tbuckley/cabot-search huggingface dataset:
Abstract P1-07-02: Significance of RB-ZEB axis in EMT phenotype of breast cancer and inhibition of ZEB by CDK4/6 inhibitor
Authors: Y Arima, M Hosonaga, H Saya
Journal: Cancer Research (2013)

Abstract The retinoblastoma protein (pRB) is a key tumor suppressor that regulates the progression of cell cycles from G1 to S phase. pRB is often inactivated due to mutation, very low level expression or hyperphosphorylation by cyclin-dependent kinases (CDKs) in many cancers. We found that knockdown of pRB induced the expression of ZEB1 (zinc finger E-box binding homeobox 1), which is one of the transcriptional repressors of the E-cadherin gene, and led to epithelial-mesenchymal transition (EMT) through the ZEB-dependent pathways in breast cancer cells. EMT is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype, and is associated with an invasive and metastatic potential in cancers. We found that siRNA-mediated depletion of ZEB in pRB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial-cell marker expressions. We also found that knockdown of ZEB1 reduced the dissemination of breast cancer cells in bone marrow from primary tumors growing in mammary fat pads of nude mice. We then conducted a screen with an existing drug library for inhibitors of ZEB1 expressions and identified several hits, including CDK inhibitors. We confirmed that the CDK4/6 inhibitor, Palbociclib (PD0332991), suppressed breast cancer cell proliferation and invasiveness in vitro, and the treatment with the PD0332991 suppressed tumor growth in vivo using an orthotopic xenograft breast cancer model. In terms of cancer stemness, we found that the treatment of PD0332991 decreased the CD44+/CD24Low/- breast cancer stem cell population. We also determined that CDK4 inhibitors blocked tumorsphere formations, which are a characteristic of stem-like cancer cells. p16INK4a (p16) is an endogenous CDK4/6 inhibitor, and we found that knockdown of p16 increased the CD44+/CD24Low/- breast cancer stem cell population in estrogen receptor-negative breast cancer. CDK4/6 inhibitors appear to substitute for the p16 functions which suppress cancer stemness. Our findings indicate that the CDK4/6 inhibitor affects tumor progression, not only through cell cycle control, but also through the suppression of EMT and stem-like properties of cancer cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-07-02.
Role of nitric oxide in reactive hyperemia in human forearm vessels.
Authors: T Tagawa, T Imaizumi, T Endo, M Shiramoto, Y Harasawa, A Takeshita
Journal: Circulation (1994)

BACKGROUND The role of nitric oxide (NO) in reactive hyperemia (RH) is not well known. We investigated whether NO plays a role in RH in human forearm vessels by examining the effects of NG-monomethyl-L-arginine (L-NMMA), a blocker of NO synthesis, on reactive hyperemic flow. METHODS AND RESULTS Forearm blood flow (FBF) was measured by strain-gauge plethysmography with a venous occlusion technique. The left brachial artery was cannulated for drug infusion and direct measurement of arterial pressure. To produce RH, blood flow to the forearm was prevented by inflation of a cuff on the upper arm to suprasystolic pressure for intervals of 3 and 10 minutes. After the release of arterial occlusion (AO), FBF was measured every 15 seconds for 3 minutes. Resting FBF was 4.3 +/- 0.3 mL.min-1.100 mL-1 before 3 minutes of AO and 4.1 +/- 0.6 mL.min-1.100 mL-1 before 10 minutes of AO. FBF increased to 32.3 +/- 1.9 and 38.2 +/- 3.1 mL.min-1.100 mL-1 immediately after 3 and 10 minutes of AO, respectively, and gradually decayed (n = 13). Intra-arterial infusion of L-NMMA (4 mumol/min for 5 minutes) decreased baseline FBF (P &lt; .01) without changes in arterial pressure. L-NMMA did not affect the peak reactive hyperemic FBF after 3 and 10 minutes of AO. L-NMMA significantly decreased total reactive hyperemic flow (flow debt repayment) by 20% to 30% after 3 and 10 minutes of AO. Simultaneous infusion of L-arginine (a precursor of NO) with L-NMMA reversed the effects of L-NMMA. CONCLUSIONS Our results suggest that NO plays a minimal role in vasodilation at peak RH but plays a modest yet significant role in maintaining vasodilation after peak vasodilation. Our results also suggest that reactive hyperemia in human forearms is caused largely by mechanisms other than NO.
Anatomic Features and Surgical Strategies in Double-Outlet Right Ventricle
Authors: S. Kleinert, T. Sano, R.G. Weintraub, R.B.B. Mee, T.R. Karl, J.L. Wilkinson
Journal: Circulation (1997)

The objective of this study was to review anatomic features and surgical strategies in children with double-outlet right ventricle (DORV) and to assess risk factors for early mortality.Records were reviewed of all children with DORV undergoing surgery between 1978 and 1993. Noncomplex patients (group 1) had atrioventricular (AV) concordance, a single ventricular septal defect (VSD), balanced ventricles, no straddling AV valves, and no major pulmonary artery anomaly. Group 2 (complex) comprised all remaining patients. Independent risk factors analyzed included location of the main VSD, presence of additional VSDs, coarctation, ventricular outflow obstruction, ventricular hypoplasia, age at operation, operation before 1985, previous palliation, and type of definitive operation. Of 193 patients, 117 were in group 1 and 76 in group 2. In 148 patients, biventricular repair was undertaken, including 111 of 117 group 1 patients and 37 of 76 group 2 patients. Early mortality was higher among group 2 patients undergoing biventricular repair than among group 1 patients (8 of 37 versus 4 of 111, P<.005) and higher than group 2 patients undergoing a Fontan procedure (none of 29, P<.01). Aortic arch obstruction, operation before 1985, and multiple VSDs were significant risk factors for mortality. Age <1 month (P<.05) and multiple VSDs (P<.005) were independent risk factors after definitive repair. Up-to-date follow-up is available on 144 surviving patients, with 127 (88%) in New York Heart Association class I and the remaining 17 in class II. Overall 10-year survival probability was 81%, whereas probability of survival, free from reoperation (after definitive surgery), was 65% at 10 years.Biventricular repair can be achieved in most patients with DORV with low risk. In complex DORV, a Fontan procedure is associated with a lower surgical mortality.
Dosimetry of Technetium-99m Red Blood Cells Labeled in Vivo
Authors: JAMES A. PONTO
Journal: Clinical Nuclear Medicine (1988)

Mean organ doses received from Tc-99m red blood cells labeled in vivo were calculated by the MIRD method using biodistribution data reported in the literature. The organ receiving the greatest dose was found to be the heart, followed closely by the bladder and stomach. Relatively high doses are also received by the blood, spleen, and lungs. Intermediate absorbed doses are received by the thyroid and kidneys, whereas organs with small blood concentrations and the remainder of the body receive the smallest doses. The major portion of the absorbed doses delivered to the stomach and the thyroid is due to the presence of free pertechnetate.
Alternative prescribing and negligence
Authors: D. R Blake
Journal: BMJ (2003)

Negligence is the lack of proper care and attention; carelessness or an act of carelessness. A negligent act may be of no consequence. It may be of the utmost consequence and for the licensed medical profession, a negligent act can lead to criminal charges and removal of your name from the Medical Register. We are trained to avoid negligence and are now regularly audited to ensure this. Fear of negligence determines much of modern medical practice. Are similar standards applied to others?

> There would have been no form of redress if the treatment had failed 

My story concerns an alternative medical practitioner/pharmacist, an example of the kind of non-traditional practitioner, with apparent training in holistic medicine, that the House of Lords and other bodies have recommended.

It was a damp Friday evening when I set out from a lecture to return on the train to Bath. Walking along the crowded pavements I was troubled once again by a recurrent low back pain, a longstanding complaint relieved …
he loved my son's smile
Authors: Peter Manu
Journal: Annals of Internal Medicine (2007)

Ad Libitum1 May 2007he loved my son's smilePeter Manu, MDPeter Manu, MDFrom Syosset, NY 11791.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-146-9-200705010-00006 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail of course a busy ... Author, Article, and Disclosure InformationAffiliations: From Syosset, NY 11791.Current Author Address: Peter Manu, MD, 201 Fen Way, Syosset, NY 11791. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 2007Volume 146, Issue 9Page: 639 ePublished: 1 May 2007 Issue Published: 1 May 2007 Copyright & PermissionsCopyright © 2007 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study
Authors: C. L Mollerup
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Aim</b>: To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery. <b>Design</b>: Register based, controlled retrospective follow up study. <b>Setting</b>: Tertiary hospitals in Denmark. <b>Participants</b>: 674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed. <b>Main outcome measures</b>: Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones. <b>Results</b>: Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones. <b>Conclusions</b>: The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.
Gastroduodenal damage induced by anti-inflammatory drugs: Authors' reply
Authors: R S B Ehsanullah, M C Page, J R Wood, G Tildesley
Journal: BMJ (1988)

causing low output and death.In the remaining 21 patients the cause of death was unrelated to mechanical valve failure.All of the patients in whom this phenomenon of triangulation of the aortic root was noted had undergone aortic valve replacement using the Starr-Edwards model No 2320, in which the three cage struts are cloth covered.This model was discontinued in 1976 and the current models use three stellite struts without the cloth covering.While the older models probably had greater potential to cause outflow obstruction with incorporation of the cloth covered struts into the aortic wall, the tendency to cause triangular deformity with this style of valve prosthesis remains.Although the risk of acute failure and the operative mortality associated with artificial heart valves are small, the medium and long term morbidity is not negligible.Current mechanical prostheses may well prove superior to those used previously but they are not trouble free.Conservative valve reconstruction needs to be encouraged.
Mechanical factors and patellofemoral osteoarthrosis.
Authors: B B Seedholm, T Takeda, M Tsubuku, V Wright
Journal: Annals of the Rheumatic Diseases (1979)

This paper investigates the possible role of mechanical stress in the development of the osteoarthrotic lesions frequently observed in the patellofemoral compartment of the knee joint. First the location of these destructive lesions was determined by studying the location and pattern of contact in the patellofemoral joint. The study was carried out on 39 cadaveric knees for the range of flexion 0 degrees -120 degrees. It was shown that the lesions were localised to the areas corresponding to the range of flexion 40 degrees -80 degrees. These areas have been shown to be subjected to a low stress for most of the time and to a much higher stress for only part of the time. This mode of stressing this area of the cartilage is a consequence of the style of life of the average Western man in which the most predominant activity is level walking, during which the load and in turn the stress are much lower than they are during other ambulatory activities such as ramp and stair ascent and descent. The same area of the cartilage seems to be subject to a similar mode of stress during sedentary occupations. It is suggested that this mode of stressing the cartilage conditions it chemically, and hence mechanically, to transmit low stresses, so that when the much less frequent but higher stresses are applied it cannot transmit them without sustaining some damage.
Endothelin antiserum decreases volume-stimulated and basal plasma concentration of atrial natriuretic peptide.
Authors: F Fyhrquist, M L Sirviö, K Helin, O Saijonmaa, K Metsärinne, I Paakkari, A Järvinen, I Tikkanen
Journal: Circulation (1993)

BACKGROUND Endothelin-1 (ET-1) is the most powerful factor known to release atrial natriuretic peptide (ANP) in vivo and in cultured cardiac myocytes or preparations of atrium. We tested the role of endogenous ET-1 in the regulation of ANP release by passive immunization in anesthetized rats. METHODS AND RESULTS Intravenous injection of antiserum against ET-1 was shown to decrease basal and volume-stimulated plasma concentrations of ANP, whereas control serum was without effect. Antiserum generated in rabbits cross-reacted 100% with endothelin-2 and -3. In pentobarbital-anesthetized Wistar rats treated with ET-1 antiserum, plasma ANP concentration measured by radioimmunoassay was reduced by 37% from starting level after 10 minutes and by 30% after 60 minutes. Control rat serum had no effect on plasma ANP. Rapid intravenous infusion of 8 mL of 0.9% NaCl caused a sixfold increase of plasma ANP concentration in control rats but only twofold in rats pretreated with ET-1 antiserum (P &lt; .01). This effect of ET-1 antiserum was dose dependent. ET-1 antiserum changed neither blood pressure nor heart rate significantly in anesthetized rats. Pretreatment with ET-1 antiserum did not affect the initial hypotensive response to intravenous ET-1 0.5 nmol/kg but significantly attenuated the subsequent hypertensive response to endothelin. CONCLUSIONS Endothelin may be a physiological modulator of both basal and stimulated ANP release.
Potential endocervical pathogens before termination.
Authors: A. L. Blackwell, K. Wareham, S. J. Emery, P. D. Thomas
Journal: BMJ (1992)

Potential endocervical pathogens before termination EDITOR, -Mike Cohn and Peter Stewart report the prevalence of potential pathogens in the cervical canal before termination ofpregnancy.'An associa- tion between one of these pathogens (Chlamydia trachomatis) and increased morbidity after termination of pregnancy has also been reported.24We recently conducted an audit of the effect of screening for C trachomatis (MicroTrak, Syva) and treatment in women seeking termination of pregnancy at Taunton and Somerset Hospitals.We
Strategies in developing promising histone deacetylase inhibitors
Authors: Lei Zhang, Hao Fang, Wenfang Xu
Journal: Medicinal Research Reviews (2009)

Abstract Histone deacetylases (HDACs) are a family of enzymes that have been of interest in drug discovery for more than 30 years. Inhibitors of HDACs are potential therapeutics for various diseases, such as neurodegenerative diseases, inflammation, viral infection, and especially cancer. Most HDAC inhibitors (HDACi) are designed for cancer therapy. In 2006, suberoylanilide hydroxamic acid was approved by the US Food and Drug Administration for once‐daily oral treatment of advanced cutaneous T‐cell lymphoma. In the meantime, there have been aggressive efforts to bring HDACi to the market for every major tumor type, either as a single therapy or in combination, and a number of compounds are currently undergoing clinical trials. Multiple strategies have been applied to the rational design of drugs targeting HDACs by taking advantage of the new developments in proteomics, chemogenomics, cheminformatics, and computational chemistry/biology. Herein, we review the current methods successfully used in developing novel HDACi. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 4, 585–602, 2010
Psychosomatic Inter-Relationships in the Management of Childhood Asthma
Authors: P. Pinkerton
Journal: Psychotherapy and Psychosomatics (1971)

Selected case extracts are presented on video tape to illustrate the thesis that management and after care in childhood asthma is not only determined by the degree of pathophysiologic impairment in any given case, but also by the type of psychogenetic contribution both in terms of interpersonal relationship and the patient's intrapsychic structure. The conclusion which emerges is that, while asthma in childhood is a genetically determined disorder based upon immuno-physiologic vulnerability of the bronchial system, emotional factors may profoundly influence the therapeutic response and, therefore, justify detailed study and analysis.
Is liver cancer a stem cell—derived disease?
Authors: Ronald A. Faris, Douglas C. Hixson
Journal: Hepatology (1994)

In transgenic mice bearing the Simian Virus 40 large T antigen under the control of the human anti–thrombin III regulatory sequences, a step–wise progression toward hepatocellular carcinoma is observed. We have used two monoclonal antibodies (A6 and G7) developed against a surface antigen expressed in oval cells from dipin–treated mice, to analyze the emergence of such preneoplastic populations in the livers of anti–thrombin III Simian Virus 40 T transgenic mice. We show that a unique population of small heterogenous epithelial cells, which probably corresponds to oval and/or transitional cells according to their morphological features, consistently appears at approximately the 10th week after birth and proliferates thereafter. This oval cell–like population stained positively for A6 and G7 monoclonal antibodies. Furthermore, different subpopulations usually recognized as possible precursors of carcinoma cells including hyperplastic foci and neoplastic nodules as well as carcinoma cells, were also positive for A6 but not G7 monoclonal antibodies. Stimulation of cell proliferation by partial hepatectomy performed at the time of emergence of the oval–like cells resulted in a rapid increase in the number of oval/transitional A6–positive cells. Our findings support the view that a common mechanism may be involved in the development of carcinomas that are induced by chemical carcinogens and in transgenic mice expressing a potent oncogene under the control of a hepatic specific promoter. In addition, our findings demonstrate a specific precursor–product relationship between the appearance of the oval/transitional cells and the development of neoplastic hepatocytes in this transgenic model.
Hospital bed utilisation in the NHS and Kaiser Permanente
Authors: Margaret E Allen
Journal: BMJ (2004)

Editor—It took 35 clinicians and managers, travelling to and staying in California, to discover that the NHS can learn from Kaiser's approach to day bed use.1

I have been a Kaiser patient, have recently spent a year working in the NHS, and have now returned to work as a family practice mid-level clinician in the Medicare system in California. I could have told you for a fraction of the cost that beds are managed tightly here, with support from more cost effective support services, a more practical philosophical lifestyle approach, and less turf protection among doctors than in the NHS.

Money is not only being wasted on kind but absurd day bed use in the United Kingdom but also on junkets to California, New York, Minnesota, and Louisiana by NHS staff looking for solutions to the NHS workforce crisis.

Well trained, mid-level providers, such as the inaccurately named physician assistants, could tap a reservoir of skill and experience available to augment the inadequate NHS workforce. Accessing this group would not take staff away from nursing but would take advantage of ethnic and gender diversity. A national programme of training, evaluation, and registration could be set up quite easily, and physician assistants added to the NHS workforce in a comparatively short time, providing continuity on the wards, and liaison with general practitioners.
TCT-170 Cost-effectiveness Analysis Of Left Atrial Appendage Occlusion Device Compared With 7 Oral Anticoagulants For Stroke Prevention In Atrial Fibrillation
Authors: Vivian W. Lee, Bryan Yan, Ines Chow, Ping Ching Tsai, Yat-Yin Lam
Journal: Journal of the American College of Cardiology (2014)
Eczema Vaccinatum — A Timely Reminder
Authors: Allon E Moses, Ronit Cohen-Poradosu
Journal: New England Journal of Medicine (2002)

Figure 1. Ten days after being vaccinated against smallpox, a 27-year-old man was hospitalized with a high fever, facial edema, and an umbilicated, vesicular, crusting rash on his face, neck, upper chest, and hands (Panel A). He had a history of atopic dermatitis. Eczema vaccinatum was diagnosed. As the vesicular rash became disseminated, supraglottic edema with shortness of breath developed. The patient was transferred to the intensive care unit and received vaccinia immune globulin and supportive care. Over the next two weeks extensive crusting of the facial lesions occurred (Panel B). Cultures of vesicular fluid grew vaccinia virus, and skin . . .
The elusive physiologic role of Factor XII
Authors: Alvin H. Schmaier
Journal: Journal of Clinical Investigation (2008)

Physiologic hemostasis upon injury involves many plasma proteins in a well-regulated cascade of proteolytic reactions to form a clot. Deficiency of blood coagulation Factors VIII, IX, or XI is associated with hemophilia. Factor XII (FXII) autoactivates by contact with a variety of artificial or biologic negatively charged surfaces (contact activation), resulting in blood coagulation and activation of the inflammatory kallikrein-kinin and complement systems. However, surprisingly, individuals deficient in FXII rarely suffer from bleeding disorders. Most biologic surfaces that activate FXII become expressed in disease states. Investigators have long searched for physiologic activators of FXII and its role in vivo. In this issue of the JCI, Maas et al. show that misfolded protein aggregates produced during systemic amyloidosis allow for plasma FXIIa and prekallikrein activation and increased formation of kallikrein–C1 inhibitor complexes, without Factor XIa activation and coagulation (see the related article beginning on page 3208). This study describes a novel biologic surface for FXII activation and activity, which initiates inflammatory events independent of hemostasis.