tbuckley/cabot-search huggingface dataset:
Abstract 2551: The Nampt inhibitor MPC-9528 synergizes with DNA damaging agents
Authors: Ryan T. Terry-Lorenzo, Thomas B. Douce, Harry A. Austin, J. Jay Boniface, Daniel M. Cimbora, Tracey C. Fleischer, Robert O. Carlson
Journal: Cancer Research (2011)

Abstract Background: MPC-9528 reduces cellular NAD levels and causes cell death, by blocking the NAD salvage pathway through inhibition of nicotinamide phosphoribosyltransferase (Nampt). Many DNA damaging agents also reduce cellular NAD levels, by activating the NAD consuming enzyme poly(ADP-ribose) polymerase (Parp). We hypothesized that the combination of a Nampt inhibitor and a DNA damaging agent would synergize in killing cancer cells, due to a combined effect on NAD levels through two independent mechanisms. Methods: Cellular NAD was measured using a coupled enzymatic assay. Drug combination experiments were performed in HCT116 colon carcinoma cells, using measurement of ATP levels as a cell viability endpoint. Synergy, antagonism, or additivity was assessed using the MacSynergy II program. Results: In HCT116 cells, saturating doses of MPC-9528 induced depletion of NAD with a half-life of 5 hours and a decrease in ATP that was delayed approximately 14 hours relative to NAD. Lower, sublethal concentrations of MPC-9528 induced partial NAD depletion without a concomitant ATP loss. At these sublethal concentrations, MPC-9528 was found to synergize with the DNA alkylating agents temozolomide and streptozotocin, which are known to activate Parp. Additionally, MPC-9528 was found to synergize with two structurally different thymidylate synthase inhibitors, 5-fluorouracil (5-FU) and raltitrexed, neither of which have been reported to activate Parp. Individually, 5-FU and raltitrexed each caused NAD depletion in HCT116 cells, which was enhanced by combination with MPC-9528. Furthermore, both 5-FU- and raltitrexed-mediated NAD depletion and synergy with MPC-9528 were completely blocked by the Parp inhibitor olaparib. Conclusions: Parp activation induced by the alkylating agents temozolomide and streptozotocin, or by the thymidylate synthase inhibitors 5-FU and raltitrexed, is the basis for tumoricidal synergy with the Nampt inhibitor MPC-9528. This synergy is a direct consequence of the NAD depletion resulting from Parp activation coupled with the inhibition of NAD synthesis due to Nampt inhibition. These results provide a basis for clinical combination of MPC-9528 with the agents studied here or with related agents that induce Parp activation. 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 2551. doi:10.1158/1538-7445.AM2011-2551
For the short-term: Are women just looking for a few pair of genes?
Authors: Lynn Carol Miller, William C. Pedersen, Allison R. Johnson, Anila D. Putcha
Journal: Behavioral and Brain Sciences (2000)

Although we find Gangestad &amp; Simpson's argument intriguing, we question some of its underlying assumptions, including: (1) that fluctuating asymmetry (FA) is consistently heritable; (2) that symmetry is driving the effects; (3) that use of parametric tests with FA is appropriate; and (4) that a short-term mating strategy produces more offspring than a long-term strategy.
Eradicate commercial interests from official medical education
Authors: P. Vercellini, P. Vigano, E. Somigliana
Journal: BMJ (2014)

Dyer describes international initiatives to promote public disclosure of payments from industry to doctors, thereby enabling patients to tell whether their treatment might be influenced by commercial interests.1 Coombes suggests that messages from key opinion leaders paid by drug companies to advise on marketing strategies, present at conferences, or write in medical …
Maternal Pregnancy Levels of <i>trans</i> -Nonachlor and Oxychlordane and Prevalence of Cryptorchidism and Hypospadias in Boys
Authors: Britton Trabert, Matthew P. Longnecker, John W. Brock, Mark A. Klebanoff, Katherine A. McGlynn
Journal: Environmental Health Perspectives (2011)

The etiologies of the male urogenital anomalies--cryptorchidism and hypospadias--are poorly understood. Given positive associations between chlordane isomers and testicular germ cell tumors, it is reasonable to assume that chlordanes might also be associated with other testicular dysgenesis syndrome disorders, namely cryptorchidism and hypospadias.To examine whether exposure to in utero chlordane is related to cryptorchidism and hypospadias, we evaluated levels of chlordane derivatives, trans-nonachlor and oxychlordane, among pregnant women enrolled in the Collaborative Perinatal Project (CPP).From 1959 to 1965, the CPP enrolled pregnant women at 12 U.S. medical centers. We analyzed serum trans-nonachlor and oxychlordane levels measured in third-trimester serum from the mothers of 217 sons with cryptorchidism, 197 sons with hypospadias, and 557 sons with neither condition. Adjusted odds ratios (ORs) and 95% confidence intervals were calculated using conditional logistic regression.The quartile-specific ORs for cryptorchidism or hypospadias show no notable associations with trans-nonachlor or oxychlordane. Further, there were no significant trends with increasing quartile of maternal trans-nonachlor or oxychlordane level in either cryptorchidism or hypospadias (p-trend all > 0.45).The results do not support an association between chlordane levels and cryptorchidism or hypospadias. It is unlikely that current chlordane exposure is related to the development of either anomaly, given that serum chlordane levels at the time of sample collection, the early 1960s, were considerably higher than levels at present.
Shot to the Heart
Authors: Lance E Sullenberger, Mary Jo Rohrer
Journal: New England Journal of Medicine (2003)

A 29-year-old soldier on active duty in the Army who was involved in the forward combat zone of Afghanistan required emergency evaluation for a shrapnel wound to the chest. Chest radiography (Panel A) showed a metallic fragment (arrows) within the cardiac silhouette. Off-axis transthoracic echocardiographic images (apical two-chamber view, Panel B) showed that the shrapnel (arrow) was located within the apex of the left ventricle (LV). The left ventricular wall motion was normal. The patient was asymptomatic. The fragment was left in place, and the patient was still asymptomatic three months later.
Worksite Health Promotion and Health Care Costs and Utilization-Reply
Authors: Robert C. Jones
Journal: JAMA (1987)

<h3>In Reply.—</h3> In their Letter to the Editor, Sciacca et al raise several issues relating to our article on the impact of a health promotion program. We seek to address these concerns. One can agree that, just as a longer period of observation would be desirable to capture any long-term impact of health promotion programs, a longer baseline period would have been welcome if the data had been available. As can be seen in the article, however, what is striking about the data at baseline (1979) is not the dissimilarity in the three groups studied (two Live for Life [LFL] groups and one non-LFL group) but their similarities. For example, in 1979 the three groups showed 405, 408, and 406 mean hospital days per 1000 employees, respectively. On the issue of health care measures, the investigators were careful to note in the article that diagnostic data were not available. We
Comparison of Ximelagatran with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement
Authors: Charles W. Francis, Scott D. Berkowitz, Philip C. Comp, Jay R. Lieberman, Jeffrey S. Ginsberg, Guy Paiement, Gary R. Peters, Anne W. Roth, Jennifer McElhattan, Clifford W. Colwell
Journal: New England Journal of Medicine (2003)

In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of ximelagatran is superior to warfarin.
Vascular Radionuclide Imaging: A Clinical Atlas
Authors: David A. Turner
Journal: JAMA (1984)

Vascular Radionuclide Imaging:   A Clinical Atlas is a slender volume that deals with many aspects of cardiovascular nuclear medicine. The first chapter is a superficial, three-page discourse on clinical aspects of thromboembolism, peripheral vascular disease, disease of the aorta, portal hypertension, lymphedema, intracardiac shunts, and other cardiac conditions. It also contains a paragraph on radiation dosimetry.  Subsequent chapters discuss radionuclide venography, radionuclide angiography by peripheral venous and intra-arterial injection, radionuclide lymphangiography of the lower extremities, and many aspects of nuclear cardiology. Each of the latter chapters consists of a brief discussion of the radionuclide technique in question, followed by numerous figures. Some unusual images are included, for example, scintigrams of the abdomen after injection of technetium Tc 99m-macroaggregated albumin into branches of the celiac artery.  This book would be more useful if the authors had provided more complete documentation of the reliability of diagnostic criteria presented within, which seldom are
Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation
Authors: S. Önder Alpdogan, Sydney X. Lu, Neel Patel, Suzanne McGoldrick, David Suh, Tulin Budak-Alpdogan, Odette M. Smith, Jeremy Grubin, Christopher King, Gabrielle L. Goldberg, Vanessa M. Hubbard, Adam A. Kochman, Marcel R. M. van den Brink
Journal: Blood (2008)
EXPERIMENTS ON THE RÔLE OF LYMPHOID TISSUE IN THE RESISTANCE TO EXPERIMENTAL TUBERCULOSIS IN MICE
Authors: James B. Murphy, Arthur W. M. Ellis
Journal: The Journal of Experimental Medicine (1914)

Mice either normal or splenectomized after exposure to X-ray are markedly more susceptible to bovine tuberculosis than are normal animals. Animals splenectomized a short time prior to inoculation are also more susceptible than normal, while those splenectomized eight to ten days before inoculation have about the same resistance as normal. The mice splenectomized three to four weeks before inoculation have a resistance increased over the normal, as has already been shown by Lewis and Margot. As X-ray in the doses used apparently affects only the lymphoid tissue and as the hypertrophy of the remaining lymphoid tissue after splenectomy is so rapid that the circulating lymphocytes may be much above the normal by the third week, it is concluded that this evidence, taken with the well known association of the lymphocytes with tuberculous lesions, points strongly to the lymphocyte as an important agent in the defensive mechanism against tuberculosis.
193 DECREASE OF PORTAL PRESSURE VIA TIPS CORRECTS CONTRACTILE MECHANISMS IN GASTRIC MUCOSA OF HUMAN CIRRHOSIS
Authors: J. Trebicka, A. Krag, C. Wix, M. Granzow, S. Klein, B. Appenrodt, S. Saller, J. Heller, T. Sauerbruch
Journal: Journal of Hepatology (2011)
Treatment With Off-Label Omalizumab In Chronic Idiopathic Histaminergic Urticaria - Angioedema Resistant To Conventional Treatment
Authors: Y.V. Rijo, P. Palao, N. Prior, A. Fiandor, M.C. Lopez-serrano, S. Olalde, M.C. Torres, S. Quirce, T. Caballero
Journal: Journal of Allergy and Clinical Immunology (2014)
AN OLD-TIME QUACK EYE DOCTORTHE CHEVALIER JOHN TAYLOR.
Authors: BROWN PUSEY
Journal: JAMA (1903)

Indexed under the heading "Charlatans," in the magnificent library of ophthalmologic literature of Dr. Casey Wood, there is to be found "The Life and Etraordinary History of the Chevalier, John Taylor, Ophthalmiator, Pontificial, Imperial and Royal; in two volumes; written from authentic materials and published by his son, John Taylor, Oculist; London, 1761." In looking this book over, I happened on Chapter V of the second volume, which is an oration said to have been delivered in the streets of Oxford. I quote this chapter extensively, and when one has read it, I think no apology from me will be necessary for calling attention to it; and when one realizes that this oration is said to have been delivered in the public streets, and after Taylor had sent "his harbingers before him" to deliver his hand bills, I believe the desire is natural to inquire as to what manner
Pharmacological Characterizations of Adrenergic Receptors in Human Adipocytes
Authors: Thomas W. Burns, Paul E. Langley, Boyd E. Terry, David B. Bylund, Brian B. Hoffman, Michael D. Tharp, Robert J. Lefkowitz, J. Adolfo García-Saínz, John N. Fain
Journal: Journal of Clinical Investigation (1981)

Three types of adrenergic receptors, beta, alpha-1, and alpha-2, were identified in human adipocytes, isolated from properitoneal adipose tissue, using both the binding of radioactive ligands and the effects of adrenergic agents on receptor-specific biochemical responses. Adrenergic binding studies showed the following results: [3H]dihydroalprenolol binding (beta adrenergic) Bmax 280 fmol/mg protein, KD 0.38 nM; [3H]para-aminoclonidine binding (alpha-2 adrenergic) Bmax 166 fmol/mg protein, KD 0.49 nM; [3H]WB 4101 binding (alpha-1 adrenergic) Bmax 303 fmol/mg protein, KD 0.86 nM. In adipocytes from subcutaneous adipose tissue, [3H]dihydroergocryptine binding indicated the presence of alpha-2 but not alpha-1 receptors.
Decreased RECK Expression Indicating Proteolytic Imbalance in Prostate Cancer is Associated with Higher Tumor Aggressiveness and Risk of Prostate-Specific Antigen Relapse after Radical Prostatectomy
Authors: Anja Rabien, Mick Burkhardt, Monika Jung, Florian Fritzsche, Martin Ringsdorf, Hanka Schicktanz, Stefan A. Loening, Glen Kristiansen, Klaus Jung
Journal: European Urology (2006)
The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients
Authors: Ruo-Kai Lin, Yi-Shuan Hsieh, Pinpin Lin, Han-Shui Hsu, Chih-Yi Chen, Yen-An Tang, Chung-Fan Lee, Yi-Ching Wang
Journal: Journal of Clinical Investigation (2010)

DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in many human diseases, including cancer. The tobacco-specific carcinogen NNK also induces DNA methylation. However, the role of DNMT1-mediated methylation in tobacco carcinogenesis remains unclear. Here we used human and mouse lung cancer samples and cell lines to determine a mechanism whereby NNK induced DNMT1 expression and activity. We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation. NNK also induced betaTrCP translocation to the cytoplasm via the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) shuttling protein, resulting in DNMT1 nuclear accumulation and hypermethylation of the promoters of tumor suppressor genes. Fluorescence immunohistochemistry (IHC) of lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers were characterized by disruption of the DNMT1/betaTrCP interaction and DNMT1 nuclear accumulation. Importantly, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. We believe that the NNK-induced DNMT1 accumulation and subsequent hypermethylation of the promoter of tumor suppressor genes may lead to tumorigenesis and poor prognosis and provide an important link between tobacco smoking and lung cancer. Furthermore, this mechanism may also be involved in other smoking-related human diseases.
STUDIES ON A SUBSTANCE THAT PROMOTES TUMOR HOMOGRAFT SURVIVAL (THE "ENHANCING SUBSTANCE")
Authors: A. A. Kandutsch, U. Reinert-Wenck
Journal: The Journal of Experimental Medicine (1957)

Using the death of mice due to the growth of tumor homografts as an end point, the distribution and properties of a tumor homograft-promoting substance(s), the "enhancing substance," were studied. Activity was most largely present in tumor and spleen tissues while that in the liver, kidney, and stomach was relatively slight. Activity was widely distributed in fractions prepared from tumor. Although DNAP and crude RNAP fractions were active, activity could not be associated with either RNA or DNA. The fraction possessing the highest concentration of activity was a residue fraction which was insoluble in water or in dilute or strong saline solutions. Extraction of lyophilized tumor with acetone or 3:1 alcohol:ether reduced, but did not eliminate, activity in the insoluble fraction. However, activity was completely lost after extraction with 80 per cent alcohol at room temperature. Enhancing activity of a tumor fraction was irreversibly lost after exposure for 1 hour to a solution more acid than pH 5 or more alkaline than pH 9. Activity was completely lost after exposure to 50 per cent urea or 90 per cent phenol. Activity was not altered by incubation with trypsin, hyaluronidase, DNAase or the receptor-destroying enzyme of V. cholerae, but it was decreased when trypsin or hyaluronidase was injected with the incubated tumor fraction. Activity was rapidly destroyed by treatment with dilute solutions of sodium periodate at pH 7. Under similar conditions, treatment with KMnO(4) resulted in less extensive destruction of activity while H(2)O(2), K(2)Cr(2)O(7), and NaIO(4) previously inactivated by reaction with glucose had no apparent effect on activity. These results are interpreted as indicating the presence of both carbohydrate and protein in the structure of the activity substance.
Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition
Authors: S Javadov
Journal: Cardiovascular Research (2000)

Objective: Diminishing oxidative stress may protect the heart against ischaemia–reperfusion injury by preventing opening of the mitochondrial permeability transition (MPT) pore. The general anaesthetic agent propofol, a free radical scavenger, has been investigated for its effect on the MPT and its cardioprotective action following global and cardioplegic ischaemic arrest. Method: Isolated perfused Wistar rat hearts were subjected to either warm global ischaemia (Langendorff) or cold St. Thomas' cardioplegia (working heart mode) in the presence or absence of propofol. MPT pore opening was determined using [3H]-2-deoxyglucose-6-phosphate ([3H]-DOG-6P) entrapment. The respiratory function of isolated mitochondria was also determined for evidence of oxidative stress. Results: Propofol (2 μg/ml) significantly improved the functional recovery of Langendorff hearts on reperfusion (left ventricular developed pressure from 28.4±6.2 to 53.3±7.3 mmHg and left ventricular end diastolic pressure from 52.9±4.3 to 37.5±3.9 mmHg). Recovery was also improved in propofol (4 μg/ml) treated working hearts following cold cardioplegic arrest. External cardiac work on reperfusion improved from 0.42±0.05 to 0.60±0.03 J/s, representing 45–64% of baseline values, when compared to controls (P<0.05). Propofol inhibited MPT pore opening during reperfusion, [3H]-DOG-6P entrapment being 16.7 vs. 22.5 ratio units in controls (P<0.05). Mitochondria isolated from non-ischaemic, propofol-treated hearts exhibited increased respiratory chain activity and were less sensitive to calcium-induced MPT pore opening. Conclusion: Propofol confers significant protection against global normothermic ischaemia and during cold cardioplegic arrest. This effect is associated with less opening of mitochondrial MPT pores, probably as a result of diminished oxidative stress. Propofol may be a useful adjunct to cardioplegic solutions in heart surgery.
MAPPING AND ABLATION OF VENTRICULAR ARRHYTHMIAS ORIGINATING FROM RIGHT VENTRICULAR PAPILLARY MUSCLES
Authors: Miki Yokokawa, Thomas Crawford, Timir S. Baman, Karl J. IIg, Sanjaya K. Gupta, Eric Good, Aman Chugh, Krit Jongnarangsin, Frank Pelosi, Hakan Oral, Fred Morady, Frank Bogun
Journal: Journal of the American College of Cardiology (2010)
Mediastinal and Subcutaneous Emphysema in Diabetic Coma With Vomiting
Authors: Paul M. Beigelman
Journal: JAMA (1969)

Four patients with severe diabetic ketoacidosis in coma had proven mediastinal and subcutaneous emphysema and, in each patient, the probable cause was emesis. There was no evidence of esophageal laceration or rupture. Recovery was complete without surgical intervention or other specific therapy for the emphysema.
THE DIAGNOSIS OF PYELONEPHRITISBASED ON THE ABNORMAL RETENTION AND THE DELAYED EXCRETION OF METHYLENE BLUE.
Authors: EDWIN BEER
Journal: JAMA (1907)

The following report on what I believe to be a useful differential diagnostic symptom between simple involvement of the pelvis of the kidney and involvement of the pelvis and the parenchyma of that organ, is preliminary to a more detailed publication based on further clinical and experimental data. There are two types of pyelitis, acute and chronic. In both the parenchyma may be involved, as autopsy of such cases shows. How can we determine whether the parenchyma is involved? As far as one can judge from the literature there is no symptom which reliably differentiates between pyelitis and pyelonephritis. A patient, without palpable kidney tumor, without tenderness over the kidney areas, is suffering from a chronic pyuria. Despite careful bladder irrigations and in some cases despite drainage of the bladder (3 cases reported by Osler), the pyuria continues. Cystoscopy shows a chronic cystitis and by means of ureteral catheterization it
Atrial natriuretic peptide distribution in fetal and failed adult human hearts.
Authors: H Tsuchimochi, F Kurimoto, K Ieki, H Koyama, F Takaku, M Kawana, S Kimata, Y Yazaki
Journal: Circulation (1988)

The distributions of atrial natriuretic peptide (ANP) in human hearts during the developmental stage and in adult pathological states was examined with an antibody specific to human alpha-ANP. With immunoblotting and immunofluorescence methods, we found that a 17-kDa protein, which is a pro ANP, was expressed in human fetal ventricles, in which the numbers of myofibers containing ANP granules were more abundant in the subendocardial region than the subepicardial region. As determined by radioimmunoassay, the content of immunoreactive ANP (per milligram protein) in the developing heart was greatest in the left atrium and occurred decreasingly in the right atrium, right ventricle, and left ventricle, respectively. Because ANP content in the left ventricle declined during the progress of gestation in developing hearts and because it was very low, if ever detectable, in normal adult hearts, ventricular ANP expression appears to be developmentally regulated from the early gestational stage. However, it was reexpressed in the ventricles of patients who had suffered from severe congestive heart failure. In this situation, we found that the ventricular ANP expression was more marked in patients with dilated cardiomyopathy than in patients with severe valvular disease. Interestingly, in the ventricles of patients with dilated cardiomyopathy, ANP contents were higher in the left ventricular free wall than in the right ventricular free wall, although the left ventricular subendocardium contained more ANP than the subepicardium, showing a transmural gradient similar to that expressed in fetal ventricles. Thus, the expression of ANP in human ventricles is developmentally regulated from the early gestational stage, and even adult ventricular myofibers can synthesize ANP during severe congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)