tbuckley/cabot-search huggingface dataset:
Phenotypic characterization of human cytolytic T lymphocytes in mixed lymphocyte culture.
Authors: A Moretta, M C Mingari, B F Haynes, R P Sekaly, L Moretta, A S Fauci
Journal: The Journal of Experimental Medicine (1981)

Mixed lymphocyte reaction (MLR)-activated T cells were analyzed according to the expression of various cell surface markers by the specific cytotoxic T lymphocytes (CTL) generated in the MLR. CTL were found exclusively in a population of MLR-activated T cells that lacked detectable Fc gamma R but that expressed a surface antigen recognized by the 4F2 monoclonal antibody. In contrast, CTL were found in both the Ia-positive and Ia-negative cells after MLR activation. Thus, the specific CTL generated in the allogeneic MLR can be identified and isolated by virtue of the expression of a particular cell surface marker.
Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in <i>IDH</i>-Mutant Gliomas
Authors: Hiroaki Wakimoto, Shota Tanaka, William T. Curry, Franziska Loebel, Dan Zhao, Kensuke Tateishi, Juxiang Chen, Lindsay K. Klofas, Nina Lelic, James C. Kim, Dora Dias-Santagata, Leif W. Ellisen, Darrell R. Borger, Sarah-Maria Fendt, Matthew G. Vander Heiden, Tracy T. Batchelor, A. John Iafrate, Daniel P. Cahill, Andrew S. Chi
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898–909. ©2014 AACR.
Effective lipid lowering diets including lean meat
Authors: G F Watts, W Ahmed, J Quiney, R Houlston, P Jackson, C Iles, B Lewis
Journal: BMJ (1988)

The plasma lipid and lipoprotein responses to two modified isoenergetic diets including meat were studied in 15 free living men with hyperlipidaemia (mean plasma cholesterol and triglyceride concentrations 8·1 and 3·4 mmol/l). A reference diet (diet A, 42% energy from fat, ratio of polyunsaturated to saturated fatty acids (P:S ratio) 0·2) was compared with a fat reduced diet (diet B, 35% energy from fat, P:S ratio 0·5) and with a further fat modified diet supplemented with fibre (diet C, 27% energy from fat, P:S ratio 1·0). Daily intake of meat and meat products (180 g/day) was the same in each dietary period; that in diet A had a fat content typical of the average British diet, whereas that in diets B and C was based on very lean meat and meat products. During consumption of diet B the plasma cholesterol concentration fell by 8·6% and low density lipoprotein cholesterol by 11%. During consumption of diet C plasma cholesterol fell by 18·5% and low density lipoprotein cholesterol by 23·8%. Triglyceride and high density lipoprotein cholesterol concentrations and body weight did not change appreciably during the study. A modified diet including a moderate amount of lean meat and meat products is compatible with a reduced lipoprotein mediated risk of atherosclerotic heart disease.
Reconstitution of interleukin-2
Authors: C.R. Franks, L. Thomas Vlasveld, ElaineM. Rankin, Sjoerd Rodenhuis, WimM.J. Vuist, JosH. Beijnen, AnneM. Hilton, Ria Dubbelman, Annemarie Hekman
Journal: The Lancet (1990)
Perflubron Reduces Lung Inflammation in Respiratory Syncytial Virus Infection by Inhibiting Chemokine Expression and Nuclear Factor–<b>κ</b>B Activation
Authors: Helene A. Haeberle, Frances Nesti, Hans-Juergen Dieterich, Zoran Gatalica, Roberto P. Garofalo
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Airway mucosa inflammation plays a critical role in the pathogenesis of lower respiratory tract infections caused by respiratory syncytial virus (RSV), the major etiologic agent of bronchiolitis in infancy. Type and intensity of cellular infiltration are dictated by inflammatory chemokines, which are rapidly and abundantly induced in lung tissue by RSV. This process is, to a large extent, transcriptionally regulated by RSV-mediated activation of the nuclear factor–κB. The administration of a perfluorocarbon (PFC) liquid, such as perflubron, during partial liquid ventilation improves lung function and also reduces inflammation. In this study we demonstrate that treatment of BALB/c mice with perflubron intranasally 6 hours after RSV infection significantly inhibited lung cellular inflammation as well as the expression of the chemokines RANTES, MIP-1α, MIP-1β, and MIP-2, compared with phosphate-buffered saline–treated control mice. However, perflubron treatment did not affect RSV replication. Strikingly, treatment with perflubron abrogated nuclear factor–κB activation in lung of RSV-infected mice. These results demonstrate a novel mechanism by which PFC may exert antiinflammatory activity and suggest that partial liquid ventilation with PFC may be considered in future clinical trials for infants with severe RSV infections requiring mechanical ventilation.
Infrastructure, funding and follow-up in a programme of noninvasive ventilation
Authors: P. Leger, G. Laier-Groeneveld
Journal: European Respiratory Journal (2002)

Originating from centres charged with the care of patients with chronic respiratory insufficiency, noninvasive ventilation (NIV) has been used increasingly in chronic and acute respiratory failure during the last decade. Despite a considerable number of series and randomised studies advocating access to NIV for units that treat acute or chronic ventilatory failure, the number of units and the proportion of total ventilatory support remains poor. This is due to lack of education, as many units treat only a few patients per year. Indication, technique, education, monitoring and home care require special experience and a special environment and there is a wide range throughout Europe. With respect to home care in particular, there are many organisations, which range from totally private to hospital based or run for profit. A concerted action, funded by the European Union, will soon provide valuable information about the practice of home ventilation in Europe based on a European survey.
Identification of Genetic Variants in Base Excision Repair Pathway and Their Associations with Risk of Esophageal Squamous Cell Carcinoma
Authors: Bingtao Hao, Haijian Wang, Kaixin Zhou, Yi Li, Xiaoping Chen, Gangqiao Zhou, Yunping Zhu, Xiaoping Miao, Wen Tan, Qingyi Wei, Dongxin Lin, Fuchu He
Journal: Cancer Research (2004)

Abstract The etiology of esophageal squamous cell carcinoma (ESCC) has been shown to be associated with genetic and certain environmental factors that produce DNA damage. Base excision repair (BER) genes are responsible for repair of DNA damage caused by reactive oxygen species and other electrophiles and therefore are good candidate susceptibility genes for ESCC. We first screened eight BER genes for new and potential functional polymorphisms by resequencing 27 DNA samples. We then identified and genotyped for important tagging single nucleotide polymorphisms (SNPs) in a case-control study of 419 patients with newly diagnosed esophageal cancer and 480 healthy controls by frequency matching on age and sex. The association between genotypes and ESCC risk was estimated by unconditional multivariate logistic regression analysis, and stepwise regression procedure was used for constructing the final logistic regression model. We identified 129 SNPs in the eight BER genes, including 18 SNPs that cause amino acid changes. In the final model, 4 SNPs, including 2 in the coding regions (ADPRT Val762Ala and MBD4 Glu346Lys) and others in noncoding regions (LIG3 A3704G and XRCC1 T-77C), remained as significant predictors for the risk of ESCC. The adjusted odd ratios were 1.25 [95% confidence interval (CI) 1.02–1.53] for the ADPRT 762Ala allele, 1.25 (95% CI 1.02–1.53) for the MBD4 346 Lys allele, 0.78 (95% CI 0.63–0.97) for the LIG3 3704G allele, and 1.38 (95% CI 1.01–1.89) for the XRCC1–77C allele. In addition, we observed a significant gene-gene interaction between XRCC1 Gln399Arg and ADPRT Val762Ala. The results suggest that the polymorphisms in five BER genes may be associated with the susceptibility to ESCC in a Chinese population.
Improved Prognosis for Older Adolescents With Acute Lymphoblastic Leukemia
Authors: Ching-Hon Pui, Deqing Pei, Dario Campana, W. Paul Bowman, John T. Sandlund, Sue C. Kaste, Raul C. Ribeiro, Jeffrey E. Rubnitz, Elaine Coustan-Smith, Sima Jeha, Cheng Cheng, Monika L. Metzger, Deepa Bhojwani, Hiroto Inaba, Susana C. Raimondi, Mihaela Onciu, Scott C. Howard, Wing Leung, James R. Downing, William E. Evans, Mary V. Relling
Journal: Journal of Clinical Oncology (2010)

The prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients. We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group.
Genetic variation in the nuclear factor κB pathway in relation to susceptibility to rheumatoid arthritis
Authors: R Dieguez-Gonzalez, S Akar, M Calaza, E Perez-Pampin, J Costas, M Torres, J L Vicario, M L Velloso, F Navarro, J Narvaez, B Joven, G Herrero-Beaumont, I Gonzalez-Alvaro, B Fernandez-Gutierrez, A R de la Serna, L Carreño, J Lopez-Longo, R Caliz, M D Collado-Escobar, F J Blanco, C Fernandez-Lopez, A Balsa, D Pascual-Salcedo, J J Gomez-Reino, A Gonzalez
Journal: Annals of the Rheumatic Diseases (2008)

To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappaB pathway, the major intracellular pathway in RA pathogenesis.Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkappaB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls.No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant.We did not find any major effect among the explored members of the NFkappaB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.
Increased plasma concentration of cross-linked fibrin polymers in acute myocardial infarction.
Authors: C W Francis, D G Connaghan, W L Scott, V J Marder
Journal: Circulation (1987)

Thrombin cleaves fibrinopeptides from fibrinogen, converting it to fibrin monomer, and activates factor XIII, which catalyzes the formation of intermolecular epsilon-(gamma-glutamyl)-lysine bonds to stabilize the fibrin polymer. The formation of factor XIIIa-catalyzed fibrin polymers during clotting of plasma and purified fibrinogen in vivo was followed by a sodium dodecyl sulfate agarose gel technique, and an increase in both amount and size of gamma-chain cross-linked polymers was demonstrated before visible clot formation. Plasma from patients presenting with acute myocardial infarction showed increases in the plasma concentration of fibrin polymer and in the proportion of total fibrinogen present as polymer, as determined by a quantitative adaptation of the electrophoretic technique. The plasma concentration in patients with subendocardial or transmural myocardial infarction showed significant (p less than .005) increases to 4.0 +/- 1.0% and 3.6 +/- .8%, respectively, as compared with the concentration in normal plasma (0.8 +/- 0.1%). There was no difference in plasma concentration in samples from patients with transmural compared with those with subendocardial myocardial infarction. This study provides the first demonstration of factor XIIIa cross-linked fibrin polymers in thrombotic disease and indicates the presence of increased activity of both thrombin and factor XIIIa in patients with acute myocardial infarction.
Hymenoptera venom allergy: analysis of double positivity to honey bee and <i>Vespula</i> venom by estimation of IgE antibodies to species‐specific major allergens Api m1 and Ves v5
Authors: U. R. Müller, N. Johansen, A. B. Petersen, J. Fromberg‐Nielsen, G. Haeberli
Journal: Allergy (2008)

Background: In patients with hymenoptera venom allergy diagnostic tests are often positive with honey bee and Vespula venom causing problems in selection of venoms for immunotherapy. Methods: 100 patients each with allergic reactions to Vespula or honey bee stings and positive i.e. skin tests to the respective venom, were analysed for serum IgE to bee venom, Vespula venom and crossreacting carbohydrate determinants (CCDs) by UNICAP (CAP) and ADVIA Centaur (ADVIA). IgE‐antibodies to species specific recombinant major allergens (SSMA) Api m1 for bee venom and Ves v5 for Vespula venom, were determined by ADVIA. 30 history and skin test negative patients served as controls. Results: By CAP sensitivity was 1.0 for bee and 0.91 for Vespula venom, by ADVIA 0.99 for bee and 0.91 for Vespula venom. None of the controls were positive with either test. Double positivity was observed in 59% of allergic patients by CAP, in 32% by ADVIA. slgE to Api m1 was detected in 97% of bee and 17% of Vespula venom allergic patients, slgE to Ves v5 in 87% of Vespula and 17% of bee venom allergic patients. slgE to CCDs were present in 37% of all allergic patients and in 56% of those with double positivity and were more frequent in bee than in Vespula venom allergic patients. Conclusions: Double positivity of IgE to bee and Vespula venom is often caused by crossreactions, especially to CCDs. IgE to both Api m1 and Ves v5 indicates true double sensitization and immunotherapy with both venoms.
Role of Cytoplasmic Tail of the Type 1A Angiotensin II Receptor in Agonist– and Phorbol Ester–Induced Desensitization
Authors: Hua Tang, Deng Fu Guo, James P. Porter, Yoshio Wanaka, Tadashi Inagami
Journal: Circulation Research (1998)

Abstract —To investigate mechanisms underlying the agonist-induced desensitization of the type 1A angiotensin II receptor (AT 1A -R), we have stably expressed in Chinese hamster ovary (CHO) cells the wild-type receptor and truncated mutants lacking varying lengths of the cytoplasmic tail. Assay of inositol 1,4,5-trisphosphate (IP 3 ) formation in response to agonist demonstrated that the truncated mutants T318, T328, and T348 lacking the last 42, 32, or 12 amino acid residues, respectively, couple with G q protein with an efficiency similar to that of full-length receptors, whereas coupling of G q protein was abolished in the T310 truncated mutant devoid of the carboxyl-terminal 50 amino acids. Exposure of CHO/AT 1A -R cells expressing the wild-type AT 1A -R to angiotensin II resulted in rapid and dose-dependent homologous desensitization of receptor-mediated IP 3 formation, which was independent of the receptor internalization. Mastoparan, an activator of G protein–coupled receptor kinase (GRK), induced desensitization of the AT 1A -R. The agonist-induced desensitization of the receptor was largely prevented by heparin, a potent inhibitor of GRK, whereas it was only partially attenuated by a protein kinase C (PKC)-specific inhibitor. The homologous or heterologous desensitization of the receptor was greatly impaired in the truncated mutants T318 and T328, lacking the Ser/Thr-rich (13 or 12 Ser/Thr residues) cytoplasmic tail of the AT 1A -R. Deletion of the last two Ser residues, including one PKC consensus site in the receptor tail, prevented only phorbol 12-myristate 13-acetate–induced desensitization by 30%. Moreover, we found an agonist-induced translocation of a heparin-sensitive kinase activity. The angiotensin II–stimulated heparin-sensitive kinase could phosphorylate a thioredoxin fusion protein containing the entire AT 1A -R cytoplasmic tail (N 295 to E 359 ), which lacks consensus phosphorylation sites for GRK1, GRK2, and GRK3. The heparin-sensitive kinase may not be GRK2, GRK3, or GRK6 expressed in CHO/AT 1A -R cells, since angiotensin II did not induce translocation of these receptor kinases. Potential Ser/Thr phosphorylation sites located between S 328 and S 347 in the cytoplasmic tail of AT 1A -R seem to play a critical role in the heterologous and homologous desensitization of the receptor. A heparin-sensitive kinase other than GRK2, GRK3, or GRK6 may be involved in the agonist-induced homologous desensitization of the AT 1A -R.
Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans
Authors: Panithaya Chareonthaitawee, Philipp A. Kaufmann, Ornella Rimoldi, Paolo G. Camici
Journal: Cardiovascular Research (2001)

Objective: Absolute myocardial blood flow (MBF) is not well-defined in large normal populations, and appears to be heterogeneous in both humans and animals. These factors contribute to the difficulties in defining resting MBF to hibernating myocardium. We therefore assessed absolute baseline and hyperemic MBF in a large population of normal humans. Methods: MBF was quantified by positron emission tomography with oxygen-15-labeled water at baseline and during hyperemia induced by either adenosine or dipyridamole in 131 men and 38 women, aged 21–86 (mean 46±12) years. MBF was corrected for workload using the rate-pressure product (RPP). Results: Uncorrected baseline MBF ranged from 0.590 to 2.050 (mean 0.985±0.230) ml/min/g (coefficient of variation=27%), and corrected MBF from 0.736 to 2.428 (mean 1.330±0.316) ml/min/g (coefficient of variation=24%). MBF in the inferior region was significantly (P<0.0001) lower than either the anterior or lateral regions. Baseline MBF in females was significantly (P<0.001) higher than in males. Conclusions: These results confirm the heterogeneity of MBF in normals and highlight the difficulty in establishing the lower limit of normal MBF.
Primary Myxedema with Thyrotrophin-Binding Inhibitor Immunoglobulins
Authors: KONISHI JUNJI
Journal: Annals of Internal Medicine (1985)

In a screening of 43 patients with primary myxedema, 9 patients were found to have IgG that inhibits the binding of 125I-thyrotrophin to its receptor (thyrotrophin-binding inhibitor immunoglobulins). Preparations of IgG from these patients did not stimulate thyroidal cyclic adenosine monophosphate generation and blocked thyroid stimulation by thyrotrophin in vitro. Clinical and laboratory features of 15 patients with this inhibitor, including 6 who were previously known, were compared with those of patients without the inhibitor. The patients with inhibitor, 2 men and 13 women, had onset of their hypothyroidism from age 2 to 49 years, and thyroid uptake in these patients was significantly lower than that in patients without inhibitor. Transient hypothyroidism was seen in all 5 infants born to 4 mothers having potent inhibitor immunoglobulins. These clinical findings indicate that thyrotrophin-receptor-blocking antibodies play a pathogenic role in a group of patients with primary myxedema.
Effect of pregnancy planning and fertility treatment on cognitive outcomes in children at ages 3 and 5: longitudinal cohort study
Authors: C. Carson, Y. Kelly, J. J. Kurinczuk, A. Sacker, M. Redshaw, M. A. Quigley
Journal: BMJ (2011)

<b>Objective</b> To investigate how pregnancy planning, time to conception, and infertility treatment influence cognitive development at ages 3 and 5. <b>Design</b> Prospective population based cohort study. <b>Setting</b> Millennium Cohort Study in the United Kingdom. <b>Participants</b> 18 818 children recruited at 9 months and followed up at 3 and 5 years. 11 790 singletons with available data on pregnancy, cognitive outcomes, and confounders were included in analyses at age 3 and 12 136 at age 5. <b>Exposure measures</b> Mothers reported whether the pregnancy was planned, and their feelings when first pregnant; those in whom the pregnancy was planned provided time to conception, and details of any assisted reproductive technologies. The population was divided into “unplanned” (unplanned and unhappy), “mistimed” (unplanned but happy), “planned” (planned, time to conception &lt;12 months), “subfertile” (planned, time to conception ≥12 months), “induced ovulation” (received clomiphene citrate), and “assisted reproduction” (in vitro fertilisation or intracytoplasmic sperm injection). The “planned” group was the comparison group in all analyses. <b>Outcome measures</b> Three components of the British Ability Scales (BAS II). Naming vocabulary assessed verbal ability at age 3; this test was repeated at age 5 with the picture similarities and pattern construction subscales, which measure non-verbal and spatial abilities. <b>Results</b> In unadjusted analyses, the scores on all scales in children from unplanned pregnancies were significantly lower than in those from planned pregnancies—for example, the difference in mean verbal ability score at age 3 was −4.8 (95% confidence interval −6.0 to −3.7; P&lt;0.05), equivalent to an average delay of four months. After adjustment for sociodemographic factors these differences were attenuated: −0.3 (−1.3 to 0.7), equivalent to no delay. Children born after assisted reproduction performed consistently better in verbal ability tests (3.8 (−0.2 to 7.9) at age 3 and 3.5 (0.2 to 6.8) at age 5), which suggests that on average these children are three to four months ahead; this difference did not completely disappear with adjustment for confounders. Children born after infertility treatment had lower mean scores in non-verbal tests (−1.2 (−4.1 to 1.6) after assisted reproduction and −1.5 (−3.5 to 0.4) after induced ovulation) and in spatial ability tests (−2.7 (−6.9 to 1.6) after assisted reproduction), though the differences were not significant. <b>Conclusions</b> Pregnancy planning, subfertility, or assisted reproduction do not adversely affect children’s cognitive development at age 3 or 5. The differences observed in the unadjusted analyses are almost entirely explained by marked inequalities in socioeconomic circumstances between the groups.