tbuckley/cabot-search huggingface dataset:
Antioxidant Enzymes Mediate Survival of Breast Cancer Cells Deprived of Extracellular Matrix
Authors: Calli A. Davison, Sienna M. Durbin, Matthew R. Thau, Victoria R. Zellmer, Sarah E. Chapman, Justin Diener, Connor Wathen, W. Matthew Leevy, Zachary T. Schafer
Journal: Cancer Research (2013)

Metastasis by cancer cells relies upon the acquisition of the ability to evade anoikis, a cell death process elicited by detachment from extracellular matrix (ECM). The molecular mechanisms that ECM-detached cancer cells use to survive are not understood. Striking increases in reactive oxygen species (ROS) occur in ECM-detached mammary epithelial cells, threatening cell viability by inhibiting ATP production, suggesting that ROS must be neutralized if cells are to survive ECM-detachment. Here, we report the discovery of a prominent role for antioxidant enzymes, including catalase and superoxide dismutase, in facilitating the survival of breast cancer cells after ECM-detachment. Enhanced expression of antioxidant enzymes in nonmalignant mammary epithelial cells detached from ECM resulted in ATP elevation and survival in the luminal space of mammary acini. Conversely, silencing antioxidant enzyme expression in multiple breast cancer cell lines caused ATP reduction and compromised anchorage-independent growth. Notably, antioxidant enzyme-deficient cancer cells were compromised in their ability to form tumors in mice. In aggregate, our results reveal a vital role for antioxidant enzyme activity in maintaining metabolic activity and anchorage-independent growth in breast cancer cells. Furthermore, these findings imply that eliminating antioxidant enzyme activity may be an effective strategy to enhance susceptibility to cell death in cancer cells that may otherwise survive ECM-detachment.
Mortality Trends in Subjects With and Without Diabetes During 33 Years of Follow-up
Authors: Stefan P.O. Jansson, Dan K.G. Andersson, Kurt Svärdsudd
Journal: Diabetes Care (2009)

OBJECTIVE Mortality rates have declined substantially over the past decades in the general population, but the situation among diabetic subjects is less clear. The aim of this study was to analyze mortality trends in diabetic and nondiabetic subjects during 1972–2004. RESEARCH DESIGN AND METHODS Since 1972, all patients with diabetes are entered in a diabetes register at Laxå Primary Health Care Center; 776 incident cases were recorded up to 2001. The register has been supplemented with a nondiabetic population of 3,880 subjects and with data from the National Cause of Death Register during 1972 to 2004. RESULTS During the 33-year follow-up period, 233 (62.0%) diabetic women and 240 (60.0%) diabetic men and 995 (52.9%) nondiabetic women and 1,082 (54.1%) nondiabetic men died. The age-adjusted hazard ratio (HR) for all-cause mortality among diabetic and nondiabetic subjects was 1.17 (P &amp;lt; 0.0021) for all, 1.22 (P &amp;lt; 0.007) for women, and 1.13 (P = 0.095) for men. The corresponding cardiovascular disease (CVD) mortality HRs were 1.33 (P &amp;lt; 0.0001), 1.41 (P &amp;lt; 0.0003), and 1.27 (P &amp;lt; 0.0093), respectively. The CVD mortality reduction across time was significant in nondiabetic subjects (P &amp;lt; 0.0001) and in men with diabetes (P = 0.014) but not in diabetic women (P = 0.69). The results regarding coronary heart disease (CHD) were similar (P &amp;lt; 0.0001, P &amp;lt; 0.006, and P = 0.17, respectively). The CVD and CHD mortality rate change across time was fairly linear in all groups. CONCLUSIONS Diabetic subjects had less mortality rate reduction during follow-up than nondiabetic subjects. However the excess mortality risk for diabetic subjects was smaller than that found in other studies.
Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination
Authors: Muneer G Hasham, Nina M Donghia, Eliot Coffey, Jane Maynard, Kathy J Snow, Jacquelyn Ames, Robert Y Wilpan, Yishu He, Benjamin L King, Kevin D Mills
Journal: Nature Immunology (2010)
A randomized, phase IIa exploratory trial to assess the safety and preliminary efficacy of LEO 43204 in patients with actinic keratosis
Authors: S. Sinnya, J.M. Tan, T.W. Prow, C. Primiero, E. McEniery, J. Selmer, M.L. Østerdal, H.P. Soyer
Journal: British Journal of Dermatology (2015)

BackgroundLEO 43204 is a novel ingenol derivative in development for the treatment of actinic keratosis.
Studies on the Metabolic Error in Refsum's Disease*
Authors: Daniel Steinberg, Charles E. Mize, Joel Avigan, Henry M. Fales, Lorentz Eldjarn, Kenneth Try, Oddvar Stokke, Sigvald Refsum
Journal: Journal of Clinical Investigation (1967)

Studies utilizing mevalonic acid-2-14C and D2O as precursors failed to provide evidence for an appreciable rate of endogenous biosynthesis of phytanic acid in a patient with Refsum's disease.
Common Hepatic Lipase Gene Promoter Variant Determines Clinical Response to Intensive Lipid-Lowering Treatment
Authors: Alberto Zambon, Samir S. Deeb, B. Greg Brown, John E. Hokanson, John D. Brunzell
Journal: Circulation (2001)

Background —The common −514 C → T polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL 2 cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects. Methods and Results —Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by 14 C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the CC genotype had the greatest decrease in HL activity ( P &lt;0.005 versus TC and TT by ANOVA) and the greatest improvement in LDL density ( P &lt;0.005) and HDL 2 -C ( P &lt;0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of TC and none of the TT patients ( P &lt;0.001). Conclusions —In middle-aged men with established CAD and dyslipidemia, the HL gene −514 C → T polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.
In vivo electrophysiological effects of lidocaine in canine acute myocardial infarction.
Authors: J Kupersmith, E M Antman, B F Hoffman
Journal: Circulation Research (1975)

Lidocaine was administered as a rapid intravenous bolus injection followed by a constant-rate intravenous infusion to nine dogs with 2-hour-old myocardial infarctions. Bipolar electrograms were recorded from and effective refractory periods were determined in the infarcted and normal zones of the heart. Intervals (Q-EG) were measured from the onset of the QRS complex in a standard electrocardiogram limb lead to the major deflection of the recorded electrograms from the normal and infarcted zones. QRS duration and serum lidocaine concentration were also determined. At serum concentrations considered to be therapeutic, lidocaine prolonged the Q-EG intervals in the infarcted zones of the heart 17-26% at peak effect (P less than 0.01), but it had no effect on the Q-EG intervals in the normal zone except for a slight (1.5%) prolongation shortly after the initial intravenous bolus injection. Lidocaine also had no effect on QRS duration. Similarly, lidocaine prolonged the effective refractory period of the infarcted zone 23% (P less than 0.01) at peak effect but had no effect on the effective refractory period of the normal zone. Prior to lidocaine administration, the mean effective refractory period of the normal zone was 26 msec longer than that of the infarcted zone, but at peak drug effect the disparity in refractoriness was reduced to 1 msec. The present study thus shows that lidocaine has different effects in infarcted and normal zones of the heart. In delaying activation and prolonging the effective refractory period of the infarcted zone of the heart, lidocaine has local anesthetic actions which might explain its effectiveness in curtailing ventricular arrhythmias after acute myocardial infarction.
T and B cell in hapten-specific carrier-determined tolerance.
Authors: Y Borel, C L Reinisch, S F Schlossman
Journal: The Journal of Experimental Medicine (1975)

BDF1 mice were made tolerant by a single i.v. injection of 1 mg of DNAP-gamma1 or by weekly i.v. injections of 0.2 mg of DNP-gamma1 given for a month. In both instances, spleen cells of tolerant animals were fractionated to obtain pure populations of T cells (nonimmunoglobulin-bearing cells), referred to as tolerant T cells, and B cells (immunoglobulin-bearing cells) referred to as tolerant B cells (immunoglobulin-bearing cells) referred to as tolerant B cells. The control cells were similarly fractionated to obtain normal T and B cells. Mixtures of tolerant T cells and normal B cells, or conversely, normal T cells and tolerant B cells were used to repopulate lethally irradiated recipients. These recipients were then immunized with dinitrophenyl-keyhole limpet haemocyanin and in certain instances with other antigen horse red blood cells. The immune response to both antigens was measured using the direct hemolytic plaque assay. It was found that both T and B cells were tolerant and that tolerance was hapten specific at both T- and B-cell levels. While B-cell tolerance was demonstrated at a 1/1 T/B ratio, a 4/1 T/B ratio was necessary to show T-cell tolerance. Thus, the hapten-specific carrier-determined tolerance involves not only B cells but also T cells. The implication of this finding for the cellular mechanism of tolerance in an experimental model closely related to self tolerance is discussed.
Flow motion waves with high and low frequency in severe ischaemia before and after percutaneous transluminal angioplasty
Authors: U. Hoffmann, E. Schneider, A. Bollinger
Journal: Cardiovascular Research (1990)

Study of objective – The aim was to evaluate skin flux and prevalence of low and high frequency flow motion waves in patients with severe ischaemia due to peripheral arterial occlusive disease before and after percutaneous transluminal angioplasty (PTA) with and without local thrombolysis. Design – Flow motion was recorded by the laser Doppler technique at the dorsum of the foot before, one day, and one month after PTA. The results were separately analysed in patients with successful and unsuccessful treatment. Subjects – 18 patients with rest pain or incipient gangrene were included. Mean pretreatment systolic ankle pressure was 55.8(SD 25.5) mm Hg, and mean transcutaneous Po2 at 43°C was 5.2(9.4) mm Hg. Arteriography revealed relevant stenoses or occlusions of the femoropopliteal and calf arteries. Measurements and results – Before treatment two patterns of flow motion with characteristic frequency ranges were observed at the foot dorsum and at a probe temperature of 32°C: low frequency (LF) waves with a mean frequency of 2.2(0.5) cycles·min−1 and a mean amplitude of 0.73(0.42) arbitrary units (AU) and high frequency (HF) waves with a mean frequency of 22.6(4.2) cycles·min−1 and a mean amplitude of 0.39(0.33) AU. PTA was successful in 11 of the 18 patients. After successful treatment, prevalence of HF waves decreased from 10/11 to 4/11 cases (p<0.00l), but remained nearly unchanged after failed procedure. Prevalence of LF waves before and after PTA did not differ significantly. Conclusions – Our data support the hypothesis that HF waves represent a reaction of skin microcirculation to severe ischaemia. With reference to animal studies it is proposed that HF waves originate from terminal arterioles. They may function as a compensatory mechanism of flow regulation involved in pathophysiology of ischaemia.
Clinical evaluation of the 14C fat absorption test
Authors: P. J. Burrows, J. S. Fleming, E. S. Garnett, D. M, Ackery, D. G. Colin-Jones, J. Bamforth
Journal: Gut (1974)

The absorption of <sup>14</sup>C-labelled glyceryl tripalmitate was tested in 62 patients by determining the maximum specific activity of CO<sub>2</sub> in the breath after an oral dose. A significant correlation with faecal fat excretion was found. The absorption of <sup>14</sup>C labelled palmitic acid was tested subsequently in 54 patients. In cases of pancreatic steatorrhoea, normal absorption of palmitic acid with impaired absorption of glyceryl tripalmitate was found, whereas in most patients with coeliac disease the absorption of both substances was depressed to the same extent.
Diphtheria Toxin–Epidermal Growth Factor Fusion Protein DAB389EGF for the Treatment of Bladder Cancer
Authors: Xiaoping Yang, Elizabeth Kessler, Lih-Jen Su, Andrew Thorburn, Arthur E. Frankel, Yuan Li, Francisco G. La Rosa, Jingping Shen, Chuan-Yuan Li, Marileila Varella-Garcia, L. Michael Glodé, Thomas W. Flaig
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The novel fusion protein, DAB389EGF, is composed of both the catalytic and the translocation domains of diphtheria toxin that are fused to the human EGF, providing a targeting and a toxicity component. We tested DAB389EGF for antitumor activity in both in vitro and in vivo urinary bladder cancer models. Experimental Design: Human bladder cancer lines were treated with DAB389EGF and assessed for growth inhibition and clonogenic suppression. Using 6- to 8-week-old female athymic nude mice implanted orthotopically with HTB9 cells, DAB389EGF was administered intravesically twice weekly for 2 weeks. The response of the luciferase-expressing HTB9 cells was monitored via bioluminescence as the primary endpoint. Results: Treatment response with DAB389EGF was specific and robust, with an IC50 ranging from 0.5 to 15 ng/mL in eight tested bladder cancer cell lines, but greater than 50 ng/mL in the EGF receptor (EGFR)-negative H520 control cell line. Simulating short-duration intravesical therapy used clinically, a 2-hour treatment exposure of DAB389EGF (10 ng/mL) produced clonogenic suppression in three selected bladder cancer cell lines. In vivo, luciferase activity was suppressed in five of six mice treated with DAB389EGF [70 μL (1 ng/μL) per mouse], as compared with only one of six mice treated with a control diphtheria toxin (DT) fusion protein. Histologic assessment of tumor clearance correlated with the bioluminescent changes observed with DAB389EGF treatment. Immunocompetent mice treated with intravesical DAB389EGF did not show any nonspecific systemic toxicity. Conclusions: The intravesical delivery of targeted toxin fusion proteins is a novel treatment approach for non–muscle-invasive urinary bladder cancer. With appropriate targeting, the treatments are effective and well-tolerated in vivo. Clin Cancer Res; 19(1); 148–57. ©2012 AACR.
Vaccine-associated immune and WT-1 responses are associated with better relapse-free survival in patients with AML in remission treated with a GM-CSF secreting leukemia vaccine and autologous stem cell transplant (ASCT)
Authors: I. Borrello, H. Levitsky, L. Damon, C. Linker, D. Deangelo, E. Alyea, W. Stock, D. Sher, A. Donnelly, K. Hege
Journal: Journal of Clinical Oncology (2005)

6539 Background: Preclinical models have demonstrated the efficacy of GM-CSF secreting cancer vaccines (GVAX) accompanied by vaccine-primed lymphocyte infusion following ASCT. Methods: Patients (Pts) ≤ 60 years old with de novo AML (excluding M3) were enrolled. Leukemia cells were harvested at diagnosis followed by induction and consolidation chemotherapy and ASCT. A single pretransplant vaccine composed of irradiated autologous leukemia cells mixed with GM-CSF gene-modified K562 cells (CG9962) was given followed by collection of vaccine-primed lymphocytes that were reinfused with the stem cell graft. Posttransplant vaccinations were initiated at week 6 (or upon platelet engraftment) and given every 3 weeks (10x107 tumor cells + 4x107 CG9962 cells) x 8 vaccinations. Results: 54 pts were enrolled, 45 (83%) achieved a complete remission, and 27 (50%) proceeded to ASCT. Delayed-type hypersensitivity (DTH) reactions to autologous tumor were induced post vaccination in 43% of pts and this was associated with a trend toward longer relapse-free survival (RFS) (100% vs. 60%, p = 0.08) with a median follow up of 13 months. Antibodies reactive against autologous tumor were induced in 33% and against CG9962 cells in 93%, but no correlation with relapse was noted. Minimal residual disease (MRD) was monitored by quantitative analysis of peripheral blood (PB) and bone marrow (BM) for WT-1, a leukemia-associated gene, by RT-PCR. A decrease in WT-1 in PB (median ∼ 1 log) was noted in 69% of pts following the single pretransplant vaccination and this was associated with longer RFS (80% vs. 0%, p = 0.02). Post transplant, 75% of pts demonstrated clearance of WT-1 from PB and this was also associated with improved RFS (90% vs. 20%, p = 0.002). WT-1 remained detectable in the BM in 63% of pts, most likely representing background expression in normal hematopoietic progenitors. Conclusions: Induction of an immune response to vaccination and a vaccine-associated decrease in MRD as monitored by WT-1 is associated with longer RFS. Clearance of WT-1 from the blood following ASCT appears to predict for better outcome. No significant financial relationships to disclose.
Heparin Disrupts the CXCR4/SDF-1 Axis and Impairs the Functional Capacity of Bone Marrow–Derived Mononuclear Cells Used for Cardiovascular Repair
Authors: Florian H. Seeger, Tina Rasper, Ariane Fischer, Marion Muhly-Reinholz, Eduard Hergenreider, David M. Leistner, Katharina Sommer, Yosif Manavski, Reinhard Henschler, Emmanouil Chavakis, Birgit Assmus, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2012)

Cell therapy is a promising option for the treatment of acute or chronic myocardial ischemia. The intracoronary infusion of cells imposes the potential risk of cell clotting, which may be prevented by the addition of anticoagulants. However, a comprehensive analysis of the effects of anticoagulants on the function of the cells is missing.Here, we investigated the effects of heparin and the thrombin inhibitor bivalirudin on bone marrow-derived mononuclear cell (BMC) functional activity and homing capacity.Heparin, but not bivalirudin profoundly and dose-dependently inhibited basal and stromal cell-derived factor 1 (SDF-1)-induced BMC migration. Incubation of BMCs with 20 U/mL heparin for 30 minutes abrogated SDF-1-induced BMC invasion (16±8% of control; P<0.01), whereas no effects on apoptosis or colony formation were observed (80±33% and 100±44% of control, respectively). Pretreatment of BMCs with heparin significantly reduced the homing of the injected cells in a mouse ear-wound model (69±10% of control; P<0.05). In contrast, bivalirudin did not inhibit in vivo homing of BMCs. Mechanistically, heparin binds to both, the chemoattractant SDF-1 and its receptor, chemokine receptor 4 (CXCR4), blocking CXCR4 internalization as well as SDF-1/CXCR4 signaling after SDF-1 stimulation.Heparin blocks SDF-1/CXCR4 signaling by binding to the ligand as well as the receptor, thereby interfering with migration and homing of BMCs. In contrast, the thrombin inhibitor bivalirudin did not interfere with BMC homing or SDF-1/CXCR4 signaling. These findings suggest that bivalirudin but not heparin might be recommended as an anticoagulant for intracoronary infusion of BMCs for cell therapy after cardiac ischemia.
Acid-base and metabolic disturbances in fulminant hepatic failure.
Authors: C O Record, R A Iles, R D Cohen, R Williams
Journal: Gut (1975)

In 28 patients with fulminant hepatic failure alkalaemia was present in 49 of a total of 65 observations. Alkalaemia was due primarlily to a low Pa, C02 in 30 instances and to raised plasma bicarbonate in 16 instances. Blood lactate, pyruvate, and acetoacetate were significantly raised, and in individual cases, blood citrate, succinate, and fumarate were elevated. Blood citrate rose progressively as the clinical condition worsened. Metabolic acidosis was only present in four patients. In three of these patients, all of whom had taken an overdose of paracetamol, the acidosis was severe, present before the onset of clinical heparic failure, and associated with hypoglycaemiaand mild hypotension. In two of these patients the acidosis was shown to be due to accumulation of lactic acid. Plasma free fatty acid concentrations were elevated out of proportion to the degree of ketosis.
Living unrelated renal transplantation
Authors: M R Said, J J Curtis
Journal: Journal of the American Society of Nephrology (1998)

Transplant centers are turning to emotionally related or living unrelated kidney donors more often than in the past. Such donors are a benefit to the patient with end-stage renal disease, yet concern about their use persists. In the United States, the use of related donors has been well established in most centers. Nonetheless, there had been a reluctance to use nonrelatives that only recently has started to change. Most physicians agree that kidney transplant results are improved with living unrelated donor utilization. The transplant community needs to be watchful of the living unrelated donor operation. Both the welfare of the donor and the possibility of a "slippery slope" toward kidney bartering are considerations that need careful monitoring.
The Decision To No Longer Live on Chronic Hemodialysis
Authors: F. PATRICK MCKEGNEY, PAUL LANGE
Journal: American Journal of Psychiatry (1971)

Most patients receiving chronic hemodialysis consider withdrawing from it if the "quality of life" available to them and/or their families is not sufficient. It would benefit most patients to openly discuss this option with the staff early in the program, thus making it a legitimate topic for discussion later when they may consider it more strongly. The authors' data suggest that this procedure will decrease the morbidity and mortality of patients receiving dialysis.
Extreme Makeover: Transformation of the Veterans Health Care System
Authors: Kenneth W. Kizer, R. Adams Dudley
Journal: Annual Review of Public Health (2009)

The veterans health care system administered by the U.S. Department of Veterans Affairs (VA) was established after World War I to provide health care for veterans who suffered from conditions related to their military service. It has grown to be the nation's largest integrated health care system. As the system grew, a number of factors contributed to its becoming increasingly dysfunctional. By the mid-1990s, VA health care was widely criticized for providing fragmented and disjointed care of unpredictable and irregular quality, which was expensive, difficult to access, and insensitive to individual needs. Between 1995 and 1999, the VA health care system was reengineered, focusing especially on management accountability, care coordination, quality improvement, resource allocation, and information management. Numerous systemic changes were implemented, producing dramatically improved quality, service, and operational efficiency. VA health care is now considered among the best in America, and the VA transformation is viewed as a model for health care reform.