tbuckley/cabot-search huggingface dataset:
Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
Authors: Nicholas Veomett, Tao Dao, Hong Liu, Jingyi Xiang, Dmitry Pankov, Leonid Dubrovsky, Joseph A. Whitten, Sun-Mi Park, Tatyana Korontsvit, Victoria Zakhaleva, Emily Casey, Michael Curcio, Michael G. Kharas, Richard J. O'Reilly, Cheng Liu, David A. Scheinberg
Journal: Clinical Cancer Research (2014)

Abstract Purpose: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)–derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell–based immunotherapy. We previously reported ESK1, a high avidity (Kd &amp;lt; 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1+ and HLA-A*02:01+ leukemia and solid tumor cell lines. Experimental Design: We engineered a second-generation mAb, ESKM, to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared with native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01+ transgenic mice. Results: ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/mL, but ESKM was about 5- to 10-fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 days vs. 6.5 days), but an identical biodistribution pattern in C57BL/6J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared with the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage. Conclusions: The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein. Clin Cancer Res; 20(15); 4036–46. ©2014 AACR.
Clinical Implications for Four Drugs of the DSM-IV Distinction Between Substance Dependence With and Without a Physiological Component
Authors: Marc A. Schuckit, Jean-Bernard Daeppen, George P. Danko, Megan L. Tripp, Tom L. Smith, Ti.-K. Li, Victor M. Hesselbrock, Kathleen K. Bucholz
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: The DSM-IV work group asked researchers and clinicians to subtype substance dependent individuals according to the presence or absence of physiological symptoms. A recent report from the Collaborative Study on the Genetics of Alcoholism demonstrated that among alcohol-dependent men and women, a history of tolerance or withdrawal was associated with a more severe clinical course, especially for individuals with histories of alcohol withdrawal. This article evaluates similar distinctions among subjects in the collaborative study who were dependent on marijuana, cocaine, amphetamines, or opiates. METHOD: Structured interviews gathered information from 1,457 individuals with a lifetime diagnosis of marijuana dependence, 1,262 with histories of cocaine dependence, 647 with amphetamine dependence, and 368 subjects with opiate dependence. For each drug, the clinical course was compared for subjects whose dependence included a history of withdrawal (group 1), those dependent on each drug who denied withdrawal but reported tolerance (group 2), and those who denied both tolerance and withdrawal (group 3). RESULTS: The proportion of dependent individuals who denied tolerance or withdrawal (group 3) ranged from 30% for marijuana to 4% for opiates. For each substance, individuals in groups 1 and 2 evidenced more severe substance-related problems and at least a trend for greater intensities of exposure to the drug; those reporting withdrawal (group 1) showed the greatest intensity of problems. CONCLUSIONS: The designation of dependence in the context of tolerance or withdrawal identifies individuals with more severe clinical histories. These results support the importance of the designation of a physiological component to dependence, especially for people who have experienced a withdrawal syndrome.
Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.
Authors: S Meri, V Koistinen, A Miettinen, T Törnroth, I J Seppälä
Journal: The Journal of Experimental Medicine (1992)

Immunopathological evidence suggests that activation of the alternative pathway of complement (AP) is involved in membranoproliferative glomerulonephritis (MPGN) and in immunoglobulin A nephropathy. In this report we describe an AP dysfunction-associated factor that was isolated from the serum and urine of a patient with hypocomplementemic MPGN. Extensive glomerular deposits of C3, properdin, and of the terminal complement components were observed in the kidney of the patient. In her serum the AP hemolytic activity was virtually absent. When mixed with fresh normal serum, the patient's serum induced a 96% C3 conversion during a 30-min incubation at +37 degrees C. This activity was found to be due to a circulating factor that by immunochemical characterization proved to be a 46-kD monoclonal immunoglobulin lambda light (L) chain dimer (lambda L). Purified lambda L, but not control lambda or kappa L chains from patients with L chain disease, activated the AP in a dose- and ionic strength-dependent manner. Functionally, lambda L was differentiated from C3 nephritic factor (an autoantibody against the AP C3 convertase, C3bBb) by its inability to bind to and stabilize the C3bBb enzyme. Instead, lambda L was observed to interact directly with the AP control factor H. Thus, lambda L represents a novel type of immunoglobulin-related AP-activating factor with the capacity to initiate alternative complement pathway activation in the fluid phase.
The calcipotriol dose–irritation relationship: 48 hour occlusive testing in healthy volunteers using Finn Chambers <sup>®</sup>
Authors: None Fullerton, None Benfeldt, None Roed Petersen, None Birk Jensen, None Serup
Journal: British Journal of Dermatology (1998)

Calcipotriol is widely used in the treatment of psoriasis. Adverse lesional and perilesional irritation may occur. Allergy may occasionally be suspected. Allergy patch testing with calcipotriol may be difficult or impossible because calcipotriol is a local irritant. The aim of the present study was to assess the calcipotriol dose–irritation relationship, and establish a non‐irritant patch test concentration for calcipotriol allergy patch testing. The study was a prospective, double‐blind, randomized, dose titration evaluation in 180 healthy volunteers never previously exposed to calcipotriol. All individuals were patch tested with a calcipotriol dilution series (range 0.016–250 μg/mL). Clinical reading of test sites and measurement of erythema using a Minolta ChromaMeter were performed on days 2 and 3. Laser Doppler perfusion imaging of cutaneous blood flow was performed on day 3. Doubtful reactions (score ½) and weak reactions (score 1) were frequent and observed even at low dose exposure. Reactions declined in strength between the readings on day 2 and day 3. Only score 2 reactions with moderate erythema and some infiltration showed a threshold of no irritation. This threshold was confirmed by colorimetry and flowmetry. Cases of suspected allergy to calcipotriol may, to avoid irritant reaction and false positive readings, be patch tested with calcipotriol 2 μg/mL citrate‐buffered isopropanol solution applied under occlusion for 48 h using small Finn Chambers®. Score ½ and 1 reactions are likely to reflect irritation. A positive test should be repeated after a minimum period of 3 months to ensure its consistency over time. A repeated open application test may be indicated.
Redistribution of 99mTc-sestamibi and 201Tl in the presence of a severe coronary artery stenosis.
Authors: A J Sinusas, J D Bergin, N C Edwards, D D Watson, M Ruiz, R W Makuch, W H Smith, G A Beller
Journal: Circulation (1994)

99mTc-labeled methoxyisobutyl isonitrile (99mTc-sestamibi) is a myocardial perfusion agent that clears slowly from the myocardium. This study evaluates the early and late myocardial distributions of 99mTc-sestamibi and 201Tl in the presence of low-flow ischemia to determine whether 99mTc-sestamibi demonstrates rest "redistribution."Low-flow ischemia was produced in 18 anesthetized, open-chest dogs by partial occlusion of the left anterior descending coronary artery. Dogs were injected intravenously with 99mTc-sestamibi, 301Tl, and radiolabeled microspheres during sustained low-flow ischemia. The hearts were excised either 20 minutes (group 1, 10 dogs) or 2.5 hours (group 2, 8 dogs) after injection for gamma well counting to evaluate the early and late myocardial distributions of these radiotracers, relative to microsphere flow. The early myocardial distributions of 99mTc-sestamibi and 201Tl were comparable and correlated with the flow deficit (group 1). We observed a significant difference in myocardial 201Tl (P = .005) and 99mTc-sestamibi (P < .0001) activities between groups 1 and 2 dogs relative to flow, suggesting some redistribution of both tracers. Myocardial slices were imaged postmortem with a gamma camera, and 99mTc-sestamibi defect intensity was quantified. There was excellent correlation (r = .97) between the early relative 99mTc-sestamibi defect intensity on postmortem images and the flow deficit (group 1). Among group 2 dogs, the correlation was good (r = .87), but the 99mTc-sestamibi defect was less severe than the flow deficit, again suggesting redistribution.The myocardial distributions of 99mTc-sestamibi and 201Tl early after injection are comparable and proportional to flow. Under conditions of sustained low flow, there was detectable rest "redistribution" of 99mTc-sestamibi verified by both gamma well counting and high-resolution postmortem imaging of myocardial slices. Whether this degree of 99mTc-sestamibi rest redistribution will be detectable by serial clinical imaging remains uncertain. Nevertheless, these data suggest that imaging should be delayed after the resting injection of 99mTc-sestamibi when assessing myocardial viability in the presence of a critical stenosis.
The Utility of the Transtubular Potassium Gradient in the Evaluation of Hyperkalemia
Authors: Michael J. Choi, Fuad N. Ziyadeh
Journal: Journal of the American Society of Nephrology (2008)

The transtubular potassium gradient (TTKG) is used to gauge renal potassium secretion by the cortical collecting duct, indirectly assessing mineralocorticoid bioactivity in patients who have hypo- or hyperkalemia. TTKG values <6 indicate an inappropriate renal response to hyperkalemia, whereas values >2 during hypokalemia point to renal loss. Hypokalemia is not addressed here. Studies supporting the usefulness of the TTKG in hyperkalemia are limited to case series. This calculation may be most useful in distinguishing hyperkalemic patients who have mineralocorticoid deficiency versus resistance by observing a change in TTKG values after physiologic or pharmacologic doses of mineralocorticoids.
Rearrangement of the cytoskeletal network induced by platelet-derived growth factor in rat hepatic stellate cells: role of different intracellular signalling pathways
Authors: Antonio Di Sario, Emanuele Bendia, Gianluca Svegliati-Baroni, Marco Marzioni, Francesco Ridolfi, Luciano Trozzi, Laura Ugili, Stefania Saccomanno, Anne Marie Jezequel, Antonio Benedetti
Journal: Journal of Hepatology (2002)
Hemoglobin A1c and the Progression of Coronary Artery Calcification Among Adults Without Diabetes
Authors: April P. Carson, Michael W. Steffes, J. Jeffrey Carr, Yongin Kim, Myron D. Gross, Mercedes R. Carnethon, Jared P. Reis, Catherine M. Loria, David R. Jacobs, Cora E. Lewis
Journal: Diabetes Care (2014)

OBJECTIVE Higher levels of hemoglobin A1c (HbA1c) are associated with increased cardiovascular disease risk among individuals without diabetes and may also be positively associated with coronary artery calcification (CAC). This study investigated the association of HbA1c with CAC progression in the Coronary Artery Risk Development in Young Adults study. RESEARCH DESIGN AND METHODS We included 2,076 participants with HbA1c and noncontrast computed tomography (CT) assessed at baseline (2005–2006), and CT repeated 5 years later (2010–2011). CAC progression was defined as 1) incident CAC (increase &amp;gt;0 Agatston units among those with no CAC at baseline), 2) any CAC progression (increase &amp;gt;10 Agatston units between examinations), and 3) advanced CAC progression (increase &amp;gt;100 Agatston units between examinations). RESULTS During the 5-year follow-up period, 12.9% of participants without baseline CAC developed incident CAC; among all participants, 18.2% had any CAC progression and 5.4% had advanced CAC progression. Higher HbA1c was associated with incident CAC (risk ratio [RR] = 1.45; 95% CI 1.02, 2.06), any CAC progression (RR = 1.51; 95% CI 1.16, 1.96), and advanced CAC progression (RR = 2.42; 95% CI 1.47, 3.99) after adjustment for sociodemographic factors. Additional adjustment for cardiovascular risk factors attenuated the associations of HbA1c with incident CAC (RR = 1.05; 95% CI 0.74, 1.49) and any CAC progression (RR = 1.13; 95% CI 0.87, 1.47). In contrast, the association of HbA1c with advanced CAC progression persisted in multivariable adjusted models (RR = 1.78; 95% CI 1.08, 2.95). CONCLUSIONS Higher HbA1c was independently associated with advanced CAC progression among individuals without diabetes, while the associations with incident CAC and any CAC progression were accounted for by other established cardiovascular risk factors.
Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737
Authors: Keryn M. Lucas, Nethia Mohana-Kumaran, Diana Lau, Xu Dong Zhang, Peter Hersey, David C. Huang, Wolfgang Weninger, Nikolas K. Haass, John D. Allen
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a small-molecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound. Experimental Design: The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA–mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model. Results: MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics. Conclusion: Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers. Clin Cancer Res; 18(3); 783–95. ©2011 AACR.
Contribution of genetic variation to transgenerational inheritance of DNA methylation
Authors: Allan F McRae, Joseph E Powell, Anjali K Henders, Lisa Bowdler, Gibran Hemani, Sonia Shah, Jodie N Painter, Nicholas G Martin, Peter M Visscher, Grant W Montgomery
Journal: Genome biology (2014)

Abstract Background Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, although concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheral blood leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations. Results The correlations from the various available relative pairs indicate that on average the similarity in DNA methylation between relatives is predominantly due to genetic effects with any common environmental or zygotic effects being limited. The average heritability of DNA methylation measured at probes with no known SNPs is estimated as 0.187. The ten most heritable methylation probes were investigated with a genome-wide association study, all showing highly statistically significant cis mQTLs. Further investigation of one of these cis mQTL, found in the MHC region of chromosome 6, showed the most significantly associated SNP was also associated with over 200 other DNA methylation probes in this region and the gene expression level of 9 genes. Conclusions The majority of transgenerational similarity in DNA methylation is attributable to genetic effects, and approximately 20% of individual differences in DNA methylation in the population are caused by DNA sequence variation that is not located within CpG sites.
The immunogenic part of infliximab is the F(ab')2, but measuring antibodies to the intact infliximab molecule is more clinically useful
Authors: S. Ben-Horin, M. Yavzori, L. Katz, U. Kopylov, O. Picard, E. Fudim, D. Coscas, S. Bar-Meir, I. Goldstein, Y. Chowers
Journal: Gut (2010)

<h3>Objectives</h3> To localise the immunogenic part of infliximab and evaluate the clinical usefulness of measuring antibodies against infliximab fragments. <h3>Design</h3> Observational study. <h3>Settings</h3> A specialised inflammatory bowel disease (IBD) centre in a tertiary hospital. <h3>Interventions</h3> Serum was collected from patients with IBD and controls. Antibodies against whole infliximab (ATI) and against the digested Fc, F(ab′)<sub>2</sub> and F(ab′) fragments were measured by a specifically developed ELISA and by western blotting. A separate ELISA was used to determine infliximab levels in serum. <h3>Results</h3> 109 serum samples from 62 infliximab-treated patients were tested along with 64 control samples. Anti-F(ab′)<sub>2</sub> antibodies were found in 28/42 (67%) samples with positive ATI, all from infliximab-exposed patients. Anti-F(ab′)<sub>2</sub> antibodies were also present in 26 of the remaining 67 (39%) samples from exposed patients despite absent ATI. No specific anti-Fc antibodies were detected. Low trough infliximab level and high ATI level was found in 10/12 patients (83%) with complete loss of response to infliximab, but in only 5/14 patients (36%, p=0.02) who regained response to intensified infliximab regimen and in 2/24 patients (8%, p&lt;0.001) in maintained remission while on 5 mg/kg/8 week infliximab treatment. Although Anti-F(ab′)<sub>2</sub> antibodies showed similar test characteristics to ATI in patients losing response to infliximab, they were also detected in 61% of patients in maintained remission, thereby limiting their clinical usefulness. No cross reactivity to adalimumab was noted. <h3>Conclusions</h3> F(ab′)<sub>2</sub> is the immunogenic fragment of infliximab. However, ATI level in serum—combined with measurement of trough infliximab level—is better correlated with the clinical response to infliximab or with its loss.
ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—Summary Article
Authors: Gabriel Gregoratos, Jonathan Abrams, Andrew E Epstein, Roger A Freedman, David L Hayes, Mark A Hlatky, Richard E Kerber, Gerald V Naccarelli, Mark H Schoenfeld, Michael J Silka, Stephen L Winters, Raymond J Gibbons, Elliott M Antman, Joseph S Alpert, Gabriel Gregoratos, Loren F Hiratzka, David P Faxon, Alice K Jacobs, Valentin Fuster, Sidney C Smith
Journal: Journal of the American College of Cardiology (2002)
Intrathoracic and abdominal pressure variations as an efficient method for cardiopulmonary resuscitation: Studies in dogs compared with computer model results
Authors: R. BEYAR, Y. KISHON, E. KIMMEL, H. NEUFELD, U. DINNAR
Journal: Cardiovascular Research (1985)

Intrathoracic pressure variations are currently proposed as the main flow-generation mechanisms in standard and modified cardiopulmonary resuscitation (CPR) techniques. A method of changing pressure within the thorax and abdomen without any degree of heart compression was developed and tested in dogs. Intrathoracic and abdominal pressure waves were induced by cyclic inflation and deflation of the lungs and of perithoracic and periabdominal balloons. Various modes of CPR, depending on the rate of cycling, the use of a periabdominal balloon inflation, and a delay between the abdominal and thoracic pressure waves, were studied during ventricular fibrillation. During artificial systole (high intrathoracic pressure phase), the pressure which developed in the right ventricle (96.7 +/- 20.5 mmHg) was higher than the pressure in the aorta (89.3 +/- 20.5 mmHg, p less than 0.001). In artificial diastole (low intrathoracic pressure phase), the right ventricular pressure (11.7 +/- 2.6 mmHg) was lower than the aortic pressure (17.5 +/- 3.3 mmHg, p less than 0.001). The average flow in the carotid artery was 21.7 +/- 7.8 ml . min-1, which was 18 +/- 6% of the baseline carotid flow before CPR. Three different factors were found to improve the efficiency of CPR: periabdominal balloon inflation simultaneous with the intrathoracic pressure waves; increased frequency of the pressure waves from 60 to 100 cycles per minute; and inflation of the periabdominal balloon 50 to 100 ms before the thoracic balloon. Blood-gas and acid-base balance analysis during CPR revealed well-oxygenated arterial blood with a marked respiratory alkalosis and a slowly developing metabolic acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)