tbuckley/cabot-search huggingface dataset:
Abstract P5-09-17: Prognostic significance of progesterone receptor in hormonal receptor-positive breast cancer: Association with endocrine resistance
Authors: SY Bae, SK Lee, JH Lee, H Lee, M Kim, J Kim, WH Kil, JE Lee, SJ Nam
Journal: Cancer Research (2013)

Abstract Background: Endocrine therapy has dramatic improvements of prognosis in patients with hormonal receptor positive breast cancer. However, long-term follow up shows that endocrine resistance is still major clinical concern. Although the value of estrogen receptor (ER) level can predict response to endocrine treatment in hormonal receptor positive breast cancers, few markers are available that can predict response to endocrine treatment. We attempted to identify molecular markers, especially progesterone receptor (PR), associated with endocrine failure in breast cancer. Methods: We reviewed the medical records of 2513 breast cancer patients who underwent breast surgery and endocrine therapy at Samsung Medical Center between March 2007 and July 2011. Patients were compared according to ER and PR expression and to assess the clinical and biological features of ER+positive/PR-negative breast cancers to understand how PR might be a useful marker of these activities. ER and PR expression accessed using Allred score, the ‘positive” was defined that total score is larger than 2. Results PR negative tumors were found more frequently in postmenopausal women (post- 11.2% vs. pre- 2.5%, P &amp;lt; 0.001) and PR negative tumors were significantly associated with higher grade, higher level of Ki 67 and more expression of EGFR and CK5/6. In Kaplan-Meier analysis and multivariate analysis, PR negativity was significantly poorer prognostic factor of DFS (HR 3.1, 95% CI 1.2-8.2, P = 0.021) and OS (HR 89.8, 95% CI 3.4-2352.3, P = 0.007). Stratified by the menopausal status, there was not shown significant difference of survival between the PR+ and PR- tumor in postmenopausal women (DFS, HR 2.1, 95% CI 0.4-10.8, P = 0.381; OS, HR 10.6, 95% CI 0.6-171.4, P = 0.096). However, PR negative tumors showed an association with poor outcome in premenopausal women (DFS, HR 7.2, 95% CI 2.5-20.6, P &amp;lt;0.001; OS, HR 24.6, 95% CI 2.2-275.6, P = 0.009). Conclusion: In HR positive breast cancers, PR negative tumors were found more frequently in elderly, postmenopausal women. However, PR negative tumors are shown more aggressive and poorer survival than PR positive tumors despite of endocrine therapy, especially in premenopausal women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-17.
A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma
Authors: Irene M. Ghobrial, Nikhil C. Munshi, Brianna N. Harris, Peipei Shi, Nichole M. Porter, Robert L. Schlossman, Jacob P. Laubach, Kenneth C. Anderson, Durisala Desaiah, Scott P. Myrand, James E. Wooldridge, Paul G. Richardson, Rafat Abonour
Journal: American Journal of Hematology (2011)

Abstract The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional “3 + 3” design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m 2 : Days 8, 11, 15, and 18; seven subsequent 21‐day cycles, 1.3 mg/m 2 : Days 1, 4, 8, and 11). Twenty‐three patients received treatment; all patients received prior systemic therapy. Most patients received ≥3 regimens; 17 patients were bortezomib‐refractory. A median of four treatment cycles (range 1–24) was completed. No dose‐limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug‐related Grade 3/4 toxicities were thrombocytopenia ( n = 6) and anemia ( n = 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 of a 21‐day cycle. The combination was well‐tolerated and demonstrated some antimyeloma activity. Am. J. Hematol. 2011. © 2011 Wiley‐Liss, Inc.
Factors influencing cadmium accumulation and its toxicity to marine organisms
Authors: David W. Engel, Bruce A. Fowler
Journal: Environmental Health Perspectives (1979)

The toxicity of dissolved cadmium to a variety of marine animals has been found to be related to salinity, with decreased toxicity observed at higher salinities. Recent data from our laboratory have demonstrated that the toxicity of cadmium to estuarine shrimp and larval fish is a function of free cadmium ion concentration, which in turn is controlled by the chloride concentration of the water. As the chloride concentration (i.e., salinity of the water) increases, the concentration of free cadmium ion decreases relative to total dissolved metal, due to its complexation with chloride ions. These observations have been given further support by measurements involving the uptake of 115mCd by shrimp which showed that accumulation of 115mCd and chloride concentration also are inversely related. Experiments also have been conducted on the physiological effects of cadmium on the respiration of excised oyster gill tissue. Although tissues from oysters exposed for 14 days to 0.1 ppm total dissolved cadmium accumulated significant quantities of metal, no measurable effects on respiration rates were detected. Higher doses (0.3 and 0.6 ppm) caused both mortalities of oysters and accelerated respiration of excised oyster gill. Exposure to 0.1 ppm cadmium also caused the induction of and/or increased binding of cadmium to a specific low molecular weight protein in oysters. This protein appeared to have a detoxification function at low cadmium exposure levels, but in animals exposed to 0.6 ppm cadmium the induction mechanism apparently became saturated, allowing the excess cadmium to bind critical sites with resultant damage.
638 Analysis of the involvement of PKR protein in resistance to therapy for chronic hepatitis C virus infection
Authors: G MACQUILLAN, P CATERINA, W BASTIAANDEBOER, M PLATTEN, W REED, G JEFFREY
Journal: Hepatology (2003)

As a major therapy for hepatitis B virus (HBV) infection, Interferon alpha (IFN-alpha) triggers intracellular signal transduction including JAK-STAT pathway to produce various antiviral effector mechanisms. However, patients with chronic hepatitis B usually show low response to IFN-alpha treatment and the underlying mechanism remains unclear. In the present study, HepG2 and HepG2.2.15 cells were used to examine the Type I IFN receptors expression, phosphorylation and methylation of STAT1. STAT1–PIAS1 interaction in cells was tested by protein co-immunoprecipitation. The potential improvement of S-adenosylmethionine (SAM) in the antiviral effect of IFN-alpha was also investigated. Our data demonstrated that both chains of the Type I IFN receptors were expressed for a much higher extent in HepG2.2.15 cells than in HepG2 cells. HBV inhibited dramatically the methylation rather than the phosphorylation of STAT1, which was consistent with an increased STAT1–PIAS1 interaction. Combined with IFN-alpha, SAM treatment effectively improved STAT1 methylation and attenuated STAT1–PIAS1 binding, followed by increased PKR and 2′,5′-OAS mRNA expression, thus significantly reducing the HBsAg, HBeAg protein levels and HBV DNA load in the supernatant of HepG2.2.15 cells. Less STAT1 methylation and subsequent increased STAT1–PIAS1 interaction are involved in the mechanism of the IFN-alpha-antagonistic activity of HBV. By improving STAT1 methylation, SAM can enhance the antiviral effect of IFN-alpha.
Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.
Authors: M Mevorach, A Giacca, Y Aharon, M Hawkins, H Shamoon, L Rossetti
Journal: Journal of Clinical Investigation (1998)

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.
Stopping smoking: the importance of nicotine addiction
Authors: A. HILTON
Journal: Thorax (2000)

The Royal College of Physicians has produced several reports on the adverse effects of smoking on health in the past 40 years.1-5 Its latest report entitled “Nicotine Addiction in Britain” emphasises the importance and role of nicotine addiction as a major factor in making many smokers unable to stop.6 Recognition of the addictive nature of nicotine has important implications for the way that nicotine products should be regulated in society, and one important conclusion of the report is that tobacco based nicotine products should be subject to the same regulatory control as any other drug delivery device. However, the report also argues that nicotine addiction should become recognised and accepted as a medical problem, much as any other manifestation of drug addiction, and this argument has special relevance to respiratory physicians.

Most people who attempt to stop smoking relapse within a very short time and, in the USA, less than 10% of smokers who stop for one day remain non-smokers at 12 months.7 Nicotine replacement therapy has been shown to improve cessation rates in many controlled randomised studies, …
Runx2 Is a Novel Regulator of Mammary Epithelial Cell Fate in Development and Breast Cancer
Authors: Thomas W. Owens, Renee L. Rogers, Sarah A. Best, Anita Ledger, Anne-Marie Mooney, Alison Ferguson, Paul Shore, Alexander Swarbrick, Christopher J. Ormandy, Peter T. Simpson, Jason S. Carroll, Jane E. Visvader, Matthew J. Naylor
Journal: Cancer Research (2014)

Regulators of differentiated cell fate can offer targets for managing cancer development and progression. Here, we identify Runx2 as a new regulator of epithelial cell fate in mammary gland development and breast cancer. Runx2 is expressed in the epithelium of pregnant mice in a strict temporally and hormonally regulated manner. During pregnancy, Runx2 genetic deletion impaired alveolar differentiation in a manner that disrupted alveolar progenitor cell populations. Conversely, exogenous transgenic expression of Runx2 in mammary epithelial cells blocked milk production, suggesting that the decrease in endogenous Runx2 observed late in pregnancy is necessary for full differentiation. In addition, overexpression of Runx2 drove epithelial-to-mesenchymal transition-like changes in normal mammary epithelial cells, whereas Runx2 deletion in basal breast cancer cells inhibited cellular phenotypes associated with tumorigenesis. Notably, loss of Runx2 expression increased tumor latency and enhanced overall survival in a mouse model of breast cancer, with Runx2-deficient tumors exhibiting reduced cell proliferation. Together, our results establish a previously unreported function for Runx2 in breast cancer that may offer a novel generalized route for therapeutic interventions. Cancer Res; 74(18); 5277-86. ©2014 AACR.
Hugh Hussey, MD, former JAMA editor, dead at 71
Authors: Phil Gunby
Journal: JAMA (1982)

Hugh Hudson Hussey, MD, editor of The Journal of the American Medical Association from Jan 1, 1970, until Oct 1, 1973, and editor emeritus until his retirement in 1976, was looking forward to toasting the start of JAMA 's second century of publication in a few months.  But it was not to be. He died of metastatic lung carcinoma on Nov 6—less than a week before his 72nd birthday.  Almost until his death, Hussey continued to pursue what might be termed the third phase of his career. This was in Dallas, where he and his wife of 47 years, Wilhelmina Gude Hussey (who also worked at the AMA for four years on a scientific proofreading assignment), moved in 1976. One goal was to be near their son John Christopher (Kit) Hussey, his wife Jane, and two grandsons. (Kit Hussey, an American Airlines pilot, also has ties with JAMA , three of
Progression of Atherosclerosis as Assessed by Carotid Intima-Media Thickness in Patients With HIV Infection
Authors: Priscilla Y. Hsue, Joan C. Lo, Arlana Franklin, Ann F. Bolger, Jeffrey N. Martin, Steven G. Deeks, David D. Waters
Journal: Circulation (2004)

HIV-infected patients may be at increased risk for coronary events. The purpose of this study was to identify predictors of carotid intima-media thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1 year.We measured blood lipids, inflammatory markers, and IMT in 148 HIV-infected adults (mean age, 45+/-8 years) and in 63 age- and sex-matched HIV-uninfected control subjects. The mean duration of HIV infection was 11 years, and the median duration of protease inhibitor treatment was 3.3 years. Mean baseline IMT was 0.91+/-0.33 mm in HIV patients and 0.74+/-0.17 mm in control subjects (P=0.0001). Multivariable predictors of baseline IMT in HIV patients were age (P<0.001), LDL cholesterol (P<0.001), cigarette pack-years (P=0.005), Latino race (P=0.062), and hypertension (P=0.074). When the control group was added to the analysis, HIV infection was an independent predictor of IMT (P=0.001). The rate of progression among the 121 HIV patients with a repeated IMT measurement at 1 year was 0.074+/-0.13 mm, compared with -0.006+/-0.05 mm in 27 control subjects (P=0.002). Age (P<0.001), Latino race (P=0.02), and nadir CD4 count < or =200 (P=0.082) were multivariable predictors of IMT progression.Carotid IMT is higher in HIV patients than in age-matched control subjects and progresses much more rapidly than previously reported rates in non-HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary risk factors and with nadir CD4 count < or =200, suggesting that immunodeficiency and traditional coronary risk factors may contribute to atherosclerosis.
East Africa faces starvation as rising food prices worsen effect of war and drought
Authors: Peter Moszynski
Journal: BMJ (2008)

Google, the search engine giant, has launched Google Health, a free service for patients offering a personal electronic medical record (www.google.com/health).But the move has prompted fears over the security of health information stored in this way.President George Bush has promoted electronic health records as a means of reducing medical errors and cutting the costs of health care in the United States.But uptake has so far been slow.The new Google service will compete with similar services offered by other commercial internet health services, such as WebMD.Electronic medical histories are also stored by major health insurance companies.An individual will be able to create an account, protected by a password, and enter personal medical records, either by keying them in or by importing electronic records from hospitals, laboratories, and pharmacies that are Google Health partners.When new information is added the service will check for potential interactions between drugs, allergies, and conditions.Patients can also search for doctors by specialty or location and for hospitals, and they can permit their doctors or others to see their medical information and add to it.The New York Times reported that the service was popular when tested among patients at the Cleveland Clinic in Ohio earlier this year (www.nytimes.com,20 May, "Google offers personal health records on the web").The system allowed clinic patients to add information when they saw doctors who were not affiliated with the clinic, said Martin Harris, the clinic's chief information officer.But Pamela Hartzband and Jerome Groopman, both from Harvard University, complained in the New England Journal of Medicine in April (2008;358:1656-8) that electronic health records have led to a sea of results being pasted from previous records, instead of being focused and selective.Furthermore, they said that electronic records have "become a powerful vehicle for per-Fears over security as Google launches free electronic health records service for patients UK NEWS Finding a solution to hospital associated infections, p 1210 World NEWS Italian police arrest drug officials over alleged falsification of data, p 1208 bmj.com
Well-Tolerated Bacteremia of Five Years' Duration
Authors: Scott W. Younkin
Journal: JAMA (1982)

AFTER the introduction of organisms into the bloodstream from a focus of infection, bacteremia generally persists for a period of seconds to minutes, with the clearance of organisms by serum bactericidal factors in concert with fixed and circulating phagocytic cells. In endothelial infections, bacteremia is of much longer duration. In this report, we describe a patient who experienced at least five years of persistent<i>Staphylococcus epidermidis</i>bacteremia 15 years after complete repair of a tetralogy of Fallot. This case is unique both because of the duration of bacteremia and the eventual successful cure of the infection with a combination of antibiotics without surgical intervention. <h3>Report of a Case</h3> A 39-year-old man, cyanotic from birth and with limited exercise tolerance during childhood, underwent cardiac catheterization at age 13 years that demonstrated a high ventricular septal defect (VSD) and a pulmonary outflow tract gradient of 85 mm Hg. Pulmonary valvulotomy was performed
Preferential liver gene expression with polypropylenimine dendrimers
Authors: Andreas G. Schatzlein, Bernd H. Zinselmeyer, Adurrahim Elouzi, Christine Dufes, Ya Tsz A. Chim, Clive J. Roberts, Martyn C. Davies, Avril Munro, Alexander I. Gray, Ijeoma F. Uchegbu
Journal: Journal of Controlled Release (2004)
Beware of Drug Holidays before HIV Salvage Therapy
Authors: Bernard Hirschel
Journal: New England Journal of Medicine (2003)

Not unlike its human host, the human immunodeficiency virus (HIV) is often unfaithful while reproducing. Copies made are not completely true to the original; a mistake occurs about once every 10,000 nucleotides. This may not seem like much, until we remember the enormous production rate of the virus, which guarantees that every possible mutation will arise at each position of the genome every day. Errors in reproduction, as well as recombination between the two RNA genomes, drive the diversification of HIV into quasi-species and strains.Antiretroviral treatment has diverse effects, including selection for mutants with decreased drug sensitivity that progressively . . .
Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry
Authors: Emelia J Benjamin, Kenneth M Rice, Dan E Arking, Arne Pfeufer, Charlotte van Noord, Albert V Smith, Renate B Schnabel, Joshua C Bis, Eric Boerwinkle, Moritz F Sinner, Abbas Dehghan, Steven A Lubitz, Ralph B D'Agostino Sr, Thomas Lumley, Georg B Ehret, Jan Heeringa, Thor Aspelund, Christopher Newton-Cheh, Martin G Larson, Kristin D Marciante, Elsayed Z Soliman, Fernando Rivadeneira, Thomas J Wang, Gudny Eiríksdottir, Daniel Levy, Bruce M Psaty, Man Li, Alanna M Chamberlain, Albert Hofman, Ramachandran S Vasan, Tamara B Harris, Jerome I Rotter, W H Linda Kao, Sunil K Agarwal, Bruno H Ch Stricker, Ke Wang, Lenore J Launer, Nicholas L Smith, Aravinda Chakravarti, André G Uitterlinden, Philip A Wolf, Nona Sotoodehnia, Anna Köttgen, Cornelia M van Duijn, Thomas Meitinger, Martina Mueller, Siegfried Perz, Gerhard Steinbeck, H-Erich Wichmann, Kathryn L Lunetta, Susan R Heckbert, Vilmundur Gudnason, Alvaro Alonso, Stefan Kääb, Patrick T Ellinor, Jacqueline C M Witteman
Journal: Nature Genetics (2009)
Interferon (IFN)‐α, IFN‐γ, interleukin (IL)‐2, and arachidonic acid metabolites modulate IL‐4‐induced IgE synthesis similarly in healthy persons and in atopic dermatitis patients
Authors: J. Punnonen, K. Punnonen, C. T. Jansén, K. Kalimo
Journal: Allergy (1993)

The role of cytokines and arachidonic acid metabolites in the regulation of IgE production in healthy persons and in atopic dermatitis patients with elevated IgE levels was studied. Interleukin‐4 (IL‐4) induced IgE production in peripheral blood mononuclear cells (PBMCs) of all donors, and no significant difference was found between the amounts of IgE produced by healthy persons and atopic dermatitis patients. Similarly, recombinant interferon (IFN)‐α and IFN‐γ, as well as IL‐2, inhibited IL‐4‐induced IgE production to a similar extent in both study groups. To evaluate the role of arachidonic acid (AA) metabolites in the regulation of IgE production, we added indomethacin, an inhibitor of the cyclooxygenase pathway, or nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway, to IL‐4‐treated cultures. Both indomethacin and NDGA strongly inhibited IL‐4‐induced IgE production. They also inhibited IL‐4‐induced IgG4 synthesis. No significant difference in the amount of inhibition was found between the two study groups. We were unable to restore the NDGA‐induced inhibition of IgE‐production by adding leukotrienes B 4 , C 4 , D 4 , or 5‐HETE to the NDGA‐treated cultures. PGE 2 also failed to restore the indomethacin‐mediated inhibitory effect. Consequently, NDGA‐ and indomethacin‐mediated inhibitory effects do not appear to be mediated by any single factor studied. Collectively, our results show IFNs and IL‐2 to be similar in effect in the modulation of IL‐4‐induced IgE synthesis in healthy and atopic persons. In addition, our results show the importance of AA metabolites in the regulation of IgE and IgG4 synthesis in normal persons as well as in atopic dermatitis patients.