tbuckley/cabot-search huggingface dataset:
3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibition modulates vasopressin-stimulated Ca2+ responses in rat A10 vascular smooth muscle cells.
Authors: L L Ng, J E Davies, R J Wojcikiewicz
Journal: Circulation Research (1994)

Previous evidence has indicated a role for changes in cell membrane cholesterol in the modulation of [Ca2+]i responses and smooth muscle contraction to vascular agonists. However, the actions of plasma cholesterol-lowering agents such as 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (eg, simvastatin) have not been defined. Such agents may in addition affect isoprenoid intermediates that may play a role in signal transduction pathways involving G proteins. Arginine vasopressin-induced [Ca2+]i responses in A10 rat vascular myocytes were therefore studied in vitro. Vasopressin stimulated an initial peak [Ca2+]i that was independent of extracellular Ca2+ entry and a subsequent plateau that was dependent on Ca2+ influx, mainly through receptor-operated dihydropyridine-insensitive divalent cation channels. Simvastatin-treated A10 cells (5 mg/L for 24 hours) showed a normal initial peak response to vasopressin, but the plateau phase of Ca2+ entry was significantly impaired. By use of Mn2+ quenching of intracellular fura 2 to measure divalent cation entry, the maximal rate of vasopressin-stimulated Mn2+ entry was impaired in simvastatin-treated cells by 52%. Mevalonate (1 mmol/L for 4 hours at 37 degrees C) reversed all the changes in simvastatin-treated cells. There were no associated changes in total cellular cholesterol or fluorescence anisotropy measurements with simvastatin treatment. Measurements of inositol-1,4,5-trisphosphate mass showed that simvastatin did not impair the initial peak response to vasopressin but significantly reduced the subsequent plateau phase. These changes were also reversed with mevalonate incubation. These findings suggest that simvastatin has additional effects on [Ca2+]i homeostasis that are independent of changes in total cell cholesterol.
Banishing “I” and “we” from accounts of metacognition
Authors: Bryce Huebner, Daniel C. Dennett
Journal: Behavioral and Brain Sciences (2009)

Abstract Carruthers offers a promising model for how “we” know the propositional contents of “our” own minds. Unfortunately, in retaining talk of first-person access to mental states, his suggestions assume that a higher-order self is already “in the loop.” We invite Carruthers to eliminate the first-person from his model and to develop a more thoroughly third-person model of metacognition.
Précis of <i>The brain and emotion</i>
Authors: Edmund T. Rolls
Journal: Behavioral and Brain Sciences (2000)

The topics treated in The brain and emotion include the definition, nature, and functions of emotion (Ch. 3); the neural bases of emotion (Ch. 4); reward, punishment, and emotion in brain design (Ch. 10); a theory of consciousness and its application to understanding emotion and pleasure (Ch. 9); and neural networks and emotion-related learning (Appendix). The approach is that emotions can be considered as states elicited by reinforcers (rewards and punishers). This approach helps with understanding the functions of emotion, with classifying different emotions, and in understanding what information-processing systems in the brain are involved in emotion, and how they are involved. The hypothesis is developed that brains are designed around reward- and punishment-evaluation systems, because this is the way that genes can build a complex system that will produce appropriate but flexible behavior to increase fitness (Ch. 10). By specifying goals rather than particular behavioral patterns of responses, genes leave much more open the possible behavioral strategies that might be required to increase fitness. The importance of reward and punishment systems in brain design also provides a basis for understanding the brain mechanisms of motivation, as described in Chapters 2 for appetite and feeding, 5 for brain-stimulation reward, 6 for addiction, 7 for thirst, and 8 for sexual behavior.
Skin test resensitization after allergological study in patients with immediate allergic reactions to betalactams
Authors: M.C. Moya, M.J. Torres, J.A. Cornejo-Garcia, C. Mayorga, C. Antunez, J.L. Rodriguez-Bada, M. Blanca, C. Juarez
Journal: Journal of Allergy and Clinical Immunology (2003)
Poliovirus receptor CD155-targeted oncolysis of glioma
Authors: Melinda K Merrill, Guenter Bernhardt, John H Sampson, Carol J Wikstrand, Darell D Bigner, Matthias Gromeier
Journal: Neuro-Oncology (2004)

Cell adhesion molecules of the immunoglobulin superfamily are aberrantly expressed in malignant glioma. Amongst these, the human poliovirus receptor CD155 provides a molecular target for therapeutic intervention with oncolytic poliovirus recombinants. Poliovirus has been genetically modified through insertion of regulatory sequences derived from human rhinovirus type 2 to selectively replicate within and destroy cancerous cells. Efficacious oncolysis mediated by poliovirus derivatives depends on the presence of CD155 in targeted tumors. To prepare oncolytic polioviruses for clinical application, we have developed a series of assays in high-grade malignant glioma (HGL) to characterize CD155 expression levels and susceptibility to oncolytic poliovirus recombinants. Analysis of 6 HGL cases indicates that CD155 is expressed in these tumors and in primary cell lines derived from these tumors. Upregulation of the molecular target CD155 rendered explant cultures of all studied tumors highly susceptible to a prototype oncolytic poliovirus recombinant. Our observations support the clinical application of such agents against HGL.
Telomerase Expression Predicts Unfavorable Outcome in Osteosarcoma
Authors: Robert P. Sanders, Rachid Drissi, Catherine A. Billups, Najat C. Daw, Marcus B. Valentine, Jeffrey S. Dome
Journal: Journal of Clinical Oncology (2004)

Osteosarcoma is distinct from most cancers in that the majority of osteosarcomas lack telomerase expression and use the alternative lengthening of telomeres (ALT) mechanism to maintain telomeres. Laboratory studies suggest that compared with ALT, telomerase expression is associated with increased tumor aggressiveness. We evaluated the clinical significance of telomerase expression in human osteosarcoma.Fifty-six osteosarcomas from 51 patients treated at St Jude Children's Research Hospital between 1982 and 2003 were evaluated for telomerase enzyme activity, mRNA expression of the catalytic component of telomerase (TERT), and presence of the ALT pathway.Outcome analysis was based on TERT mRNA expression in the primary tumor samples from 44 patients. Fourteen primary tumors expressed TERT mRNA (32%; eight TERT only, six TERT and ALT) and 30 did not express TERT mRNA (68%; 29 ALT, one no ALT). Progression-free survival (PFS) was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 21.4% +/- 9.5% v 63.7% +/- 11.1%; P =.014). Likewise, overall survival was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 42.9% +/- 12.2% v 70.0% +/- 9.9%; P =.031). Among 31 patients with nonmetastatic disease at diagnosis, PFS was lower in the TERT-positive group compared with the TERT-negative group (3-year estimates, 33.3% +/- 13.6% v 72.0% +/- 11.5%; P =.092).Telomerase expression in primary tumor samples is associated with decreased PFS and OS in patients with osteosarcoma. Additional studies are warranted to better define the clinical utility of this molecular marker.
A Contribution to the Treatment of Pus in the Pelvis
Authors: J. F. Jordan
Journal: BMJ (1899)

LAMEDIAL JOURH X3 more than mention in this place. 3I again must say tlhat not al], tlhoulgh a vrely large numbel of curvatures, are due to pelvic deviation; it is, tlhere- fore.those only for which prevention is here proposed.
Widespread Increase in Myeloid Calcifying Cells Contributes to Ectopic Vascular Calcification in Type 2 Diabetes
Authors: Gian Paolo Fadini, Mattia Albiero, Lisa Menegazzo, Elisa Boscaro, Saula Vigili de Kreutzenberg, Carlo Agostini, Anna Cabrelle, Gianni Binotto, Marcello Rattazzi, Elisa Bertacco, Roberta Bertorelle, Lorena Biasini, Monica Mion, Mario Plebani, Giulio Ceolotto, Annalisa Angelini, Chiara Castellani, Mirko Menegolo, Franco Grego, Stefanie Dimmeler, Florian Seeger, Andreas Zeiher, Antonio Tiengo, Angelo Avogaro
Journal: Circulation Research (2011)

Acquisition of a procalcific phenotype by resident or circulating cells is important for calcification of atherosclerotic plaques, which is common in diabetes.We aim to identify and characterize circulating calcifying cells, and to delineate a pathophysiological role for these cells in type 2 diabetes.We demonstrate for the first time that a distinct subpopulation of circulating cells expressing osteocalcin and bone alkaline phosphatase (OC(+)BAP(+)) has procalcific activity in vitro and in vivo. The study of naïve patients with chronic myeloid leukemia indicated that OC(+)BAP(+) cells have a myeloid origin. Myeloid calcifying OC(+)BAP(+) cells (MCCs) could be differentiated from peripheral blood mononuclear cells, and generation of MCCs was closely associated with expression of the osteogenic transcription factor Runx2. In gender-mismatched bone marrow-transplanted humans, circulating MCCs had a much longer half-life compared with OC(-)BAP(-) cells, suggesting they belong to a stable cell repertoire. The percentage of MCCs was higher in peripheral blood and bone marrow of type 2 diabetic patients compared with controls but was lowered toward normal levels by optimization of glycemic control. Furthermore, diabetic carotid endoarterectomy specimens showed higher degree of calcification and amounts of cells expressing OC and BAP in the α-smooth muscle actin-negative areas surrounding calcified nodules, where CD68(+) macrophages colocalize. High glucose increased calcification by MCCs in vitro, and hypoxia may regulate MCC generation in vitro and in vivo.These data identify a novel type of blood-derived procalcific cells potentially involved in atherosclerotic calcification of diabetic patients.
T-cell-deficient mice produce more antihapten antibodies against syngeneic than against allogeneic erythrocyte conjugates.
Authors: S Koskimies, O Mäkelä
Journal: The Journal of Experimental Medicine (1976)

T-cell-deficient mice, either anti-thymocyte serum treated or nude mice, were immunized with hapten (4-hydroxy-3,5-dinitrophenyl acetic acid, NNP) conjugates of syngeneic, allogeneic, or xenogeneic erythrocytes. Immunization with syngeneic conjugates led to a stronger anti-NNP response than immunization with allogeneic or xenogeneic conjugates. A study of congenic mouse strains suggested that a prerequisite for this effect was that immunogenic erythrocytes and responding animals shared H-2-controlled characteristics. F1 hybrid erythrocyte conjugates injected into F1 hybrid mice behaved like other syngeneic erythrocytes. The same erythrocyte conjugates injected into either parental strain induced a weak response indistinguishable from the response to allogeneic erythrocyte conjugates. Parental erythrocyte conjugates injected into F1 mice induced an anti-NNP response that was significantly lower than the response to F1 erythrocyte conjugates but significantly higher than the response to allogeneic conjugates. The response of normal mice to syngeneic erythrocytes was weaker than the response of T-cell-deficient mice, which could have been caused by suppressor T cells. Their response to allogeneic conjugates was higher than the response of T-cell-deficient mice and the response to xenogeneic conjugates higher still. This was probably due to allo- or xenoreactive helper cells.
De-Repression of <i>PDGFRβ</i> Transcription Promotes Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Glioblastoma Patients
Authors: David Akhavan, Alexandra L. Pourzia, Alex A. Nourian, Kevin J. Williams, David Nathanson, Ivan Babic, Genaro R. Villa, Kazuhiro Tanaka, Ali Nael, Huijun Yang, Julie Dang, Harry V. Vinters, William H. Yong, Mitchell Flagg, Fuyuhiko Tamanoi, Takashi Sasayama, C. David James, Harley I. Kornblum, Tim F. Cloughesy, Webster K. Cavenee, Steven J. Bensinger, Paul S. Mischel
Journal: Cancer Discovery (2013)

Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here, we show the first example of this alternate mechanism in brain tumors by showing that EGF receptor (EGFR)-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing platelet-derived growth factor receptor β (PDGFRβ). Mechanistic studies show that EGFRvIII signaling actively suppresses PDGFRβ transcription in an mTORC1- and extracellular signal-regulated kinase-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRβ signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRβ signaling potently suppresses tumor growth in vivo. These data identify a novel, nongenetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy.These results provide the fi rst clinical and biologic evidence for receptor tyrosinekinase (RTK) "switching" as a mechanism of resistance to EGFR inhibitors in GBM and provide a molecular explanation of how tumors can become "addicted" to a non amplified, nonmutated, physiologically regulated RTK to evade targeted treatment.
Some Histochemical Observations on the Human Aortic Wall in Atherosclerosis
Authors: MAURICE SANDLER, GEOFFREY H. BOURNE
Journal: Circulation Research (1960)

A decrease in the ATPase (heat stable) and 5-nucleotidase of atherosclerotic regions in human aortae has been demonstrated. An increase in the breakdown of TPN, as measured by phosphate release, of the atherosclerotic aorta as a whole has been shown. No change was observed in the breakdown of DPN, as measured by phosphate release, between the normal or atherosclerotic aorta. No reactivity for glucose-1 or glucose-6-phosphate or β-glycerophosphate was found in the intima or media. The possible implications in the development of atheroma are discussed.
THE INCIDENCE OF CONGENITAL SYPHILIS IN AN INSTITUTION FOR THE FEEBLE-MINDED
Authors: Chas. S. Woodall
Journal: American Journal of Psychiatry (1930)

1. The Wassermann, Kahn, and Hinton reactions were applied to 1314 feeble-minded patients and many retests were done. The Hinton was found to be twice as sensitive as are the other two tests. The need for repeated tests was established. 2. The diagnosis of syphilis was based upon serological and clinical findings and the percentage obtained was 7.2 per cent. Congenital syphilis was present in 6.5 per cent of the cases. Clinical as well as serological evidence is of great value. 3. Defective heredity was present in 16 per cent of our congenital luetics and this factor lowers our figures of incidence. 4. The writer believes that certain cases of mental defect are due to congenital syphilis. How many are thus caused has not been established, nor has the nature of the disease process been elucidated.
Phase I study with weekly cisplatin-paclitaxel and concurrent radiotherapy in patients with carcinoma of the cervix uteri
Authors: S Pignata, P Frezza, S Tramontana, F Perrone, R Tambaro, G Casella, E Ferrari, F Iodice, R De Vivo, P Ricchi, F Tramontana, G Silvestro
Journal: Annals of Oncology (2000)
Klf15 Orchestrates Circadian Nitrogen Homeostasis
Authors: Darwin Jeyaraj, Frank A.J.L. Scheer, Jürgen A. Ripperger, Saptarsi M. Haldar, Yuan Lu, Domenick A. Prosdocimo, Sam J. Eapen, Betty L. Eapen, Yingjie Cui, Ganapathi H. Mahabeleshwar, Hyoung-gon Lee, Mark A. Smith, Gemma Casadesus, Eric M. Mintz, Haipeng Sun, Yibin Wang, Kathryn M. Ramsey, Joseph Bass, Steven A. Shea, Urs Albrecht, Mukesh K. Jain
Journal: Cell Metabolism (2012)
The Role of Exhaled Nitric Oxide (FENO) in Eosinophilic Esophagitis: A Pilot Study to Evaluate the Correlation of Exhaled Nitric Oxide and Esophageal Eosinophils
Authors: S.D. Stanga, S.L. Page, C. Dinakar
Journal: Journal of Allergy and Clinical Immunology (2012)
L'Epiphysiolyse de la Hanche
Authors: A. St. J. Dixon
Journal: Annals of the Rheumatic Diseases (1963)

MR. ALEXANDER KATES (London) offered a most convincing case for the operation of dislocation of the toes as a modification of Fowler's operation and an alternative to the mutilating amputation of the toes.In his operation, with an ellipse of skin excised from the plantar surface of the foot in addition to the removal of the metatarsal heads, the weight-bearing metatarsal pad is restored to its normal position.This simple operation offered a dramatic relief of one of the more persistent disabilities of the rheumatoid patient.
Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes.
Authors: D E Wilson, A Hata, L K Kwong, A Lingam, J Shuhua, D N Ridinger, C Yeager, K C Kaltenborn, P H Iverius, J M Lalouel
Journal: Journal of Clinical Investigation (1993)

A proband with chylomicronemia, pancreatitis, and non-insulin-dependent diabetes (NIDDM) bears two different mutations in exon 3 of the lipoprotein lipase (LPL) gene: a missense mutation, 75Arg-->Ser, inherited through the paternal line and a truncation, 73Tyr-->Ter, through the maternal line. NIDDM appeared to be independently segregating. The R75S mutant was studied in extracts and media from transfected COS-1 cells. Detectable amounts of catalytically competent R75S LPL suggested destabilization of the active homodimer as with exon 5 mutants (Hata et al. 1992. J. Biol. Chem. 267:20132-20139). Hydrolysis of a short-chain fatty acid ester indicated that R75S does not directly affect activation of LPL by apoC-II. Subjects with NIDDM and wild-type LPL, and nondiabetic middle-aged carriers of the 73Tyr-->Ter truncation had moderate hypertriglyceridemia (260-521 mg/dl) and reduced high density lipoprotein cholesterol. A maternal aunt with NIDDM carried the truncation. Her phenotype (triglycerides of 5,300 mg/dl, eruptive xanthomatosis, and recurrent pancreatitis) was as severe as that in homozygotes or compound heterozygotes. We conclude: (a) diabetic carriers of dysfunctional LPL alleles are at risk for severe lipemia; and (b) the physiologic defects in NIDDM may be additive or synergistic with heterozygous LPL deficiency.
THE POTENTIAL OF FARNESYLTRANSFERASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS
Authors: Jackson B. Gibbs, Allen Oliff
Journal: The Annual Review of Pharmacology and Toxicology (1997)

Mutant ras oncogenes and alterations in the mitogenic signaling pathways that they regulate are associated with a wide variety of solid tumors and leukemias for which existing chemotherapeutics have limited utility. Of the possible approaches to inhibit Ras function, much attention has focused on a posttranslational modification, farnesylation, which is required for the subcellular localization of Ras to the plasma membrane and is critical to Ras cell-transforming activity. Inhibitors of the enzyme that catalyzes Ras farnesylation, farnesyl-protein transferase (FPTase), have been developed. These compounds inhibit the tumorigenic phenotypes of ras-transformed cells and human tumor cells in cell culture and in animal models. Moreover, FPTase inhibitors have not demonstrated toxicity to normal cells in culture or to normal tissues in mice. FPTase inhibitors are among the first small molecule compounds designed from studies of oncogenes that might serve as novel cancer chemotherapeutics.
CpG Island Methylator Phenotype Associates with Low-Degree Chromosomal Abnormalities in Colorectal Cancer
Authors: Yu-Wei Cheng, Hanna Pincas, Manny D. Bacolod, Gunter Schemmann, Sarah F. Giardina, Jianmin Huang, Sandra Barral, Kamran Idrees, Sajid A. Khan, Zhaoshi Zeng, Shoshana Rosenberg, Daniel A. Notterman, Jurg Ott, Philip Paty, Francis Barany
Journal: Clinical Cancer Research (2008)

Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers.We determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays.The identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively).CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.
Mapping a Locus for Familial Thoracic Aortic Aneurysms and Dissections ( <i>TAAD2</i> ) to 3p24–25
Authors: Sumera N. Hasham, Marcia C. Willing, Dong-chuan Guo, Ann Muilenburg, Rumin He, Van T. Tran, Steven E. Scherer, Sanjay S. Shete, Dianna M. Milewicz
Journal: Circulation (2003)

Familial thoracic aortic aneurysms and dissections (TAAD) occur as part of known syndromes such as Marfan syndrome but can also be inherited in families in an autosomal dominant manner as an isolated condition. Previous studies have mapped genes causing nonsyndromic familial TAAD to 5q13-15 (TAAD1) and 11q23.2-q24 (FAA1). Further genetic heterogeneity for the condition was evident by the presence of TAAD in some families not linked to these known loci.A 4-generation family with dominant mode of inheritance of TAAD was studied. Affected status was determined by dilation of the ascending aorta, surgical repair of an aneurysm or dissection, or death as the result of aortic dissection. None of the family members evaluated met the diagnostic criteria for Marfan syndrome. After exclusion of known loci for familial TAAD, a genome-wide scan was carried out to map the defective gene causing the disease in the family. A locus was mapped to a 25-cM region on 3p24-25 with a maximum multipoint logarithm of the odds score of 4.28.A third locus for nonsyndromic TAAD was mapped to 3p24-25 and termed the TAAD2 locus. This locus overlaps a previously mapped second locus for Marfan syndrome, termed the MFS2 locus. Future characterization of the TAAD2 gene will determine if TAAD2 is allelic to MFS2. In addition, identification of the TAAD2 gene will improve the presymptomatic diagnosis of individuals with this life-threatening genetic syndrome and provide information concerning the pathogenesis of the disease.