tbuckley/cabot-search huggingface dataset:
Immunohistochemical Detection of c-erbB-2 and p53 in Benign Breast Disease and Breast Cancer Risk
Authors: Thomas E. Rohan, Warren Hartwick, Anthony B. Miller, Rita A. Kandel
Journal: JNCI Journal of the National Cancer Institute (1998)

We studied the associations between c-erbB-2 protein overexpression and p53 protein accumulation in benign breast tissue and the risk of subsequent breast cancer.We conducted a case-control study nested within the cohort of 4888 women in the National Breast Screening Study (NBSS) who were diagnosed with benign breast disease during active follow-up. Case subjects were the women who subsequently developed breast cancer (ductal carcinoma in situ [DCIS] or invasive carcinoma). Control subjects were matched to each case subject on NBSS study arm, screening center, year of birth, and age at diagnosis of benign breast disease. Histologic sections of benign and cancerous breast tissues were analyzed immunohistochemically. Information on potential confounding factors was obtained by use of a self-administered lifestyle questionnaire.Accumulation of p53 protein was associated with an increased risk of progression to breast cancer (adjusted odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.01-6.40), whereas c-erbB-2 protein overexpression was not (adjusted OR = 0.65; 95% CI = 0.27-1.53). The findings for c-erbB-2 and p53 did not differ among strata defined by menopausal status, allocation within the NBSS, history of breast disease, and whether the benign breast disease was detected at a scheduled screen or between screens. The results were also similar after exclusion of case subjects whose diagnosis of breast cancer occurred within 1 year of their diagnosis of benign breast disease and after exclusion of subjects with DCIS.p53 protein accumulation, but not c-erbB-2 protein overexpression, appears to be associated with an increased risk of progression to breast cancer in women with benign breast disease.
TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to tumour necrosis factor blockade
Authors: A W R van Kuijk, C A Wijbrandts, M Vinkenoog, T S Zheng, K A Reedquist, P P Tak
Journal: Annals of the Rheumatic Diseases (2009)

To investigate the expression of tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) in the inflamed synovium of patients with arthritis, as TWEAK blockade has been observed to have a beneficial effect in an animal model of rheumatoid arthritis (RA).Synovial tissue (ST) biopsies were obtained from 6 early, methotrexate-naive patients with RA as well as 13 patients with RA and 16 patients with psoriatic arthritis (PsA) who were matched for treatment and disease duration. Serial ST samples were obtained from a separate cohort of 13 patients with RA before and after infliximab treatment. TWEAK and Fn14 expression was evaluated by immunohistochemistry and digital image analysis.TWEAK and Fn14 were clearly expressed in ST of patients with RA and PsA. TWEAK expression was significantly higher in RA (sub)lining samples compared to PsA (p = 0.005 and p = 0.014, respectively), but Fn14 expression was comparable. Double immunofluorescence showed TWEAK and Fn14 expression on fibroblast-like synoviocytes and macrophages, but not T cells. Of interest, persistent TWEAK and Fn14 expression was found after anti-TNF therapy.TWEAK and Fn14 are abundantly expressed in the inflamed synovium of patients with RA and PsA. This raises the possibility that blocking TWEAK/Fn14 signalling could be of therapeutic benefit in inflammatory arthritis.
EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: A potential mechanism of EGFR-driven antagonism of apoptosis
Authors: Xinyu Cao, Hu Zhu, Francis Ali-Osman, Hui-Wen Lo
Journal: Molecular Cancer (2011)

Epidermal growth factor receptor (EGFR) plays an essential role in normal development, tumorigenesis and malignant biology of human cancers, and is known to undergo intracellular trafficking to subcellular organelles. Although several studies have shown that EGFR translocates into the mitochondria in cancer cells, it remains unclear whether mitochondrially localized EGFR has an impact on the cells and whether EGFRvIII, a constitutively activated variant of EGFR, undergoes mitochondrial transport similar to EGFR.We report that both receptors translocate into the mitochondria of human glioblastoma and breast cancer cells, following treatments with the apoptosis inducers, staurosporine and anisomycin, and with an EGFR kinase inhibitor. Using mutant EGFR/EGFRvIII receptors engineered to undergo enriched intracellular trafficking into the mitochondria, we showed that glioblastoma cells expressing the mitochondrially enriched EGFRvIII were more resistant to staurosporine- and anisomycin-induced growth suppression and apoptosis and were highly resistant to EGFR kinase inhibitor-mediated growth inhibition.These findings indicate that apoptosis inducers and EGFR-targeted inhibitors enhance mitochondrial translocalization of both EGFR and EGFRvIII and that mitochondrial accumulation of these receptors contributes to tumor drug resistance. The findings also provide evidence for a potential link between the mitochondrial EGFR pathway and apoptosis.
New Methods for Labeling RGD Peptides with Bromine-76
Authors: Lixin Lang, Weihua Li, Hong-Mei Jia, De-Cai Fang, Shushu Zhang, Xilin Sun, Lei Zhu, Ying Ma, Baozhong Shen, Dale O. Kiesewetter, Gang Niu, Xiaoyuan Chen
Journal: Theranostics (2011)

Direct bromination of the tyrosine residues of peptides and antibodies with bromine-76, to create probes for PET imaging, has been reported. For peptides that do not contain tyrosine residues, however, a prosthetic group is required to achieve labeling via conjugation to other functional groups such as terminal α-amines or lysine ε-amines. The goal of this study was to develop new strategies for labeling small peptides with Br-76 using either a direct labeling method or a prosthetic group, depending on the available functional group on the peptides. A new labeling agent, N-succinimidyl-3-[(76)Br]bromo-2,6-dimethoxybenzoate ([(76)Br]SBDMB) was prepared for cyclic RGD peptide labeling. N-succinimidyl-2, 6-dimethoxybenzoate was also used to pre-attach a 2, 6-dimethoxybenzoyl (DMB) moiety to the peptide, which could then be labeled with Br-76. A competitive cell binding assay was performed to determine the binding affinity of the brominated peptides. PET imaging of U87MG human glioblastoma xenografted mice was performed using [(76)Br]-BrE[c(RGDyK)](2) and [(76)Br]-BrDMB-E[c(RGDyK)](2). An ex vivo biodistribution assay was performed to confirm PET quantification. The mechanisms of bromination reaction between DMB-c(RGDyK) and the brominating agent CH(3)COOBr were investigated with the SCRF-B3LYP/6-31G* method with the Gaussian 09 program package. The yield for direct labeling of c(RGDyK) and E[c(RGDyK)](2) using chloramine-T and peracetic acid at ambient temperature was greater than 50%. The yield for [(76)Br]SBDMB was over 60% using peracetic acid. The conjugation yields for labeling c(RGDfK) and c(RGDyK) were over 70% using the prosthetic group at room temperature. Labeling yield for pre-conjugated peptides was over 60%. SDMB conjugation and bromination did not affect the binding affinity of the peptides with integrin receptors. Both [(76)Br]Br-E[c(RGDyK)](2) and [(76)Br]BrDMB-E[c(RGDyK)](2) showed high tumor uptake in U87MG tumor bearing mice. The specificity of the imaging tracers was confirmed by decreased tumor uptake after co-administration of unlabeled dimeric RGD peptides. The energy barrier of the transition state of bromination for the dimethoxybenzoyl group was about 9 kcal/mol lower than that for the tyrosine residue. In conclusion, the newly developed N-succinimidyl-2, 6-dimethoxybenzoate molecule can be used either for one step labeling through pre-conjugation or as the precursor for a Br-76 labeled prosthetic group for indirect labeling. Radiobromination on a dimethoxybenzoyl group has selectivity over radiobromination on tyrosine. The energy barrier difference of the transition states of bromination between the dimethoxybenzoyl group and the tyrosine residue may account for the reaction selectivity when both groups are present in the same molecule.
CXCL12 Mediates Immunosuppression in the Lymphoma Microenvironment after Allogeneic Transplantation of Hematopoietic Cells
Authors: Christoph Dürr, Dietmar Pfeifer, Rainer Claus, Annette Schmitt-Graeff, Ulrike V. Gerlach, Ralph Graeser, Sophie Krüger, Armin Gerbitz, Robert S. Negrin, Jürgen Finke, Robert Zeiser
Journal: Cancer Research (2010)

Abstract Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT. Cancer Res; 70(24); 10170–81. ©2010 AACR.
Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis
Authors: Marije F. Bakker
Journal: Annals of Internal Medicine (2012)

Background: Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. Objective: To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)–based treatment strategy for tight control in early RA increases its effectiveness. Design: A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) Setting: 7 hospitals in the Netherlands. Patients: 236 patients with early RA (duration <1 year). Intervention: Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. Measurements: The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. Results: Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. Limitation: A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. Conclusion: Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. Primary Funding Source: Catharijne Foundation.
Is There a Single Underlying Factor for the Metabolic Syndrome in Adolescents?
Authors: Chaoyang Li, Earl S. Ford
Journal: Diabetes Care (2007)

The lack of a universally applicable model for the metabolic syndrome in the pediatric population makes it difficult to define this syndrome and compare its prevalence across studies and diverse populations. We sought to assess whether a single underlying factor could represent the metabolic syndrome in adolescents.Using data from the National Health and Nutrition Examination Survey (1999-2002), we conducted a confirmatory factor analysis to assess the validity of waist circumference, triglycerides, fasting insulin, and systolic blood pressure (SBP) as potential phenotypic traits for the metabolic syndrome in adolescents aged 12-17 years (n = 1,262). A multiple-group approach was used to test the invariance in factor loadings across sex and race/ethnicity.The estimates of factor loadings for the total sample were 0.76, 0.46, 0.81, and 0.42 for waist circumference, triglycerides, fasting insulin, and SBP, respectively. The goodness-of-fit indexes were adequate for the total sample (comparative fit index, 0.99; standardized root mean square residual, 0.02), Caucasian boys (1.0; 0.01), African-American boys (0.99; 0.03), Mexican-American boys (1.0; 0.01), Mexican-American girls (1.0; 0.01), and Caucasian girls (0.95; 0.04) and acceptable for African-American girls (0.94; 0.05). There were no significant differences in factor loadings of the four measured variables between boys and girls and among the three racial or ethnic subgroups.The metabolic syndrome as a single underlying factor for the four simple phenotypic traits may be plausible in adolescents. The proposed model appears to be generalizable across sex and race/ethnicity.
2-Methylthioadenosine[beta-32P]diphosphate. An agonist and radioligand for the receptor that inhibits the accumulation of cyclic AMP in intact blood platelets.
Authors: D E Macfarlane, P C Srivastava, D C Mills
Journal: Journal of Clinical Investigation (1983)

2-Methylthio-ADP and its radioactive analogue [beta-32P]2-methylthio-ADP were synthesized and used to investigate platelet receptors for ADP. 2-Methylthio-ADP induced platelet aggregation and shape change, and inhibited cyclic AMP accumulation in platelets exposed to prostaglandin E1. Compared with ADP, 2-methylthio-ADP was 3-5 times as active as an aggregating agent and 150-200 times as active as an inhibitor of cyclic AMP accumulation. Binding of [beta-32P]2-methylthio-ADP to platelets was measured after centrifuging them through silicone oil to separate platelets from their suspension medium. Binding was reversible, saturable, and specific, with between 400 and 1,200 sites/cell in different platelet preparations. There was no evidence for a second class of binding sites with different affinity. The second order association rate constant was approximately 3.5 X 10(6) M-1 S-1, and the first order dissociation rate was 0.024 s-1, both measured at 23 degrees C. The dissociation equilibrium constant (approximately 15 nM) was about three times higher than the concentration giving half-maximal inhibition of prostaglandin E1-stimulated cyclic AMP accumulation in platelet-rich plasma. Binding was inhibited by ADP (Ki = 3.5 microM), ATP (7 microM), 2-azido-ADP (0.12 microM), inosine diphosphate (IDP, 150 microM), guanosine diphosphate (GDP, 350 microM), and AMP (800 microM). Binding of 2-methylthio-ADP was also blocked by the non-cell-penetrating thiol reagent, p-mercuribenzene sulphonate, a reagent that blocks the inhibition of adenylate cyclase by ADP, but which does not block the ability of ADP to induce aggregation or platelet shape change. The amount of 2-methylthio-ADP bound at saturation was independent of pH in the range 6-8, but the affinity was reduced at pH 6 compared with pH 6.5-8.0. The dissociation constant was not temperature dependent in the range 32 degrees -40 degrees C, whereas the rate of dissociation of 2-methylthio-ADP from platelets after the addition of an excess of ADP approximately doubled over this range. The activation energy for dissociation was approximately 15 kcal/mol. Our results support the conclusion that platelets have a receptor for ADP, which inhibits cyclic AMP accumulation, and which has a sulphydryl group in the binding pocket.
Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma
Authors: S. Patil, R.A. Figlin, T.E. Hutson, M.D. Michaelson, S. Négrier, S.T. Kim, X. Huang, R.J. Motzer
Journal: Annals of Oncology (2010)
Thoracoscopic Lung Volume Reduction Surgery Reduces Dyspnea and Improves Exercise Capacity in Patients with Emphysema
Authors: CESAR A. KELLER, GREGG RUPPEL, ALAN HIBBETT, JOAN OSTERLOH, KEITH S. NAUNHEIM
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Improved ventilation and exercise capacity follows thoracoscopic lung volume reduction surgery (TLVRS) in patients with severe emphysema. This improvement could be related to changes in inspiratory and expiratory flows following surgery, with consequent improvement in dyspnea indices. Changes in inspiratory/expiratory flows at rest and exercise and their relation to subjective improvement in dyspnea after TLVRS are not well known. We studied 25 patients with severe emphysema who underwent unilateral TLVRS performed in well-defined zones with decreased perfusion in nuclear medicine lung scans. Early follow-up after surgery (4.2 ± 0.8 mo) showed significant improvements in exercise tolerance: The distance covered over a 6 min walk test increased from 934 ± 297 to 1,071 ± 241 ft (p = 0.01). Exercise tolerance using a bicycle ergometer showed increased exercise endurance from 4.43 ± 1.7 to 5.71 ± 1.8 min (p < 0.001). The maximum workload tolerated increased from 37 ± 19 to 52 ± 21 W (p < 0.01) and Vo 2 max changed from 9.7 ± 2 to 11.8 ± 3 (ml-kg)/min (p < 0.01). This increment was achieved by generating significantly larger minute ventilation (V˙ e), from 24 ± 11 to 29 ± 10 L/min, reached through larger tidal volumes (increasing from 951 ± 330 to 1,145 ± 367 ml), while maintaining the same maximum respiratory rates. Increased V˙ e was also accompanied by significant increases in both average inspiratory and expiratory flows measured during exercise: from 0.89 ± 0.41 L/s to 1.06 ± 0.08 L/s, and from 0.77 ± 0.37 to 0.90 ± 0.32 L/s respectively (p < 0.01). The parallel increment in flows resulted in constant Ti/Ttot relationship. These functional changes correlated with increased inspiratory flows at rest measured with pulmonary function tests (forced inspiratory volume in one s [FIV1], expiratory flows [FVC, FEV1], and increased maximum voluntary ventilation [MVV]) following the surgically induced reduction in residual volume (RV). These objective changes occurred parallel to improved dyspnea indices. The Baseline Focal Score was 3.36 ± 1.47 and the Transition Focal Score was 6.12 ± 0.7. The objectively measured variables at rest that best correlated with subjective improvement in dyspnea were the change in MVV, change in resting arterial PaO2 , and change in FEV1 following TLVRS. Exercise variables did not have significant correlation with subjective markers indicating improvement in dyspnea, with the exception of the change in Dyspneic Index [(V˙E/MVV)100] at maximum exercise.
Perception of pain in the minimally conscious state with PET activation: an observational study
Authors: Mélanie Boly, Marie-Elisabeth Faymonville, Caroline Schnakers, Philippe Peigneux, Bernard Lambermont, Christophe Phillips, Patrizio Lancellotti, Andre Luxen, Maurice Lamy, Gustave Moonen, Pierre Maquet, Steven Laureys
Journal: The Lancet Neurology (2008)
Changes in mitochondrial DNA in cardiac hypertrophy in the rat.
Authors: C Rajamanickam, S Merten, B Kwiatkowska-Patzer, C H Chuang, R Zak, M Rabinowitz
Journal: Circulation Research (1979)

We studied DNA (mtDNA) replication in adult female rat hearts undergoing hypertrophy secondary to constriction of the ascending aorta. MtDNA was measured in isolated mitochondria by a fluorometric method adapted for that purpose. The conditions for removal of contaminating nuclear DNA were developed, and the purity of the mtDNA was assessed from its molecular conformation (open and closed circles) and by renaturation-kinetic analysis. The mtDNA concentration in mitochondria, expressed as micrograms of DNA per milligram of mitochondrial protein, increased 2, 4, and 7 days postoperatively by 21, 73, and 98%, respectively. Similar results were obtained when mtDNA was expressed per nonomole of cytochrome a. The population of replicative intermediates of mtDNA was analyzed by electron microscopy. In normal hearts, we observed molecular forms characteristic of animal mtDNA, such as circular monomers and dimers, catenated molecules, D-loops, expanded D-loops, and gapped molecules. D-loop frequency, which was near 50% in the mtDNA of control hearts, was markedly reduced to 5-7% in hypertrophying hearts. This result indicates that the increase in replicative flux of mtDNA is associated with the removal of a block in the conversion of D-loops to other intermediates.
Correlation of the extent of tumor volume resection and patient survival in surgery of glioblastoma multiforme with high-field intraoperative MRI guidance
Authors: D. Kuhnt, A. Becker, O. Ganslandt, M. Bauer, M. Buchfelder, C. Nimsky
Journal: Neuro-Oncology (2011)

Extent of resection (EOR) still remains controversial in therapy of glioblastoma multiforme (GBM). However, an increasing number of studies favor maximum EOR as being associated with longer patient survival. One hundred thirty-five GBM patients underwent tumor resection aided by 1.5T intraoperative MRI (iMRI) and integrated multimodal navigation. Tumor volume was quantified by manual segmentation. The influences of EOR, patient age, recurrent tumor, tumor localization, and gender on survival time were examined. Intraoperative MRI detected residual tumor volume in 88 patients. In 19 patients surgery was continued; further resection resulted in final gross total resection (GTR) for 9 patients (GTR increased from 47 [34.80%] to 56 [41.49%] patients). Tumor volumes were significantly reduced from 34.25 ± 23.68% (first iMRI) to 1.22 ± 16.24% (final iMRI). According to Kaplan-Meier estimates, median survival was 14 months (95% confidence interval [CI]: 11.7-16.2) for EOR ≥ 98% and 9 months (95% CI: 7.4-10.5) for EOR <98% (P< .0001); it was 9 months (95% CI: 7.3-10.7) for patients ≥ 65 years and 12 months (95% CI: 8.4-15.6) for patients <65 years (P < .05). Multivariate analysis showed a hazard ratio of 0.39 (95% CI: 0.24-0.63; P = .001) for EOR ≥ 98% and 0.61 (95% CI: 0.38-0.97; P < .05) for patient age <65 years. To our knowledge, this is the largest study including correlation of iMRI, tumor volumetry, and survival time. We demonstrate that navigation guidance and iMRI significantly contribute to optimal EOR with low postoperative morbidity, where EOR ≥ 98% and patient age <65 years are associated with significant survival advantages. Thus, maximum EOR should be the surgical goal in GBM surgery while preserving neurological function.