tbuckley/cabot-search huggingface dataset:
PERSISTENCE OF TYPE-SPECIFIC ANTIBODIES IN MAN FOLLOWING INFECTION WITH GROUP A STREPTOCOCCI
Authors: Rebecca C. Lancefield
Journal: The Journal of Experimental Medicine (1959)

Whole blood or sera were collected from individuals who had had infections with Group A streptococci of known serological type as long ago as 10 to 32 years. Most of these patients had not been treated with chemotherapeutic drugs. By means of bactericidal tests with all these sera, and mouse protection tests with some, type-specific antibodies could be demonstrated in at least half of them after a lapse of many years, the longest interval being 32 years. Two biological methods for estimating the amount of M antigen produced by Group A streptococci are described. By selecting strains for use by these methods, optimal proportions of M antigen and antibody could be employed in the tests and small amounts of antibody were, therefore, demonstrable. The assay methods for M antigen are also of value for other experimental purposes.
Thymic dendritic cells traffic to thymi of allogeneic recipients and prolong graft survival
Authors: Steven R. Duncan, Nickolas G. Capetanakis, Brian R. Lawson, Argyrios N. Theofilopoulos
Journal: Journal of Clinical Investigation (2002)

We have demonstrated that murine thymic dendritic cells (DCs) isolated from donor mice have the capability to home to thymi of fully allogeneic recipients after intravenous injections, where they induce T cell deletions and prolong donor-strain airway and skin graft survival. In contrast, infused splenic DCs immigrated poorly to thymi, and did not affect graft survival. These findings suggest that preferential homing may be an important mechanistic difference among subpopulations of DCs that mediate immune functions and illustrate a novel methodology that could have utility for induction of specific immunologic nonreactivity to allografts, or other disease-associated antigens.
Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart
Authors: Florian Hofmann, Larissa Fabritz, Juliane Stieber, Joachim Schmitt, Paulus Kirchhof, Andreas Ludwig, Stefan Herrmann
Journal: Cardiovascular Research (2012)

AimsCardiac hypertrophy is accompanied by reprogramming of gene expression, where the altered expression of ion channels decreases electrical stability and increases the risk of life-threatening arrhythmias. However, the underlying mechanisms are not fully understood. Here, we analysed the role of the depolarizing current If which has been hypothesized to contribute to arrhythmogenesis in the hypertrophied ventricle.
Preoperative Serum Caveolin-1 as a Prognostic Marker for Recurrence in a Radical Prostatectomy Cohort
Authors: Salahaldin A. Tahir, Anna Frolov, Teresa G. Hayes, Martha P. Mims, Brian J. Miles, Seth P. Lerner, Thomas M. Wheeler, Gustavo Ayala, Timothy C. Thompson, Dov Kadmon
Journal: Clinical Cancer Research (2006)

Up-regulation of caveolin-1 (cav-1) is associated with virulent prostate cancer, and serum cav-1 levels are elevated in prostate cancer patients but not in benign prostatic hyperplasia. In this study, we evaluated the potential of high preoperative serum cav-1 levels to predict biochemical progression of prostate cancer. The value of the combined preoperative markers, prostate-specific antigen (PSA), biopsy Gleason score, and serum cav-1 for predicting biochemical recurrence was also investigated.Serum samples taken from 419 prostate cancer patients before radical prostatectomy were selected from our Specialized Programs of Research Excellence prostate cancer serum and tissue bank. Serum samples were obtained 0 to 180 days before surgery and all patients had complete data on age, sex, race, stage at enrollment, and follow-up for biochemical recurrence. Serum cav-1 levels were measured according to our previously reported ELISA protocol.Cav-1 levels were measured in the sera of 419 prostate cancer patients; the mean serum level was 4.52 ng/mL (median 1.01 ng/mL). Patients with high serum cav-1 levels had a 2.7-fold (P = 0.0493) greater risk of developing biochemical recurrence compared with those with low serum cav-1 levels. Importantly, patients with serum PSA >/= 10 ng/mL and elevated levels of serum cav-1 had 2.44 times higher risk (P = 0.0256) of developing biochemical recurrence compared with patients with low levels of cav-1. In addition, high serum cav-1 levels combined with increasing biopsy Gleason score predicted much shorter recurrence-free survival in the group of patients with PSA >/= 10 ng/mL (P = 0.0353). Cav-1 was also able to distinguish between high- and low- risk patients with biopsy Gleason score of seven, after adjusting, for patients PSA levels (P = 0.0429).Overall, elevated preoperative levels of serum cav-1 predict decreased time to cancer recurrence. In the subset of patients with serum PSA of >/=10 ng/mL, the combination of serum cav-1 and biopsy Gleason score has the capacity to predict time to biochemical recurrence.
Fluid Shear Stress and NO Decrease the Activity of the Hydroxy-Methylglutaryl Coenzyme A Reductase in Endothelial Cells via the AMP-Activated Protein Kinase and FoxO1
Authors: Beate Fisslthaler, Ingrid Fleming, Benjamin Keserü, Kenneth Walsh, Rudi Busse
Journal: Circulation Research (2007)

The rate-limiting enzyme for cholesterol synthesis, the hydroxy-methylglutaryl coenzyme A reductase (HCR), is phosphorylated by the AMP-activated protein kinase (AMPK). As shear stress activates the AMPK in endothelial cells, we determined whether it affects HCR activity and subsequent HCR-dependent signaling. Shear stress (12 dynes cm(-2)) rapidly increased the phosphorylation and activity (6.5- and 4-fold, respectively) of the AMPK in cultured endothelial cells and the activated AMPK phosphorylated the HCR in vitro. Moreover, shear stress and the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated endothelial HCR activity by 37% and 33%, respectively. Inhibition of NO production attenuated the acute shear stress-induced phosphorylation of the AMPK and the decrease in HCR activity. Prolonged shear stress (18 hours) led to a significant (50%) decrease in HCR mRNA expression that was dependent on NO, AMPK, and the subsequent phosphorylation and degradation of FoxO1a. Correspondingly, the downregulation of FoxO (small interfering RNA) decreased HCR expression. Prolonged shear stress also attenuated the bradykinin-induced activation of Ras and extracellular signal-regulated kinase 1/2, a phenomenon that was comparable to the effects of cerivastatin and that was reversed by mevalonate and thus attributed to HCR inhibition. A decrease (35%) in HCR expression was also detected in femoral arteries from mice following voluntary exercise, and the bradykinin-induced vasodilatation of the mouse hindlimb was attenuated by both exercise and the HCR inhibitor cerivastatin. These data indicate that fluid shear stress regulates the activity and expression of the HCR in endothelial cells and determines responsiveness to stimuli, such as bradykinin via a mechanism involving NO, AMPK, FoxO1a, and p21Ras.
Phase I Trial of Lenalidomide and CCI-779 in Patients With Relapsed Multiple Myeloma: Evidence for Lenalidomide–CCI-779 Interaction via P-Glycoprotein
Authors: Craig C. Hofmeister, Xiaoxia Yang, Flavia Pichiorri, Ping Chen, Darlene M. Rozewski, Amy J. Johnson, Seungsoo Lee, Zhongfa Liu, Celia L. Garr, Erinn M. Hade, Jia Ji, Larry J. Schaaf, Don M. Benson, Eric H. Kraut, William J. Hicks, Kenneth K. Chan, Ching-Shih Chen, Sherif S. Farag, Michael R. Grever, John C. Byrd, Mitch A. Phelps
Journal: Journal of Clinical Oncology (2011)

Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.
Cognitive functions in primary CNS lymphoma after single or combined modality regimens
Authors: D. D. Correa, W. Shi, L. E. Abrey, L. M. DeAngelis, A. M. Omuro, M. B. Deutsch, H. T. Thaler
Journal: Neuro-Oncology (2011)

The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.
Abnormalities of Fragile Histidine Triad Genomic and Complementary DNAs in Cervical Cancer: Association With Human Papillomavirus Type
Authors: Carolyn Y. Muller, John D. O'Boyle, Kwun M. Fong, Ignacio I. Wistuba, Eric Biesterveld, Mohsen Ahmadian, David S. Miller, Adi F. Gazdar, John D. Minna
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Chromosome 3p14.2 contains FRA3B, the most active chromosome breakage site in the human genome. The fragile histidine triad (FHIT) gene, a putative tumor suppressor gene, overlaps FRA3B. Human papillomavirus (HPV), a known cofactor in cervical carcinogenesis, can integrate into FRA3B. We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types. Methods: Eleven cell lines, 40 tumors (20 fresh and 20 archival), and 10 normal cervical epithelia were examined. Two intragenic polymorphic markers (D3S1300 and D3S4103) and the polymerase chain reaction (PCR) were used to examine FHIT LOH. Reverse transcription-PCR (RT-PCR) analysis and single-strand conformation polymorphism analysis of RT-PCR products were used to characterize FHIT transcripts. Oncogenic HPV types were identified by PCR, using general and type-specific primers. Results: All normal epithelia, 19 of 20 fresh tumors and nine of 11 cell lines expressed wild-type and, occasionally, exon 8-deleted FHIT transcripts. Additional aberrant FHIT transcripts were seen in nine of 20 fresh tumors and in seven of 11 cell lines. DNA sequencing of the aberrant transcripts revealed a variety of insertions and deletions but no point mutations. Three cell lines also had homozygous FHIT deletions. Oncogenic HPV types (i.e., 16, 18, 31, and 33) were detected in 18 of 20 archival tumors, and, in these tumors, LOH within FHIT was identified in nine of 16 informative cases. HPV 16 was found to be associated with LOH in the FHIT/FRA3B region (P = .041). Conclusion: FHIT/FRA3B is frequently altered in cervical cancer, demonstrating LOH, occasional homozygous deletions, and frequent aberrant transcripts not found in normal epithelia. However, the presence of wild-type transcripts and the lack of protein-altering point mutations raise questions about FHIT's function as a classic tumor suppressor gene in cervical tissue.
Magnetic resonance microscopy and histopathology: Comparative approach of bromobenzene-induced hepatotoxicity in the rat
Authors: Marielle Delnomdedieu, Laurence W. Hedlund, Robert R. Maronpot, Allan G. Johnson
Journal: Hepatology (1998)

The development of magnetic resonance (MR) microscopy has provided new approaches to histology and histopathology. Recent work has shown the promise of increased sensitivity in animal models of chemically induced hepatotoxicity. However, the field is so new that there is little experience to relate changes seen in MR micrographs to the more traditional optical images stained with hematoxylin and eosin. This work compares the sensitivity and reproducibility of MR microscopy with conventional histopathology in detecting bromobenzene-induced hepatotoxicity in the rat. A time-course study was undertaken to provide a range of histopathologies. Specimens were studied at 24, 48, 72, and 96 hours after exposure to 10% of the median lethal dose of bromobenzene. Using 4 animals per group (a total of 32 rats) added statistical significance to the study and defined a range of interanimal variability over 96 hours. This work shows that MR microscopy, besides being nondestructive and three-dimensional, is at least as sensitive as conventional hematoxylin-eosin staining in detecting bromobenzene-induced centrilobular lesions and recovery of the hepatocellular architecture in the rat. This study further suggests that, as we begin to understand the underlying mechanisms of contrast in MR histology, MR may, in fact, supply even higher specificity than more traditional studies: variations were observed in MR images of treated livers at a given time point that could be not be differentiated based on the grading of necrosis and inflammation on hematoxylin-eosin-stained sections.
Beta 1 integrin-mediated interaction with extracellular matrix proteins regulates cytokine gene expression in synovial fluid cells of rheumatoid arthritis patients.
Authors: S Miyake, H Yagita, T Maruyama, H Hashimoto, N Miyasaka, K Okumura
Journal: The Journal of Experimental Medicine (1993)

Inflammatory cytokines have been implicated in the pathogenesis of rheumatoid arthritis (RA), whereas the mechanisms for constitutive production of inflammatory cytokines in affected joints are largely unknown. Recently, integrin-mediated interaction with extracellular matrix (ECM) proteins has been demonstrated to play a role in regulating cytokine production in T cells and monocytes. In this study, we investigated the contribution of the beta 1 integrin-mediated interaction with ECM proteins to the persistent cytokine gene expression in RA synovial fluid mononuclear cells (SFMNC). We examined mRNA expression of 14 cytokines in the SFMNC of three RA patients, which were either fresh or cultured overnight in serum-free medium on ECM-coated plates, by polymerase chain reaction with a panel of oligonucleotide primers specific for each cytokine. The persistent expression of various cytokine mRNA found in fresh SFMNC was maintained after overnight culture in serum-free medium on ECM proteins, especially on laminin (LM), but not on serum albumin. This effect of LM was inhibited by an anti-integrin beta 1 chain (CD29) mAb, as well as by an anti-CD3 mAb, indicating an important role of the beta 1 integrin-mediated interaction with ECM proteins in regulating persistent cytokine gene expression in RA SFMNC, and a key role of T cells in regulating inflammatory monokine production.
Angiotensin converting enzyme (ACE) inhibitor-induced cough and substance P.
Authors: M. Tomaki, M. Ichinose, M. Miura, Y. Hirayama, N. Kageyama, H. Yamauchi, K. Shirato
Journal: Thorax (1996)

Angiotensin converting enzyme (ACE) inhibitors cause coughing in 5-10% of patients, but the exact mechanisms of this effect are still unclear. In the airways ACE degrades substance P so the cough mechanism may be related to this peptide.Nine patients who developed a cough and five patients who did not develop a cough when taking the ACE inhibitor enalapril (2.5 or 5.0 mg/day) for hypertension were enrolled in the study. No subjects had respiratory disease and the respiratory function of all subjects was normal. One month after stopping enalapril, inhalation of hypertonic saline (4%) was performed using an ultrasonic nebuliser for 15-30 minutes to induce sputum. The concentration of substance P in the sputum sample was measured by radioimmunoassay. In four of the nine cases with a cough enalapril was given again for 1-2 weeks and the concentration of substance P in the induced sputum was again measured.One month after stopping enalapril the mean (SE) concentration of substance P in the sputum of the group with a cough was 16.6 (3.0) fmol/ml, significantly higher than that in the subjects without a cough (0.9 (0.5) fmol/ml). All four subjects in the group with a cough who were given a repeat dose of enalapril developed a cough again, but the concentrations of substance P in the induced sputum while taking enalapril (17.9 (3.2) fmol/ml) were similar to the values whilst off enalapril (20.0 (2.5) fmol/ml).The mechanisms of ACE inhibitor-induced coughing may involve substance P mediated airway priming. However, the final triggering of the ACE inhibitor-induced coughing is unlikely to be due to this peptide.
Outcomes of Stent Thrombosis and Restenosis During Extended Follow-Up of Patients Treated With Bare-Metal Coronary Stents
Authors: Brendan Doyle, Charanjit S. Rihal, Crochan J. O’Sullivan, Ryan J. Lennon, Heather J. Wiste, Malcolm Bell, John Bresnahan, David R. Holmes
Journal: Circulation (2007)

Concern regarding risk of late thrombosis after "off-label" treatment with drug-eluting stents has prompted increased use of bare-metal stents (BMS) in current practice. The sequelae of late BMS failures, however, have been poorly characterized.We performed a retrospective study of 4503 consecutive patients treated with at least 1 BMS and dual antiplatelet therapy between 1994 and 2000. The cumulative incidence of stent thrombosis was 0.5% at 30 days (95% CI, 0.3% to 0.7%), 0.8% at 1 year (95% CI, 0.6% to 1.1%), and 2.0% at 10 years (95% CI, 1.5% to 2.5%). Risk of late (30 days to 1 year) and very late (>1 year) BMS thrombosis was increased among patients considered off label for drug-eluting stent use (P=0.024). When saphenous vein graft interventions were excluded, however, risk after off-label use was not significantly increased (P=0.23). Other correlates included vein graft intervention, prior myocardial infarction (MI), peripheral vascular disease, and ulcerated lesion (P<0.001). Mortality was markedly increased after late and very late BMS thrombosis, particularly during the first 30 days (hazard ratios, 22 [95% CI, 3.1 to 159] and 40 [95% CI, 15 to 107], respectively). The 10-year incidence of clinical restenosis was 18.1% (95% CI, 16.5% to 19.7%), presenting with MI in 2.1% (95% CI, 1.6% to 2.6%). Restenosis presenting with MI was associated with increased mortality compared with no restenosis (hazard ratio, 2.37; P<0.001) and with restenosis with a non-MI presentation (hazard ratio, 2.42; P<0.001).The incidence of BMS thrombosis and of MI caused by restenosis during extended follow-up is significant. Both complications are associated with mortality.
Case-control study of stroke and the quality of hypertension control in north west England
Authors: X. Du, K. Cruickshank, R. McNamee, M. Saraee, J. Sourbutts, A. Summers, N. Roberts, E. Walton, S. Holmes
Journal: BMJ (1997)

<h3>Abstract</h3> <b>Objective:</b> To examine the risk of stroke in relation to quality of hypertension control in routine general practice across an entire health district. <b>Design:</b> Population based matched case-control study. <b>Setting:</b> East Lancashire Health District with a participating population of 388 821 aged (80. <b>Subjects:</b> Cases were patients under 80 with their first stroke identified from a population based stroke register between 1 July 1994 and 30 June 1995. For each case two controls matched with the case for age and sex were selected from the same practice register. Hypertension was defined as systolic blood pressure !160 mm Hg or diastolic blood pressure !95 mm Hg, or both, on at least two occasions within any three month period or any history of treatment with antihypertensive drugs. <b>Main outcome measures:</b> Prevalence of hypertension and quality of control of hypertension (assessed by using the mean blood pressure recorded before stroke) and odds ratios of stroke (derived from conditional logistic regression). <b>Results:</b> Records of 267 cases and 534 controls were examined; 61% and 42% of these subjects respectively were hypertensive. Compared with non-hypertensive subjects hypertensive patients receiving treatment whose average pre-event systolic blood pressure was controlled to &lt;140 mm Hg had an adjusted odds ratio for stroke of 1.3 (95% confidence interval 0.6 to 2.7). Those fairly well controlled (140-149 mm Hg), moderately controlled (150-159 mm Hg), or poorly controlled (!160 mm Hg) or untreated had progressively raised odds ratios of 1.6, 2.2, 3.2, and 3.5 respectively. Results for diastolic pressure were similar; both were independent of initial pressures before treatment. Around 21% of strokes were thus attributable to inadequate control with treatment, or 46 first events yearly per 100 000 population aged 40-79. <b>Conclusions:</b> Risk of stroke was clearly related to quality of control of blood pressure with treatment. In routine practice consistent control of blood pressure to below 150/90 mm Hg seems to be required for optimal stroke prevention. <h3>Key messages</h3> A case-control study based on the community stroke register and practice records showed a prevalence of hypertension of 61% for stroke patients and 42% in controls Quality of control of blood pressure was clearly related to the risk of stroke, independent of baseline blood pressure Detection and treatment rates of hypertension were high but control of blood pressure to below 150/90 mm Hg in treated hypertensive patients was only 33% in cases and 42% in controls When achieving optimal control of hypertension (to &lt;150/90 mm Hg) in the most at risk and treatable age range (40-79 years) 86 hypertensive patients currently not well controlled need to be treated over five years to prevent one stroke