tbuckley/cabot-search huggingface dataset:
Targeting Matrilysin and Its Impact on Tumor Growth <i>In vivo</i>: The Potential Implications in Breast Cancer Therapy
Authors: Wen G. Jiang, Gaynor Davies, Tracey A. Martin, Christian Parr, Gareth Watkins, Malcolm D. Mason, Kefah Mokbel, Robert E. Mansel
Journal: Clinical Cancer Research (2005)

Matrilysin (MMP-7) is a metalloproteinase that is involved in the degradation of extracellular matrix, invasion, and tumor progression. The current study examined if targeting matrilysin using retroviral ribozyme transgenes may have an impact on breast cancer cells and may have clinical implications.Retroviral hammerhead ribozyme transgenes were designed to specifically target human matrilysin mRNA. The breast cancer cell MDA-MB-231 was transfected with either a retroviral matrilysin transgene or a control retroviral transgene. Stably transfected cells were tested for their invasiveness and migratory properties in vitro. The cells were also used in creating a tumor model in athymic nude mice in which the growth of tumors and levels of matrilysin were assessed. In addition, levels of both protein and mRNA of matrilysin were investigated in a cohort of human breast tumors.Expression of matrilysin in MDA-MB-231 was successfully eliminated by the retroviral hammerhead ribozyme transgene for matrilysin as revealed by reverse transcription-PCR. Matrilysin transgene-transduced cancer cells (MDA-MB-231DeltaMatrilysin) exhibited a significantly lower degree of invasion (number of invading cells 16.0 +/- 2.5) compared with wild type (MDA-MB-231(WT); 26.2 +/- 6.2, P < 0.05) or control transgene-transduced cancer cells (MDA-MB-231pRevTRE; 25.3 +/- 4.2, P < 0.01). However, the rate of growth of the cells in vitro was not significantly affected. In the in vivo tumor model, MDA-MB-231DeltaMatrilysin tumors, which had very low levels of immunoreactive matrilysin, grew at a significantly lower rate (0.24 +/- 0.03 cm3, 4 weeks after inoculation) compared with the wild-type MDA-MB-231(WT) (1.46 +/- 0.04 cm3) and MDA-MB-231pRevTRE (1.12 +/- 1.0 cm3) tumors. In human breast tumors, breast cancer cells stained matrilysin at a significantly higher density, compared with normal mammary epithelium. The highest level of matrilysin was seen in high-grade tumors and that from patients with moderate and poor prognosis. Finally, high levels of matrilysin were significantly linked with a poor long-term survival (P = 0.0143).Matrilysin, which is aberrantly expressed in human breast tumors, can be effectively eliminated from breast cancer cells by way of hammerhead ribozyme transgene. Elimination of matrilysin is associated with low invasiveness and slow tumor growth. Taken together, the study suggests that targeting matrilysin may have important therapeutic implications.
Testing Ironclad Practices-Reply
Authors: Paul S. Swerdlow
Journal: JAMA (1992)

<h3>In Reply.</h3> —Dr Crosby lucidly illustrates the misuse of iron in the treatment of anemia unrelated to iron deficiency. Patients also misuse over-the-counter iron preparations. Self-treatment can result in significant iron overload or delayed diagnoses since iron deficiency anemia, a major clue for diagnosing chronic blood loss, may not develop. Crosby emphasizes that when treating anemia, "iron is the proper treatment for iron deficiency anemia and that anemia alone." This is an excellent and general rule that is too often ignored. My Editorial was not intended to detract from, or to encourage testing of, this particular medical principle. The major point was that some common practices or even standards of care seem contrary to medical principles and that such disagreements must be resolved. Zauber et al<sup>1</sup>could have tried to reason with individual physicians about iron supplementation or submitted an editorial with their viewpoint. I suspect, however, that such
Targeting Proteases in Atherosclerosis
Authors: Daniel I. Simon, Mukesh K. Jain
Journal: Circulation (2011)

T he initiation, progression, and complications of athero- sclerosis are mediated by a complex interplay of hematopoietic cells, vascular cells, and the extracellular matrix in response to metabolic (eg, hyperlipidemia, diabetes mellitus) and environmental (eg, smoking) injury. 1 Antiatherosclerotic therapies are currently limited to statins and their lipidlowering and pleiotropic anti-inflammatory effects, to angiotensin-converting enzyme inhibitors and their local effects on vascular cell proliferation and plaque progression independently of blood pressure lowering, and to antiplatelet agents and their role in preventing the thrombotic complications of plaque rupture and superficial endothelial cell (EC) erosion. 2,3However, although these therapies have been shown to reduce event rates by Ϸ20% to 40% in randomized, placebo-controlled clinical trials, absolute event rates remain high.For example, recurrent ischemic events after index acute coronary syndrome presentation occur in Ͼ20% of patients by 36 months despite optimal medical therapy and revascularization. 4This failure of drug and device therapies represents an enormous unmet clinical need.In contrast to effective disease-modifying therapies in psoriasis, rheumatoid arthritis, and multiple sclerosis, targeted antiatherosclerotic therapies have remained elusive.In this issue of Circulation, Miyazaki and colleagues 5 have identified m-calpain (calpain 2 and its regulatory domain, calpain 4) as a novel protease target for the modulation of atherogenesis.
Unintentional Non–Fire-Related Carbon Monoxide Exposures—United States, 2001-2003
Authors: Madhavi Vajani, J. Lee Annest, Michael F. Ballesteros, Julie Gilchrist, A. Stock, Usa Prevention
Journal: JAMA (2005)

Carbon monoxide (CO) is a colorless, odorless, poisonous gas that results from incomplete combustion of fuels (e.g., natural or liquefied petroleum gas, oil, wood, coal, or other fuels). CO sources (e.g., furnaces, generators, gas heaters, and motor vehicles) are common in homes or work environments and can put persons at risk for CO exposure and poisoning. Most signs and symptoms of CO exposure are nonspecific (e.g., headache or nausea) and can be mistakenly attributed to other causes, such as viral illnesses. Undetected or unsuspected CO exposure can result in death. To examine fatal and nonfatal unintentional, non-fire-related CO exposures, CDC analyzed 2001-2003 data on emergency department (ED) visits from the National Electronic Injury Surveillance System All Injury Program (NEISS-AIP) and 2001-2002 death certificate data from the National Vital Statistics System (NVSS). During 2001-2003, an estimated 15,200 persons with confirmed or possible non-fire-related CO exposure were treated annually in hospital EDs. In addition, during 2001-2002, an average of 480 persons died annually from non-fire-related CO poisoning. Although males and females were equally likely to visit an ED for CO exposure, males were 2.3 times more likely to die from CO poisoning. Most (64%) of the nonfatal CO exposures occurred in homes. Efforts are needed to educate the public about preventing CO exposure.
Apoptosis pathways as promising targets for skin cancer therapy
Authors: J. Eberle, L.F. Fecker, T. Forschner, C. Ulrich, J. Röwert-Huber, E. Stockfleth
Journal: British Journal of Dermatology (2007)

Summary Apoptosis pathways provide efficient safeguard mechanisms against cancer that are mediated via cell-intrinsic responses and immune-mediated extrinsic signals. Intrinsic pro-apoptotic pathways are largely controlled by p53 and Bcl-2 proteins, whereas the extrinsic induction of apoptosis is initiated by death ligands, such as tumour necrosis factor-alpha (TNF-α), CD95L/FasL and TNF-related apoptosis-inducing ligand (TRAIL), or by granzyme B. Initiation of these pathways results in the induction of a caspase cascade leading to cell death. The inactivation of pro-apoptotic pathways is elementary for tumourigenesis and may be responsible for therapy resistance. Thus, apoptosis-based strategies represent important tools for the development of effective tumour therapies. The aim of these therapies is to restore p53 activity, downregulate anti-apoptotic Bcl-2 proteins or NF-κB activity, and to upregulate extrinsic, death receptor-mediated pathways. The initial results of apoptosis-based strategies are proving promising. Also, topical treatments for actinic keratosis (AK), such as cyclo-oxygenase-2 inhibitors (e.g. diclofenac 3% gel), have been shown to trigger pro-apoptotic pathways. There is hope that pro-apoptotic strategies will lead to pronounced therapeutic success against skin cancer. Importantly, the involvement of the different pro-apoptotic pathways in specific tumour types needs to be unravelled and understood in order to evaluate drug effectiveness, as well as to modify and optimise therapeutic approaches.
Geographical Variation in Risk HLA-DQB1 Genotypes for Type 1 Diabetes and Signs of β-Cell Autoimmunity in a High-Incidence Country
Authors: Marika Kukko, Suvi M. Virtanen, Anna Toivonen, Satu Simell, Sari Korhonen, Jorma Ilonen, Olli Simel, Mikael Knip
Journal: Diabetes Care (2004)

OBJECTIVE—To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of β-cell autoimmunity among three geographical regions in Finland. RESEARCH DESIGN AND METHODS—The series comprised 4,642 children with increased HLA-DQB1–defined genetic risk of type 1 diabetes from the Diabetes Prediction and Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 (25.9%) in Tampere. These children were examined frequently for the emergence of signs of β-cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A). RESULTS—The high- and moderate-risk genotypes were unevenly distributed among the three areas (P &amp;lt; 0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P &amp;lt; 0.001) or Tampere regions (27.2%; P &amp;lt; 0.001). This genotype was associated with an increased frequency of ICA seroconversion relative to the moderate risk genotypes (hazard ratio 1.89, 95% CI 1.36–2.62). Seroconversions to ICA positivity occurred less commonly in Tampere than in Turku (0.47, 0.28–0.75), whereas the seroconversion rate in Oulu did not differ from that in Turku (0.72, 0.51–1.03). The Tampere-Turku difference persisted after adjustment for risk genotypes, sex, and time of birth (before January 1998 versus later). Seroconversion for at least one additional autoantibody was also less frequent in Tampere than in Turku (0.39, 0.16–0.82). CONCLUSIONS—These data show that in Finland, the country with the highest incidence of type 1 diabetes in the world, both the frequency of the high-risk HLA-DQB1 genotype and the risk of seroconversion to autoantibody positivity show geographical variation. The difference in seroconversion rate could not be explained by the difference in HLA-DQB1–defined disease susceptibility, implying that the impact of environmental triggers of diabetes-associated autoimmunity may differ between the three regions studied.
Evaluation of Routine Serial Fluoroscopic Examinations of the Heart in the Postero-anterior and Oblique Views at Specific Degrees of Rotation
Authors: MAY G. WILSON, NATHAN EPSTEIN, HELEN N. HELPER, KATHARINE HAIN
Journal: Circulation (1953)

An evaluation of 2973 serial fluoroscopic examinations at specific degrees of rotation for 500 subjects 2 to 21 years of age, made by 35 different observers with an average of five examiners per patient, is presented. In the postero-anterior view, 1 per cent showed convexity of the pulmonary segment. In the right anterior oblique position 1 per cent showed retrodisplacement of the esophagus. The angle of clearance of the left ventricle in the left anterior oblique position was less than 55 degrees in 99 per cent of the fluoroscopic examinations. In addition, 1393 routine serial fluoroscopic examinations of 100 patients with inactive rheumatic heart disease, 4 to 48 years of age, were analyzed. There was a total of 49 observers, an average of 8 per patient. The angle of clearance of the left ventricle ranged between 55 and 70 degrees. There was left auricular enlargement in 98 patients. It is concluded that fluoroscopic examination at specific degrees of rotation is a reliable procedure for detecting cardiac chamber abnormality, and should be included as part of the routine examination.
DURATION OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE DETECTION OF ANTIBODY
Authors: C.Robert Horsburgh, Janine Jason, IraM. Longini, KennethH. Mayer, Gerald Schochetman, GeorgeW. Rutherford, GeorgeR. SEAGE, ChinYih Ou, ScottD. Holmberg, Charles Schable, AlanR. Lifson, JohnW. Ward, BruceL. Evatt, HaroldW. Jaffe
Journal: The Lancet (1989)
Expansion of Bcr-Abl-Positive Leukemic Stem Cells Is Dependent on Hedgehog Pathway Activation
Authors: Christine Dierks, Ronak Beigi, Gui-Rong Guo, Katja Zirlik, Mario R. Stegert, Paul Manley, Christopher Trussell, Annette Schmitt-Graeff, Klemens Landwerlin, Hendrik Veelken, Markus Warmuth
Journal: Cancer Cell (2008)
Mechanisms mediating the coronary vascular response to behavioral stress in the dog.
Authors: G E Billman, D C Randall
Journal: Circulation Research (1981)

Left circumflex coronary blood flow (CBF) was measured in eight mongrel dogs with 8 MHz continuous wave Doppler flow transducers during classical aversive conditioning. The cardiovascular condition response consisted of significant (P less than 0.01) increases in: (1) mean aortic pressure (16.1%), (2) d(left ventricular pressure)/dt (64.2%), and (3) heart rate (63.2%). The coronary vascular response to behavioral stress consisted of an initial late diastolic decrease in CBF (12.5%) between 5 and 10 seconds after conditional stimulus onset, followed by a significant increase in CBF (96.8%). Concurrently, late diastolic coronary vascular resistance (CVR) first significantly increased (21.9%), then significantly decreased (39.8%). The increase in CVR was attenuated by cardiac pacing and converted into a significant decrease after alpha-receptor blockade. The decrease in CVR was reduced either by cardiac pacing or cardioselective beta-receptor blockage and eliminated by the combination of alpha- and beta-receptor blockade. Thus, these data indicate that the coronary vascular response to stress consisted of two components: an initial alpha-adrenergic coronary vasoconstriction, followed by a more complex vasodilation which was probably mediated by metabolites released secondarily to increases in heart rate and inotropic state.
The Current State of Public Health in China
Authors: Liming Lee
Journal: Annual Review of Public Health (2004)

In the past 50 years, China has made great achievements in controlling infectious diseases and improving the public's health and hygiene. However, in the twenty-first century, owing to the negative effects brought on by aging of the population and the burdens of diseases, urbanization, industrialization, and globalization, Chinese public health officials are encountering greater difficulties than ever. Old operating models of public health cannot meet present requirements. The main problems are poor capacity to respond to public health emergencies, severe inequality of health care services, and lagging development of public health information systems. Public health in China can gradually meet the requirements of social development and the increasing public demand for health care services only when the public health is directed by informatization, globalization, technification, and humanization.
Are Estrogens Protective or Risk Factors in Brain Injury and Neurodegeneration? Reevaluation after the Women’s Health Initiative
Authors: Phyllis M. Wise, Dena B. Dubal, Shane W. Rau, Candice M. Brown, Shotaro Suzuki
Journal: Endocrine Reviews (2005)

Estrogens are essential for normal reproductive function. In addition, they exert important, complex, and diverse nonreproductive actions on multiple tissues. Although accumulating evidence from basic science studies using animal models suggests that estradiol plays a critical neuroprotective role against multiple types of neurodegenerative diseases and injuries, recent clinical studies have reported either inconclusive or untoward effects of hormone therapy on the brain. We focus herein on the work that we have done during the past 6 yr that strongly suggests that low levels of estradiol therapy exert dramatic protective actions in the adult injured brain. Our results reveal that 17β-estradiol slows the progression of this injury and diminishes the extent of cell death by suppressing apoptotic cell death pathways and enhancing expression of genes that optimize cell survival. Furthermore, we have found that estrogen receptors play a pivotal functional role in neuroprotection. Together, these results carry broad implications for the selective targeting of estrogen receptors in the treatment of neurodegenerative conditions resulting from disease or injury, particularly for aging, postmenopausal women.
Loss of Salmeterol Bronchoprotection against Exercise in Relation to ADRB2 Arg16Gly Polymorphism and Exhaled Nitric Oxide
Authors: Matteo Bonini, Perdita Permaul, Tejaswini Kulkarni, Shamsah Kazani, Alex Segal, Christine A. Sorkness, Michael E. Wechsler, Elliot Israel
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

β2-Agonists are the treatment of choice for exercise-induced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of β2-agonists.To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection.A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 μg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV1, response to salmeterol, degree of EIB, and exhaled nitric oxide (FE(NO)) at baseline were examined for their association with loss of bronchoprotection (LOB).The maximum exercise-induced FEV1 fall was 27.9 ± 1.4% during the run-in period, 8.1 ± 1.2% (70.3 ± 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 ± 3.2% (18.9 ± 11.5% bronchoprotection) after 2 weeks of salmeterol (P = 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FeNO values at baseline were significantly related to the LOB (r = 0.47; P = 0.01). Mean change was a 74 ± 13% LOB in subjects with FE(NO) levels greater than 50 ppb and a 7 ± 16% gain in bronchoprotection in those with FE(NO) levels less than 25 ppb (P = 0.01).The LOB that occurs with chronic long-acting β2-agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE(NO) was associated with marked LOB. Use of long-acting β2-agonists before achieving a reduction in FeNO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).
Glcci1 Deficiency Leads to Proteinuria
Authors: Yukino Nishibori, Kan Katayama, Mataleena Parikka, Ásmundur Oddsson, Masatoshi Nukui, Kjell Hultenby, Annika Wernerson, Bing He, Lwaki Ebarasi, Elisabeth Raschperger, Jenny Norlin, Mathias Uhlén, Jaakko Patrakka, Christer Betsholtz, Karl Tryggvason
Journal: Journal of the American Society of Nephrology (2011)

Unbiased transcriptome profiling and functional genomics approaches identified glucocorticoid-induced transcript 1 (GLCCI1) as being a transcript highly specific for the glomerulus, but its role in glomerular development and disease is unknown. Here, we report that mouse glomeruli express far greater amounts of Glcci1 protein compared with the rest of the kidney. RT-PCR and Western blotting demonstrated that mouse glomerular Glcci1 is approximately 60 kD and localizes to the cytoplasm of podocytes in mature glomeruli. In the fetal kidney, intense Glcci1 expression occurs at the capillary-loop stage of glomerular development. Using gene knockdown in zebrafish with morpholinos, morphants lacking Glcci1 function had collapsed glomeruli with foot-process effacement. Permeability studies of the glomerular filtration barrier in these zebrafish morphants demonstrated a disruption of the selective glomerular permeability filter. Taken together, these data suggest that Glcci1 promotes the normal development and maintenance of podocyte structure and function.
Phenotypes of peripheral blood lymphoid cells in patients with asbestos-related pleural lesions
Authors: M Ozesmi, G Hillerdal, A Karlsson-Parra, U Forsum
Journal: European Respiratory Journal (1988)

Asbestos-related parietal pleural plaques develop slowly and are of little clinical significance. Other asbestos-related pleural reactions, for example acute exudative pleurisy and progressive pleural fibrosis, are of clinical importance. The pathogenesis of these reactions is unknown, but one hypothesis is that immunological disturbances are involved. To investigate this hypothesis a phenotypic characterization of lymphoid cells was performed in the peripheral blood of 45 patients with asbestos-related pleural lesions; 20 with pleural plaques (PP), 15 with diffuse pleural fibrosis (DPF), and 10 with benign asbestos pleural effusion (BAPE). Twenty-four healthy blood donors were used as controls. All asbestos groups together had a significantly higher percentage of B-cells than the controls. The percentage number of "helper/inducer" T-cells was significantly lower in the BAPE and DPF groups than in the control and PP groups. Thus, significant aberrations in peripheral blood lymphoid cells were found in patients with DPF and BAPE. This differed from patients with PP only who were similar to normals.
Detection of Brain Tumor Cells in the Peripheral Blood by a Telomerase Promoter-Based Assay
Authors: Kelly M. MacArthur, Gary D. Kao, Sanjay Chandrasekaran, Michelle Alonso-Basanta, Christina Chapman, Robert A. Lustig, E. Paul Wileyto, Stephen M. Hahn, Jay F. Dorsey
Journal: Cancer Research (2014)

Blood tests to detect circulating tumor cells (CTC) offer great potential to monitor disease status, gauge prognosis, and guide treatment decisions for patients with cancer. For patients with brain tumors, such as aggressive glioblastoma multiforme, CTC assays are needed that do not rely on expression of cancer cell surface biomarkers like epithelial cell adhesion molecules that brain tumors tend to lack. Here, we describe a strategy to detect CTC based on telomerase activity, which is elevated in nearly all tumor cells but not normal cells. This strategy uses an adenoviral detection system that is shown to successfully detect CTC in patients with brain tumors. Clinical data suggest that this assay might assist interpretation of treatment response in patients receiving radiotherapy, for example, to differentiate pseudoprogression from true tumor progression. These results support further development of this assay as a generalized method to detect CTC in patients with cancer.