tbuckley/cabot-search huggingface dataset:
249. Fusion Intrabodies as Anti-Huntington Gene Therapy
Authors: Julie McLear, Jack Webster, Nikolas Webster, Anne Messer
Journal: Molecular Therapy (2006)

Huntington's Disease (HD) is an autosomal-dominant single gene mutation resulting in a polyglutamine repeat expansion. Pathology results from 37 or more copies of the CAG trinucleotide repeat, with age of onset being inversely related to the number of repeats. Symptoms, usually beginning at mid-life, include motor dysfunction, cognitive and emotional disturbances. Misfolding of the huntingtin protein and formation of high molecular weight molecules have been correlated with brain pathology in humans and mouse models of the disease. Intracellularly expressed single-chain Fv (scFv) antibodies (intrabodies) were engineered to bind adjacent to the expanded polyglutamine, in order to inhibit the pathogenic effects of misfolded mutant huntingtin protein. Intrabodies are small, have a high affinity to antigen and produce a lower immune response compared to traditional extracellular antibodies. Their characteristic increased specificity and potential for genetic engineering make them an ideal candidate for gene therapy. Engineered intrabodies specific for huntingtin have been characterized and show potential in vitro and in vivo, but rescue is incomplete. In order to increase efficacy in vivo, novel fusion intrabodies have now been engineered. Wildtype huntingtin is predominantly localized to the cytoplasm. However, the mutant form, particularly N-terminal fragments, is often nuclear. A nuclear export signal (NES) was recently discovered on the carboxyl-terminus of huntingtin, suggesting that huntingtin can shuttle between the nucleus and cytoplasm. It has been suggested that the NES is lost in mutant huntingtin. Therefore, in order to maintain huntingtin in the cytoplasm, we have introduced intrabody with either an N or C terminal NES. Preliminarily, N terminal NES- intrabody showed reduction of aggregates in 3 cell lines, making this a promising intervention. Previous studies suggest that overexpression of the molecular chaperone, heat shock protein 70 (HSP 70), reduces poly Q aggregation in vitro. HSP 70 was therefore fused to intrabody to determine if aggregation was reduced when compared to intrabody expression alone. In cultures, intrabody-HSP 70 fusion protein reduced aggregates more effectively than intrabody or HSP 70 alone, or dual transfections of the two plasmids as separate constructs. Once efficacy of the novel fusion proteins has been further established in vitro, the most promising of these fusion intrabodies will be packaged into viral vectors. The infection and transformation of neurons will be analyzed for reduction of huntingtin pathology. This approach of using fusion intrabodies to counteract the effects of misfolded proteins that are the first step in neurodegeneration is applicable to a series of disorders, including Alzheimer's, Parkinson's, and prion diseases. This work is supported by the High Q Foundation and NIH.
How did he learn to speak Russian?
Authors: I. D Conacher
Journal: BMJ (2009)

At the international congress conference dinner, the seating plan had been really mixed. Opposite me sat a husband and wife from the United States. This was their second visit to Europe. Small talk? Not much and exhausted before the soup. On my left was a softly spoken, elderly German whose English was hard work, bearing in mind that my German was non-existent: niceties were over before the soup. On my right sat a Russian who, I surmised, had to be reasonably fluent in the conference …
1024. An Oncolytic Conditionally Replicating Adenovirus for Hormone-Dependent and Hormone-Independent Prostate Cancer
Authors: Wing-Shing Cheng, Helena Dzojic, Berith Nilsson, Thomas H. Totterman, Magnus Essand
Journal: Molecular Therapy (2005)

The use of conditionally replicating adenoviruses offers an attractive complementary treatment strategy for localized prostate cancer. We have produced a replicating adenovirus, Ad[I/PPT-E1A], where E1A gene expression is controlled by a recombinant regulatory sequence designated PPT. The PPT sequence comprises a PSA enhancer, a PSMA enhancer and a TARP promoter and it is shielded from transcriptional interference from adenoviral backbone sequences by an H19 insulator. Ad[I/PPT-E1A] yields prostate-specific E1A protein expression, viral replication and cytolysis in vitro. Furthermore, Ad[I/PPT-E1A] considerably regresses the growth of subcutaneous LNCaP prostate tumors in nude mice. Importantly, viral replication and cytolytic effect of Ad[I/PPT-E1A] are independent on the testosterone levels in the prostate cancer cell. This may be beneficial in a clinical setting since many prostate cancer patients are treated with androgen withdrawal. In conclusion, Ad[I/PPT-E1A] may prove to be useful in the treatment of localized prostate cancer.
Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche
Authors: Hayley Davis, Shazia Irshad, Mukesh Bansal, Hannah Rafferty, Tatjana Boitsova, Chiara Bardella, Emma Jaeger, Annabelle Lewis, Luke Freeman-Mills, Francesc C Giner, Pedro Rodenas-Cuadrado, Sreelakshmi Mallappa, Susan Clark, Huw Thomas, Rosemary Jeffery, Richard Poulsom, Manuel Rodriguez-Justo, Marco Novelli, Runjan Chetty, Andrew Silver, Owen J Sansom, Florian R Greten, Lai Mun Wang, James E East, Ian Tomlinson, Simon J Leedham
Journal: Nature Medicine (2014)
CARBONIC ACID AN INDEX OF DANGER IN GIVING CHLOROFORM, AND HOW TO LESSEN THE DANGER.
Authors: THOMAS R. EVANS
Journal: JAMA (1892)

We assume in this brief paper, from several analogies, that the activity of the respiration as shown by the amount of CO<sub>2</sub>exhaled, is an index of danger in administering chloroform, and renders the production of anæsthesia more difficult. Hence, we argue the comparative safety and ease of administration to weakly persons, and the danger and frequent difficulty to the mechanic. For this reason doubtless its safety in military life has been much overrated. The more muscle the more C0<sub>2</sub>generated, greater seems the danger, and greater the amount of chloroform required. The latter statement is well proven in dogs and rabbits, they being chloroformed with much difficulty. The majority of deaths from chloroform are probably superinduced by asphyxia, not, however, commencing in the lungs, as the older physiologists taught, but in the systemic capillaries. We will consider the administration of chloroform, with respect to greater safety, under the conditions
The Culdotomy FourS Two U procedure for transvaginal access to the peritoneal cavity
Authors: M. Tanaka, T. Sagawa, M. Hashimoto, Y. Mizumoto, H. Yoshimoto, R. Yamazaki, T. Kasai, M. Inoue
Journal: Endoscopy (2009)

A reliable method of transvaginal access is needed for natural orifice transluminal endoscopic surgery. We introduce a new culdotomy procedure, using a technique for the creation of space in the cul-de-sac, transvaginal ultrasound, and a newly developed umbrella Hakko needle. An artificially developed, saline-containing space in the cul-de-sac was punctured by an umbrella Hakko needle from the vagina under the guidance of ultrasound. The vaginal walls on both sides of the needle were incised with an electric scalpel. In five cases with benign gynecological tumors, culdotomy was successfully performed. Operating time was less than 10 minutes and blood loss was less than 10 mL. There were no culdotomy-associated complications. This procedure, named Culdotomy FourS Two U, is a simple, safe, and reliable method for entry into the cul-de-sac in transvaginal gynecological surgeries and may have future applications in transluminal endoscopic surgery through the vagina.
Financing Medical Education: An Analysis of Alternative Policies and Mechanisms
Authors: John H. Lorant
Journal: JAMA (1971)

Problems of financing are not easily distinguished from those facing medical education, the US health care system, or society at large. It is not surprising that research and training grants tend to increase the emphasis on activities other than physician education. Nor is it surprising that physicians are relatively well off in matters of income, that government financial assistance varies between states, that physician location is positively correlated with population growth, or that socioeconomic groups are unevenly represented in medical school enrollment.  Neither is it startling to find that the diverse sources and effects of financing are reflected in real differences among medical schools—in terms of their wealth, student quality, mix of activities, and types of physicians graduated. As a review of existing knowledge, this factcrammed report may contain very few surprises for faculty, alumni, and students alike.  However, as an attempted synthesis—which brings common knowledge and original research to
Training Physicians: The Case of Internal Medicine
Authors: Neil S. Cherniack
Journal: JAMA (1995)

On Black Tuesday in 1987, many prestigious internal medicine residency programs failed to fill for the first time ever with US medical school graduates. This led to an intensive examination of residency training by chairpersons, deans, and others. As part of this effort, the authors launched an analysis, summarized in<i>Training Physicians</i>, to try to understand the reasons for the lack of popularity of what had been regarded (at least by internists) as the premier residency. The book draws from three diverse sources: a 17-year survey of internal medicine residency programs carried out by the University of Chicago Center for Health Administration Studies, interviews with 55 prominent internists, and a literature survey. Over the six years in which it was prepared, the authors developed larger objectives, and they attempt to use the material they gathered on internal medicine residency training to formulate insights into what has gone wrong with American
Effects of acetylsalicylic acid on the ductus arteriosus and circulation in fetal lambs in utero.
Authors: M A Heymann, A M Rudolph
Journal: Circulation Research (1976)

Intra-arterial and intravenous catheters were inserted in six fetal lambs at 125-130 days of gestation. On the following day, fetal arterial pressures and blood gases were monitored and fetal cardiac output and its distribution were measured by injection of radionuclide-labeled microspheres 15 mum in diameter. Acetylsalicylic acid, 55-90 mg/kg of estimated fetal weight, then was administered into the fetal stomach. Fetal pulmonary arterial pressure rose significantly after an average of 58 minutes, increasing the pressure difference between the pulmonary artery and the aorta from 2 +/- 0.3 (SEM) mm Hg during control to 11.2 +/- 1.6 mm Hg. Resistance across the ductus arteriosus rose from 4.2 +/- 0.5 (SEM) to 27.4 +/- 4.01 units, and flow fell from 495 +/- 44 (SEM) to 409 +/- 20 ml/minute. The proportion of combined ventricular output distributed to the placenta, adrenals, heart, and lungs increased, whereas the proportion of combined ventricular output distributed to the brain, liver, intestine, kidneys, and upper and lower body fell. In two fetuses infusion of prostaglandin E1 reversed the pulmonary hypertension. Inhibition of prostaglandin synthesis in fetal lambs produced constriction of the ductus arteriosus and redistribution of cardiac output. It is probable that prostaglandins, particularly E1, are involved in regulation of blood flow through the ductus arteriosus and various vascular beds in the normal resting fetus.
Abstract 162: Biomarker identification of residual triple negative breast cancer (TNBC) after standard neoadjuvant chemotherapy (NCT)
Authors: Joohyuk Sohn, Shuyling Liu, Huiqin Chen, Xiaolong Meng, Kim-Anh Do, Gordon B. Mills, Gabriel N. Hortobagyi, Funda Meric-Bernstam, Ana M. Gonzalez-Angulo
Journal: Cancer Research (2012)

Abstract Backgrounds Residual TNBC after standard NCT has a poor prognosis. The aim of this study was to identify biomarkers that correlate with prognosis and can be used as novel therapeutic targets in this disease Methods 54 residual TNBC were identified. Protein was extracted and 76 antibiotics to proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPA). Univariable and multivariable Cox proportional hazard model ratios were fitted for each protein and simultaneously. Cross-validation was also performed. The coefficient in the multivariable Cox model were used to calculate a risk score (RS) for each sample. Results The unsupervised clustering analysis of the proteomic profiles for the 54 residual breast cancers and 76 proteins divided the tumors into two groups without significant survival difference. Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that IGFPB2, LKB1, and S6 were significant predictors in relapse free survival (RFS). RS model calculated based on multivariable analysis was 0.3746*IGFPB2-0.8852*LKB1+0.6012*S6, AUC=0.807. Employing crossvalidation the model was found to be reproducible. Multivariable analysis suggested that RS was an independent predictor of RFS (HR: 2.705, 95% CI 1.549 to 4.723, P-value=0.0005). Conclusions We identified a RS of three biomarkers that predict outcome in patients with residual TNBC that could be studied as therapeutic targets for this disease. 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 162. doi:1538-7445.AM2012-162
BIOLOGICAL AND PHYSICAL PROPERTIES OF THE HEMOTOXIN OF STREPTOCOCCI
Authors: Percy D. Meader, George H. Robinson
Journal: The Journal of Experimental Medicine (1920)

The hemotoxin of streptococcus is a labile substance affected by centrifugation or shaking. It is adsorbed by various organic and inorganic substances. Hemotoxin is produced within a wide range of hydrogen ion concentrations. It is neither in nor on the bacterial cell but is free in the culture medium. It is probably not an enzyme. There are at least two substances which are essential to the medium for the elaboration of hemotoxin, one of which is phosphorus; the other is a substance of unknown composition. The unknown component is present in small quantities in unfiltered muscle infusion, but is more abundantly supplied by blood serum and kidney infusion. This substance is not an albumin, globulin, primary or secondary proteose, metaprotein, or peptone of the medium or enriching fluid. It is water-soluble, is destroyed by boiling in alkaline solution and by prolonged heating, and is removed to a considerable extent by passage through a diatomaceous filter.
The protective effect of thalidomide on left ventricular function in a rat model of diabetic cardiomyopathy
Authors: Dae‐Hee Kim, Yong‐Jin Kim, Sung‐A Chang, Hye‐Won Lee, Ha‐Na Kim, Hyung‐Kwan Kim, Hyuk‐Jae Chang, Dae‐Won Sohn, Young‐Bae Park
Journal: European Journal of Heart Failure (2010)
"Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.
Authors: D T Hung, T K Vu, V I Wheaton, I F Charo, N A Nelken, N Esmon, C T Esmon, S R Coughlin
Journal: Journal of Clinical Investigation (1992)

Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were found to be specific antagonists of receptor activation by thrombin. The effectiveness of these designed antagonists in blocking thrombin-induced platelet activation suggests a model for thrombin-receptor interaction and possible strategies for the development of novel antithrombotic agents.
A SIMPLE TEST TO DIFFERENTIATE BETWEEN OBSTRUCTIVE AND OTHER TYPES OF JAUNDICE
Authors: M. A. Blankenhorn
Journal: JAMA (1931)

<h3>To the Editor:</h3> —Dr. Loewy's criticism of my recent paper on jaundice is valid criticism—if the galactose tolerance test of liver function is as good as Dr. Loewy thinks it is. My estimate of the galactose test for liver function, as shown by not mentioning it, is shared by most writers of textbooks in this country dealing with the clinical aspects of jaundice. I may mention that Osler's Modern Medicine, 1926, describes seven tests but not galactose; the Oxford System (Rolleston's Treatment of the Subject) does not mention it; Blumer's Bedside Diagnosis describes eight tests but not galactose; Oxford Monographs on Diagnosis and Treatment lists twenty-five tests, among them galactose, but makes no comment on its use or estimate of its value. In current literature of this country, the galactose test has been discussed but generally discarded. Snell, Greene and Rowntree (<i>Arch. Int. Med.</i><b>36:</b>273 [Aug.] 1925), after a
CLASSIFICATION OF MENTAL DISORDERS
Authors: G. W. T. H. Fleming
Journal: BMJ (1934)

c) Exhaustion.7. Trauma.* (a) Injuries.*(b) Operations.(c) Sun-or heat-stroke.(d) Electric shock.8. Toxic factors.'A.Chemical.(a) Alcohol.* (b) Narcotic drugs.-*(c) Mineral poisons.*(d) Other poisons.B. Infective.(a) Syphilis.(i) Congenital. (ii) _Acquired.(b) Puerperal fever.(c) Influenza.*(d) Thie specific fevers.(e) Tuberculosis.*(f) Focal sepsis.*(g) Other infections.*c.Metabolic.*9.Deficiency diseases (pellagra, beri-beri, etc.).*10.Diseases of the nervous system. 11.Diseases of other systems.*(a) Haemopoietic system.*(b) Cardiovascular system.*(c) Respiratory system.*(d) Gastro-intestinal system.*(e) Genito-urinary system.*(f) Endocrine system.12.No factor ascertained.13.No history obtained.
PERCUTANEOUS CORONARY INTERVENTION WITH HALF DOSE FIBRINOLYSIS VERSUS PRIMARY PERCUTANEOUS CORONARY INTERVENTION IN ST ELEVATION MYOCARDIAL INFARCTION: EVIDENCE FROM A META-ANALYSIS
Authors: Ramez S. Nairooz, Karam F. Ayoub, Partha Sardar, Zubair Ahmed, Tarek Helmy, H. Vernon Anderson
Journal: Journal of the American College of Cardiology (2015)
Abstract 3087: CD24 regulates tumor cell behaviour in a c-Src dependent fashion
Authors: Niko P. Bretz, Thomas Schlange, Alexei V. Salnikov, Aurelia Noske, Claudia Perne, Gerhard Moldenhauer, Glen Kristiansen, Peter Altevogt
Journal: Cancer Research (2012)

Abstract CD24 is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties like invasion, proliferation and adhesion in vitro and tumor growth in vivo. However, little is known about the mechanisms by which CD24 mediates these effects. Here we have analyzed functional consequences of CD24 knock-down or over-expression in human cancer cell lines of different tumor entities (ovarian, lung, glioma). We show that presence or absence of CD24 was crucial to regulate the amount and activity of c-Src in lipid rafts. CD24-mediated effects on tyrosine-phosphorylated c-Src had impact on regulation of target genes affecting tumor cell invasion, proliferation and apoptosis. Invasive potential of tumor cells was controlled by the expression of the tissue factor pathway inhibitor-2 (TFPI-2), a potent inhibitor of extracellular matrix degradation that can block tumor cell invasion and metastasis. Silencing of CD24 or c-Src enhanced TFPI-2 expression and diminished invasion of SKOV3ip and A549 cells into matrigelTM. Conversely, over-expression of CD24 reduced TFPI-2 expression and enhanced invasion. Furthermore, an inverse correlation between expression of CD24 and TFPI-2 was observed by immunohistochemical analysis of primary breast cancers (N = 1174). TFPI-2 expression was highest in CD24 negative samples and lowered with increasing CD24 expression. Patients with a CD24 low/TFPI-2 high phenotype showed significantly better survival compared to CD24 high/TFPI-2 low patients (p=0.001). Additionally, STAT3 expression and phosphorylation were reduced by CD24 silencing. Diminished STAT3 activity was confirmed by specific reporter assays. Src depletion abrogated levels of p-STAT3 (Y705). In line with that, expression of classical STAT3 target genes like MCL-1, Cyclin D1 and Survivin was reduced after CD24 knock-down. Suppressed cell proliferation and enhanced apoptosis were observed in CD24 knock-down cells, suggesting a pivotal role of regulated target genes. An antibody to CD24 was effective in reducing tumor growth of lung- and pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-activity in the tumor and altered expression of STAT3 target genes. Our results provide evidence that CD24 regulates TFPI-2 and STAT3 activity via the c-Src non receptor tyrosin kinase. Targeting of CD24 by antibodies could represent a novel strategy for anti tumor therapy. 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 3087. doi:1538-7445.AM2012-3087
Herpes Zoster and Neoplastic Disease
Authors: Arthur R. Rhodes
Journal: JAMA (1976)

<h3>To the Editor.—</h3> I read the case of a child with vesicular groin rash (235:2238, 1976) and the consultant's reply to the question: Should this child (with possible herpes zoster) be investigated for underlying disease? Assuming the child's rash was herpes zoster, I would like to disagree with Dr Wehrle's reply that "approximately 10% of patients with herpes zoster will have underlying problems." Available information indicates that only 1% or less of patients with localized herpes zoster (LHZ) have underlying disease. Hope-Simpson<sup>1</sup>found trauma and sinusitis were associated events in 192 patients with LHZ, but none of this group had underlying malignant disease. Of 100 patients with LHZ studied by Juel-Jensen,<sup>2</sup>none had unsuspected malignant disease, while three patients had preexisting lymphoreticular disease or carcinoma. Burgoon et al studied 206 patients with LHZ (164:265, 1957); one had lymphoblastoma. In Molin's 706 patients with LHZ,<sup>3</sup>six had malignant
Vertebral changes in ochronosis.
Authors: R Lagier, S Sit'aj
Journal: Annals of the Rheumatic Diseases (1974)

This discussion of ochronotic spinal changes is based on the post mortem examination of a 50-year-old woman who had been hospitalized for 3 years with schizophrenia and ochronosis.Clinical articular manifestations of ochronosis were present but slight in the limbs, the spine was stiff, and radiography of Accepted for publication May 17, 1973.the vertebral column showed pathognomonic ochro- notic changes. Material and methodsFrontal and sagittal planes of an anterior slice from the lumbar column were studied (T 11071/69); each fragment was x-rayed, decalcified, and embedded in celloidin (paraffin for some small pieces).(a) Posterior aspect of slice: intervertebral discs are (b) Anterior view: bony bridges join the vertebrae giving a pigmented and show penetration ofbone which may lead to bamboo aspect.Occasional islands ofpigmented cartilage vertebral ankylosing (L1-2), and to marginal bony bridges are visible on the surface, especially in spaces L3-4 and occasionally incorporating islands ofdisc (the crater seen in L4-5L3 is an artefact)