be left out of clinical commissioning, warns BMA
Authors: H. Jaques
Journal: BMJ (2012)

The emerging clinical commissioning groups (CCGs) in England must include ordinary GPs in their planning processes, the chairman of the BMA’s General Practitioners Committee has said.

Speaking at the annual conference of local medical committees in Liverpool this week, Laurence Buckman emphasised that CCGs are membership organisations and must seek the views of the GPs in their constituent practices.

“CCGs are our creatures, not just another version of the PCTs [primary care trusts] they replace,” he said. “GPs should be telling them what to do, not the other way round.”

To facilitate GPs’ involvement, local medical committees—the longstanding groups that represent GPs—must work with CCGs and not “withdraw …
Phase I Trial of <sup>177</sup>Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate Cancer
Authors: Neil H. Bander, Matthew I. Milowsky, David M. Nanus, Lale Kostakoglu, Shankar Vallabhajosula, Stanley J. Goldsmith
Journal: Journal of Clinical Oncology (2005)

To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of (177)Lutetium-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((177)Lu-J591) in patients with androgen-independent prostate cancer (PC).Thirty-five patients with progressing androgen-independent PC received (177)Lu-J591. All patients underwent (177)Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments.Thirty-five patients received (177)Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m(2), and the 70-mCi/m(2) dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m(2) was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m(2) could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing >or= 50% declines in prostate-specific antigen (PSA) levels lasting from 3+ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21+ months).The MTD of (177)Lu-J591 is 70 mCi/m(2). Multiple doses of 30 mCi/m(2) are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.
Adhesion of mammalian cells to polymer surfaces: from physical chemistry of surfaces to selective adhesion on defined patterns
Authors: J.-L. Dewez, J.-B. Lhoest, E. Detrait, V. Berger, C.C. Dupont-Gillain, L.-M. Vincent, Y.-J. Schneider, P. Bertrand, P.G. Rouxhet
Journal: Biomaterials (1998)
Calcineurin Expression, Activation, and Function in Cardiac Pressure-Overload Hypertrophy
Authors: Hae W. Lim, Leon J. De Windt, Leonard Steinberg, Tyler Taigen, Sandra A. Witt, Thomas R. Kimball, Jeffery D. Molkentin
Journal: Circulation (2000)

Background —Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin. Methods and Results —We showed that calcineurin enzymatic activity is increased 3.2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy. Conclusions —These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.
A Clinical Study of a Case of Cyst of the Cerebellum: Weakness of Spinal Muscles: Death from Failure of Respiration
Authors: J. H. Jackson, J. S. R. Russell
Journal: BMJ (1894)

0UU main object in recording this case is to emphasise a point in the symptomatology of cerebellar disease to which little attention has been paid.There is evidence of paresis of tile trunk muscles, a direct result, we believe, of the structural damage to the cerebellum produced by the cyst.We record the case also as it exemplifies a mode of dying in ,cases of intracranial tumour first pointed out by the late Dr. Hilton Fagge-death by failure of respiration.It lhas long been maintained by one of us (J.H. J.) that destructive lebions of the cerebellum, of its middle lobe at least, produce true motor paresis or paralysis, and that the trunk muscles are first and most afected, those of the in- ferior extremities next in order and severity, and those of the superior extremities last and least.Thus the degree and order of involvement of the different parts mentioned is the reverse of that which obtains in a destructive lesion of the -cerebrum attended by paralysis, for in most cases of hemi- plegia the arm suffers most, the leg less, and the trunk least.The recent experimental investigations of one of us (J. S. R. R.) appear to support these views on motor repre- sentation by the cerebellum.The results of these experiments in dogs and monkeys seem to prove the existence of motor paresis as one factor in the causation of the inability ,on the part of the animal to, walk or stand after ablation of parts or the whole of the cerebellum; and it was evident that in the dogs the posterior extremities suffered far more than the anterior.The condition of the trunk muscles could not be so well judged of in these animals, but in monkeys, after extirpation of the whole of the cerebellum, the paresis of the back muscles was so great that the animal was unable to sit up.