tbuckley/cabot-search huggingface dataset:
The Nuclear Factor-κB Pathway Controls the Progression of Prostate Cancer to Androgen-Independent Growth
Authors: Ren Jie Jin, Yongsoo Lho, Linda Connelly, Yongqing Wang, Xiuping Yu, Leshana Saint Jean, Thomas C. Case, Katharine Ellwood-Yen, Charles L. Sawyers, Neil A. Bhowmick, Timothy S. Blackwell, Fiona E. Yull, Robert J. Matusik
Journal: Cancer Research (2008)

Abstract Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an “androgen-independent” stage that results in renewed growth and spread of the cancer. Both nuclear factor-κB (NF-κB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-κB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-κB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-κB signaling in vivo by the absence of the IκBα inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-κB pathway was activated in the ARR2PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IκBα+/− haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-κB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-κB pathway may be a potential target for therapy against androgen-independent prostate cancer. [Cancer Res 2008;68(16):6762–9]
Legal View of Insanity Commitments.
Authors: E. C. Spitzka
Journal: JAMA (1891)

<h3>To the Editor:</h3> —In reference to your editorial citation of David McAdam's (at present Judge of the Superior Court of New York) " Legal View of Insanity Commitments," permit me to state that they have become a laughing-stock among all judges, lawyers and physicians who have any knowledge of the subject-matter, or familiarity with the daily and hourly emergencies to which the physician called upon to deal with the problems of insanity is exposed. His loud and positive declarations were the outcome of an agitation of the subject, provoked by the publicity given to the commitment of one of my private patients. The learned judge has construed for himself a remarkable dilemma. On the one hand he states that his judicial action added no force to the commitment, and that he had indulged in this action in 7,000 cases, on the other he—or at all events the Court over which he
Interactions between 8-L-arginine vasopressin and prostaglandin E2 in human mononuclear phagocytes.
Authors: R Locher, W Vetter, L H Block
Journal: Journal of Clinical Investigation (1983)

The effect of 8-L-arginine vasopressin (AVP) on biosynthesis of prostaglandins in human mononuclear phagocytes was examined. AVP, oxytocin, and deamino-(8-D-arginine) vasopressin (dDAVP) affected prostaglandin biosynthesis in a rank order that parallels their pressor but not antidiuretic activity (AVP greater than oxytocin greater than dDAVP). Radioimmunoassay, incorporation studies using [14C]arachidonic acid and radiometric thin-layer chromatography, revealed prostaglandin E2 (PGE2) to be the only prostaglandin synthesized by the mononuclear phagocytes. While high concentrations of PGE2 elevated cytoplasmic levels of cyclic AMP by five- to sevenfold above basal values, low concentrations of PGE2 that are released by the cells in the presence of AVP failed to increase cyclic AMP content in the cells. However, PGE2 at concentrations that do not alter cyclic AMP levels markedly interferes with the activity of AVP. This effect is, however, very time dependent. Addition of PGE2 to the cells 30 min before AVP, was followed by a period of unresponsiveness to the hormone that lasts at least 30 min. Pretreatment of the cells with indomethacin enhanced the AVP-mediated accumulation of intracellular cyclic AMP level. PGE2 did not modify [3H]AVP binding, indicating that its inhibitory effect on the activity of the peptide is not due to downregulation of vasopressin receptors.
A Polymorphism in the <i>TC21</i> Promoter Associates with an Unfavorable Tamoxifen Treatment Outcome in Breast Cancer
Authors: Matjaž Rokavec, Werner Schroth, Sandra M.C. Amaral, Peter Fritz, Lydia Antoniadou, Damjan Glavač, Wolfgang Simon, Matthias Schwab, Michel Eichelbaum, Hiltrud Brauch
Journal: Cancer Research (2008)

Abstract Tamoxifen therapy is a standard in the treatment of estrogen receptor (ER)-positive breast cancer; however, its efficacy varies widely among patients. In addition to interpatient differences in the tamoxifen-metabolizing capacity, there is growing evidence that crosstalk between ER and growth factor signaling contributes to tamoxifen resistance. We focused on TC21, a member of the Ras superfamily, to investigate the influence of the TC21 −582C&amp;gt;T promoter polymorphism on TC21 expression and treatment outcome. Immunohistochemical analyses of breast tumors revealed a higher TC21 expression in ER-negative compared with ER-positive tumors. Expression in ER-positive tumors was higher in carriers of the T allele in an allele dose–dependent manner. Quantitative real-time PCR analyses showed that TC21 mRNA expression is decreased after transfection of ERα in ER-negative breast cancer cells MDA-MB-231, UACC893, and BT-20. In MCF7 ER-positive cells, TC21 expression decreased with 17β-estradiol treatment and increased after treatment with tamoxifen metabolites, 4-OH-tamoxifen, or endoxifen. In patients treated with adjuvant mono tamoxifen, high cytoplasmic TC21 tumor expression or the carriership of the −582T allele conferred increased recurrence rates [n = 45: hazard ratio (HR), 3.06; 95% confidence interval (95% CI), 1.16–8.05; n = 206: HR, 1.79; 95% CI, 1.08–3.00, respectively]. A combined analysis with the data of the known tamoxifen predictor CYP2D6 showed an improvement of outcome prediction compared with CYP2D6 or TC21 genotype status alone (per mutated gene HR, 2.35; 95% CI, 1.34–4.14). Our functional and patient-based results suggest that the TC21 −582C&amp;gt;T polymorphism improves prediction of tamoxifen treatment outcome in breast cancer. [Cancer Res 2008;68(23):9799–808]
Mechanisms responsible for sympathetic activation by cigarette smoking in humans.
Authors: G Grassi, G Seravalle, D A Calhoun, G B Bolla, C Giannattasio, M Marabini, A Del Bo, G Mancia
Journal: Circulation (1994)

BACKGROUND The pressor and tachycardic effects of cigarette smoking are associated with an increase in plasma catecholamines, suggesting the dependence of these effects on adrenergic stimulation. Whether the stimulation occurs at a central or a peripheral level and whether reflex mechanisms are involved is unknown. METHODS AND RESULTS In nine normotensive healthy subjects (age, 33.0 +/- 3.5 years, mean +/- SEM), we measured blood pressure (Finapres device), heart rate (ECG), calf blood flow and vascular resistance (venous occlusion plethysmography), plasma norepinephrine and epinephrine (high-performance liquid chromatography assay), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) while subjects were smoking a filter cigarette (nicotine content, 1.1 mg) or were in control condition. Cigarette smoking (which raised plasma nicotine measured by high-performance liquid chromatography from 1.0 +/- 0.9 to 44.2 +/- 7.1 ng/mL) markedly and significantly increased mean arterial pressure (+13.2 +/- 2.3%), heart rate (+30.3 +/- 4.7%), calf vascular resistance (+12.1 +/- 4.9%), plasma norepinephrine (+34.8 +/- 7.0%), and plasma epinephrine (+90.5 +/- 39.0%). In contrast, muscle sympathetic nerve activity showed a marked reduction (integrated activity -31.8 +/- 5.1%, P &lt; .01). The reduction was inversely related to the increase in mean arterial pressure (r = -.67, P &lt; .05), but the slope of the relation was markedly less (-54.1 +/- 7.5%, P &lt; .05) than that obtained by intravenous infusion of phenylephrine in absence of smoking. The hemodynamic and neurohumoral changes were still visible 30 minutes after smoking and occurred again on smoking a second cigarette. Sham smoking was devoid of any hemodynamic and neurohumoral effect. CONCLUSIONS These data support the hypothesis that in humans the sympathetic activation induced by smoking depends on an increased release and/or a reduced clearance of catecholamines at the neuroeffector junctions. Central sympathetic activity is inhibited by smoking, presumably via a baroreceptor stimulation triggered by the smoking-related pressor response. The baroreflex is impaired by smoking, however, indicating that partial inability to reflexly counteract the effect of sympathetic activation is also responsible for the pressor response.
Psychological sequelae to elective sterilisation: a prospective study.
Authors: M Thiery, A Goethals
Journal: BMJ (1982)

Mr. Peter Cooper and others (February 13 p. 461) have reported their experience with elective tubal sterilization.  In the early 70s we initiated a prospective study on the psychological evaluation and guidance of electively sterilized couples; at present our elective tubal interval sterilization series numbers several hundred cases.  Our results suggest that the entire evaluation including the couples history (personal and social characteristics fertility contraceptive history motivation and indication) provides a basis for reliable prognosis of positive postoperative adjustment.  Postoperative interviews have a very important counseling effect as well:  they provide support during the working-through period and help the understanding of any alterations of the menstrual pattern.  As could be anticipated women sterilized on a completely voluntary basis have less difficulty in assimilating the effects of the operation.  Prediction of the reaction is more difficult when the preoperative interview coincides with pregnancy or tubal ligation is combined with a cesarean section.  Clinically it is important to keep in mind that the administration of contraceptive depot preparations to women waiting for interval sterilization may induce negative psychological reactions that will become manifest during the postoperative assimilation process.  The high response to the call-up for poststerilization evaluation and the high proportion of satisfied individuals constitute evidence of the value of both the selection and follow-up procedures practiced.  (full text)
Focus on diabetes
Authors: Fiona Godlee
Journal: BMJ (2007)

Diabetes affects more than 2 million people in the United Kingdom and more than 170 million across the world. Type 2 diabetes accounts for over 90% of cases. The burden of this condition for patients, their families, and healthcare systems is immense and growing. WHO estimates that global prevalence of diabetes will more than double over the next quarter century to affect 366 million people by 2030.

As diabetes becomes more of a global problem, the debate on whether to introduce population based mass screening is hotting up. Two papers in this week's BMJ from Helen Eborall and colleagues (doi: 10.1136/bmj.39303.723449.55, doi: 10.1136/bmj.39308.392176.BE) explore the psychological effect …
1248 GENOTYPIC AND PHENOTYPIC CHARACTERIZATION OF HCV RESISTANCE FROM A MULTIPLE DOSE CLINICAL TRIAL OF GS-9451, A NOVEL NS3 PROTEASE INHIBITOR
Authors: K.A. Wong, A. Bae, K. Ku, H. Dvory-Sobol, J. Waters, M.D. Miller, H. Mo
Journal: Journal of Hepatology (2011)
Intestinal Expression of Interleukin 9 (IL-9) Induces Mast Cell-Mediated Intestinal Permeability
Authors: K.R. Groschwitz, E.E. Forbes, E.B. Brandt, R. Ahrens, F.D. Finkelman, P. Abonia, M.E. Rothenberg, S.P. Hogan
Journal: Journal of Allergy and Clinical Immunology (2007)
Abstract 491: Endoglin suppresses prostate cancer invasion through two distinct type II TGF-β receptors
Authors: Michael J. Breen, Diarmuid M. Moran, Raymond C. Bergan
Journal: Cancer Research (2012)

Abstract Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. Death from PCa results from the development of metastatic disease, yet the processes underlying progression from localized to invasive and ultimately metastatic disease remain poorly understood. Our group has previously shown that endoglin, an auxiliary TGF-β superfamily receptor, is lost with PCa progression. Restoration of endoglin expression inhibits PCa cell migration, invasion, and metastasis in pre-clinical models. Endoglin-mediated suppression of PCa invasion (EMSI) is mediated through the type I TGF-β receptor ALK2 and the downstream effector Smad1. Given that TGF-β signaling minimally requires both a type I and a type II TGF-β receptor (RII), we sought to determine the RII(s) involved in EMSI. We now show that silencing of either the type IIA activin receptor (ActRII) or the type II bone morphogenic protein receptor (BMPRII) abrogates endoglin's invasion suppressive effects. Surprisingly, ActRII and BMPR2 have opposite effects on downstream Smad1 signaling: ActRII promotes basal and endoglin-mediated Smad1 transcriptional activity dependent on its kinase domain, while BMPR2 suppresses Smad1 transcriptional activity independent of its kinase domain but dependent on its cytoplasmic tail. Moreover, we show that engagement of distinct BMP-responsive R-Smads (i.e. Smad1, Smad5, &amp; Smad8) does not account for differential signaling and confirm that Smad1 is the main mediator downstream of endoglin. We posit the existence of two parallel pathways that are required for EMSI: an ActRII / ALK2 / Smad1 pathway and a second, as-yet-uncharacterized pathway involving BMPR2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 491. doi:1538-7445.AM2012-491
Isolation of Chlamydia trachomatis from the liver of a patient with prolonged fever.
Authors: M Dan, L D Tyrrell, G Goldsand
Journal: Gut (1987)

Chlamydia trachomatis was isolated from liver biopsy specimens on two separate occasions in a young, sexually inactive patient with a 10 month history of recurrent episodes of fever, chills, and abdominal pain. Liver function tests showed a five fold increase in alkaline phosphatase, and a 20 fold increase in 59-nucleotidase. Liver histology changes consisted of mild inflammatory infiltrates in the portal tracts. Treatment with doxycycline was followed by complete recovery. We are not aware of any previous report describing isolation of this organism from the liver parenchyma, or of C trachomatis infection presenting as fever of obscure origin.
Lp(a) Lipoprotein Redux — From Curious Molecule to Causal Risk Factor
Authors: Sekar Kathiresan
Journal: New England Journal of Medicine (2009)

Lp(a) lipoprotein, which was initially described in 1963,1 is a circulating macromolecule consisting of a low-density lipoprotein (LDL) particle that is covalently linked to a protein called apolipoprotein(a). Plasma Lp(a) lipoprotein has been proposed as a risk factor for coronary artery disease.2 Lp(a) lipoprotein is an unusual molecule in that concentrations of it vary widely among human populations (e.g., there is a marked increase in persons of African and South Asian ancestry), and more than 90% of this variability is determined by inherited DNA sequence variation. A key unresolved question has been whether an elevated plasma level of Lp(a) lipoprotein . . .
Ragaglitazar Improves Glycemic Control and Lipid Profile in Type 2 Diabetic Subjects
Authors: Mohammed F. Saad, Susan Greco, Kwame Osei, Andrew J. Lewin, Christopher Edwards, Margarita Nunez, Rickey R. Reinhardt
Journal: Diabetes Care (2004)

OBJECTIVE—Ragaglitazar is a novel insulin sensitizer with dual peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-α stimulating activities that improve plasma glucose and lipid profiles. The aim of the present dose-ranging study was to assess the efficacy and safety of ragaglitazar in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—This study included 177 hypertriglyceridemic type 2 diabetic subjects who participated in a 12-week, double-blind, parallel, randomized, placebo-controlled dose-ranging study (open pioglitazone arm). Subjects received ragaglitazar (0.1, 1, 4, or 10 mg), placebo, or pioglitazone (45 mg). Efficacy parameters included fasting plasma levels of triglycerides and glucose (FPG) along with other lipid levels, A1C, and insulin. RESULTS—Ragaglitazar in doses of 1, 4, and 10 mg resulted in a significant decrease from baseline as compared with placebo in FPG (−48, −74, −77 mg/dl) and triglycerides (−40, −62, −51%), free fatty acids (−36, −54, −62%), apolipoprotein B (−13, −29, −25%), LDL cholesterol (−14 and −19% for 4- and 10-mg groups), and total cholesterol (−16 and −15% for 4 and 10 mg) and a significant increase in HDL cholesterol (20 and 31% for 1- and 4-mg groups, respectively). Changes in triglycerides and FPG for pioglitazone treatment were similar to 1 mg ragaglitazar. Mean A1C values of the 1-, 4-, and 10-mg ragaglitazar and pioglitazone groups were significantly reduced compared with placebo (−0.5, −1.3, −1.1, and −0.3%, respectively). Common adverse events were edema, weight increase, leukopenia, and anemia. CONCLUSIONS—Ragaglitazar provided glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided significant improvement in the lipid profile.
EFFICACY OF PRIMARY STENTING FOR AORTO-ILIAC ARTERY DISEASE
Authors: Yoshimitsu Soga, Daizo Kawasaki, Kenji Suzuki, Hirano Keisuke, Ryoji Koshida, Jyunichi Tasaki, MIchiaki Higashitani, Yoshiaki Shintani, Terutoshi Yamaoka, Suematsu Nobuhiro, Hiroki Takahashi
Journal: Journal of the American College of Cardiology (2012)
Squamous Cell Carcinoma of the Nail Bed
Authors: Peter I. Long
Journal: JAMA (1978)

PRIMARY carcinoma originating in the nail bed is a rare disease, with only 53 biopsy-proved cases to date. Thirtyseven cases have been classified as squamous cell carcinoma,<sup>1</sup>ten as Bowen's carcinoma in situ,<sup>2,3</sup>and six as basal cell carcinoma.<sup>4</sup>Nineteen of the cases have been reported in the last ten years (35% of the total). We present the 38th reported case of primary squamous cell carcinoma. Physicians should be aware of the possibility of carcinoma existing in chronic inflammatory nail lesions. <h3>Report of a Case</h3> An 86-year-old man was admitted to the Veterans Administration Hospital, Dayton, Ohio, on Feb 7, 1977. He complained of pain under the right thumbnail and of loss of a portion of the nail for two years. The onset of symptoms was gradual, and he was certain that he had not injured his thumb. The patient felt that there was "something" under the nail.
RUNX1–ETO deregulates the proliferation and growth factor responsiveness of human hematopoietic progenitor cells downstream of the myeloid transcription factor, MYCT1
Authors: K Liddiard, A K Burnett, R L Darley, A Tonks
Journal: Leukemia (2011)

To elucidate mechanisms by which RUNX1–ETO, the common acute myeloid leukemia t(8;21) fusion protein, primes hematopoietic cells for oncogenic transformation, we previously carried out Affymetrix gene expression profiling of RUNX1–ETO-expressing human CD34+ progenitor cells. We identified the MYC target gene, MYCT1, as a gene significantly upregulated at an early developmental stage that could be integral to RUNX1–ETO-mediated leukemic phenotype. To determine whether increased MYCT1 expression recapitulates the RUNX1–ETO phenotype, we performed retroviral transduction of MYCT1 as a single molecular abnormality into hematopoietic cell lines and normal human cord blood-derived CD34+ progenitor cells. In the absence of commercially available MYCT1 antibody, retroviral expression vectors, containing full-length MYCT1 coding sequence with (MYCT1-HA) or without (MYCT1) the addition of a C-terminal HA antigen tag, were also generated (Supplementary Materials and methods and Supplementary Figure S1), and transgenic MYCT1 over-expression was confirmed at the mRNA and protein levels (Supplementary Figure S2). Functional validation (Supplementary Figure S3) was provided by replication of the reduced viability of MYCT1-expressing murine myeloid 32D cells in the absence of WEHI-3B-conditioned medium reported by Yin et al.
Doxycycline-lnduced Esophageal Ulcers in Physicians
Authors: Arthur D. Shiff
Journal: JAMA (1986)

To the Editor.—  In a one-week period I saw two physicians who developed severe odynophagia after ingesting doxycycline late in the evening before going to sleep. Both had taken it by means of self-prescription for acne, and both had normal esophagograms. Because of persistence of symptoms, endoscopy was performed, which revealed deep ulcerations in the midesophagus. The patients became asymptomatic after antacid therapy and a soft diet.  It has been recommended that tetracyclines be taken with large quantities of water to prevent stasis in the esophagus with resultant ulceration. Such is known to occur especially when the medication is taken at bedtime. 1,2 Many physicians are also taking doxycycline before traveling to developing countries to reduce the risk of traveler's diarrhea. Due to the easy accessibility and perhaps increased utilization of this medication, physicians should be aware of the potential for esophageal ulceration especially if the medication is taken at
Type-Dependent Integration Frequency of Human Papillomavirus Genomes in Cervical Lesions
Authors: Svetlana Vinokurova, Nicolas Wentzensen, Irene Kraus, Ruediger Klaes, Corina Driesch, Peter Melsheimer, Fjodor Kisseljov, Mattias Dürst, Achim Schneider, Magnus von Knebel Doeberitz
Journal: Cancer Research (2008)

Chromosomal integration of high-risk human papillomavirus (HR-HPV) genomes is believed to represent a significant event in the pathogenesis of cervical cancer associated with progression from preneoplastic lesions to invasive carcinomas. This hypothesis is based on experimental data suggesting that integration-dependent disruption of HR-HPV E2 gene functions is important to achieve neoplastic transformation and on clinical data gathered by analyzing lesions induced by human papillomavirus (HPV) 16 and 18 that revealed integrated viral genome copies in the vast majority of cervical cancer cells. However, a substantial fraction of cervical cancers is associated with other HR-HPV types for which virtually no data concerning their integration status have been reported so far. Here, we compared integration frequencies of the five most common oncogenic HPV types (HPV16, 18, 31, 33, and 45) in a series of 835 cervical samples using a specific mRNA-based PCR assay (Amplification of Papillomavirus Oncogene Transcripts). Most precancerous lesions displayed exclusively episomal viral genomes, whereas 62% of the carcinomas had integrated viral genomes. However, the frequency of integrated HR-HPV genomes showed marked differences for individual HR-HPV types. HPV16, 18, and 45 were found substantially more often in the integrated state compared with HPV types 31 and 33. The analysis of the median age of patients with high-grade precancerous lesions and invasive cancers suggests that precancers induced by HPV types 18, 16, and 45 progress to invasive cervical cancer in substantially less time compared with precancers induced by HPV types 31 and 33. These findings suggest that integration of oncogenic HPV genomes in cervical lesions is a consequence rather than the cause of chromosomal instability induced by deregulated HR-HPV E6-E7 oncogene expression. Distinct HR-HPV types apparently provoke chromosomal instability in their host cells to a different extent than is reflected by their integration frequencies in advanced lesions and the time required for CIN 3 lesions to progress to invasive cancer.