tbuckley/cabot-search huggingface dataset:
MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence
Authors: Jeong-Yeon Lee, Hee-Young Won, Ji-Hye Park, Hye-Yeon Kim, Hee-Joo Choi, Dong-Hui Shin, Ju-Hee Kang, Jong-Kyu Woo, Seung-Hyun Oh, Taekwon Son, Jin-Woo Choi, Sehwan Kim, Hyung-Yong Kim, Kijong Yi, Ki-Seok Jang, Young-Ha Oh, Gu Kong
Journal: Journal of Clinical Investigation (2015)

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.
Campaign Aims to Boost Adult Vaccinations
Authors: Rebecca Voelker
Journal: JAMA (2009)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
MEDICAL OR TISSUE ASEPSIS.
Authors: T. J. McGILLICUDDY
Journal: JAMA (1898)

<h3>MOTTO:—CLEANSE AND STRENGTHEN.</h3> Medical asepsis is but the inward application of the principle contained in the ordinary surgical asepsis, supplemented by the enhancement of the bactericidal properties of the blood serum. The words cleanse and strengthen include all the essentials of tissue or medical asepsis. Wherever water will flow, no matter how small the stream, it will cleanse, and the cleansing power will be proportionate to the size and number of the streams. Water has been used for ages for its curative action in disease, but not, to my knowledge, with the idea of establishing an aseptic condition of the tissues by effecting and maintaining tissue cleanliness. While to many, the presentation may seem a novelty, it is founded on years of careful study and practical application. The absence of any authorities on tissue asepsis as such, and its proven value in practice, will be sufficient apology for this paper.
The utility of DNA microarrays for characterizing genotoxicity.
Authors: Ronald K Newton, Marilyn Aardema, Jiri Aubrecht
Journal: Environmental Health Perspectives (2004)

Microarrays provide an unprecedented opportunity for comprehensive concurrent analysis of thousands of genes. The global analysis of the response of genes to a toxic insult (toxicogenomics), as opposed to the historical method of examining a few select genes, provides a more complete picture of toxicologically significant events. Here we examine the utility of microarrays for providing mechanistic insights into the response of cells to DNA damage. Our data indicate that the value of the technology is in its potential to provide mechanistic insight into the mode of action of a genotoxic compound. Array-based expression profiling may be useful for differentiating compounds that interact directly with DNA from those compounds that are genotoxic via a secondary mechanism. As such, genomic microarrays may serve as a valuable alternative methodology that helps discriminate between these two classes of compounds. Key words: biomarkers, gene expression profile, genetic toxicology, mechanism of action, toxicogenomics.
Health service or sickness service?
Authors: E Slater
Journal: BMJ (1971)

<h3>Abstract</h3> SNAREs are undoubtedly one of the core elements of synaptic transmission. On the contrary to the well characterized function of their SNARE domains bringing the plasma and vesicular membranes together, the level of contribution of their juxtamembrane domain (JMD) and the transmembrane domain (TMD) to the vesicle fusion is still under debate. To elucidate this issue, we analyzed three groups of STX1A mutations: 1) elongation of STX1A’s JMD by three amino acid insertions in the junction of SNARE-JMD or JMD-TMD; 2) charge reversal mutations in STX1A’s JMD; and 3) palmitoylation deficiency mutations in STX1A’s TMD. We found that both JMD elongations and charge reversal mutations have position dependent differential effects on Ca<sup>2+</sup>-evoked and spontaneous neurotransmitter release in cultured murine hippocampal neurons. Importantly, we show that STX1A’s JMD regulates the palmitoylation of STX1A’s TMD and loss of STX1A palmitoylation either through charge reversal mutation K260E or by loss of TMD cysteines particularly inhibits spontaneous vesicle fusion. Interestingly, the retinal ribbon specific STX3B has a glutamate in the position corresponding to the K260E mutation in STX1A and mutating it with E259K acts as a molecular on-switch. Furthermore, palmitoylation of post-synaptic STX3A can be induced by the exchange of its JMD with STX1A’s JMD together with the incorporation of two cysteines into its TMD. Forced palmitoylation of STX3A dramatically enhances spontaneous vesicle fusion suggesting that STX1A regulates spontaneous release through two distinct mechanisms: one through the C-terminal half of its SNARE domain and the other through the palmitoylation of its TMD.
Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone.
Authors: J C Marshall, G D Case, T W Valk, K P Corley, S E Sauder, R P Kelch
Journal: Journal of Clinical Investigation (1983)

Prepubertal girls and gonadotropin-releasing hormone (GnRH)-deficient females secrete follicle-stimulating hormone (FSH) preferentially in response to intravenous GnRH. With continued pulsatile GnRH stimulation, FSH secretion is reduced when plasma estradiol (E2) is increasing. To delineate the mechanisms involved in these changing gonadotropin responses, e studied the effect of low dose (0.025 micrograms/kg) pulsatile injections of GnRH in females with varying degrees and/or duration of endogenous GnRH deficiency (idiopathic panhypopituitarism, PHP; isolated growth hormone deficiency, IGHD; isolated gonadotropin deficiency, IGD; and anorexia nervosa, AN; both at low body weight and after weight regain). In patients presumed to have the most severe GnRH deficiency (PHP), responses of both FSH and luteinizing hormone (LH) were small and delayed, and no increase in plasma estradiol occurred during the 5 d of GnRH injections. In patients previously exposed to prepubertal or adult levels of endogenous GnRH secretion (IGHD, IGD, AN at low body weight), a rapid initial FSH response occurred that subsequently declined when plasma estradiol rose to concentrations greater than 40-50 pg/ml. Prior therapy with estrogen (micronized estradiol, Estrace) abolished FSH responses but LH responses were only slightly impaired. The degree of FSH response was dependent upon the time of initiation of estrogen relative to the onset of GnRH injections. Administration of estrogen after the first GnRH injection inhibited gonadotropin responses, whereas later estrogen therapy (after 1 d of GnRH pulses) blunted the GnRH induced FSH secretion without significantly impairing the LH response. In weight-regained anorexic patients who had spontaneous pulsatile LH secretion and a mean basal plasma estradiol concentration of 53 +/- 15 pg/ml, administration of GnRH pulses did not change plasma LH and a minimal FSH response was seen. The data indicate that the pattern of gonadotropin responses to low dose GnRH injections depends upon the degree of previous exposure of the pituitary to endogenous GnRH. Furthermore, estradiol selectively inhibits FSH secretion by a direct action on the pituitary gland. This action of estradiol provides an explanation for the selective reduction in FSH responses to GnRH seen during pubertal maturation in girls and during the mid-follicular stage of the menstrual cycle.
Gang Membership, Violence, and Psychiatric Morbidity
Authors: Jeremy W Coid, Simone Ullrich, Robert Keers, Paul Bebbington, Bianca L Destavola, Constantinos Kallis, Min Yang, David Reiss, Rachel Jenkins, Peter Donnelly
Journal: American Journal of Psychiatry (2013)

Gang members engage in many high-risk activities associated with psychiatric morbidity, particularly violence-related ones. The authors investigated associations between gang membership, violent behavior, psychiatric morbidity, and use of mental health services.The authors conducted a cross-sectional survey of 4,664 men 18-34 years of age in Great Britain using random location sampling. The survey oversampled men from areas with high levels of violence and gang activities. Participants completed questionnaires covering gang membership, violence, use of mental health services, and psychiatric diagnoses measured using standardized screening instruments.Violent men and gang members had higher prevalences of mental disorders and use of psychiatric services than nonviolent men, but a lower prevalence of depression. Violent ruminative thinking, violent victimization, and fear of further victimization accounted for the high levels of psychosis and anxiety disorders in gang members, and with service use in gang members and other violent men. Associations with antisocial personality disorder, substance misuse, and suicide attempts were explained by factors other than violence.Gang members show inordinately high levels of psychiatric morbidity, placing a heavy burden on mental health services. Traumatization and fear of further violence, exceptionally prevalent in gang members, are associated with service use. Gang membership should be routinely assessed in individuals presenting to health care services in areas with high levels of violence and gang activity. Health care professionals may have an important role in promoting desistence from gang activity.
An Account of a Case of Mollities Ossium
Authors: E. L. Ormerod
Journal: BMJ (1859)

discharge from the left ear, with occasional shooting pain behind each, m-ore especially on sittinig up in bed, when she has also some "giddiness".Her appetite is improving; but she is allowed only beef-tea.The pulse is as yesterday.The tongue cleani and moist.Jan. 11th.The discharge from the ear continues.The pulse has got up to 90, but is soft and readily compressed.The "pain and feeling of heaviness" on lifting the head from the pillow are not so great.The tongue is cleani and moist; the gtums are less tender.She was allowed pudding extra daily.Jan. 12th.She is still doing well.The pu-lse has gone clown to 8t.The skin is cool and moist.The discharge from the ear continues, but in diminislhed amount.She takes her pudding and beef-tea with a good appetite.Jan. 14th.There is still slight purtulent discharge from the ear.The" giddiness and sense of weight in the head", though mulch diminished, are still felt on sitting up in bed.Still she sits up in bed and talks cheerfully to her friends.Jan. 16th.She has gone on well since the 14th.There is still a slight puirulent discharge from the left ear, and some giddiness on rising in bed.The strabismus is scarcely perceptible.Jan. 18th.She is doing well in every respect; there has been no discharge from the ear during last night or this morn- ing.She was allowed to have broth, pudding, and an egg daily.Jan. 2')cnd.She is out of bed.There is no pain in the head, but still slight giddiness, and occasional sense of weight, which she attributes to weakness.Jan. 24th.She has got up each day without any unfavotur- able symiptoms, and with gradual improvement in strength.TMr. Shaw has given permission for her to leave the Hospital to-m-orrow.Jan. '25th.She walked out of the Hospital to-day, merely suipported by the arm of a friend, and complaining only of " feeling rather weak."She had taken no medicine since the 8th.Jan. 26th.MIr.Brend visited her, by Mr. Shaw's request, at her own house.She had slept well the previous night.She was then cheerful, anid free from pain, except slight aching of the forelhead, and occasional slight giddiness on sitting up.On * I once saw a case of pericarditis, which resulted from ulceration of the cesophagus.The ulcer in its progress opened at last into the pericardium, and so permitted the contents of the stomach to pass into the pericardium.This is the only case of pneunio-pericardium which I have ever seen.The air, of course, came from the stomach in this instance.By gently pressing upon the stomach, its contents were readily forced, and seen to pass, up the cesophagus, and so through the ulcerated opening into the pericardium.
Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy.
Authors: B Kyu, A Matsumori, Y Sato, I Okada, N M Chapman, S Tracy
Journal: Circulation (1992)

BACKGROUND In our model of dilated cardiomyopathy (DCM), cardiac dilatation and hypertrophy developed after inoculation of encephalomyocarditis virus (EMCV), but the infectious virus was isolated only early after infection. In this study, we investigated whether viral RNA could be detected at later times using the polymerase chain reaction (PCR). METHODS AND RESULTS In the in vitro study, FL (human amnion) cells infected with EMCV were harvested for RNA extraction, and viral cDNA was synthesized by reverse transcription with random hexamers. Using oligonucleotide primers with homology to the 5' noncoding region of EMCV, we enzymatically amplified a 121-base pair band, which was homologous to a probe specific for EMCV as demonstrated by Southern blot hybridization. The sensitivity of this PCR technique was at the level of about 10(2)-10(3) copies of viral RNA genome. In the in vivo study, four-week-old DBA/2 mice were inoculated with EMCV intraperitoneally (10 pfu/mouse) and killed on days 1,2,3,5,7,10,14,18,28,60, and 90. The hearts were divided into three parts for purification of total RNA, histopathological examination, and to culture for infectious virus. The infectious virus was isolated from the heart after the second day but never after the 14th day. The viral genome was detectable by PCR on the second day, when very little mononuclear cell infiltration around the blood vessels was histologically visible. Positive PCR signals were observed in all hearts through day 14. Viral RNA was also detected in four of six 28-day samples, four of six 60-day samples, and two of seven 90-day samples when diffuse myocardial fibrosis was prominent, but myocardial necrosis or cellular infiltration had disappeared. CONCLUSIONS The persistence of EMCV RNA was shown by PCR in the chronic stage of EMCV-induced myocarditis, a time when the inflammatory reaction had largely subsided. The PCR is a potentially useful method to test possible viral etiologies in idiopathic heart muscle disease or DCM.
Relevance of Coronary Microvascular Flow Impairment to Long-Term Remodeling and Systolic Dysfunction in Hypertrophic Cardiomyopathy
Authors: Iacopo Olivotto, Franco Cecchi, Roberto Gistri, Roberto Lorenzoni, Giampaolo Chiriatti, Francesca Girolami, Francesca Torricelli, Paolo G. Camici
Journal: Journal of the American College of Cardiology (2006)
Abstract LB-75: Concomitant use of panitumumab (Pmab) had no clinically significant effect on irinotecan (Iri) pharmacokinetics (PK)
Authors: Hagen Kennecke, Chi-Yuan Wu, Eric Chen, Jeffrey Infante, Alin Chen, Bing Gao, Brian Smith, Jason Litten, Bing-Bing Yang
Journal: Cancer Research (2010)

Abstract Background: Pmab, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFR), is indicated for treatment of EGFR-expressing, chemorefractory, metastatic colorectal cancer (mCRC). This study examined effects of Pmab on Iri PK when used as combination therapy in patients (pts) with mCRC. Methods: This phase 1, open-label, multicenter, single-arm study enrolled pts with mCRC without prior exposure to an EGFR inhibitor. Pts could not have CYP3A4 inhibiting or inducing medications ≥ 2 weeks before enrollment or UGT1A1*28 TA7/7, TA7/8, and TA8/8 polymorphisms. Pts received Iri (180 mg/m2, 90-min IV infusion) on day 1 cycle 1 followed by Pmab (6 mg/kg, 60-min IV infusion) on day 4 cycle 1. After 2 weeks (day 1 cycle 2), pts received Pmab followed immediately by Iri. Pmab and Iri were administered thereafter every 2 weeks until disease progression or intolerability. Plasma samples for Iri and its active metabolite SN-38 were collected pre-dose and up to 72 hours after Iri infusion in cycles 1 and 2. Primary endpoints were Cmax and AUC of Iri (PK subset), and secondary endpoints included rates of adverse events (AEs). Results: 28 pts enrolled; 19 of 27 pts who received treatment met PK evaluability criteria (dosed per protocol for 2 cycles with no reductions/delays). PK profiles of Iri with or without Pmab were nearly superimposable. 90% confidence intervals for the ratios of geometric means for Iri Cmax and AUC with or without Pmab were within a prespecified 0.70 to 1.43 interval, suggesting that Pmab had no impact on Iri PK. Similar results were seen for SN-38 PK. AEs were as expected for Iri plus Pmab combination therapy. Conclusions: Pmab in combination with Iri was generally well tolerated by pts with mCRC. Pmab had no significant effects on Iri PK.PK Profiles of Iri and SN-38 Ratio of Geometric Means Point Estimate Cycle (N = 19)Geometric Mean(Cycle 2 vs Cycle 1)90% CIIri Cmax (ng/mL)115400.9800.894 - 1.074 21510 AUC0-inf (ng·hr/mL)1112000.8980.819-0.985 210100 SN-38 Cmax (ng/mL)125.90.8230.731-0.926 221.3 AUC0-inf (ng·hr/mL)1a3260.8650.773 - 0.968 2b282 aN = 17; bN = 16; CI, Confidence interval; Iri, Irinotecan Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-75.
Systolic Heart Failure
Authors: John J.V. McMurray
Journal: New England Journal of Medicine (2010)

A 74-year-old man with a history of hypertension and myocardial infarction that had occurred in the remote past presents with breathlessness on exertion. On examination, his pulse is 76 beats per minute and his blood pressure is 121/74 mm Hg. There is jugular venous distention and edema in the lower limbs; the lungs are clear. An echocardiogram shows left ventricular dilatation and an ejection fraction of 33%. How should his case be managed?
Von Willebrand's Disease
Authors: B. Hagedorn
Journal: JAMA (1971)

Von Willebrand's disease is a familial hemorrhagic condition. There is no single test for diagnosis, no agreement on the pathogenesis, and no evidence as to the genetics of inheritance. Seven abnormalities have been reported to characterize the disease: prolonged bleeding time, capillary abnormality, thrombocytopathy, reduced blood-clotting factor VIII levels in the plasma, overresponse of factor VIII to transfusion, and reduced platelet adhesiveness both in vivo and in vitro. Generally, the triad of prolonged bleeding time, reduced platelet adhesiveness, and reduced plasmatic factor VIII characterizes the typical case, although some believe that the patient's factor VIII response to transfusion is the most important single finding.
Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC
Authors: V Fehring, U Schaeper, K Ahrens, A Santel, O Keil, M Eisermann, K Giese, Jörg Kaufmann
Journal: Molecular Therapy (2014)

Posttranscriptional gene silencing by RNA interference can be therapeutically exploited to inhibit pathophysiological gene expression. However, in contrast to the established effectiveness of RNAi in vitro, safe and effective delivery of siRNAs to specific organs and cell types in vivo remains the major hurdle. Here, we report the development and in vivo characterization of a novel siRNA delivery system (DACC lipoplex) suitable for modulating target gene expression specifically in the lung vasculature. Systemic administration of DACC in mice delivered siRNA cargo functionally to the lung pulmonary endothelium. A single dose of DACC lipoplexes administered by bolus injection or by infusion was sufficient to specifically silence genes expressed in pulmonary endothelial cells such as CD31, Tie-2, VE-cadherin, or BMP-R2. When tested in a mouse model for lung cancer, repeated treatment with DACC/siRNA(CD31) reduced formation of lung metastases and increased life span in a mouse model of experimental lung metastasis.
Biologic False-Positive Reaction for Syphilis
Authors: Nicholas J. Fiumara
Journal: New England Journal of Medicine (1963)

ONCE upon a time the physician was hard put to distinguish between the true-positive blood test for syphilis and the biologic false-positive reaction. Only time and exhaustive clinical and epidemiologic studies made a disposition of infection or no infection possible. There was rejoicing when the physician could happily proclaim that the patient had a biologic false-positive reaction and not syphilis.Time and the introduction of the treponemal tests have made it possible to ascertain quickly, and within limits quite accurately, whether or not a patient with a reactive reagin test has syphilis.Time and the recent advances in the nature . . .