tbuckley/cabot-search huggingface dataset:
Abstract 3507: Facilitating pixantrone-induced DNA damage and subsequent cell kill through formaldehyde activation and improvements in drug design
Authors: Benny J. Evison, Oula C. Mansour, Brad E. Sleebs, Keith G. Watson, Ada Rephaeli, Abraham Nudelman, Don R. Phillips, Suzanne M. Cutts
Journal: Cancer Research (2010)

Abstract Pixantrone is a novel aza-anthracenedione originally developed to improve the therapeutic profile of mitoxantrone, a DNA-interactive agent currently used in the clinical management of a range of haematological malignancies and solid tumours. Like mitoxantrone, pixantrone interacts with DNA via intercalation and stimulates topoisomerase II-mediated DNA cleavage, presumably by stabilising the cleavable complex. Despite the drug's ability to stimulate DNA cleavage via topoisomerase II impairment, this form of DNA damage does not directly correlate with drug cytotoxicity, suggesting that pixantrone may be operating by a distinct, currently undefined mechanism of cell kill. A novel form of pixantrone-DNA interaction has recently emerged in which the drug can be efficiently activated by formaldehyde to yield covalent drug-DNA adducts. In cellular systems, pixantrone exhibits a mild synergistic relationship with the formaldehyde-releasing prodrug AN-9, indicating a favourable role for formaldehyde in mediating pixantrone-induced cell kill. A variety of methods including in vitro transcription and mass spectrometry have established that formaldehyde-activated pixantrone is a monofunctional DNA alkylator that binds selectively to CpG and CpA dinucleotides via the exocyclic N2 amino group of guanine within DNA. Crucially, formaldehyde provides the methylene bridge that covalently links DNA with a single drug side-chain. A major functional limitation of the monoadduct is its poor intrinsic stability (t1/2 = 75 min). It was subsequently rationalised that an increase in drug side-chain length may permit the drug to completely bridge the two strands of duplex DNA, much like an interstrand crosslink. Accordingly, new anthracenediones were synthesised that incorporated symmetrical side chains of the nature -NH-(CH2)n-NH2 (where n = 2—5). An in vitro crosslinking assay demonstrated that side-chain extension generally conferred a remarkable increase in the temporal stability of formaldehyde-activated anthracenedione-DNA adducts. A clear and direct relationship existed between side-chain length and drug-DNA adduct half-life with MX5 (n = 5) exhibiting exceptional stability (t1/2 &amp;gt; 2 days). Significantly, the enhanced drug-DNA adduct stability was reflected in breast adenocarcinoma MCF-7 cells where derivatives with longer side-chains were synergistic in combination with the formaldehyde-releasing prodrug AN-9. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3507.
An Instructive Component in T Helper Cell Type 2 (Th2) Development Mediated by Gata-3
Authors: J. David Farrar, Wenjun Ouyang, Max Löhning, Mario Assenmacher, Andreas Radbruch, Osami Kanagawa, Kenneth M. Murphy
Journal: The Journal of Experimental Medicine (2001)

Although interleukin (IL)-12 and IL-4 polarize naive CD4+ T cells toward T helper cell type 1 (Th1) or Th2 phenotypes, it is not known whether cytokines instruct the developmental fate in uncommitted progenitors or select for outgrowth of cells that have stochastically committed to a particular fate. To distinguish these instructive and selective models, we used surface affinity matrix technology to isolate committed progenitors based on cytokine secretion phenotype and developed retroviral-based tagging approaches to directly monitor individual progenitor fate decisions at the clonal and population levels. We observe IL-4–dependent redirection of phenotype in cells that have already committed to a non–IL-4–producing fate, inconsistent with predictions of the selective model. Further, retroviral tagging of naive progenitors with the Th2-specific transcription factor GATA-3 provided direct evidence for instructive differentiation, and no evidence for the selective outgrowth of cells committed to either the Th1 or Th2 fate. These data would seem to exclude selection as an exclusive mechanism in Th1/Th2 differentiation, and support an instructive model of cytokine-driven transcriptional programming of cell fate decisions.
The influence of potassium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects
Authors: Hans R. Brunner, Leslie Baer, Jean E. Sealey, John G. G. Ledingham, John H. Laragh
Journal: Journal of Clinical Investigation (1970)

The effect of potassium administration and of dietary potassium deprivation on plasma renin activity and aldosterone excretion has been studied in 10 normal subjects and in 12 hypertensive patients maintained on a constant dietary regimen. Potassium administration reduced plasma renin activity in 18 of 28 studies of both normal and hypertensive subjects. Suppression of renin often occurred despite sodium diuresis induced by potassium administration. The renin suppression was related to induced changes in plasma potassium concentration and urinary potassium excretion. The failure of suppression of plasma renin in 10 studies could be accounted for by the smaller amounts of potassium administered to these subjects, together with a possibly overriding influence of an induced sodium diuresis. In six studies potassium deprivation invariably increased plasma renin activity even though a tendency for sodium retention often accompanied this procedure. The data indicate that both the suppression of plasma renin activity induced by potassium administration and the stimulation of renin activity which follows potassium depletion occur independently of associated changes in either aldosterone secretion or in sodium balance. However, the results do suggest that in various situations, the influence of potassium on plasma renin activity may be either amplified or preempted by changes in sodium balance. These interactions between potassium and plasma renin could be mediated by an ill-defined extrarenal pathway. But the findings are more consistent with an intrarenal action of potassium ions to modify renin release. Potassium might modify renin secretion directly by acting on the juxtaglomerular cells or by a change in its tubular reabsorption or secretion. The effects of potassium ions on renin secretion might also be mediated indirectly via an induced change in tubular sodium transport.
Discriminatory laws threaten effective response to HIV/AIDS, conference hears
Authors: P. Chatterjee
Journal: BMJ (2014)

Laws that criminalise vulnerable populations are key barriers to an effective response to HIV and AIDS, the 20th International AIDS Conference in Melbourne has heard. 

The GAP report by UNAIDS,1 released just ahead of the conference, noted that the number of people who were newly infected with HIV had continued to decline in most parts of the world and that AIDS related deaths had fallen by 35% since their peak in 2005. But it warned that punitive laws that discriminate against key populations—such as men who have sex with men, people who inject drugs, sex workers, and transgender people—persist and threaten …
Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets
Authors: Joel Montane, Loraine Bischoff, Galina Soukhatcheva, Derek L. Dai, Gijs Hardenberg, Megan K. Levings, Paul C. Orban, Timothy J. Kieffer, Rusung Tan, C. Bruce Verchere
Journal: Journal of Clinical Investigation (2011)

Type 1 diabetes is characterized by destruction of insulin-producing β cells in the pancreatic islets by effector T cells. Tregs, defined by the markers CD4 and FoxP3, regulate immune responses by suppressing effector T cells and are recruited to sites of action by the chemokine CCL22. Here, we demonstrate that production of CCL22 in islets after intrapancreatic duct injection of double-stranded adeno-associated virus encoding CCL22 recruits endogenous Tregs to the islets and confers long-term protection from autoimmune diabetes in NOD mice. In addition, adenoviral expression of CCL22 in syngeneic islet transplants in diabetic NOD recipients prevented β cell destruction by autoreactive T cells and thereby delayed recurrence of diabetes. CCL22 expression increased the frequency of Tregs, produced higher levels of TGF-β in the CD4+ T cell population near islets, and decreased the frequency of circulating autoreactive CD8+ T cells and CD8+ IFN-γ–producing T cells. The protective effect of CCL22 was abrogated by depletion of Tregs with a CD25-specific antibody. Our results indicate that islet expression of CCL22 recruits Tregs and attenuates autoimmune destruction of β cells. CCL22-mediated recruitment of Tregs to islets may be a novel therapeutic strategy for type 1 diabetes.
Postinfarctional remodeling: increased dye intensity in the myocardial risk area after angioplasty of infarct-related coronary artery is associated with reduction of ventricular volumes
Authors: Gianni Destro, Paolo Marino, Enrico Barbieri, Andrea Zorzi, Giovanna Brighetti, Massimiliano Maines, Monica Carletti, Piero Zardini
Journal: Journal of the American College of Cardiology (2001)
False Positive Quitter's Nail
Authors: J.A. Frederick
Journal: New England Journal of Medicine (1994)

To the Editor: Quitter's nail (April 7 issue)1 can be a false positive sign of smoking cessation. The same week you illustrated this physical sign, I was pleased to observe it in a patient with asthma who smoked heavily. My joy turned to sorrow, however, when she reported having switched to a “low tar” filter cigarette at the indicated time and was smoking more than ever to sustain her nicotine level!
Comparative Proteomic Profiles of Meningioma Subtypes
Authors: Hiroaki Okamoto, Jie Li, Alexander O. Vortmeyer, Howard Jaffe, Youn-Soo Lee, Sven Gläsker, Tae-Sung Sohn, Weifen Zeng, Barbara Ikejiri, Martin A. Proescholdt, Christina Mayer, Robert J. Weil, Edward H. Oldfield, Zhengping Zhuang
Journal: Cancer Research (2006)

Abstract Meningiomas are classified into three groups (benign, atypical, and anaplastic) based on morphologic characteristics. Atypical meningiomas, which are WHO grade 2 tumors, and anaplastic meningiomas, which are WHO grade 3 tumors, exhibit an increased risk of recurrence and premature death compared with benign WHO grade 1 tumors. Although atypical and anaplastic meningiomas account for &amp;lt;10% of all of meningiomas, it can be difficult to distinguish them from benign meningiomas by morphologic criteria alone. We used selective tissue microdissection to examine 24 human meningiomas and did two-dimensional gel electrophoresis to determine protein expression patterns. Proteins expressed differentially by meningiomas of each WHO grade were identified and sequenced. Proteomic analysis revealed protein expression patterns unique to WHO grade 1, 2, and 3 meningiomas and identified 24 proteins that distinguish each subtype. Fifteen proteins showed significant changes in expression level between benign and atypical meningiomas, whereas nine distinguished atypical from anaplastic meningiomas. Differential protein expression was confirmed by Western blotting and immunohistochemistry. We established differential proteomic profiles that characterize and distinguish meningiomas of increasing grades. The proteins and proteomic profiles enhance understanding of the pathogenesis of meningiomas and have implications for diagnosis, prognosis, and treatment. (Cancer Res 2006; 66(20): 10199-204)
405 SERUM LEVELS OF CHEMERIN, VASPIN, VISFATIN AND SPECAM-1 IN PATIENTS WITH CHRONIC HEPATITIS C
Authors: M. Kukla, K. Zwirska-Korczala, A. Gabriel, M. Waluga, W. Mazur, A. Berdowska, B. Rybus-Kalinowska, M. Kalinowski, E. Woźniak-Grygiel, R. Bułdak
Journal: Journal of Hepatology (2009)
Functional rescue “in vitro” of cytotoxic activity by Rab27a gene reposition in griscelli syndrome-type 2
Authors: Joao Bizario, Fabiola Castro, Jerome Feldmann, Gael Menasche, Erasmo Casella, Eugenia Carnide, Cristina Jacob, Antonio Carlos, Pastorino Lilian Cristofani, Genieve Saint-Basille
Journal: Journal of Allergy and Clinical Immunology (2002)
Pseudo-hydrodynamic Delivery of Helper-dependent Adenoviral Vectors into Non-human Primates for Liver-directed Gene Therapy
Authors: Nicola Brunetti-Pierri, Gary E Stapleton, Donna J Palmer, Yu Zuo, Viraj P Mane, Milton J Finegold, Arthur L Beaudet, Michelle M Leland, Charles E Mullins, Philip Ng
Journal: Molecular Therapy (2007)

Helper-dependent adenoviral vectors (HDAds) are attractive for liver-directed gene therapy because they can mediate long-term, high-level transgene expression without chronic toxicity. However, systemic delivery requires high vector doses for efficient hepatic transduction, resulting in dose-dependent acute toxicity. Clearly, strategies to improve hepatic transduction with low vector doses are needed. In this regard, we have previously shown that hydrodynamic injection of helper-dependent adenoviral vectors into mice results in increased hepatic transduction, reduced systemic vector dissemination, and reduced pro-inflammatory cytokines compared with conventional injection and thus has the potential to improve dramatically the therapeutic index of helper-dependent adenoviral vectors. Unfortunately, the rapid, large-volume injection used in this method cannot be applied to larger animals. Therefore, we have developed a novel balloon occlusion catheter-based method to mimic hydrodynamic injection of helper-dependent adenoviral vectors into non-human primates that does not require rapid, large-volume injection. Using a low, clinically relevant vector dose, this minimally invasive method results in high-efficiency hepatic transduction with minimal toxicity and stable long-term transgene expression for at least 413 days.
Abstract 4507: SL-501, a next-generation targeted therapy directed to IL-3R, inhibits the growth of tyrosine kinase inhibitor-resistant CML cells
Authors: Christopher Brooks, Kenneth Hoberman, Ivan Bergstein, Eric Rowinsky
Journal: Cancer Research (2014)

Abstract Although imatinib and other tyrosine kinase inhibitors (TKIs) achieve high response rates in patients with chronic myeloid leukemia (CML), patients can fail these therapies or develop specific mutations that render TKIs ineffective. Moreover, TKIs have limited effectiveness against CML cancer stem cells (CSCs). It was previously shown that SL-401, a novel targeted therapy directed to the interleukin 3 receptor (IL-3R), inhibits the growth of CML tumor bulk and CSCs, both of which over express IL-3R. SL-501 is a next-generation targeted therapy also directed to IL-3R. SL-501 has approximately 4-fold increased binding affinity for IL-3R and a more than 30-fold increase in potency against acute myeloid leukemia (AML) cells compared to SL-401. In this study, we assessed the activity of SL-501 against a panel of TKI-sensitive and TKI-resistant CML cell lines. KBM5, KBM5-STI, K562, and BV173 cells were treated with SL-501 (range: 5 - 21,000 pg) for 24 or 48 hours and assessed for viability and apoptosis. We found that SL-501 reduced the absolute cell number of all cell lines tested in a dose-dependent manner with IC50s of 20 pM, 21 pM, 31.5 nM, and 3.9 nM, respectively; these concentrations are readily achieved at tolerable doses in the clinic. Moreover, SL-501 significantly reduced the number of imatinib-resistant KBM5-STI viable cells by more than 5-fold after 48 hours. Using caspase and lactate dehydrogenase (LDH) release assays, we also found that SL-501 alone induced apoptosis of all cell lines tested by more than 40% after 24 hours. The combination of SL-501 with TKIs (imatinib, dasatinib, or nilotinib) had an enhanced effect on apoptosis in KBM5, K562, and BV173 cells 24 hours post-treatment. Taken together, these findings indicate that SL-501, a novel next-generation IL-3-targeted therapeutic, may be effective at treating TKI-resistant CML. These promising results together with the IL-3R expression pattern on CML blasts and CSCs warrant further development of SL-501 in CML and, in particular, TKI-resistant CML. Citation Format: Christopher Brooks, Kenneth Hoberman, Ivan Bergstein, Eric Rowinsky. SL-501, a next-generation targeted therapy directed to IL-3R, inhibits the growth of tyrosine kinase inhibitor-resistant CML cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4507. doi:10.1158/1538-7445.AM2014-4507
Cullen's sign, a feature in liver disease.
Authors: T A Mabin, M Gelfand
Journal: BMJ (1974)

Cullen's sign, a discoloration caused by blood around the umbilicus, has been described many times in association with a ruptured ectopic pregnancy or acute pancreatitis (Smith and Wright, 1935; Fallis, 1937).Though Hofstatter first reported its occurrence in 1909, he did not relate it to any underlying disorder, and it was Cullen (1918) who first recognized its relevance to ruptured ectopic pregnancy.A similar discoloration in the flanks was also described in acute pancreatitis by Turner in 1920, and this particular sign now bears his name.Cullen's sign has rarely been described except in these conditions.In 1922 Stemnberg reported it in association with a case of adenocarcinoma of the liver, and it was described in a case of possible cirrhosis with portal hypertension by Hellendal in 1934.We report its occurrence in two patients who were admitted to Harare Hospital within six months of each other, both diagnosed as having primary carcinoma of the liver.
TGF-β1–induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis
Authors: Lisa Y. Beppu, Arjun A. Anilkumar, Robert O. Newbury, Ranjan Dohil, David H. Broide, Seema S. Aceves
Journal: Journal of Allergy and Clinical Immunology (2014)
Intestinal absorption of dietary cadmium in women depends on body iron stores and fiber intake.
Authors: M Berglund, A Akesson, B Nermell, M Vahter
Journal: Environmental Health Perspectives (1994)

Measurements of intake and uptake of cadmium in relation to diet composition were carried out in 57 nonsmoking women, 20-50 years of age. A vegetarian/high-fiber diet and a mixed-diet group were constructed based on results from a food frequency questionnaire. Duplicate diets and the corresponding feces were collected during 4 consecutive days in parallel with dietary recording of type and amount of food ingested for determination of the dietary intake of cadmium and various nutrients. Blood and 24-hr urine samples were collected for determination of cadmium, hemoglobin, ferritin, and zinc. There were no differences in the intake of nutrients between the mixed-diet and the high-fiber diet groups, except for a significantly higher intake of fiber (p < 0.001) and cadmium (p < 0.002) in the high-fiber group. Fecal cadmium corresponded to 98% in the mixed-diet group and 100% in the high-fiber diet group. No differences in blood cadmium (BCd) or urinary cadmium (UCd) between groups could be detected. There was a tendency toward higher BCd and UCd concentrations with increasing fiber intake; however, the concentrations were not statistically significant at the 5% level, indicating an inhibitory effect of fiber on the gastrointestinal absorption of cadmium. Sixty-seven percent of the women had serum ferritin < 30 micrograms/l, indicating reduced body iron stores, which were highly associated with higher BCd (irrespective of fiber intake). BCd was mainly correlated with UCd, serum ferritin, age, anf fibre intake. UCd and serum ferritin explained almost 60% of the variation in BCd.(ABSTRACT TRUNCATED AT 250 WORDS)
Haemodynamic effects of balloon septostomy in tricuspid atresia.
Authors: S. P. Singh, R. Astley, C. G. Parsons
Journal: BMJ (1968)

MEDICAJHRNA 225 he had been after the myocardial infarction in March 1967.Thereafter he was maintained on lignocaine infusion 1 mg./min.to a maximum of 500 mg. in 24 hours and remained in sinus rhythm for 48 hours with only occasional extrasystoles.By this time the infusion had been discontinued and he felt well, was in sinus rhythm 80/min., and the blood pressure was 120/70.At this time he suddenly relapsed to the original dysrhythmia- supraventricular tachycardia with right bundle-branch block.On this occasion, as an alternative to further electrical cardioversion but while being monitored on the " cardioverter," he was given a sharp blow on the sternum with no effect.A similar heavy thump with the ulnar side of the clenched fist on the precordium at the cardiac apex immediately induced sinus rhythm with left bundle- branch block (see Fig.).Over the next few days he had runs of ventricular extrasystoles, bigeminy, and multifocal extrasystoles requiring further lignocaine infusion followed by tabs.phenytoin 100 mg.t.i d.
Diseases of the Nervous System: Described for Practitioners and Students
Authors: Gunter R. Haase
Journal: JAMA (1971)

<b>Clinical Neurology</b>, by Bernard J. Alpers and Elliott L. Mancall, ed 6; 1,072 pp, 236 illus, $32, Philadelphia: F. A. Davis Co., 1971. Unlike good wines, textbooks in medicine do not usually improve in the process of aging, and authors or publishers frequently seek to inject new vigor through new collaborators or editors. Two well-known neurologic textbooks appear now in new editions. Sir Francis Walshe's<i>Diseases of the Nervous System</i>, first published in 1940, has now reached its 11th edition. In the foreword, Sir Francis stresses his intention to keep the work selective, and the book has not significantly changed in size. The material is presented in two parts, the first dealing with the fundamental aspects of neurologic diagnosis, while the second describes diseases of the nervous system commonly encountered. Chapters on the relationship of liver disease to neurologic disorder and on lead poisoning are contributed by Dr. J. M.
Late Ulceration Twenty Years after Implantation of Radon Seeds
Authors: John G. Downing, David W. Folan
Journal: New England Journal of Medicine (1953)

RADON, a noble gas and an immediate descendant of the metallic element, radium, finds great practical use in the interstitial radiotherapy of malignant tumors of the body. Like radium, radon in itself has little value, for it emits only alpha rays. However, its immediate decay products, radium B and radium C, emit beta and gamma rays, the therapeutically effective radiations.Radon gas is collected from a water solution of a soluble radium salt, purified and concentrated in tiny hermetically sealed containers of fine gold tubing. The radon seeds in present use are about 4 mm. long, with a wall thickness . . .
Benefit of heparin plus aspirin vs aspirin alone in unstable angina
Authors: R. Collins
Journal: JAMA (1996)

In Reply.  —We agree with Dr Collins and colleagues that the 33% reduction in risk of MI or death in patients treated with aspirin plus heparin compared with those treated with aspirin alone was not statistically significant. The P value for the 95% CI associated with the relative risk (RR) of 0.67 (95% CI, 0.44-1.02) was.057. Athough this P value does not meet the arbitrary cutoff of.05 required for statistical significance, it suggests a low probability (5.7%) that the findings occurred by chance. We believe that these findings are strengthened by the results of 2 recent trials that compared low-molecularweight heparin plus aspirin with aspirin alone in patients with unstable angina. 1,2 In both studies, adding low-molecularweight heparin to aspirin reduced the risk of MI or death during treatment. If we had included these trials in our metaanalysis, we would have found a statistically significant summary RR of 0.56 (95% CI, 0.40-0.80).