tbuckley/cabot-search huggingface dataset:
Abstract 3141: Epithelial-to-mesenchymal transition and therapy resistance in BRCA1-associated breast cancer
Authors: Martine Van Miltenburg, Jos Jonkers
Journal: Cancer Research (2014)

Abstract Despite progress in the treatment of breast cancer, patients with triple-negative breast cancer (TNBC) have limited means for therapy. Since TNBCs do not express HER2, estrogen and progesterone receptors, TNBC patients cannot be treated with Herceptin or endocrine therapy. TNBCs frequently harbor defects in homologous recombination (HR) due to (epi)genetic inactivation of BRCA1, making them sensitive to the clinical PARP1 inhibitor olaparib. However, long-term treatment of BRCA1-deficient mouse mammary tumors with olaparib results in drug resistance. The growing awareness that epithelial-to-mesenchymal transition (EMT) may influence therapy response prompted us to investigate whether olaparib sensitivity of BRCA1-deficient TNBCs is affected by MET, a known EMT inducer that is over-expressed in TNBC and associated with poor survival. For this purpose we have developed a breast cancer GEMM-ESC pipeline, using female GEMM-ESCs derived from our well-validated K14cre;Brca1F/F;Trp53F/F (KB1P) mouse model, of which females spontaneously develop BRCA1-deficient TNBC due to cre-mediated deletion of Brca1 and Trp53 in epithelial tissues. The MET proto-oncogene, was introduced in the Col1a1 locus and resulting KB1P-MET ESCs were injected into blastocysts and good quality chimeras were monitored for mammary tumor formation. Our preliminary data show that BRCA1-deficient mouse mammary tumors with engineered overexpression of MET show accelerated growth, undergo EMT and show intrinsic resistance to olaparib. The underlying mechanisms are, however, unclear. Currently we are studying the impact of EMT-regulators on BRCA1-associated mammary tumorigenesis and assess the contribution of EMT-regulators to olaparib resistance in genetically engineered mouse models of BRCA1-associated breast cancer. Together, these studies will provide novel insights into the roles of EMT regulators in BRCA1-associated breast tumor development, metastasis and therapy resistance. Citation Format: Martine Van Miltenburg, Jos Jonkers. Epithelial-to-mesenchymal transition and therapy resistance in BRCA1-associated breast cancer. [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 3141. doi:10.1158/1538-7445.AM2014-3141
Insect Vectors of Disease
Authors: Vlado A. Getting
Journal: New England Journal of Medicine (1945)

SINCE December 7, 1941, all Americans have become conscious of war — for Japan had suddenly burst America's bubble of isolationism. Although many persons considered the United States as self-sufficient and apart from the rest of the world, and therefore safe from the conflagration of war, public-health officials, however, have been deeply concerned, fearful of the involvement of the country in a global war, with its inevitable rise in infectious diseases and death.1 Since time immemorial, wars have been attended by pestilence and death.Under war conditions, many of the safeguards of the health of both the military and civilian . . .
Influence of Cardiac Sympathetic and Vagal Nerve Stimulation on the Relation Between Left Ventricular Diastolic Pressure and Myocardial Segment Length
Authors: J. H. MITCHELL, R. J. LINDEN, S. J. SARNOFF
Journal: Circulation Research (1960)

During the continuous and simultaneous recording of left ventricular diastolic pressures and changes in the length of a segment of left ventricular myocardium it was demonstrated that neither cardiac sympathetic nor vagal efferent nerve stimulation produces a change in ventricular myocardial extensibility. It was further shown that, at the heart rates studied, autonomic nerve stimulation does not modify the end-diastolic pressurelength curve. These data indicate that, during cardiac sympathetic stimulation, the augmented ventricular stroke work from any given end-diastolic Pressure is accomplished without a change in end-diastolic fiber length. Evidence was obtained, however, which suggests that the abbreviation of diastole at high imposed heart rates or large stroke volumes may leave an inadequate time for ventricular relaxation to take place and for inertial and viscous factors to be dissipated. Under these circumstances, sympathetic stimulation, by shortening systole and thereby lengthening diastole, permits the ventricle to remain on its "normal" pressure-length curve. This component of cardiac sympathetic efferent activity is peculiarly appropriate to the tachycardia that occurs with increased sympathetic outflow to the heart.
Predictive Tests for Cancer Chemotherapy
Authors: Emil Frei, Herbert Lazarus
Journal: New England Journal of Medicine (1978)

Elsewhere in this issue of the Journal Salmon and his associates describe an in vitro assay for the effectiveness of antitumor agents that strongly correlates with tumor response in man.The capacity to determine the sensitivity of bacterial pathogens in vitro to antibiotics has had a profound and favorable influence on the selection of effective agents for the treatment of patients with infectious diseases. The stakes are as high, if not higher, in cancer chemotherapy. Thus, for most patients with disseminated cancer, the lack of an antitumor effect with chemotherapeutic agents is followed by a progressive downhill course and death, . . .
Gro Harlem Brundtland wins WHO election
Authors: J. Wise
Journal: BMJ (1998)

Dr Gro Harlem Brundtland, the former prime minister of Norway, has been nominated as the next director general of the World Health Organisation.

The nomination of someone from outside the WHO is likely to be welcomed by those who would like to see reform. In recent weeks the WHO has been rocked by accusations that Dr Fernando Antezana, the deputy director general and a leadership contender, had lied about his qualifications (24 …
Recurrent “Sudden Death”
Authors: James V. Warren
Journal: New England Journal of Medicine (1975)

“Sudden death” need not be lethal. There are an increasing number of survivors. The report in this issue (page 259) by Schaffer and Cobb on the fate of a special group of survivors of out-of-hospital resuscitation is another piece in the growing mosaic of improved emergency coronary care. In 1965 Pantridge responded to the fact that so many people die of heart attacks* before they reach the hospital by organizing his “flying squad” in Belfast, Northern Ireland.1 In this program, specially trained and equipped medical personnel were transported by vehicle to give emergency coronary care at the scene. This aroused . . .
Human Immunodeficiency Virus and the Prevalence of Undiagnosed Tuberculosis in African Gold Miners
Authors: Elizabeth L. Corbett, Salome Charalambous, Vicky M. Moloi, Katherine Fielding, Alison D. Grant, Christopher Dye, Kevin M. De Cock, Richard J. Hayes, Brian G. Williams, Gavin J. Churchyard
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

We hypothesized that rapid presentation may be a general feature of tuberculosis (TB) associated with human immunodeficiency virus (HIV) that limits the impact of HIV on the point prevalence of TB. To investigate this, we performed a cross-sectional HIV and TB disease survey with retrospective and prospective follow-up. HIV prevalence among 1,773 systematically recruited miners was 27%. TB incidence was much more strongly HIV associated (incidence rate ratio, 5.5; 95% confidence interval [CI], 3.5-8.6) than the point prevalence of undiagnosed TB disease (odds ratio, 1.7; 95% CI, 0.9-3.3). For smear-positive TB, 7 of 9 (78%) prevalent cases were HIV negative, and point prevalence was nonsignificantly lower in miners who were HIV positive (odds ratio, 0.8; 95% CI, 0.1-4.2). The calculated mean duration of smear positivity before diagnosis (point prevalence/incidence) was substantially shorter for HIV-positive than HIV-negative TB patients (0.17 and 1.15 years, respectively; ratio, 0.15; 95% CI, 0.00-0.73). HIV has considerably less impact on the point prevalence of TB disease than on TB incidence, probably because rapid disease progression increases presentation and case-finding rates. The difference in mean duration of smear positivity was particularly marked and, if generalizable, will have major implications for TB control prospects in high HIV prevalence areas.
Negative <scp>d</scp>-dimer Result To Exclude Recurrent Deep Venous Thrombosis: A Management Trial
Authors: Suman W. Rathbun, Thomas L. Whitsett, Gary E. Raskob
Journal: Annals of Internal Medicine (2004)

Background: All of the available diagnostic tests for deep venous thrombosis (DVT) have limitations for excluding acute recurrent DVT. Measurement of plasma d-dimer by using an automated quantitative assay may be useful as a rapid exclusion test in patients with suspected recurrent DVT. Objective: To test the safety of withholding additional diagnostic testing and heparin treatment in patients who have a negative d-dimer result at presentation (using the automated quantitative assay STA-Liatest d-di), regardless of their symptoms. Design: Prospective cohort study. Setting: Academic medical center in the United States. Patients: 300 consecutive patients with suspected recurrent DVT. Intervention: Patients underwent d-dimer testing at presentation. In patients with negative d-dimer results, heparin therapy was withheld, and no further diagnostic testing for DVT was done as part of the initial evaluation. Patients with positive d-dimer results underwent compression ultrasonography. Measurements: The primary outcome measure was a diagnosis of new symptomatic venous thromboembolism confirmed by diagnostic testing during the 3-month follow-up period. Results: Of the 300 study patients, the d-dimer result was negative at presentation in 134 patients (45%; negative cohort) and positive at presentation in 166 patients. Of the 166 patients, compression ultrasonography documented new DVT in 54 patients. Compression ultrasonography findings were normal in 79 patients and were inconclusive in 33 patients. After 3 months of follow-up, 1 of 134 patients in the negative cohort had confirmed venous thromboembolism (0.75% [95% CI, 0.02% to 4.09%]). Venous thromboembolism on follow-up could not be definitively excluded in 5 patients with recurrent leg symptoms and in 1 patient who died. If these patients are considered to have venous thromboembolism, the incidence during the 3-month follow-up period would be 6.0% (CI, 2.6% to 11.4%) (8 of 134 patients). Limitations: There is no accepted diagnostic reference standard for recurrent DVT. The precision of the estimate of the incidence of venous thromboembolism on follow-up and the generalizability to settings other than an academic health center should be evaluated. Conclusions: Measurement of plasma d-dimer by using the automated quantitative assay STA-Liatest d-di seems to provide a simple method for excluding acute recurrent DVT in symptomatic patients.
MEDICAL EDUCATION IN THE UNITED STATES 1979-1980
Authors: Anne E. Crowley
Journal: JAMA (1980)

This is the 80th Annual Report on Medical Education in the United States.  first report appeared on Sept 21, 1901, inThe Journal. From the first year, this annual report has appeared in the EDUCATION ISSUE ofThe Journal.  scope of medical education has expanded and become more complex over the past eight decades.  five bound volumes of the EDUCATION ISSUE provide a historical record of the development of medical education in the United States.  In the first EDUCATION ISSUE, Dr W. S. Christopher 1 defined the aim of medical education with this statement: It is the function of the physician to practice medicine; it is, therefore, the duty of the medical college to train him for that work. In the same article he wrote: The work of the medical colleges 20 years ago was such that almost any change in it was a change in the
Through the patients' eyes
Authors: F. Godlee
Journal: BMJ (2009)

If we really want to transform the quality and safety of health care, we can’t just do more of what we do now. Even doing it more efficiently won’t be enough. We have to do different things and we have to do things differently. This is the message of two articles in this week’s BMJ .

Hugh Rogers and colleagues (doi:10.1136/bmj.a2321) tell us that how we deliver and receive care is governed by a set of rules. We may not be aware of these rules, so ingrained are they in how we operate as clinicians and patients, but they …
MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia
Authors: Kasey C. Vickers, Bassem M. Shoucri, Michael G. Levin, Han Wu, Daniel S. Pearson, David Osei-Hwedieh, Francis S. Collins, Alan T. Remaley, Praveen Sethupathy
Journal: Hepatology (2012)

Cellular and plasma lipid levels are tightly controlled by complex gene regulatory mechanisms. Elevated plasma lipid content, or hyperlipidemia, is a significant risk factor for cardiovascular morbidity and mortality. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and have emerged as important modulators of lipid homeostasis, but the extent of their role has not been systematically investigated. In this study we performed high-throughput small RNA sequencing and detected ≈ 150 miRNAs in mouse liver. We then employed an unbiased, in silico strategy to identify miRNA regulatory hubs in lipid metabolism, and miR-27b was identified as the strongest such hub in human and mouse liver. In addition, hepatic miR-27b levels were determined to be sensitive to plasma hyperlipidemia, as evidenced by its ≈ 3-fold up-regulation in the liver of mice on a high-fat diet (42% calories from fat). Further, we showed in a human hepatocyte cell line (Huh7) that miR-27b regulates the expression (messenger RNA [mRNA] and protein) of several key lipid-metabolism genes, including Angptl3 and Gpam. Finally, we demonstrated that hepatic miR-27b and its target genes are inversely altered in a mouse model of dyslipidemia and atherosclerosis.miR-27b is responsive to lipid levels and controls multiple genes critical to dyslipidemia.
Complications of Insulin Pump Therapy: The Effect of Insulin Preparation
Authors: Robert S Mecklenburg, Terin S Guinn
Journal: Diabetes Care (1985)

Complications of insulin infusion pump therapy include ketoacidosis related to interruption of insulin delivery and infected infusion sites. To determine if the type of insulin used in insulin pumps is a factor influencing these complications, we compared the occurrence of inflammation and infection at infusion sites and obstruction of infusion tubing in a 6-mo crossover study of 28 patients using two different insulin preparations. The use of buffered purified pork insulin was associated with less infusion site inflammation (P = 0.0039) and infusion set obstruction (P = 0.0215) than use of unbuffered beef-pork insulin. Infected infusion sites occurred less often with buffered pure pork insulin than with unbuffered beef-pork insulin, but the difference was not statistically significant. We conclude that the type of insulin selected for use in insulin pumps influences the occurrence of adverse reactions to insulin pump therapy: buffered purified pork insulin is associated with less infusion site inflammation and infusion set obstruction than unbuffered beef-pork insulin.
Osteoporosis Among Women Who Smoke Cigarettes
Authors: Hugh H. Hussey
Journal: JAMA (1976)

In the current issue of<i>Archives of Internal Medicine</i>(136: 298-304, 1976), Daniell observes that progressive osteoporosis is apparently universal among postmenopausal women and lists factors that have been considered to play a contributory role. Among the more common factors are small constitutional size, a genetic predisposition including white ancestry, deficiencies of calcium and sex hormones, inactivity, and aging. Less frequent factors are thyrotoxicosis, malabsorption syndromes, the postgastrectomy state, collagen diseases, sustained corticosteroid excess, alcoholism, hyperthyroidism, and chronic uremia. In an earlier article,<sup>1</sup>Daniell noted that middle-aged men and women with symptomatic osteoporosis were almost exclusively heavy cigarette smokers. This observation led him to pursue two further studies in women: the incidence of vertebral compression fractures and the degree of bone density as determined by roentgenographic examination of the second metacarpal bone. Accordingly, the author examined the hospital records of women between the ages of 40 and 70 years
Nonvisualization of Suppressed Thyroid Tissue on TI-201 Scintigraphy
Authors: JACK McEWAN, CHAN PARK
Journal: Clinical Nuclear Medicine (1993)

TI-201 scintigraphy has been used to visualize thyroid tissue that is suppressed by an autonomously functioning thyroid nodule. Reports have indicated that the sensitivity of this technique rivals that obtained by 1-123 scanning after thyroid-stimulating hormone stimulation. We report a case of triiodothyronine toxicosis caused by an autonomously functioning thyroid nodule in which the suppressed thyroid tissue was not visualized on TI-201 scintigraphy. The suppressed tissue was readily identified with ultrasound imaging, which demonstrates the utility of this technique in differentiating between thyroid suppression and agenesis.
The Diabetes Control and Complications Trial -- Implications for Policy and Practice
Authors: Roz D. Lasker
Journal: New England Journal of Medicine (1993)

The results of the Diabetes Control and Complications Trial (DCCT), published in this issue of the Journal,1 demonstrate that intensive insulin therapy can delay the onset and slow the progression of retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes mellitus (IDDM). These findings, which extend those of two other recent studies,2,3 should put to rest the longstanding debate over whether attempts to improve glycemic control beyond that required to control the symptoms of diabetes are worthwhile.But the DCCT raises a new and equally challenging set of questions. The study was limited to a small subgroup of people . . .
REGULATION OF THE IMMUNE RESPONSE: SUPPRESSIVE AND ENHANCING EFFECTS OF PASSIVELY ADMINISTERED ANTIBODY
Authors: Carolyn S. Pincus, Michael E. Lamm, Victor Nussenzweig
Journal: The Journal of Experimental Medicine (1971)

The ability of passively administered antibody to suppress the immune response against homologous antigenic determinants while concomitantly enhancing the response against other unrelated determinants of the same antigen molecule has been established in two distinct antigen-antibody systems: (a) guinea pig gamma(2)-immunoglobulin + passive anti-F(ab')(2) antibody, where suppression of anti-F(ab')(2) antibody synthesis is accompanied by enhancement of the anti-Fc response; and (b) human secretory IgA + passive anti-serum IgA antibody, where suppression of antibody production against the alpha and L chains accompanies augmentation of the response to the secretory component. The mechanisms of the suppressive and enhancing effects are probably unrelated for the following reasons: (a) Enhancement of the response to certain determinants may be obtained without discernible suppression of the response to the homologous determinants; and (b) the F(ab')(2) fragments of passive antibody can mediate immune suppression but were not observed to enhance the response against the unrelated determinants of the same antigen molecule. Also, the timing for achieving maximum suppression or enhancement of antibody formation is not the same; enhancement was obtained only at a later time. Both the enhancement and suppressive effects were obtained with the purified gammaG fraction of antisera. This finding rules out an exclusive role of gammaM antibody in the enhancement phenomenon.
Morning increase in ambulatory ischemia in patients with stable coronary artery disease. Importance of physical activity and increased cardiac demand.
Authors: J D Parker, M A Testa, A H Jimenez, G H Tofler, J E Muller, J O Parker, P H Stone
Journal: Circulation (1994)

BACKGROUND The morning increase in asymptomatic ambulatory ischemia may be due to heightened coronary tone, increased physical activity, or both. If ambulatory ischemia is primarily due to physical activity, then alterations in the schedule of physical activity should be reflected in a corresponding alteration in the occurrence of ischemia. This study was designed to examine the relation between activity patterns and the frequency of ambulatory ischemic episodes and the effect of nadolol on these relations. METHODS AND RESULTS A double-blind, randomized, placebo-controlled, crossover trial of nadolol versus placebo was performed in 20 patients with stable coronary artery disease. At the end of each 2-week treatment phase, patients were hospitalized for 48 hours. In the hospital, there was a regular activity day (awaken and assume normal activities at 8:00 AM) and a delayed activity day (awaken at 8:00 AM, arise at 10:00 AM, and begin normal activity at noon). Ambulatory ECG monitoring was performed throughout the hospitalization. On the regular activity day, there was a morning increase in heart rate and in the number of ischemic episodes during therapy with placebo that began at 8:00 AM. In contrast, on the delayed activity day, there was a 4-hour phase shift of the increases in heart rate and the increase in ischemic episodes (ie, at noon) corresponding to the onset of physical activities. Therapy with nadolol caused a 50% reduction in the total number of ischemic episodes (129 versus 65, placebo versus nadolol; P &lt; .02). During nadolol therapy, there was no discernible circadian peak in the number of ischemic episodes on either activity day. During placebo treatment, 87% of ischemic episodes were preceded by an increase in heart rate &gt; or = 5 beats per minute. Although nadolol caused a significant reduction in the total number of episodes preceded by a heart rate increase compared with placebo (99 versus 38 episodes, P &lt; .04), this therapy was associated with a significant increase in the number of episodes not associated with a heart rate increase (15 versus 21 episodes, P &lt; .002). CONCLUSIONS The morning increase in ambulatory ischemic episodes is due to physical activity patterns. The majority of ischemic episodes are preceded by a heart rate increase, and it is these episodes that are primarily responsible for the morning increase in ischemia. Therapy with nadolol caused a reduction in the total number of ischemic episodes solely by reducing those episodes preceded by a heart rate increase. In contrast, nadolol caused a significant increase in the number of ischemic episodes not associated with a heart rate increase, perhaps in part because it potentiated coronary vasoconstriction.
BRAIN TUMOR EVALUATION USING PET AND Rb-82
Authors: Chi Kwan Yen, Yukio Yano, Tom F. Budinger, Robert Friedland, Steven Derenzo, Ronald Huesman
Journal: Clinical Nuclear Medicine (1981)

Yen, Chi Kwan; Yano, Yukio; Budinger, Tom F.; Friedland, Robert; Derenzo, Steven; Huesman, Ronald Author Information
O78 PROSPECTIVE COMPARISON OF LIVER AND SPLEEN STIFFNESS AND COMPOSITE SCORES, USING SUPERSONIC-SHEAR-IMAGING OR TRANSIENT ELASTOGRAPHY, FOR DETECTING CLINICALLY SIGNIFICANT PORTAL HYPERTENSION IN PATIENTS WITH CIRRHOSIS
Authors: L. Elkrief, P.-E. Rautou, M. Ronot, S. Lambert, M. Dioguardi Burgio, C. Francoz, A. Plessier, F. Durand, D. Valla, D. Lebrec, V. Vilgrain, L. Castéra
Journal: Journal of Hepatology (2014)