tbuckley/cabot-search huggingface dataset:
Preclinical leads for brain metastases of breast cancer
Authors: Diane Palmieri, Daniel Fitzgerald, Patricia Steeg
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

SY32-04 

The incidence of brain metastases of breast cancer appears to be increasing as a “sanctuary site” as chemo- and molecular therapies improve patients’ systemic survival. Brain metastases are particularly prevalent in young patients, and in patients with hormone receptor negative, Her-2+ and/or EGFR+ primary tumors. Therapeutic options are limited to whole brain or stereotactic radiation and steroids; few chemotherapeutic compounds cross the blood-brain barrier, or what is left of it as tumor cells colonize (blood-tumor barrier). The median one year survival after a diagnosis of a brain metastasis is approximately 20%.    A model system was validated using a brain-seeking derivative of the human MDA-MB-231 breast carcinoma cell line (231-BR). Upon intracardiac injection, these cells form multiple metastatic lesions within a month. Histopathologic analysis of brain sections revealed numerous micrometastases and several metastases >502 µm in area, comparable in size to those detected by imaging in the human brain, termed “clinical” metastases. Immunoflourescence staining of brain metastases in the model revealed a high proliferation rate and a negligible rate of apoptosis. In addition, the brain metastases were surrounded by activated glial cells, from both astrocytic and microglial lineages, suggestive of an ongoing tumor-host microenvironmental interaction. When a small cohort of 16 resected human brain metastases of breast cancer was stained, similar trends were found, suggesting the relevance of the model system.    For the Her-2+ subset of patients, there are many potential reasons for the increased incidence. Trastuzumab, a large monoclonal antibody to Her-2, poorly penetrates the blood-tumor barrier, rendering the brain a sanctuary site. We tested an additional hypothesis, that Her-2 overexpression changes the natural history of breast cancer to promote brain metastasis. 231-BR cells were transfected with Her-2 and signaling and in vitro growth and invasion characteristics analyzed. The Her-2 transfectants produced comparable numbers of micrometastases as control transfectants, but 2.5-3 fold greater clinical metastases in vivo. The data indicate that Her-2+ breast cancer cells extravasate into the brain and form micrometastases at rates equivalent to that of controls, but that Her-2 increases their outgrowth to clinically detectable lesions. Thus, Her-2+ overexpression stimulates brain colonization, and trastuzumab poorly penetrates the brain, resulting in the “perfect storm”. The ability of Lapatinib, an orally available small molecule tyrosine kinase inhibitor of Her-2 and EGFR, to prevent brain metastatic colonization will be discussed.
Compound Astragalus and Salvia miltiorrhiza extract inhibits cell proliferation, invasion and collagen synthesis in keloid fibroblasts by mediating transforming growth factor-β / Smad pathway
Authors: S. He, Y. Yang, X. Liu, W. Huang, X. Zhang, S. Yang, X. Zhang
Journal: British Journal of Dermatology (2011)

Background The transforming growth factor (TGF)-β/Smad pathway plays a key role in keloid development. We have previously demonstrated that compound Astragalus and Salvia miltiorrhiza extract (CASE) inhibits liver fibrosis and reduces invasion capacity of HepG2 cells by mediating the TGF-β/Smad pathway. We therefore hypothesize that CASE may also exert antifibrotic effects in keloids by mediating the TGF-β/Smad pathway. Objectives To investigate the effects of CASE on cell proliferation, invasion and collagen synthesis in keloid fibroblasts, and to explore the effects of CASE on the TGF-β/Smad signal pathway in order to elucidate its mechanisms of action. Methods The inhibitory effects of CASE on keloid fibroblasts were evaluated. Cell proliferation was studied by MTT assay; cell invasion was observed utilizing Transwell invasion chambers; and collagen synthesis in keloid fibroblasts was measured by 3H-proline incorporation assay. Expression of proteins induced by TGF-β1 and their intracellular localization in keloid fibroblasts were investigated by Western blot and immunofluorescence, respectively. Plasminogen activator inhibitor-1 (PAI-1) transcriptional activity was measured by real-time reverse transcription–polymerase chain reaction. Results CASE significantly inhibited cell proliferation induced by newborn bovine serum as well as collagen synthesis and cell invasion induced by TGF-β1 in keloid fibroblasts, while it showed weak effects on normal fibroblasts. The phosphorylation of Smad2/3 was markedly reduced by CASE treatment, while CASE exhibited stronger inhibitory effects on linker region phosphorylation (pSmad2L and pSmad3L) compared with effects on C-terminal region phosphorylation (pSmad2C and pSmad3C). In addition, CASE blocked formation of Smad2/3/4 complexes and their nuclear translocation, but upregulated Smad7 expression in a dose-dependent manner. PAI-1 mRNA and protein levels were also suppressed by CASE treatment. Conclusions These results suggest that CASE exhibits inhibitory effects on cell proliferation, invasion and collagen synthesis in keloid fibroblasts, and its mechanisms of action may involve the TGF-β/Smad pathway.
Stagnating influenza vaccine coverage rates among high-risk groups in Poland and Sweden in 2003/4 and 2004/5
Authors: M Kroneman, G A van Essen
Journal: Eurosurveillance (2007)

This paper examines influenza vaccine coverage rates (VCR) in Poland and Sweden during the 2003/4 and 2004/5 influenza seasons. An average sample of 2,500 persons was interviewed in each country and each season. Questions regarded age and possible chronic diseases, as well as information on whether they had had an influenza vaccination in the given season. Those who had not received the vaccine were also asked to give reasons for non-vaccination. About one in four (Sweden) to one in three (Poland) of the persons surveyed belonged to high-risk groups (&gt;=65 years of age or suffering from chronic diseases). In the 2004/5 season, 17% (CI 12-19%) of the Polish elderly and 45% (CI 39-50%) of the Swedish elderly were vaccinated. In Poland, 9% (CI 7-12%) of respondents younger than 65 years of age with a chronic condition were vaccinated, whereas in Sweden the corresponding rate was 12% (CI 9-16%). In both countries, the VCR did not change significantly from the previous season. Personal invitations resulted in a higher VCR. In Sweden, the most frequently mentioned reasons for not being vaccinated were the assumption of not qualifying for a vaccination and perceived resistance. In Poland in both years, perceived resistance to flu and the cost of the vaccination were the most often mentioned reasons. The influenza vaccination rates in Poland and Sweden remain far below World Health Organization (WHO) recommendations for the high-risk population. No increase in VCR as demonstrated in this study may indicate that these two countries will not be able to meet the 2010 WHO target, if no further action is taken concerning vaccine uptake.
Abstract 592: HOXD10 suppresses mammary tumor growth and metastasis coincident with decreased CD11b+Gr1+ leukocyte infiltration and angiogenesis
Authors: Suraj Kachgal, Amy Chen, Mazen Sidani, Shahrzad Afghani, Nancy J. Boudreau
Journal: Cancer Research (2014)

Abstract The tumor suppressor gene HOXD10 is frequently lost in breast cancer, and we have previously shown that restoring expression of this master transcriptional regulator can revert mammary tumor cells to a normal, polarized phenotype and inhibit their growth in nude mice (Carrio et al., Cancer Res., 2005). In addition, we showed that restoring HOXD10 also reduced VEGFA expression and decreased endothelial cell migration in vitro (Chen et al., Cancer Res., 2009). Considering the critical role of the immune system in mammary tumor progression and metastasis, we investigated whether Hoxd10 could also prevent breast tumor progression in an immunocompetent model. Metastatic 4T1 cell lines were transduced with Hoxd10 and were either orthotopically or intravenously injected into four to eight week old, female Balb/c mice. We observed a significant reduction in tumor burden at both primary at metastatic sites in tumors expressing Hoxd10. Immunohistochemical staining for CD31 of primary tumors expressing Hoxd10 revealed decreased angiogenesis. Flow cytometry and immunohistochemical staining also revealed a decrease in infiltrating Cd11b+Gr1+ leukocytes in Hoxd10-expressing tissues. Gene and protein analysis revealed that in addition to decreased VEGFA, HOXD10 also reduced expression of CCL2, a key chemokine linked to recruitment of Cd11B+Gr1+ leukocytes. Using an in vitro migration assay, we confirmed that the HOXD10-mediated reduction in CCL2 expression was directly linked to reduced recruitment of monocytes to tumor cells. Together, these data show that HOXD10 can stabilize the tumor microenvironment by coordinately reducing tumor cell growth, angiogenesis, leukocyte recruitment, and metastasis, and suggest a novel and comprehensive therapeutic approach to treat mammary tumors. Citation Format: Suraj Kachgal, Amy Chen, Mazen Sidani, Shahrzad Afghani, Nancy J. Boudreau. HOXD10 suppresses mammary tumor growth and metastasis coincident with decreased CD11b+Gr1+ leukocyte infiltration and angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2014-592
Practolol for Sinus Tachycardia in Asthma
Authors: JOHN F. BEARY
Journal: Annals of Internal Medicine (1974)

Letters1 September 1974Practolol for Sinus Tachycardia in AsthmaJOHN F. BEARY III, M.D., NICHOLAS J. FORTUIN, M.D.JOHN F. BEARY III, M.D.Search for more papers by this author, NICHOLAS J. FORTUIN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-81-3-405 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Therapy for asthma is sometimes complicated by undesirable cardiovascular stimulation from some of the frequently used drugs such as aminophylline, isoproterenol, and ephedrine. In the case described below, practolol, a cardiospecific beta-adrenergic blocking agent, was used to control sinus tachycardia and associated symptoms in a patient with severe asthma.A 63-year-old woman had had asthma for 30 years. Adequate control of bronchospasm required a regimen of ephedrine, prednisone, aminophylline by suppository, and isoproterenol by inhalation. A resting heart rate of 130 to 140 beats/min was documented repeatedly, and during severe attacks she developed heart rates of 140...References1. BARRET A: The pharmacology of practolol. Postgrad Med J 47(suppl): 7-12, 1971 Google Scholar2. MCNEILL R: The effect of beta-antagonists on the bronchi. Postgrad Med J 47(suppl) 14-16, 1971 Google Scholar3. POWLESSHINEBOURNEHAMER REJ: Selective cardiac sympathetic blockade as an adjunct to bronchodilator therapy. Thorax 24:616-618, 1969 CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Department of Medicine Cardiovascular Division The Johns Hopkins Hospital and School of Medicine Baltimore, Maryland 21205 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 September 1974Volume 81, Issue 3Page: 405-405KeywordsAsthmaCardiovascular therapyDrug therapyHeart rateInhalationIsoproterenolSuppositoryTachycardia Issue Published: 1 September 1974 PDF DownloadLoading ...
Abstract 8579: Age Related Change in Aortic Stiffness in the Thoracic and Abdominal Aorta Among African Americans: The Jackson Heart Study
Authors: Runyawan Chotenimitkhun, Craig A Hamilton, Neal Jeffries, Jane L Harman, Herman Taylor, J. J Carr, W. G Hundley
Journal: Circulation (2011)

Introduction : Age-related stiffening of the aorta is associated with increased aortic wall thickness (WT) in whites, but this relationship has not been clearly demonstrated in African Americans. We sought to determine this relationship in the Jackson Heart Study (JHS), a community-based prospective study of cardiovascular disease among 5,301 African Americans in the Jackson, Mississippi area. Hypothesis : Thoracic and abdominal measures of aortic pulse wave velocity (PWV), a measure of aortic stiffness, correlate with age related increases in WT in African Americans. Methods and Results : Beginning in 2009 (JHS Visit 3), 229 (67% women) consecutively recruited participants, aged 62+10 (39-87) years (89% hypertension, 39% diabetes, and 8% current smokers) underwent magnetic resonance imaging (MRI) measures of PWV and WT in the ascending and the descending thoracic aorta (aTA, dTA), and the abdominal aorta (AA). We determined the association between regional PWV and WT, age, gender, systolic blood pressure, body mass index, hemoglobin A1c, triglyceride, and high-density lipoprotein in a multivariable model. With age, regional PWV increased in the aTA and dTA (p&lt;0.0001 for both), but not the AA (p=0.09; Figure 1); a 10 year increase in age corresponded to a 26%, 21% and 5.7% increase in PWV in the aTA, dTA and AA, respectively. The mean WT was 3.05+0.71 mm, 3.02+0.81 mm, and 2.04+ 0.78 mm in the aTA, dTA, and AA, respectively. After controlling for all variables in the model above, PWV showed a strong inverse relationship to WT: a 1% increase in WT was associated with a 0.26% decrease in PWV (p&lt; 0.0001); this was true independent of the aortic region (p=0.08). Conclusion : Regional PWV increases with age in African Americans, but unlike whites, is inversely related to aortic WT. These data suggest that age-related stiffening of the aorta in African Americans may be related to factors that operate independent of wall thickness.
Abstract 962: Identification of a PFKFB3 inhibitor suitable for phase I trial testing that synergizes with the B-Raf inhibitor vemurafenib
Authors: Julie O'Neal, Gilles Tapolsky, Brian Clem, Sucheta Telang, Jason Chesney
Journal: Cancer Research (2014)

Abstract In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate, which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms. We recently identified the first competitive small molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), and demonstrated that this agent is selectively cytotoxic to Ras-transformed epithelial cells and displays broad anti-tumor activity. We now report the discovery of a novel 3PO-derivative, PFK158, that is markedly more potent than 3PO, has excellent pharmacokinetic properties and causes ∼80% growth inhibition in several mouse models of human-derived tumors. Importantly, IND-enabling safety and toxicity studies have demonstrated that PFK158 is well tolerated in rats and dogs, providing support for a phase 1 trial in cancer patients planned for early 2014. Once the maximum tolerated dose is identified, we intend to conduct multiple phase 1/2 trials of PFK158 in combination with targeted agents given the ability of PFK158 to suppress glucose metabolism and multiple survival mechanisms. One such targeted agent, vemurafenib, is a mutant B-Raf inhibitor that was recently FDA-approved for BRAFV600E-positive melanoma patients. Unfortunately, a multitude of resistance mechanisms have resulted in disease progression in less than one year for the majority of melanoma patients treated with vemurafenib. We hypothesized that PFK158 would sensitize vemurafenib-resistant melanoma cells and found that the addition of PFK158 to vemurafenib caused a marked increase in the apoptotic death of several melanoma cell lines in vitro. These data provide rationale for the conduct of pre-clinical studies of PFK158 combined with vemurafenib in transgenic BRAFV600E melanoma mouse models which are in turn expected to justify a phase I/II trial of the combination in BRAFV600E-positive melanoma patients. In conclusion, PFK158 is the first PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility when combined with agents that target driver oncogenes. Citation Format: Julie O'Neal, Gilles Tapolsky, Brian Clem, Sucheta Telang, Jason Chesney. Identification of a PFKFB3 inhibitor suitable for phase I trial testing that synergizes with the B-Raf inhibitor vemurafenib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 962. doi:10.1158/1538-7445.AM2014-962
Usefulness of a global clinical ichthyosis vulgaris scoring system for predicting common<i>FLG</i>null mutations in an adult caucasian population
Authors: K. Ezzedine, C. Droitcourt, C. Ged, A. Diallo, T. Hubiche, H. de Verneuil, F. Boralevi, A. Taïeb
Journal: British Journal of Dermatology (2012)

Background Loss of function FLG alleles were first identified as causative of ichthyosis vulgaris (IV) and were subsequently found to be major predisposing factors for atopic dermatitis (AD) and atopic disorders. Objectives To identify independent factors associated with the clinical IV phenotype in adult caucasian patients with AD and to assess the performance of a global clinical severity score of IV in predicting common FLG null mutations. Patients and methods This was a prospective study conducted from January 2007 to June 2008. Adult patients attending the department of dermatology with a diagnosis of AD with or without IV were eligible to participate. For each patient, five clinical signs of IV were scored from 0 to 3 – diffuse xerosis, hyperlinearity of palms, scales on legs, scalp desquamation and keratosis pilaris – and a global IV clinical severity score was derived (0–15). Age of onset of AD, SCORAD (SCORing of Atopic Dermatitis), family and personal history for other signs of atopy, and total immunoglobulin E were recorded. Genotyping was performed for R501X and 2282del4. Univariate and multivariate analysis for factors associated with AD or AD + IV were conducted. Results In univariate analysis, family history of atopy, global clinical severity scoring and 2282del4 FLG mutation were positively correlated with the AD + IV phenotype. Using multivariate analysis, SCORAD for AD (OR 0·94, P =0·01) and global clinical severity scoring for AD + IV (OR 2·62, P <0·0001) were found to be independent factors. Conclusions The 2282del4 FLG mutation was confirmed as a good marker of early‐onset disease. Moreover, our global clinical severity score yielded a good negative predictive value of common caucasian null FLG mutations.
Pre-Operative Risk Factors of Bleeding and Stroke During Left Ventricular Assist Device Support
Authors: Andrew J. Boyle, Ulrich P. Jorde, Benjamin Sun, Soon J. Park, Carmelo A. Milano, O. Howard Frazier, Kartik S. Sundareswaran, David J. Farrar, Stuart D. Russell
Journal: Journal of the American College of Cardiology (2013)
614. In Vivo and In Vitro Characterisation of Library Selected Matrix Metalloprotease Activatable Retroviruses
Authors: Irene Hartl, Richard M. Schneider, Yuansheng Sun, Stephen J. Russell, Christian J. Buchholz, Klaus Cichutek
Journal: Molecular Therapy (2004)

Viruses conditionally replicating in cancer cells form an attractive novel class of anti-tumoural agents. To engineer such viruses we couple infectivity with proteolytic activity of the target cell by modifying the envelope (Env) protein of murine leukemia virus (MLV) with blocking domains that prevent cell entry unless they are cleaved off by tumor-associated proteases like the matrix metalloproteases (MMP).
Ambulances should tailor response to situation
Authors: Marcus Müllner
Journal: BMJ (1998)

Ambulance services should be more flexible and adapt responses according to different levels of urgency, a report from the Audit Commission recommends.

A life in the fast lane, questions the current practice of dispatching a fully equipped ambulance and crew in all situations however minor. It asks whether it might be more appropriate to treat some patients at home instead of transporting them to hospital.

The commission calls on the government to reopen the case on whether …
733. Enhancement of Lentiviral-Mediated Gene Transfer in Kidney by Polycations and Detergents
Authors: Elena V. Fedorova, Lorenzo Battini, Basil Hanss, G. Luca Gusella
Journal: Molecular Therapy (2004)

We have previously shown that stable transduction of kidney can be achieved by the delivery of lentiviral vectors through the ureter and to the renal parenchyma. In this report, we utilized the same routes of delivery to assess the ability of different agents to enhance viral transduction of kidney. In particular, we focused on mannitol, a hyperosmotic agent, polybrene, a polycation that increases virus adsorption to cell surface, as well as the mild detergents polidocanol and lysophosphatidylcholine, which have been reported to improve the efficiency of transduction in a variety of epithelial tissues. These agents were tested in Balb/c mice during the ureter or intraparenchymal administration of the third generation replication-defective, self-inactivating lentiviral vectors (VVCW or VVPW) carrying EGFP, LacZ, or SEAP as reporter genes under the control of the eCMV or murine PGK promoters. Approximately 1×107 to 1×108 transducing units (TU) of the lentiviral vector were formulated in 50 μl of mannitol or polybrene solutions before delivery. Alternatively, either polidocanol or lysophosphatidylcholine was used to pretreat the kidneys for one hour prior to infusion of 108 viral TU. Transgene expression was then evaluated two weeks later by determining the expression of the reporter gene in renal cells, urine, or blood. Positive transduction of the mouse kidney was confirmed by immunohistochemical staining of the kidney for bacterial β-galactosidase or EGFP and by detection of SEAP activity in kidney extracts. Kidney transduction was observed with virus alone independently of the treatment with any of the agents and was used as control baseline. Mannitol did not affect the levels of viral transduction. However, the presence of polybrene or the pretreatment with polidocanol or lysophosphatidylcholine enhanced the lentiviral mediated gene transfer to kidney. When the lentivector preparation was centrifuged in the presence of polybrene and administered through the ureter and parenchyma, transduction efficiency increased seven- and two-fold, respectively. Retrograde ureter infusion in kidney following pretreatment with PDOC or LPC resulted in a six- or two-fold increase in transduction levels, respectively. The positive effect of these agents on gene transfer appeared not to be associated with any histological abnormality or with obvious inflammatory response within the mouse kidney.
Symptom Trends in the Last Year of Life from 1998 to 2010
Authors: Adam E. Singer, Daniella Meeker, Joan M. Teno, Joanne Lynn, June R. Lunney, Karl A. Lorenz
Journal: Annals of Internal Medicine (2015)

Despite end-of-life care receiving increased attention in recent years, it is not known whether dying patients' symptoms have improved. This cohort study describes changes in pain intensity and sym...
Capsule Endoscopy Is Feasible in Small Children
Authors: L. Aabakken, T. Scholz, A. Østensen, R. Emblem, T. Jermstad
Journal: Endoscopy (2003)

Capsule endoscopy was recently introduced for endoluminal visualization of the small bowel [1]. The clinical utility of the procedure is undisputed [2] [3] [4], and for most patients, swallowing the capsule (11 × 33 mm in size) does not pose any problems. However, use of the capsule in small children has not yet been reported.