tbuckley/cabot-search huggingface dataset:
Identification and physical mapping of a polymorphic human T cell receptor V beta gene with a frequent null allele.
Authors: P Charmley, K Wang, L Hood, D A Nickerson
Journal: The Journal of Experimental Medicine (1993)

Germline variation in genes that encode the human T cell receptors (TCRs) may have an important influence in shaping the immune T cell repertoire. In this report we describe a frequent null allele of the human V beta 18 gene, resulting from a nucleotide substitution that creates a stop codon (CGA&amp;lt;--&amp;gt;TGA). Approximately 11% of the population tested was homozygous for this null allele, indicating that this is a frequent "hole in the repertoire." We confirmed that there is a greatly reduced (undetectable) level of V beta 18 mRNA in peripheral blood lymphocytes from an individual homozygous for this null allele. In addition, all heterozygous individuals expressed detectable levels of only the functional V beta 18 allele in their peripheral blood lymphocytes. Two other DNA polymorphisms were identified in V beta 18, one of which would result in an amino acid substitution in an expressed V beta 18 gene. Genotypes for all three of these V beta 18 DNA polymorphisms were determined in a group of unrelated individuals. Statistical analyses of the associations between alleles of the V beta 18 polymorphisms and those of other DNA polymorphisms in the TCR beta locus suggested a close physical proximity between the V beta 18 gene and the 3' end of the C beta 2 region. This localization of human V beta 18 had been previously predicted by the sequence homology between human V beta 18 and mouse V beta 14, a V gene segment previously mapped to 3' of the mouse C beta genes. We confirmed this localization of the human V beta 18 gene by isolating a cosmid clone that contains both the V beta 18 and C beta 2 segments. Mapping by restriction enzyme digestion and by the polymerase chain reaction indicated that the V beta 18 gene segment is approximately 9 kb 3' of the C beta 2 gene, making this the only known human V beta gene 3' of the C beta region.
Pulmonary function preservation with targeted antibiotic use in infants with CF
Authors: Jacquelyn Zirbes, Carlos Milla
Journal: European Respiratory Journal (2011)

We hypothesized that in CF infants microbiologic surveillance with targeted antibiotic intervention preserves pulmonary function. Our program follows a standardized protocol with microbiologic surveillance performed at every visit by oropharyngeal sampling for culture. Positive cultures are treated based on antibiotic susceptibility regardless of clinical status. First detection of Pseudomonas aeruginosa (PA) is treated with a 6 week course of ciprofloxacin and 6 months of inhaled Colistin. Pulmonary function (PFT) is assessed by raised-volume rapid thoracoabdominal compression (RVRTC) and multi-breath washout (MBW). Nutritional status is monitored by weight for length Z-score (WLZ). Twenty four CF infants have participated since 2008. Mean age at diagnosis was 6.8 weeks, 16 are female. On average, 75% of the cultures per patient were positive. Only 6 of the infants had at least one positive culture for PA. In contrast 75% of the infants had at least one positive culture for S. aureus. By RVRTC parameters only 4 infants had evidence for significant obstruction. However by MBW almost all had evidence for mild ventilatory inhomogeneity (mean LCI 8.5±1.1). No correlation was found between RVRTC and MBW parameters. We did find an inverse correlation between WLZ and LCI (r=0.46). Further, we found no relationship between microbiologic results and PFT parameters. Patients with positive cultures, including those with PA, had comparable PFT results to those not infected. Thus, despite airway colonization with CF pathogens, there was no evidence for significant detrimental changes in lung function. We propose that frequent monitoring and targeted use of antibiotics preserves lung function in infants with CF.
Sir Arthur Hurst. (Born 23 July 1879, died 17 August 1944).
Authors: T Hunt
Journal: Gut (1979)

Centenary of the birth of Sir Arthur Hurst, the Society's founder.In 1935 he wrote to Dr Georges Brohee of Brussels, who was making plans to form a Societe Internationale de Gastro-Enterologie, saying 'A private Gastro-Enterological Club has been formed in Great Britain which will meet once a year in various cities the day before the Association of Physicians'.From this arose (in 1937) the British Society, which now has nearly 1000 members, and Hurst was its first President.Few physicians have stimulated more young doctors to think for themselves and to argue about causes than did Sir Arthur (Figure).His approach to bedside medicine was basically physiological, and that great change which came over internal medicine in the early years of the 20th century from the pathology of structure to that of function owes much to his example.
HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis.
Authors: G H Nabozny, J M Baisch, S Cheng, D Cosgrove, M M Griffiths, H S Luthra, C S David
Journal: The Journal of Experimental Medicine (1996)

Genetic studies have indicated that susceptibility to rheumatoid arthritis (RA) maps to the HLA-DR locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DR genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HLA-DQ molecules in arthritis, we generated transgenic mice expressing the DQA1*0301 and DQB1*0302 genes from an RA predisposing haplotype (DQ8/DR4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab0 mice, and their susceptibility to experimental collagen-induced arthritis was evaluated. The HLA-DQ8+,H-2Ab0 mice displayed good expression of the DQ8 molecule, while no surface expression of endogenous murine class II molecules could be detected. The DQ8 molecule also induced the selection of CD4+ T cells expressing a normal repertoire of V beta T cell receptors. Immunization of HLA-DQ8+,H-2Ab0 mice with bovine type II collagen (CII) induced a strong antibody response that was cross-reactive to homologous mouse CII. Also, in vitro proliferative responses against bovine CII, which were blocked in the presence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8+,H-2Ab0 mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2Aq) controls. In contrast, HLA-DQ8-,H-2Ab0 fullsibs did not generate CII antibody and were completely resistant to arthritis. Therefore, these results strongly suggest that HLA-DQ8 molecules contribute to genetic susceptibility to arthritis and also establish a novel animal model for the study of human arthritis.
Elevated Risk of Cardiovascular Disease Prior to Clinical Diagnosis of Type 2 Diabetes
Authors: Frank B. Hu, Meir J. Stampfer, Steven M. Haffner, Caren G. Solomon, Walter C. Willett, JoAnn E. Manson
Journal: Diabetes Care (2002)

OBJECTIVE—To examine whether the risk of cardiovascular disease (CVD) is elevated before clinical diagnosis of type 2 diabetes in women. RESEARCH DESIGN AND METHODS—A total of 117,629 female nurses aged 30–55 years who were free of diagnosed CVD at baseline were recruited in 1976 and followed for 20 years. RESULTS—A total of 1,508 women had diagnosed type 2 diabetes at baseline in 1976. During 20 years of follow-up, 110,227 women remained free of diabetes diagnosis and 5,894 women developed type 2 diabetes. During 2.2 million person-years of follow-up, we documented 1,556 new cases of myocardial infarction (MI), 1,405 strokes, 815 fatal coronary heart disease (CHD), and 300 fatal strokes. Among women who developed type 2 diabetes during follow-up, the age-adjusted RRs of MI were 3.75 (95% CI 3.10–4.53) for the period before the diagnosis and 4.57 (3.87–5.39) for the period after the diagnosis, compared with women who remained free of diabetes diagnosis. The multivariate RRs further adjusting for BMI, smoking, and other cardiovascular risk factors were 3.17 (2.61–3.85) and 3.97 (3.35–4.71). The risk of stroke was also significantly elevated before diagnosis of diabetes (multivariate RR = 2.30 [1.76–2.99]). Further adjustment for history of hypertension or hypercholesterolemia did not appreciably alter the results. CONCLUSIONS—Our data indicate a substantially elevated risk of CVD before clinical diagnosis of type 2 diabetes in women. These findings suggest that aggressive management of cardiovascular risk factors is warranted in individuals at increased risk for diabetes.
Evaluation of Two Phosphorylation Sites Improves the Prognostic Significance of Akt Activation in Non–Small-Cell Lung Cancer Tumors
Authors: Junji Tsurutani, Junya Fukuoka, Hiroko Tsurutani, Joanna H. Shih, Stephen M. Hewitt, William D. Travis, Jin Jen, Phillip A. Dennis
Journal: Journal of Clinical Oncology (2005)

Akt is a serine/threonine kinase that has been implicated in lung tumorigenesis and lung cancer therapeutic resistance. Full activation of Akt requires two phosphorylation events, but only one site of phosphorylation (S473) has been evaluated thus far in clinical non-small-cell lung cancer (NSCLC) specimens, which has resulted in conflicting results regarding the prognostic significance of Akt activation in NSCLC. In this study, we sought to determine whether evaluation of Akt phosphorylation at T308 would improve prognostic accuracy.Phosphospecific antibodies against T308 and S473 were validated and used in an immunohistochemical analysis of tissue microarray slides containing NSCLC specimens (n = 300) and surrounding lung tissue specimens (n = 100).Phosphorylation of either S473 or T308 was positive in most NSCSLC specimens, but was detected rarely in surrounding normal tissues. When Akt activation was defined by using both sites of phosphorylation, Akt activation was specific for NSCLC tumors versus surrounding tissue (73.4% v 0%; P < .05), was higher in adenocarcinoma than in squamous cell carcinoma (78.1% v 68.5%; P = .040), and was associated with shorter overall survival for all stages of disease (log-rank P = .041). In multivariate analyses, increased phosphorylation of T308 alone was a poor prognostic factor for stage I patients or for tumors < 5 cm (log-rank P = .011 and P = .015, respectively).These results suggest that monitoring phosphorylation of Akt at T308 improves the assessment of Akt activation, and show that Akt activation is a poor prognostic factor for all stages of NSCLC.
More Is Not Necessarily Better When Treating Hodgkin's Lymphoma
Authors: Joseph M. Connors
Journal: Journal of Clinical Oncology (2011)

this same question, 4-6 after a full course of highly effective chemotherapy, patients with a complete response (no residual mass) did not benefit from the addition of radiation. However, those with a residual mass documented by computed tomography but not investigated with positron emission tomography had a demonstrable but marginal improvement when treated with radiation with a 5-year freedom-from-treatment failure of 90% compared with 87% without radiation (95% CI for difference, 10.7% to 1.0%). Thus, with wide agreement across trials that radiation is not helpful after effective chemotherapy induces a complete response, the challenge remains to identify the small minority of patients with a residual mass who will profit from radiation. With 87% of patients already cured by their chemotherapy despite the presence of a computed tomography–documented residual mass, it is hard to justify giving radiation to all patients just to realize a 3% improvement in freedom from relapse. Indeed, the absolute numbers are daunting. Because they harbored a residual mass, 368 patients were given radiation. Of those patients, 320 (87%) did not need it, and 33 (9%) relapsed despite it; that leaves only 12 patients who benefited from the radiation of the 368 who received it. Not surprisingly, no overall survival benefit could be seen for those given radiation. A better test to identify potential residual lymphoma, perhaps positron emission tomography scanning, will be needed to better select those who need postchemotherapy radiation.
Toward a cognitive neuroscience of language
Authors: Friedemann Pulverm&uuml;ller
Journal: Behavioral and Brain Sciences (1999)

In this response to multidisciplinary commentaries on the target article, “Words in the brain's language,” additional features of the cell-assembly model are reviewed, as demanded by some of the commentators. Subsequently, methodological considerations on how to perform additional tests of neurobiological language models as well as a discussion of recent data from neuroimaging, neuropsychological, and other behavioral studies in speakers of spoken and sign languages follow. Special emphasis is put on the explanatory power of the cell-assembly model regarding neuropsychological double dissociations. Future perspectives on neural network simulations, neuronal mechanisms of syntax and semantics, and the interaction of attention mechanisms and cell assemblies are pointed out in the final paragraphs.
EXPERIMENTAL OBSERVATIONS ON THE PROPHYLAXIS AND TREATMENT OF SYPHILIS
Authors: Henry J. Nichols, John E. Walker
Journal: The Journal of Experimental Medicine (1923)

1. By inoculating the scarified surface of both sides of the scrotum of rabbits with suspensions of Treponema pallidum, 100 per cent of infections were obtained on one side or the other. Infection through the unbroken skin could not be produced. 2. By gland transfers from animals with positive local inoculations, 87.5 per cent of takes were produced. 3. These two methods were used to test the prophylactic value of 30 per cent calomel ointment, (a) Calomel ointment proved efficacious up to 8 hours after inoculation with syphilis, (b) No marked difference appeared between the action of calomel in a base of lanolin and vaseline and in a base of benzoinated lard and wax. (c) Death from mercurial poisoning was produced in rabbits by a single application of a large amount of calomel ointment. 4. The method of gland transfers was used to test the sterilizing effect of arsphenamine and neoarsphenamine on old infections in the rabbit. The infection was completely abolished in every instance, whether by one, two, or four intravenous doses. 5. Natural spirochetosis of rabbits need not be a serious complicating factor in work on syphilis in rabbits, for the following reasons. (a) In natural spirochetosis, the lesions occur on the penis and not on the scrotum. Gland transfers are negative, (b) A scrotal lesion can be produced by inoculation, but it can be distinguished from that of Treponema pallidum infection by its course, (c) In studies of generalized syphilis supposed to involve the genitalia, and in sexual transmission experiments, Treponema cuniculi may be a serious complicating factor.
Meta-analysis of the p53 Mutation Database for Mutant p53 Biological Activity Reveals a Methodologic Bias in Mutation Detection
Authors: Thierry Soussi, Bernard Asselain, Dalil Hamroun, Shunsuke Kato, Chikashi Ishioka, Mireille Claustres, Christophe Béroud
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Analyses of the pattern of p53 mutations have been essential for epidemiologic studies linking carcinogen exposure and cancer. We were concerned by the inclusion of dubious reports in the p53 databases that could lead to controversial analysis prejudicial to the scientific community. Experimental Design: We used the universal mutation database p53 database (21,717 mutations) combined with a new p53 mutant activity database (2,300 mutants) to perform functional analysis of 1,992 publications reporting p53 alterations. This analysis was done using a statistical approach similar to that of clinical meta-analyses. Results: This analysis reveals that some reports of infrequent mutations are associated with almost normal activities of p53 proteins. These particular mutations are frequently found in studies reporting multiple mutations in one tumor, silent mutations, or lacking mutation hotspots. These reports are often associated with particular methodologies, such as nested PCR, for which key controls are not satisfactory. Conclusions: We show the importance of accurate functional analysis before inferring any genetic variation. The quality of the p53 databases is essential in order to prevent erroneous analysis and/or conclusions. The availability of functional data from our new p53 web site (http://p53.free.fr and http://www.umd.be:2072/) will allow functional prescreening to identify potential artifactual data.
How They Grow Up: 41 Physically Handicapped Children and Their Families
Authors: KLAUS K. MINDE, J. D. HACKETT, D. KILLOU, S. SILVER
Journal: American Journal of Psychiatry (1972)

The authors followed 41 physically handicapped children through their first few years in school, examining the developmental process in the life of such children. They found that most of the children underwent two well-defined crises related to specific developmental hurdles between the ages of five and nine. Many of their parents could not initially deal realistically with the problem of the child's future, but with help they were able to do so later. The authors discuss their findings in the light of various developmental theories.
Studies on the Mechanism of the Age-Related Change in Swelling Ability of Human Myocardium
Authors: ROBERT R. KHON, EDWARD ROLLERSON
Journal: Circulation Research (1959)

Previous studies have shown that human myocardium loses its ability to swell at pH 11.2 with increasing age. This investigation indicated that the age-related difference does not exist at the subcellular level or after treatment with collagenase. Swelling did not correlate well with myofiber size or acid and base binding capacity. It was concluded that the increased rigidity with age is due to the development of a more rigid intercellular collagenous connective tissue.
Paucity of phosphorylcholine-specific clones in B cells expressing the VHT15 gene product.
Authors: D Primi, E Barbier, A M Drapier, P A Cazenave
Journal: The Journal of Experimental Medicine (1986)

The aim of this work was to study the cellular basis of the phenomenon of clonal dominance. To this end we analyzed two collections of BALB/c and C.B20 hybridomas that we selected on the basis of the expression of the VHT15 gene product independently from their antigen specificity. Our study demonstrates that none of the 28 BALB/c and only 2 of the 29 C.B20 hybridomas obtained have variable regions that bind PC. We conclude therefore that the domination of the immune response to PC by particular variable regions cannot be due to the establishment of clonal dominance prior to immunization.
Local <scp>l</scp> -Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis
Authors: Josef Niebauer, Severin P. Schwarzacher, Motoya Hayase, Bingyin Wang, Robert S. Kernoff, John P. Cooke, Alan C. Yeung
Journal: Circulation (1999)

Background —Local administration of l -arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of l -arginine inhibits lesion formation. Methods and Results —New Zealand White rabbits (n=56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either l -arginine (800 mg/5 mL with and without 100 μCi l -[2,3- 3 H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled l -arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676±223 versus 453±93 cpm/mg; P &lt;0.02); this was associated with significantly higher NO levels in the l -arginine–treated segments (394.4±141.6 versus 86.3±34.3 nmol/mg; P &lt;0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with l -arginine as compared with saline infusion ( P &lt;0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of l -arginine as compared with the saline-treated segments ( P &lt;0.05). Conclusions —Intramural delivery of l -arginine immediately after angioplasty causes a sustained increase in tissue l -arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.
Thalidomide: Current Role in the Treatment of Non-Plasma Cell Malignancies
Authors: Shaji Kumar, Thomas E. Witzig, S. Vincent Rajkumar
Journal: Journal of Clinical Oncology (2004)

Thalidomide, initially introduced as a sedative, was withdrawn from the market in the early 1960s after it was found to be a teratogen. However, it later found use as an investigational agent in the treatment of erythema nodosum leprosum, oral ulcers, graft versus host disease, and wasting associated with the human immunodeficiency syndrome. Its antiangiogenic properties were recognized in the early 1990s during a period where the importance of angiogenesis became increasingly apparent as a critical step in the in the proliferation and spread of malignant neoplasms. This led to the evaluation of thalidomide as an antiangiogenic agent in the treatment of several cancers. Thalidomide has already become part of standard therapy for the treatment of patients with relapsed and refractory multiple myeloma. It has also been found to have varying degree of benefit in various other malignancies. Although more clinical trials are needed, Kaposi's sarcoma and myelofibrosis represent other malignancies in which thalidomide has already demonstrated promising activity. The mechanism of action of thalidomide in cancer is still unclear, but do appear to be mediated by several other mechanisms in addition to its anti-angiogenic properties. This article reviews the current status of thalidomide for the treatment of non-plasma-cell malignancies.
The von Hippel Lindau Tumor Suppressor Limits Longevity
Authors: Roman-Ulrich Müller, Francesca Fabretti, Sibylle Zank, Volker Burst, Thomas Benzing, Bernhard Schermer
Journal: Journal of the American Society of Nephrology (2009)

Many genes are responsible for the modulation of lifespan in model organisms. In addition to regulating adaptive biologic responses that control stress signaling and longevity, some of these genes participate in tumor formation. The mechanisms that determine longevity and link regulation of lifespan with tumorigenesis are poorly understood. Here, we show that the tumor suppressor von Hippel-Lindau (VHL), which has widely known roles in renal carcinogenesis and the formation of kidney cysts, controls longevity in Caenorhabditis elegans. Loss of vhl-1 significantly increased lifespan and resulted in accelerated basal signaling of the p38 mitogen-activated protein kinase PMK-3. Furthermore, the VHL-1 effect on the regulation of lifespan was independent of the insulin/IGF-1-like signaling pathway, suggesting a mechanism for stress resistance that controls both lifespan and tumorigenesis. These findings define VHL-1 as a player in longevity signaling and connect aging, regulation of lifespan, and stress responses with formation of renal cell carcinomas.
Atherosclerotic Vascular Disease Conference
Authors: David P. Faxon, Mark A. Creager, Sidney C. Smith, Richard C. Pasternak, Jeffrey W. Olin, Michael A. Bettmann, Michael H. Criqui, Richard V. Milani, Joseph Loscalzo, John A. Kaufman, Daniel W. Jones, William H. Pearce
Journal: Circulation (2004)
Paracrinal Hedgehog Signaling Activates Pancreatic Stellate Cell by Regulating Metabolism in Pancreatic Cancer
Authors: Qinhong Xu, Wanxing Duan, Jianjun Lei, Rong Li, Liang Sheng, Xin Chen, Liang Han, Qingyong Ma
Journal: Annals of Oncology (2013)