tbuckley/cabot-search huggingface dataset:
Abstract S3-05: Patient-derived xenograft study reveals endocrine therapy resistance of ER+ breast cancer caused by distinct ESR1 gene aberrations
Authors: J Shao, S Li, RJ Crowder, RT Kitchens, SN Johnson, R Goncalves, C Phommaly, OL Griffith, C Maher, CM Perou, ER Mardis, MJ Ellis
Journal: Cancer Research (2013)

Abstract Endocrine therapy resistance occurs in 50% of estrogen receptor positive (ER+) luminal breast cancers but the underlying mechanisms are poorly understood. To gain insight, we have taken advantage of whole-genome and RNA sequencing data of five late-stage hormone-resistant luminal breast tumors all of which have been successfully established as patient-derived mouse xenograft (PDX) models. Here we describe genetic alterations in ESR1-the gene coding for ERa-in three of these five tumors. They include an ESR1 point mutation (Y537S), a gene translocation causing an in-frame fusion between N-terminal ER and C-terminal Yes-associated protein 1 (YAP1), and ESR1 gene amplification. Functional characterization of the ESR1(Y537S) mutant and ESR1-YAP1 fusion in ER+ cell lines indicated that they both possess constitutive transcriptional activity and drive hormone-independent cell proliferation, mirroring the endocrine resistance of the originating tumors and the estradiol-independent growth of the PDX tumors. ESR1 (Y537S), a known gain-of-function experimental mutation in the ligand-binding domain of ER is not seen in primary breast cancer (TCGA data), suggesting it is a mutation associated with acquired resistance. Regarding the ESR1-YAP1 fusion gene, the truncated N-terminal ER fragment lacks the hormone-dependent transactivation domain (AF2) and the ligand binding domain but retains the hormone-independent transactivation domain (AF1) and therefore drives resistance to all endocrine approaches. As for ESR1 gene amplification, the tumor of origin, though resistant to aromatase inhibition, paradoxically responded to estradiol treatment, and this was recapitulated in the PDX model. Interestingly, acquired ESR1 gene amplification also occurred in long-term estrogen-deprived breast cancer MCF-7 cells which similarly regress upon estradiol exposure. Thus, ESR1 amplification may be a biomarker for paradoxical therapy with estradiol. Together, our focused study of advanced endocrine resistant luminal breast tumors revealed three distinct mutational mechanisms affecting the ESR1 gene that drive endocrine therapy resistance. Prevalence studies using RNAseq are underway to determine the frequency of somatic changes in the ESR1 gene in advanced breast cancer samples and additional ER+ PDX models. These additional data will be presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-05.
Sarosh Dhunjishaw Vakil
Authors: J M S Pearce
Journal: BMJ (2010)

Sarosh Dhunjishaw Vakil died peacefully at his home in Preston, Lancashire, on 4 December 2009. He was born in Bombay on 3 September 1933, and he trained at and graduated from St George’s Hospital, London, in 1959. After passing the MRCP, he proceeded to postgraduate studies in neurology with Maurice Parsonage in Leeds, then as …
Mammography
Authors: Dorothea R. Peck
Journal: JAMA (1976)

THE ULTIMATE responsibility for the diagnosis of breast cancer and the decision for surgical consultation rests on the primary physician, who should be well acquainted with both the advantages and the limitations of the various modalities for diagnosing breast disease. Mammography is an accurate and widely available procedure, but it is essential for the clinician to be able to communicate with the radiologist so that he can make an informed selection of patients to be referred for mammography. The goal of every mammographic interpretation is the confirmation or exclusion of the presence of a malignant lesion. The radiologist must indicate in his report the degree of certainty of his diagnosis. Undertaken as long ago as 1913 by Salomon, mammography is not a new procedure. Later, Warren, Hicken, Leborgne, and others worked extensively on breast radiography and duct injection. However, it was not until the late 1950s and early 1960s, when
Intravesical Bleomycin in Bladder Cancer
Authors: P. H. Smith
Journal: JAMA (1976)

<h3>To the Editor.—</h3> The place of chemotherapy in the treatment of tumors of the bladder has yet to be fully evaluated. Etoglucid (Epodyl, Britain) and thiotepa have previously been used as intracavitary agents for the control of superficial bladder lesions with a 40% to 60% success rate.<sup>1-3</sup> Sadoughi et al (226:465, 1973) described the successful use of bleomycin in this way in one patient. We report our results in a further five patients, all of whom had superficial bladder tumors too extensive to remove in one operation. Results of a histologic examination in each patient showed transitional cell carcinoma, and urine cytologic tests were done in each patient before and after treatment. An evaluation of symptoms and cystoscopic appearances following treatment was made, with regular white blood cell counts and a chest roentgenogram. Fluid draining from the bladder after instillation of bleomycin was assayed to determine the amount of
GE-15 * CLONAL EVOLUTION AND INTRATUMORAL HETEROGENEITY OF LOW-GRADE GLIOMA GENOMES
Authors: B. Johnson, T. Mazor, C. Hong, M. Barnes, S. Yamamoto, H. Ueda, K. Tatsuno, K. Aihara, S. Asthana, M. Dayal, S. Nelson, J. Phillips, A. Bollen, A. Mukasa, N. Saito, H. Aburatani, M. Berger, S. Chang, B. Taylor, J. Costello
Journal: Neuro-Oncology (2014)

Low-grade gliomas frequently recur after surgical resection and may undergo malignant progression to a higher grade with a significantly worse prognosis. Understanding the origin and evolution of recurrences is critical for effectively treating residual disease to delay or prevent recurrence. Here, we extend previous work by sequencing the exomes of over 30 initial low-grade gliomas and their patient-matched recurrences to reconstruct the patterns of clonal evolution. We also sequence multiple spatially distinct samples from both initial low-grade and recurrent high-grade tumors to extensively dissect intratumoral heterogeneity. We identify a broad spectrum of genetic relatedness within tumor pairs, with the unexpected loss of canonical driver mutations upon recurrence. Therefore, resected portions of initial tumors can differ dramatically from tumorigenic portions of adjacent residual disease. The identification of common ancestral clones additionally reveals the order in which key driver mutations are acquired, allowing for a model of low-grade astrocytoma gliomagenesis. We have also previously shown that the treatment of low-grade gliomas with temozolomide induces hypermutation and alters the function of key cancer genes and their cognate pathways, potentially driving malignant progression. We extend that finding with an analysis of the evolution and intratumoral heterogeneity of additional hypermutated glioblastoma recurrences. These evolutionary trajectories have immediate ramifications for the use of mutagenic chemotherapies such as temozolomide, and for personalizing therapy to eliminate residual disease.
Marked Hypercapnia Secondary to Severe Metabolic Alkalosis
Authors: MEYER D. LIFSCHITZ
Journal: Annals of Internal Medicine (1972)

A patient had alveolar hypoventilation secondary to chronic metabolic alkalosis. Severe hypercapnia occurred without any obstructive pulmonary disease or neuromuscular weakness. Cerebrospinal fluid showed marked cerebrospinal fluid alkalosis and a diminished cerebral blood flow. Recognition of hypercapnia as a sequel of chronic metabolic alkalosis allowed correction of the underlying alkalosis and avoided the risks of unnecessary mechanical ventilation. The mechanism of alveolar hypoventilation with metabolic alkalosis, the possible role played by azotemia, and the differential diagnosis of unexplained hypercapnia are discussed.
CLINICAL CORRELATES FOR FAILURE OF PERCUTANEOUS CORONARY INTERVENTION IN ST-ELEVATION MYOCARDIAL INFARCTION
Authors: Israel Barbash, Itsik Ben-Dor, Danny Dvir, Rebecca Torguson, Zhenyi Xue, Lowell Satler, William Suddath, Kenneth Kent, Augusto Pichard, Ron Waksman
Journal: Journal of the American College of Cardiology (2012)
Cardiac Disease 1976
Authors: OGLESBY PAUL
Journal: Annals of Internal Medicine (1976)

Editorials1 October 1976Cardiac Disease 1976OGLESBY PAUL, M.D., J. Roscoe MillerOGLESBY PAUL, M.D.Search for more papers by this author, J. Roscoe MillerSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-85-4-520 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOur cardiology of 1976 has some of its origins in the description by Heberden in England of angina pectoris (first presented in 1768, published in 1772) and the work of Neubauer in Germany on the cardiac nerves (1772). About 100 years ago, F. H. Welch in England described the differences between syphilitic aortic lesions and aortic atherosclerosis (1875), Rokitansky in Austria published his great monograph on septal defects (1875), and Southey in England introduced the use of special tubes to treat anasarca (1877).Today, in 1976, lay and professional interest in cardiac disease has escalated to an astonishing height. Recognizing... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Northwestern University Chicago, Illinois PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1976Volume 85, Issue 4Page: 520-521KeywordsAnginaAtherosclerosisEdemaHeart diseasesLesionsNerves ePublished: 1 December 2008 Issue Published: 1 October 1976 PDF downloadLoading ...
Heterozygous recipient and donor HFE mutations associated with a hereditary haemochromatosis phenotype after liver transplantation
Authors: A J Wigg
Journal: Gut (2003)

We observed the development of phenotypic hereditary haemochromatosis in a non-hereditary haemochromatosis liver transplant recipient, following transplantation with a liver from a C282Y heterozygous donor. No cause for secondary iron overload was identified. Subsequent sequencing of the HFE gene of both donor and recipient revealed a strong candidate for a novel pathogenic HFE mutation. In the recipient, heterozygosity for a single base substitution in exon 1, g.18 G&gt;C, resulting in the substitution of arginine by serine at codon 6 (R6S), was detected. This R6S variation is likely to represent a novel pathogenic missense mutation of the HFE gene. An interaction between R6S heterozygosity in the recipient and C282Y heterozygosity in the donor liver is the most likely explanation for the development of iron overload in this patient. The report suggests that an hepatic defect is required for expression of hereditary haemochromatosis and that the intestinal HFE genotype is not the exclusive determinant of iron status. It also raises the possibility that a hereditary haemochromatosis phenotype may result from transplantation of C282Y heterozygous donor livers into recipients with heterozygous pathogenic HFE mutations. This possibility may have significant implications for the common practice of transplanting C282Y heterozygous livers.
Surgery, AIDS, and Hepatitis B
Authors: Lynn M. Peterson
Journal: JAMA (1991)

To the Editor.  —The recent article by Panlilio et al 1 and the accompanying editorial by Drs Gerberding and Schecter 2 draw attention to existing rates of blood exposure in operating rooms. These authors make suggestions regarding efforts to reduce blood exposure. Their suggestions seem sensible.  However, before rushing into massive implementation of extraordinary restrictions, more data should be obtained. The amount of blood is likely to be only one factor in transmitting infection. We know that a microscopic amount of blood can also have an enormous impact. Several cases of physician-acquired HIV infection have occurred with small quantities of blood. The Florida dentist's transmission of HIV to patients also indicates that minute quantities of blood in the mouth or in the presence of oral injuries may be exceedingly potent. Factors like the depth of injury, the quantity of virus, the infectious potential of the virus, and perhaps even the
Prenatal Alcohol Exposure
Authors: M. J. Friedrich
Journal: JAMA (2013)

Heavy alcohol exposure to a fetus affects the growth and body composition of the child for years, according to a study of pregnant women from an antenatal clinic serving an economically disadvantaged community in Cape Town, South Africa (Carter RC et al. Alcohol Clin Exp Res. 2012;36[11]:1973-1982).
Accumulated Lead Exposure and Risk of Age-Related Cataract in Men
Authors: Debra A. Schaumberg, Flavia Mendes, Mini Balaram, M. Reza Dana, David Sparrow, Howard Hu
Journal: JAMA (2004)

Low-level lead exposure may increase the risk for a number of chronic age-related diseases. Several studies have documented the presence of lead in lenses with cataract. The intrusion of lead into the lens may alter lens redox status and cause protein conformational changes that decrease lens transparency.To determine the relationship of cumulative lead exposure with the development of cataract.Tibial (cortical) and patellar (trabecular) bone lead levels were measured by K x-ray fluorescence between 1991 and 1999 in a subset of participants in the Normative Aging Study (NAS), a Boston-based longitudinal study of aging in men. Among the first 795 NAS participants to have bone lead levels measured, we reviewed eye examination data (collected routinely every 3-5 years) for the period after the bone lead measurements were taken. We limited the population to men aged 60 years and older who had sufficient eye examination information available (n = 642). Blood lead levels were also measured.Cataract assessment was done while masked to the lead level results. A participant was considered to have cataract if there was documentation for either eye of cataract surgery or a cataract graded clinically as 3+ or higher on a 4-point scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated as estimates of the magnitude and significance of the relationship of lead exposure with cataract, in logistic regression models.The mean age of the study participants was 69 years and cataract was identified in 122 men. The age-adjusted OR (95% CI) for cataract for men in the highest vs lowest quintile of tibia lead level was 2.68 (1.31-5.50). Further adjustment for pack-years of cigarette smoking, diabetes, blood lead levels, and intake of vitamin C, vitamin E, and carotenoids resulted in an OR of 3.19 (95% CI, 1.48-6.90). For patella lead level, there was an increased risk of cataract in the highest vs lowest quintile (OR, 1.88; 95% CI, 0.88-4.02), but the trend was not significant (P = .16). Blood lead levels, more indicative of short-term exposure levels, were not significantly associated with cataract (OR, 0.89; 95% CI, 0.46-1.72; P = .73).These epidemiological data suggest that accumulated lead exposure, such as that commonly experienced by adults in the United States, may be an important unrecognized risk factor for cataract. This research suggests that reduction of lead exposure could help decrease the global burden of cataract.
Communicating the harmful effects of medicines
Authors: J. R. Geddes, A. Cipriani, R. Horne
Journal: BMJ (2014)

Warnings may have unintended consequences

In 2004 the US Food and Drug Administration warned that antidepressants could increase suicidality in children and adolescents.1 Three years later it ordered that all antidepressants should carry an expanded black box warning, incorporating information about an increased risk of suicidal symptoms in young adults aged 18-24 years.2 These warnings were associated with widespread media coverage.3 4 5

Warnings from regulatory agencies about harms from drugs are known to reduce prescribing rates. In a linked paper Lu and colleagues (doi:10.1136/bmj.g3596) show that not only did prescribing rates decrease in this age group but there was a modest but significant increase in the rate of self poisoning, an important suicidal behavior.6 The net effect of the warning was probably counterproductive and led to more harm.

Completed suicide is such a rare event that even this large observational study lacked the power to investigate this outcome. Nevertheless, self poisoning is a major event for patients, their family, and health services. Lu and colleagues’ study is a good example of the value of a quasiexperimental pharmacoepidemiological design following a timed intervention in investigating important but uncommon adverse events.6 The findings are not only relevant to …
Relation between differential pressure and flow in the pulmonary artery of the dog
Authors: M. F. O'Rourke, W. R. Milnor
Journal: Cardiovascular Research (1971)

The relationship between blood flow and differential pressure in the main pulmonary artery, expressed as longitudinal impedance, was determined in anaesthetized open-chest dogs and compared with the impedances predicted by the Womersley theory. Blood flow was measured with an electromagnetic flowmeter, and differential pressure with double-lumen catheter or by needles piercing the vessel wall. For the first five harmonics (α = 10 to 35), the measured impedance modulus was greater than the theoretical value by an average of 18%, and flow lagged differential pressure by an average of 0·53 radians more than theory predicted. The ratio of experimental to Womersley values averaged 9.6 for the resistive component of impedance, and 0·89 for the reactive component. These discrepancies between theory and observation, which presumably arise because conditions of flow in the pulmonary artery differ from those assumed in Womersley's analysis, were qualitatively consistent with the effects expected from tapering of the artery, non-laminar blood flow, and wall viscosity.
Association Between Arterial Catheter Use and Hospital Mortality in Intensive Care Units
Authors: Hayley B. Gershengorn, Hannah Wunsch, Damon C. Scales, Ryan Zarychanski, Gordon Rubenfeld, Allan Garland
Journal: JAMA Internal Medicine (2014)

Arterial catheters are used frequently in intensive care units (ICUs). Clinical effectiveness and adverse events associated with the use of the catheters have not been formally evaluated in clinical studies.To determine whether an association exists between arterial catheter use and hospital mortality in ICU patients.Propensity-matched cohort analysis of data in the Project IMPACT database, from 2001 to 2008. A total of 139 ICUs in the United States were included. Participants were ICU patients 18 years or older.Arterial catheter use.Our main outcome was hospital mortality. We assessed a primary cohort of medical patients requiring mechanical ventilation and 9 secondary cohorts. We used propensity score-matched pairs as the primary analytic strategy. Sensitivity analyses included 4 alternative methods of comparison in the primary cohort: multivariate modeling without propensity adjustment, mixed-effects multivariate logistic regression without propensity adjustment, multivariate modeling with propensity adjustment, and stratification based on propensity quintiles.Our primary cohort consisted of 60 975 patients; 24 126 of these patients (39.6%) had an arterial catheter in place during their ICU stay, and analyses were based on 13 603 propensity score-matched pairs. We found no association between arterial catheter use and hospital mortality in medical patients requiring mechanical ventilation in the primary analysis (odds ratio [OR], 0.98; 95% CI, 0.93-1.03; P = .40) or the 4 sensitivity analyses (P ≥ .58 for all). In 8 of 9 secondary cohorts we were unable to detect an association between arterial catheter use and hospital mortality. In the cohort of patients receiving vasopressors, arterial catheter use was associated with an increased odds of death (OR, 1.08; 95% CI, 1.02-1.14; P = .008).In this propensity-matched cohort analysis, arterial catheters were not associated with improvements in hospital mortality in medical ICU patients requiring mechanical ventilation. Given the costs and potential harms associated with invasive catheters, randomized clinical trials are needed to further evaluate the usefulness of these frequently used devices.
754-2 Dual Site Atrial Pacing for the Acute and Chronic Prevention of Atrial Fibrillation: A Prospective Study
Authors: Atul Prakash, Sanjeev Saksena, Michael Hill, Julie Berg, Maria Diaz, Ryszard B. Krol, Philip Mathew, Irakli Giorgberidze, Nadeem Haque, Rahul Mehra
Journal: Journal of the American College of Cardiology (1995)
Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men
Authors: Steven A. Kaplan, E. David Crawford
Journal: Diabetes Care (2006)

We read with interest the excellent study by Pitteloud et al. (1) demonstrating that low serum total testosterone levels are associated with an adverse metabolic profile in aging men and suggesting a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in these patients. The authors concluded their report by stating that there is a need for evaluation of the potential benefits of androgen supplementation …
Prothrombin Complex Concentrates for Inhibitor Patients
Authors: John A. Penner
Journal: JAMA (1977)

To the Editor.—  Our most recent experience with the prothrombin concentrate Konyne in factor VIII inhibitor patients has shown considerable variation in potency of various lots with respect to coagulant content as well as clinical effectiveness. Another investigator has made a similar observation (Charles Abildgaard, personal communication). We would suggest the manufacturer be contacted regarding potency of their product before employing it to control bleeding in inhibitor patients.  As noted in our article (236:2061, 1976), the other commercially available prothrombin concentrate, Proplex, has undergone a change in processing and does not appear to be effective. The investigational product Auto IX continues to provide a good therapeutic response in this condition.