tbuckley/cabot-search huggingface dataset:
Tetraspanin CD151 Regulates Growth of Mammary Epithelial Cells in Three-Dimensional Extracellular Matrix: Implication for Mammary Ductal Carcinoma<i>In situ</i>
Authors: Vera Novitskaya, Hanna Romanska, Marwa Dawoud, J. Louise Jones, Fedor Berditchevski
Journal: Cancer Research (2010)

Tetraspanin CD151 is associated with laminin-binding integrins (i.e., alpha(3)beta(1), alpha(6)beta(1), and alpha(6)beta(4)) and regulates tumor cell migration and invasion. Here, we examined the role of CD151 in proliferation of mammary epithelial cells using in vitro and in vivo models. Depletion of CD151 suppressed growth of HB2 cells, a nontumorigenic breast epithelial cell line, in three-dimensional (3D) extracellular matrices (ECM) and in Matrigel-based xenografts. Whereas the presence of alpha(3)beta(1) (but not alpha(6) integrins) was necessary to support growth of HB2 cells in 3D ECM, the pro-proliferative activity of CD151 did not require direct interaction with integrins. Furthermore, depletion of CD151 potentiated formation of the internal lumen and partial restoration of polarity when HB2 cells were cultured in 3D ECM. This correlated with a decrease in phosphorylation levels of extracellular signal-regulated kinase 1/2 and cAkt in CD151-negative cells and increase in activation of caspase-3. Accordingly, the number of CD151-positive colonies with internal lumen was increased by approximately 5-fold when cells were cultured in the presence of MAP/ERK kinase (U0126) and phosphoinositide 3-kinase (LY29004) inhibitors. To establish the physiologic relevance of pro-proliferative and morphogenetic activities of CD151, we analyzed the expression of this tetraspanin in ductal carcinoma in situ (DCIS), which is characterized by neoplastic proliferation of mammary epithelial cells. Strong homogeneous membrane expression of CD151 was found to be associated with a high grade of DCIS (P = 0.004). Taken together, these results strongly suggest that CD151 complexes play a crucial role in the development of hyperproliferative diseases in the mammary gland.
High Rate of Large-Scale Hemizygous Deletions in Asexually Propagating Daphnia: Implications for the Evolution of Sex
Authors: S. Xu, A. R. Omilian, M. E. Cristescu
Journal: Molecular Biology and Evolution (2010)

The origin and maintenance of sex remains one of the most debated topics in evolutionary biology. Investigations of the molecular genetic consequences of asexuality, such as direct estimation of mutation and recombination rates in asexual lineages, are critical for explaining the prevalence of sex in nature. In this study, we use long-term mutation accumulation lines of asexually propagating Daphnia pulex and D. obtusa to examine the role of hemizygous deletion and ameiotic recombination (crossover and gene conversion) in the evolution of asexual taxa. Large-scale hemizygous deletions ranging from 2 to 30 kb are found to occur at a rate of 6.7 × 10−5 locus−1 generation−1 in D. pulex, which is one order of magnitude higher than the rate of large-scale deletions in Saccharomyces cerevisiae and Drosophila melanogaster. A conservative estimate of gene conversion and crossing over in the apomictic germ line cells of Daphnia yields a rate of 3.3 × 10−5 locus−1 generation−1. Our exceptionally high rate of large-scale segmental deletions suggests that the long-term survival of asexual Daphnia lineages is likely compromised by a high deleterious mutation pressure and that selection against deleterious mutations may play an important role in the evolution and maintenance of sex.
High Levels of Virus-Specific CD4<sup>+</sup> T Cells Predict Severe Pandemic Influenza A Virus Infection
Authors: Yan Zhao, Yong-Hong Zhang, Laura Denney, Duncan Young, Tim J. Powell, Yan-Chun Peng, Ning Li, Hui-Ping Yan, Da-Yan Wang, Yue-Long Shu, Yvonne Kendrick, Andrew J. McMichael, Ling-Pei Ho, Tao Dong
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: T-cell responses have been implicated in control and exacerbation of lung injury during influenza A virus (IAV) infection.Objectives: To examine the breadth and magnitude of influenza-specific CD4+ and CD8+ T-cell responses during acute phase of infection.Methods: Influenza-specific T-cell response to the entire pandemic H1N1/09 IAV proteome and T cell–related cytokine levels were measured in blood from previously healthy individuals with mild (n = 32) and severe (n = 16) IAV infection during the 2009 influenza pandemic. Virus-specific T-cell response in lung and blood was also performed in two acutely infected, severely ill patients using fluorescent-conjugated pdmH1N1/09 Matrix-MHC-I tetrameric complexes.Measurements and Main Results: Strong and broad CD4+ but not CD8+ T-cell responses were observed in the blood, and were higher in those with severe disease. Antigen-specific CD8+ T cells in the lungs were on average 45-fold higher compared with blood in severely ill patients. Paradoxically, in patients with severe disease, IL-17, IL-2, IL-4, and IFN-γ levels were significantly decreased.Conclusions: High levels of circulating virus-specific CD4+ T cells to two viral internal proteins (nucleoprotein and matrix) in the first phase of infection are associated with subsequent development of severe IAV infection. This finding could be an early and specific marker for ensuing clinical deterioration. Contrasting levels of antigen-specific CD8+ T cells in lungs and blood have implications on design and analysis of clinical trials for T-cell vaccines because measurements of T cells in the periphery may not reflect events in the lungs.
Circulating Growth Factor Levels Are Associated with Tumorigenesis in Neurofibromatosis Type 1
Authors: George A. Mashour, Pablo Hernáiz Driever, Melanie Hartmann, Stephanie N. Drissel, Tingguo Zhang, Bianca Scharf, Ursula Felderhoff-Müser, Sadatoshi Sakuma, Reinhard E. Friedrich, Robert L. Martuza, Victor Felix Mautner, Andreas Kurtz
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Neurofibromatosis type 1 (NF1) is characterized by systemic development of neurofibromas. Early clinical diagnosis can be ambiguous, and genetic diagnosis can be prohibitively difficult. Dysregulation of a number of growth factors has been suggested to be a mechanism of pathogenesis. This study was performed to assess the contribution of circulating growth factors for diffuse tumorigenesis and the diagnostic value of circulating growth factor identification in serum. Experimental Design: The growth stimulation of neurofibroma-derived cells by serum from NF1 patients was tested, and serum growth factor levels in a cohort of NF1 patients (n = 39) between the ages of 7 and 70 years were analyzed. Results: Concentrations of midkine (MK) and stem cell factor, but not epidermal growth factor, were substantially increased in serum of NF1 patients when compared with healthy controls. Within the NF1 group, MK levels increased dramatically at puberty from an average of 0.79 ng/mL in patients &amp;lt;18 years to 1.18 ng/mL in patients &amp;gt;18 years old. Stem cell factor and MK concentrations above a defined threshold in serum of NF1 patients are of diagnostic benefit for 96% of patients in the cohort tested. Furthermore, serum from NF1 patients enhanced proliferation of human neurofibroma-derived primary Schwann cells and endothelial cells substantially better than normal serum. Conclusions: Enhanced circulating growth factor levels contribute to diffuse tumorigenesis in NF1 and may provide the basis for molecular diagnosis.
Pseudotumor of calcaneus: Treatment with radiotherapy and replacement therapy
Authors: Rajesh Kashyap, J.N. Sarangi, V.P. Choudhry, Renu Saxena, Rajesh Malhotra
Journal: American Journal of Hematology (1998)

lymph node involvement with rt ureter compression that required a stent insertion.Brain CT showed a suprasellar lesion involving the diencephalic and chiasmatic regions (Fig. 1a).The patient was treated with CdA (2 hr-infusion of 0.14 mg/kg die × 7 days) and Dexamethasone (0.3 mg/kg die × 4 days).Therapy was well tolerated without significant hematologic toxicity (WHO G4 leukopenia duration, 3 days; no thrombocytopenia).Partial regression of the liver, kidney, and lymph node involvement and complete regression of the brain lesions (Fig. 1b) were documented 1 month later by CT.The patient was discharged on May 24 with complete regression of the neurological symptoms.On June 13 she died from an acute cerebral vascular accident (CVA) of ischemic origin (brain CT not shown).In this patient, a single cycle of CdA induced complete regression of the brain lesion.CVA as a complication of therapy with CdA has not been reported; a relationship between treatment and the final event is unlikely.
An in vitro analysis of the output of salbutamol from different nebulizers
Authors: P.W. Barry, C. O′callaghan
Journal: European Respiratory Journal (1999)

The objective of this study was to determine the particle size and mass output of salbutamol from different nebulizers used under simulated breathing conditions. Seven nebulizer/compressor combinations were assessed. Each nebulizer was charged with 5 mg salbutamol solution and connected to a breathing simulator operating at tidal volumes of 150 mL and 600 mL. Nebulizers were operated for 15 min. Salbutamol collected on the filters was measured by liquid chromatography. Aerosol particle size was determined separately by laser diffraction. The Pari LC Star nebulizer delivered the most salbutamol at both tidal volumes. The maximal output of the Medicaid Ventstream and Sidestream nebulizers was two-thirds that of the LC Star, and they delivered less salbutamol than the LC Star or LC Plus nebulizers. The Intersurgical Cirrus nebulizer delivered the least salbutamol at both tidal volumes, although there was only a small difference between the Cirrus and Ventstream or Sidestream nebulizers at 150 mL tidal volume. The LC Plus nebulizer produced larger particles, mass median diameter 5.3 microm, compared with 3.6-4.0 microm for the other nebulizers. In conclusion, there were large differences in the delivery of salbutamol between the nebulizers studied, even between nebulizers of apparently the same class, and this should be borne in mind by regulatory authorities, clinicians and researchers.
Hyperpyrexia and Anaesthesia
Authors: R. C. Brown
Journal: BMJ (1954)

A recent fatality associated with anaesthesia displayed stuch remarkable features that it was thought useful to publish a short account of it. Case ReportThe patient, a girl of 13, was subjected to operation for recurrent dislocation of the patella.No abnormality was found on physical examination.Premedication consisted of morphine, * gr. (8mg.), and atropine, 1/100 gr. (0.65 mg.), given, as it happened, two hours before induction of anaes- thesia.In the anaesthetic room the patient was perhaps (in retrospect) a little flushed, but seemed otherwise normal.Anaesthesia was induced smoothly with 0.4 g. sodium thiopentone, and continued with N20 (5 litres a minute), 02 (1.5 litres a minute), and minimal trichlorethylene (" trilene "), using Boyle's semiclosed circuit.A tourniquet was applied to the affected leg and the patient was taken into the theatre.It is regrettable, in view of what ensued, that no detailed records were made of pulse rate, blood pressure, etc., but this was regarded as a minor routine case.
Oncogenicity of a Nude Mouse Cell Line Transformed by a Human Papovavirus
Authors: J. Costa, P. M. Howley, F. Legallais, C. Yee, N. Young, A. S. Rabson
Journal: JNCI Journal of the National Cancer Institute (1977)

Primary cultures of NIH nude mouse (nu/nu) kidney cells were transformed with a human papovavirus (MMV). The transformed cell line expressed T-antigen, and MMV DNA was found to be associated with the cell DNA. When NIH nu/nu mice were inoculated with the transformed cells, they developed tumors at the injection site but failed to generate detectable levels of T-antibody. A control group of nu/+ littermates rejected the tumor inoculum but mounted an antibody response to T-antigen. It was proposed that nude mouse cells may be a suitable system to test oncogenicity of in vitro transformed cells.
<i>Helicobacter pylori</i>resistance to antibiotics in Europe and its relationship to antibiotic consumption
Authors: Francis Megraud, Samuel Coenen, Ann Versporten, Manfred Kist, Manuel Lopez-Brea, Alexander M Hirschl, Leif P Andersen, Herman Goossens, Youri Glupczynski
Journal: Gut (2012)

<h3>Objective</h3> Resistance to antibiotics is the major cause of treatment failure of <i>Helicobacter pylori</i> infection. A study was conducted to assess prospectively the antibacterial resistance rates of <i>H pylori</i> in Europe and to study the link between outpatient antibiotic use and resistance levels in different countries. <h3>Design</h3> Primary antibiotic resistance rates of <i>H pylori</i> were determined from April 2008 to June 2009 in 18 European countries. Data on yearly and cumulative use over several years of systemic antibacterial agents in ambulatory care for the period 2001–8 were expressed in Defined Daily Doses (DDD) per 1000 inhabitants per day. The fit of models and the degree of ecological association between antibiotic use and resistance data were assessed using generalised linear mixed models. <h3>Results</h3> Of 2204 patients included, <i>H pylori</i> resistance rates for adults were 17.5% for clarithromycin, 14.1% for levofloxacin and 34.9% for metronidazole, and were significantly higher for clarithromycin and levofloxacin in Western/Central and Southern Europe (&gt;20%) than in Northern European countries (&lt;10%). Model fit improved for each additional year of antibiotic use accumulated, but the best fit was obtained for 2005. A significant association was found between outpatient quinolone use and the proportion of levofloxacin resistance (p=0.0013) and between the use of long-acting macrolides only and clarithromycin resistance (p=0.036). <h3>Conclusion</h3> In many countries the high rate of clarithromycin resistance no longer allows its empirical use in standard anti-<i>H pylori</i> regimens. The knowledge of outpatient antibiotic consumption may provide a simple tool to predict the susceptibility of <i>H pylori</i> to quinolones and to macrolides and to adapt the treatment strategies.
Dual Targeting of EGFR and HER3 with MEHD7945A Overcomes Acquired Resistance to EGFR Inhibitors and Radiation
Authors: Shyhmin Huang, Chunrong Li, Eric A. Armstrong, Chimera R. Peet, Jarob Saker, Lukas C. Amler, Mark X. Sliwkowski, Paul M. Harari
Journal: Cancer Research (2012)

Abstract EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor–resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance. Cancer Res; 73(2); 824–33. ©2012 AACR.
What can we do to reduce the number of tragic cardiac events in sport?
Authors: Richard Weiler, Mark A Goldstein, Ian Beasley, Jonathan Drezner, Jiri Dvorak
Journal: British Journal of Sports Medicine (2012)

The FIFA 2006 Big Count suggested more than 265 million football players are registered worldwide,1 making football one of the most popular and highly participated sports in the world. It is therefore not surprising that tragic cardiac events afflicting footballers are broadcast to the world through intense and emotive media coverage. Media reporting influences perceptions, however, even when these media reports are meticulously searched in high-profile athletes, only about half of sudden cardiac death (SCD) cases are revealed.2 Experts in sports cardiology, sport and exercise medicine and the wider medical community learn from these awful events, which have led to improvements in pitch side and sporting acute medical care, the development of numerous practical and educational ‘sport-specific prehospital emergency care guidelines’ and the development of cardiac screening programmes to try and identify a range of structural and electrical cardiac conditions that can lead to SCD in sport. …
Oxygen or ventilation during flight for patients with neuromuscular disease?
Authors: J C Winck, M R Goncalves, N Silva
Journal: Thorax (2010)

We read with great interest the paper by Mestry et al 1 which analysed hypoxic challenge flight assessments in patients with restrictive disorders. In their study they dispute the current British Thoracic Society recommendations, demonstrating that, in this subgroup, all patients planning air travel should have a pre-flight evaluation because, even in patients with normal baseline oxygen saturation (Sao2), arterial oxygen tension (Pao2) can fall below 6.6 kPa during hypoxic challenge.

We wanted to establish whether patients with restrictive disorders (with no lung disease) should be ventilated rather than oxygenated when they are hypoxaemic during flights. In fact, as …
Responses to Unsolicited Patient E-mail Requests for Medical Advice on the World Wide Web
Authors: G Eysenbach, T L Diepgen
Journal: JAMA (1998)

Context.—The Internet is increasingly used by consumers to seek health and medical information, but online medical advice has not been explored systematically.Objective.—To explore the attitude of physicians and other providers of medical information on the Internet toward unsolicited e-mail from patients and their reaction to a fictitious acute medical problem described in such an e-mail.Design.—E-mail in December 1997 and January 1998 to Web sites from a fictitious patient describing an acute dermatological problem. Follow-up questionnaire survey to the same sites.Setting.—World Wide Web.Subjects.—Fifty-eight physicians and Web masters.Main Outcome Measures.—Response rate and types of responses.Results.—Twenty-nine (50%) responded to the fictitious patient request; 9 respondents (31%) refused to give advice without having seen the lesion, 27 (93%) recommended that the patient see a physician, and 17 (59%) explicitly mentioned the correct "diagnosis" in their reply. In response to the questionnaire, 8 (28%) of the 29 respondents said that they tended not to answer any patient e-mail, 7 (24%) said they usually reply with a standard e-mail message, and 7 (24%) said they answer each request individually.Conclusions.—Responses of physicians and Web masters to e-mail requests for medical advice vary as do approaches to handling unsolicited e-mail. Standards for physician response to unsolicited patient e-mail are needed.
A Phase I Study of Single Administration of Antibody-Directed Enzyme Prodrug Therapy with the Recombinant Anti–Carcinoembryonic Antigen Antibody-Enzyme Fusion Protein MFECP1 and a Bis-Iodo Phenol Mustard Prodrug
Authors: Astrid Mayer, Roslyn J. Francis, Surinder K. Sharma, Berend Tolner, Caroline J. Springer, Jan Martin, Geoff M. Boxer, James Bell, Alan J. Green, John A. Hartley, Clare Cruickshank, Julie Wren, Kerry A. Chester, Richard H.J. Begent
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Antibody-directed enzyme prodrug therapy is a two-stage treatment whereby a tumor-targeted antibody-enzyme complex localizes in tumor for selective conversion of prodrug. The purpose of this study was to establish optimal variables for single administration of MFECP1, a recombinant antibody-enzyme fusion protein of an anti–carcinoembryonic antigen single-chain Fv antibody and the bacterial enzyme carboxypeptidase G2 followed by a bis-iodo phenol mustard prodrug. MFECP1 is manufactured in mannosylated form to facilitate normal tissue elimination. Experimental Design: Pharmacokinetic, biodistribution, and tumor localization studies were used to test the hypothesis that MFECP1 localizes in tumor and clears from normal tissue via the liver. Firstly, safety of MFECP1 and a blood concentration of MFECP1 that would avoid systemic prodrug activation were tested. Secondly, dose escalation of prodrug was done. Thirdly, the dose of MFECP1 and timing of prodrug administration were optimized. Results: MFECP1 was safe and well tolerated, cleared rapidly via the liver, and was less immunogenic than previously used products. Eighty-fold dose escalation from the starting dose of prodrug was carried out before dose-limiting toxicity occurred. Confirmation of the presence of enzyme in tumor and DNA interstrand cross-links indicating prodrug activation were obtained for the optimal dose and time point. A total of 28 of 31 patients was evaluable for response, the best response being a 10% reduction of tumor diameter, and 11 of 28 patients had stable disease. Conclusions: Optimal conditions for effective therapy were established. A study testing repeat treatment is currently being undertaken.
Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin
Authors: William C Knowler, Elizabeth Barrett-Connor, Sarah E Fowler, Richard F Hamman, John M Lachin, Elizabeth A Walker, David M Nathan
Journal: New England Journal of Medicine (2002)

Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes.
Tachyplesin Activates the Classic Complement Pathway to Kill Tumor Cells
Authors: Jinguo Chen, Xue-Ming Xu, Charles B. Underhill, Shanmin Yang, Luping Wang, Yixin Chen, Shuigen Hong, Karen Creswell, Lurong Zhang
Journal: Cancer Research (2005)

Abstract Tachyplesin is a small, cationic peptide that possesses antitumor properties. However, little is known about its action mechanism. We used phage display to identify a protein that interacted with tachyplesin and isolated a sequence corresponding to the collagen-like domain of C1q, a key component in the complement pathway. Their interaction was subsequently confirmed by both ELISA and affinity precipitation. Tachyplesin seemed to activate the classic complement cascade because it triggered several downstream events, including the cleavage and deposition of C4 and C3 and the formation of C5b-9. When TSU tumor cells were treated with tachyplesin in the presence of serum, activated C4b and C3b could be detected on tumor cells by flow cytometry, Western blotting, and confocal microscopy. However, this effect was blocked when the tumor cells were treated with hyaluronidase or a large excess of hyaluronan, indicating that hyaluronan or related glycosaminoglycans were involved in this process. Treatment of cells with tachyplesin and serum increased in membrane permeability as indicated by the ability of FITC-dextran to enter the cytoplasm. Finally, the combination of tachyplesin and human serum markedly inhibited the proliferation and caused death of TSU cells, and these effects were attenuated if the serum was heat-inactivated or if hyaluronidase was added. Taken together, these observations suggest that tachyplesin binds to both hyaluronan on the cell surface and C1q in the serum and activates the classic complement cascade, which damages the integrity of the membranes of the tumor cells resulting in their death.