tbuckley/cabot-search huggingface dataset:
Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Authors: W A Maltese, R Defendini, R A Green, K M Sheridan, D K Donley
Journal: Journal of Clinical Investigation (1985)

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, an essential precursor for isoprenoid compounds in mammalian cells. Recent studies have shown that mevinolin, a competitive inhibitor of the reductase, inhibits cell proliferation and induces differentiation in cultured C1300 (Neuro-2A) murine neuroblastoma cells. We now report that mevinolin can inhibit neuroblastoma growth in vivo. The specific activity of HMG-CoA reductase in subcutaneous neuroblastomas increased more than 20-fold between the fifth and eighth days after tumor inoculation, and remained elevated for the remainder of the tumor lifetime in mice. The increase in reductase activity was correlated with a marked increase in tumor DNA content and exponential increase in tumor weight. Using an in vitro assay to monitor the ability of mouse serum to suppress sterol synthesis, we determined that mevinolin was inactivated or cleared from the circulation within 3-6 h after a single subcutaneous injection. However, by using subcutaneous osmotic pumps to deliver a constant infusion of mevinolin, we were able to maintain adequate blood levels of the drug for 7 d. Mevinolin (5 mg/kg per h) suppressed tumor growth (wet weight) significantly when treatment was carried out between day 1 and day 8 or between day 5 and day 12 after tumor inoculation. Histopathological examination of tumors from mevinolin-treated mice revealed few or no mitotic figures and marked cellular degeneration. Measurements of incorporation of (3H)acetate into neuroblastoma sterols and ubiquinones 24 h after implantation of osmotic pumps showed that mevinolin produced a marked inhibition of isoprenoid synthesis in the tumors in vivo. The data suggest that, in addition to their demonstrated utility as cholesterol-lowering drugs, competitive inhibitors of HMG-CoA reductase may have considerable potential as novel antineoplastic agents.
Abstract 3316: An alpha-secretase inhibitor decreases glioma stem cell growth by inhibiting the Notch pathway and LMW Cyclin E
Authors: Desiree H. Floyd, Benjamin Kefas, Olexsandr Seleverstov, Charli Dominguez, Laurey Comeau, Benjamin W. Purow
Journal: Cancer Research (2011)

Abstract The Notch pathway is deregulated in glioblastoma. Previous work suggests the inhibition of this pathway will have therapeutic benefits. The only inhibitors of Notch available block the gamma-secretase enzymatic complex necessary for processing Notch into the active form. However, Notch is also cleaved by alpha-secretase outside the plasma membrane, with the sheddases ADAM10 and 17. INCB3619 is a potent inhibitor of both ADAM10 and 17, and has been shown to inhibit growth of MCF-7 breast tumor cells when used with lapatinib. In this work, INCB3619 was used to inhibit endogenous Notch cleavage and downstream CBF-1 reporter activity in 0308 and 0822 human glioma stem cell lines. A microarray analysis of INCB3619 vs. DMSO treatment of 0308 cells identified many downregulated Notch pathway targets, but also identified new targets of INCB3619, such as CHI3L1/YKL40, an important prognostic indicator of many inflammatory diseases. Treatment of 0308 and 0822 glioma stem lines with INCB3619 inhibited their growth in culture due to a cell cycle arrest in G1 and a decrease in S phase cells. Growth inhibition by INCB3619 can be rescued with transfection of the active form of two Notch family members, NICD1 and 2. The growth inhibition of INCB3619 treated glioma stem cells is also stems from a shift in Cyclin E expression from a hyperactive low-molecular-weight form to the usual high-molecular-weight form. Also, INCB3619 induces higher expression of both p53 and p21, which can inhibit Cyclin E. Unlike with INCB3619, The treatment of glioma stem cells with DAPT, a well-known and potent gamma secretase inhibitor that cleaves Notch downstream of ADAM10 and 17, does not have a noticeable effect on Cyclin E processing or p21/p53 expression. INCB3619 therefore decreases glioma stem cell growth partly through a mechanism of Notch inhibition and also through inhibition of production of the hyperactive low-molecular-weight form of Cyclin E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3316. doi:10.1158/1538-7445.AM2011-3316
Haemoglobin AIc concentrations after initial insulin treatment for newly discovered diabetes.
Authors: J Ditzel, J J Kjaergaard
Journal: BMJ (1978)

Glycosylated haemoglobins AIa+Ib and AIc were measured serially in 10 consecutive cases of newly discovered non-acidotic diabetes before and after diet and insulin treatment. The average concentration of Hb AIc was 11.4% in untreated diabetics as compared with 4.3% in healthy controls. With prolonged optimal regulation of blood glucose Hb AIc slowly decreased to a mean concentration of 5.5%. The concentration of Hb AIc was significantly correlated with the fasting blood sugar value. The findings suggest that determining Hb AIc may give valuable information on the regulation of carbohydrate metabolism in the preceding one to two months and thus become an important aid to management.
Retroperitoneal Lymph Node Dissection with No Adjuvant Chemotherapy in Clinical Stage I Nonseminomatous Germ Cell Tumours: Long-Term Outcome and Analysis of Risk Factors of Recurrence
Authors: Nicola Nicolai, Rosalba Miceli, Andrea Necchi, Davide Biasoni, Mario Catanzaro, Angelo Milani, Luigi Piva, Giorgio Pizzocaro, Silvia Stagni, Tullio Torelli, Roberto Salvioni
Journal: European Urology (2010)
Phylogenetic resolution of complex mutational features at Y-STR DYS390 in aboriginal Australians and Papuans
Authors: P. Forster, M. Kayser, E. Meyer, L. Roewer, H. Pfeiffer, H. Benkmann, B. Brinkmann
Journal: Molecular Biology and Evolution (1998)

Y-chromosomal short tandem repeats (STRs) are used for the study of male aspects of human evolution as well as for forensic applications and paternity testing. Both applications require an understanding of the underlying mutational mechanisms that create variability. We describe complex mutations at the substructured DYS390 STR locus in 97 natives of the New Guinea/Australian region. Sequencing of short alleles in these populations indicates multirepeat deletions. All samples are further characterized using the five additional Y-STR loci DYS19, DXYS156-Y, DYS391, DYS392, and DYS393. Phylogenetic analysis of the resulting haplotypes yields ethnically specific clusters predating the settlement of Australia and Papua New Guinea (although archaic Homo sapiens or Homo erectus lineages are absent). The phylogeny confirms that DYS390 violates the stepwise mutation model and demonstrates that the DYS390 locus mutates relatively rapidly and retains its variability after structural change.
Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy
Authors: Michela Ripolone, Dario Ronchi, Raffaella Violano, Dionis Vallejo, Gigliola Fagiolari, Emanuele Barca, Valeria Lucchini, Irene Colombo, Luisa Villa, Angela Berardinelli, Umberto Balottin, Lucia Morandi, Marina Mora, Andreina Bordoni, Francesco Fortunato, Stefania Corti, Daniela Parisi, Antonio Toscano, Monica Sciacco, Salvatore DiMauro, Giacomo P. Comi, Maurizio Moggio
Journal: JAMA Neurology (2015)

The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively).
Lymphoma in a Case of Shwachman-Diamond Syndrome
Authors: Joel Verbrugge, Mark Tulchinsky
Journal: Clinical Nuclear Medicine (2011)

Shwachman-Diamond syndrome is a rare autosomal recessive multisystem disease characterized by pancreatic exocrine insufficiency, skeletal abnormalities, impaired hematopoiesis, and a predisposition to hematologic malignancies. Considerable phenotypic variability between individuals, as well as within the same individual over time, can make the diagnosis challenging. It is important to make the diagnosis because of the risk of infection, hematologic disturbances, and association with malignancy that require vigilance and close monitoring. We present PET/CT findings in a case of Shwachman-Diamond syndrome with non-Hodgkin lymphoma, the association that to the best of our knowledge has not been previously reported in the literature.
PENETRATION OF THE VIRUS OF POLIOMYELITIS FROM THE BLOOD INTO THE CEREBROSPINAL FLUID
Authors: Simon Flexner, Harold L. Amoss
Journal: The Journal of Experimental Medicine (1914)

The virus of poliomyelitis introduced into the blood may pass indirectly by way of the cerebrospinal fluid to the interstices of the central nervous organs. To reach the cerebrospinal fluid the virus must first penetrate the barrier of the choroid plexus, which operation requires time. By the inoculation test, no virus was detected in the fluid at the expiration of 48 hours, only small amounts at the expiration of 72 hours, while at the expiration of 96 hours the virus had passed more freely. The virus was still detectable in the fluid at the onset of paralysis 19 days after the intravenous injection. Pathological conditions of the leptomeninges and the cerebrospinal fluid play an important part in the pathogenesis of epidemic poliomyelitis.
Management of gastric variceal bleeding
Authors: M. Matsushita, K. Uchida, Y. Tahashi, K. Okazaki
Journal: Endoscopy (2006)

We read with interest the article by Jang et al. [1] about a case of gastric variceal bleeding that was treated by endoscopic band ligation (EBL). Treatment of gastric varices with EBL has been reported to cause massive and fatal bleeding from EBL-related ulceration [2]. We therefore believe that EBL for the treatment of gastric variceal bleeding was an inadequate management. The best preventive approach for gastric variceal bleeding has been believed to be surgery [3]. However, its high invasiveness has limited the wide application of the procedure because these patients usually have poor hepatic functional reserve [3]. Although percutaneous transhepatic obliteration (PTO) is a well-established technique in the management of gastric variceal bleeding, the procedure is associated with a high incidence of rebleeding and recurrence [3]. Transjugular intrahepatic portosystemic shunt (TIPS) is considered to be a rescue option for variceal bleeding unresponsive to pharmacological and endoscopic treatment. However, TIPS has major disadvantages, such as stenosis and occlusion of the shunt, high rebleeding rates, and induction of hepatic encephalopathy [3], and might be ineffective for gastric varices with a gastrorenal shunt because of low portosystemic gradients [4].
Attention Deficit Hyperactivity Disorder and the Gene for Dopamine Beta-Hydroxylase
Authors: Karen Wigg, Gwyneth Zai, Russell Schachar, Rosemary Tannock, Wendy Roberts, Molly Malone, James L. Kennedy, Cathy L. Barr
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) has been shown to be highly heritable, and recent molecular genetics studies have focused on candidate genes in the dopaminergic and noradrenergic systems. One recent study reported an association of an allele of the TaqI polymorphism located in the fifth intron of the gene for dopamine beta-hydroxylase (DBH). The authors' goal was to replicate this finding. METHOD: The authors investigated the linkage of the alleles and haplotypes of three polymorphisms at the DBH locus in 117 nuclear families with ADHD. RESULTS: No significant evidence was found for linkage of the TaqI alleles or haplotypes in the 117 families. However, the authors observed some evidence for biased transmission of the same allele of the TaqI polymorphism, as previously reported. CONCLUSIONS: These findings suggest that the gene for DBH should be investigated further.
Can one explanation serve two laws?
Authors: Howard N. Zelaznik, Robert W. Proctor
Journal: Behavioral and Brain Sciences (1997)

Several issues are raised concerning the notion that a single strategy explains Fitts' law and the linear speed/accuracy trade-off. Two additional concerns are discussed: (1) distance is programmed, (2) the fact that movements produced without the aid of vision obey Fitts' law does not mean that sighted movements must be explained without regard to vision.
Racial disparities in the management of hospitalized patients with cirrhosis and complications of portal hypertension: A national study
Authors: Geoffrey C. Nguyen, Dorry L. Segev, Paul J. Thuluvath
Journal: Hepatology (2007)

Having complications of portal hypertension is a harbinger of decompensated cirrhosis and warrants consideration for liver transplantation (LT). Racial disparities in LT have been reported. We sought to characterize disparities in the performing of surgical and endoscopic procedures among hospitalized patients with complications of portal hypertension. We queried the Nationwide Inpatient Sample from 1998 to 2003 to identify patients with cirrhosis and complications of portal hypertension. Logistic regression controlling for confounders was used to evaluate race as a predictor of undergoing a portosystemic shunt and LT and of dying in the hospital. Compared to whites, the adjusted odds ratios of receiving a portosystemic shunt were 0.37 (95% CI: 0.27-0.51) and 0.69 (95% CI: 0.54-0.88) for African Americans (AAs) and Hispanics, respectively. AAs with variceal bleeding were more likely to have endoscopic variceal hemostasis delayed more than 24 hours after admission than were whites (OR 1.6; 95% CI: 1.2-2.1). The adjusted odds ratios of undergoing LT were 0.32 (95% CI:0.20-0.52) and 0.46 (95% CI: 0.25-0.83) for AAs and Hispanics, respectively. Compared to whites, AAs experienced higher in-hospital mortality (OR 1.12; 95% CI: 1.01-1.24), whereas Hispanics had a lower risk of death (OR 0.83; 95% CI: 0.75-0.92). Among variceal bleeders, the odds ratio of death for AAs was 1.7 (95% CI: 1.2-2.4) compared to whites. Conclusion: AAs and Hispanics hospitalized for complications of portal hypertension were less likely to undergo a palliative shunt or LT than whites, which may contribute to the higher in-hospital mortality of AAs. Further studies are warranted to elucidate the mechanisms of these exploratory findings. (HEPATOLOGY 2007;45:1282–1289.)
Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody
Authors: C Callens, I C Moura, Y Lepelletier, S Coulon, A Renand, M Dussiot, D Ghez, M Benhamou, R C Monteiro, A Bazarbachi, O Hermine
Journal: Leukemia (2007)
Acute Laryngotracheobronchitis in Children
Authors: J. L. Emery
Journal: BMJ (1952)

TRACHEOTOMY IN LARYNGOTRACHEOBRONCHITISBRm 1067or bronchoscopy should be limited to an emergency pro- cedure prior to tracheotomy.In these cases further emphasis must be placed on repeated suction.The per- formance of a tracheotomy, and then suction using poly- thene tubing, ensures that the smaller bronchi may be reached and cleared.When necessary, the decision should be to do the tracheotomy as an elective procedure, and the exact time interval before the operation must vary with each individual case.This may range from immediately on admission up to 36 hours later.The use of tracheotomy as a last desperate expedient can only bring its performance in acute obliterative laryngotracheobronchitis into disrepute. Summary and ConclusionsThirty-nine cases of acute obliterative laryngotracheo- bronchitis are described.Their clinical course and medical treatment are given and their management is discussed, with especial reference to the use of tracheotomy.The indications for elective tracheotomy are : (1) the appearance of cyanosis ; (2) extreme fatigue; (3) increas- ing restlessness, pallor, and stridor, with an associated diminutioh of air entry.Our cases fall into three groups.(1) Immediate emergency tracheotomy (see Case 1), which is necessary where there is acute glottic obstruction. (2)Early elective tracheotomy (see Case 2) : these are the patients who rapidly deteriorate despite adequate medical treat- ment.They should be under observation for a period of one hour and then have tracheotomy performed.(3) Late elective tracheotomy (see Case 3): these patients at first respond to medical treatment, but later their con- dition deteriorates.When this occurs they should be observed for a period of one hour and then have tracheotomy performed.These cases usually do not present until 24-36 hours after admission.
In vivo blockade of tumor necrosis factor-alpha in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation.
Authors: N Clausell, S Molossi, S Sett, M Rabinovitch
Journal: Circulation (1994)

BACKGROUND We previously identified in piglet cardiac allografts an immunoinflammatory response in coronary arteries in which increased fibronectin regulated by interleukin-1 beta was associated with early evidence of intimal thickening. In the present study, we used rabbits to assess whether acute neointimal formation after cardiac transplantation was reduced by blockade of tumor necrosis factor (TNF)-alpha, which modulates interleukin-1 beta, or by cyclosporine A. METHODS AND RESULTS Sixteen rabbits underwent heterotopic cardiac transplantation and were given saline, TNF-soluble receptor (sr), or cyclosporine A. In host hearts from saline- or TNFsr-treated groups, few coronary arteries (approximately 13% to 16%) had intimal thickening, whereas values were higher in the cyclosporine A-treated group (approximately 30%). In donor hearts from the saline-treated group, however, approximately 68% of vessels had intimal thickening versus approximately 32% in TNFsr- and approximately 30% in cyclosporine A-treated groups (P &lt; .01 for both). Severity of intimal thickening assessed quantitatively as percent vessel area was approximately 38% in the saline-treated group but reduced in TNFsr- and cyclosporine A-treated groups to approximately 22% and 18%, respectively (P &lt; .01 for each). Immunohistochemistry revealed increased staining for major histocompatibility complex II, T cells, interleukin-1 beta, TNF-alpha, and fibronectin in donor coronary arteries from saline-treated animals when compared with TNFsr- and cyclosporine A-treated animals. Grade 3 myocardial rejection was observed in both saline- and TNFsr-treated groups, but only grade 1 was apparent in the cyclosporine A-treated group. CONCLUSIONS In vivo blockade of TNF-alpha suppresses the acute development of neointimal formation by selectively reducing the vascular immunoinflammatory reaction and accumulation of fibronectin, whereas cyclosporine A suppresses both the myocardial and the vascular immune reaction.
309Protection from cardiac fibrosis is induced by beta3 adrenergic receptor in cardiac myocyte through inhibition of paracrine signalling to fibroblast : proteomic analysis of the myocyte secretome
Authors: N Hermida, E Dubois-Deruy, J Hammond, J Hamelet, A Markl, M Mayr, JL Balligand
Journal: Cardiovascular Research (2014)

Background: Cardiac fibrosis is an integral part of myocardial remodelling in response to stress. Mice with cardiac myocyte-specific overexpression of beta3-adrenergic receptor (β3-AR) are protected not only from the development of hypertrophy but also cardiac fibrosis. As overexpression was restricted to cardiac myocytes (CM), we postulated that the protection involved a paracrine cross-talk to cardiac fibroblasts (CF). Methods: We developed a model of superfusion of CF in serum-free conditions with media conditioned by cultured CM with adenoviral expression of the human β3AR and treated or not with phenylephrine (PE). Cardiac extracts were analysed in wild type (WT) and heterozygote transgenic mice with cardiac myocyte-specific overexpression of human β3AR (hβ3TG) submitted to transaortic constriction (TAC) for 9 weeks. Results: Incubation of CF with medium conditioned by control CM treated with PE stimulated their proliferation, migration, myofibroblats differentiation (α-SMA expression) and pro-collagen I expression compared with medium from CM not treated with PE. This was associated with activation of the ERK pathway in CF. All these effects were abolished by heat inactivation of the media, suggesting implication of paracrinally secreted peptides. The effects of medium conditioned by untreated β3AR overexpressing CM were similar to those untreated controls. However, incubation of CF with medium of β3AR overexpressing CM treated with PE did not activate their differentiation into myofibroblats or pro-collagen I expression. Activation of the ERK pathway was also absent. To unravel the idendity of paracrine factors, the secretome of CM was submitted to shotgun proteomic analysis by LC tandem MS. Top candidates significantly downregulated in β3AR-PE conditioned medium compared with GFP-PE included CTGF, galectin-3 binding protein, plasminogen activator inhibitor 1, collagen I and III, fibronectin, thrombospondin-1. Accordingly, β3AR was associated with decreased mRNA expression of CTGF in CM in vitro. These results were confirmed in vivo after TAC stress in mice at mRNA and proteins levels (cTGF protein expression: 1.03±0.1 (WT) vs 0.51±01 (β3AR), p<0.01). Conclusion: We conclude that β3AR decreases the expression of pro-fibrotic paracrine factors such as CTGF, resulting in protection from myocardial fibrosis in response to neurohormonal stimulation.
A Psychiatric Study of the Life and Work of Dorothea Dix
Authors: WILLIAM J. BROWNE
Journal: American Journal of Psychiatry (1969)

There have been no psychiatric studies of Dorothea Dix despite the importance to psychiatry of her reforms. This paper focuses on some psychodynamic themes in her life: parental identifications, childhood deprivation and reaction formation, religious conversion and mysticism, and depressive and hypomanic states. Her experiences are compared with those of other women reformers: St. Teresa, Florence Nightingale, and Jane Addams. The author concludes that successful careers in social service stem from positive identifications, although reaction formations are also prominent.