tbuckley/cabot-search huggingface dataset:
Murine T cell receptor beta chain is encoded on chromosome 6.
Authors: N E Lee, P D'Eustachio, D Pravtcheva, F H Ruddle, S M Hedrick, M M Davis
Journal: The Journal of Experimental Medicine (1984)

Southern blot analysis of somatic cell hybrid lines indicates that the beta chain of the T cell receptor for antigen maps to chromosome 6 of the mouse. An experiment testing hybridization of the constant region of this gene to DNA from a hybrid cell line containing a translocation of chromosome 6 supports the localization of this gene to the proximal (centromeric) one-third of chromosome 6, in the same general region as the immunoglobulin kappa chain locus. This may be another indication of the shared evolutionary origins of the genes encoding both T and B cell antigen recognition.
The Ups and Downs of Transcription Factors in Melanoma
Authors: A. Santiago-Walker, M. Herlyn
Journal: JNCI Journal of the National Cancer Institute (2010)

Of the three key developmental pathways, NOTCH, WNT, and Sonic Hedgehog (SHH), the least is known about the SHH pathway in melanocyte development and melanoma.In this issue of the Journal, a study from the laboratory of Alain Mauviel is the first to connect transforming growth factor-b (TGF-b) with SHH signaling in promoting melanoma metastasis.Alexaki et al. (1) reveal that GLI2, a transcription factor traditionally downstream of SHH activation, is overexpressed in human melanoma.Melanoma cells in which GLI2 expression was higher than normal (GLI2-high cells) metastasized to bone more readily than cells in which GLI2 expression was lower (GLI2-low cells), and reduction of GLI2 expression impaired bone metastasis (1).It is known that TGF-b overexpression stimulates increased matrix protein secretion, adhesion receptor expression, and invasion of melanoma cells (2), and previous work from this group revealed GLI2 as a direct target of TGF-b and SMAD signaling (3).The current work clearly demonstrates that activation of GLI2 promotes invasion and metastasis and suppresses E-cadherin expression leading to a mesenchymal-like phenotype.Thus, TGF-b regulates invasion and migration through a novel mechanism utilizing a SHH pathway component.Likely because of deregulation of this stimulatory signaling mechanism, tumor cells often become SHH independent, and endogenous or exogenous SHH has no effect on melanoma growth and migration (M.Fukunaga-Kalabis and M. Herlyn, unpublished data).SHH antagonists, such as cyclopamine, have little effect on melanoma cells in vitro, suggesting that TGF-b hijacks the transcriptional machinery of the SHH pathway (M.Fukunaga-Kalabis and M. Herlyn, unpublished data).Stecca et al. ( 4) previously reported that GLI1, a direct GLI2 target, is required for normal melanocyte proliferation as well as growth and metastasis of melanoma cells.Therefore, GLI2 is emerging as a common target of the developmental machinery and a progression factor in melanoma.Remaining questions include how the other developmental pathways are activated in melanoma.The NOTCH pathway is constitutively active in melanomas, and expression of activated NOTCH1 induces a transformed phenotype in melanocytes (5).However, the mechanism for constitutive NOTCH activation in metastatic melanoma is unknown.Meanwhile, canonical WNT signaling is essential for melanocyte differentiation.During melanoma progression, a switch from canonical (WNT1 and WNT3A) to noncanonical (WNT5A) Wnt signaling occurs (6).Similar to SHH, these pathways are also hijacked, but likely more upstream, at the receptor rather than the transcriptional level.Also in this issue, a report from the laboratory of Gavin Robertson highlights the importance of the tumor microenvironment and cell-matrix signaling in tumor progression.The article by Huh et al. ( 7) is the first to functionally describe KLF6 as the
Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice
Authors: Hong Xiao, Peter Heeringa, Peiqi Hu, Zhi Liu, Minglang Zhao, Yasuaki Aratani, Nobuyo Maeda, Ronald J. Falk, J. Charles Jennette
Journal: Journal of Clinical Investigation (2002)

Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo(-/-)) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2-deficient (Rag2(-/-)) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 x 10(8) or 5 x 10(7) anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2(-/-) mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis.
Internally-generated activity, non-episodic memory, and emotional salience in sleep
Authors: James A. Bednar
Journal: Behavioral and Brain Sciences (2000)

(1) Substituting (as Solms does) forebrain for brainstem in the search for a dream “controller” is counterproductive, since a distributed system need have no single controller. (2) Evidence against episodic memory consolidation does not show that REM sleep has no role in other types of memory, contra Vertes &amp; Eastman. (3) A generalization of Revonsuo's “threat simulation” model in reverse is more plausible and is empirically testable. [Hobson et al.; Solms; Revonsuo; Vertes &amp; Eastman]
Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia
Authors: Michael P. Whyte, Cheryl R. Greenberg, Nada J. Salman, Michael B. Bober, William H. McAlister, Deborah Wenkert, Bradley J. Van Sickle, Jill H. Simmons, Terence S. Edgar, Martin L. Bauer, Mohamed A. Hamdan, Nick Bishop, Richard E. Lutz, Mairead McGinn, Stanley Craig, Jean N. Moore, John W. Taylor, Robert H. Cleveland, William R. Cranley, Ruth Lim, Tom D. Thacher, Jill E. Mayhew, Matthew Downs, José Luis Millán, Alison M. Skrinar, Philippe Crine, Hal Landy
Journal: New England Journal of Medicine (2012)

Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice.We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040.Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment.ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).
Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis
Authors: Divya Purushothaman, Apurva Sarin
Journal: The Journal of Experimental Medicine (2009)

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91phox to characterize the molecular link to activated T cell apoptosis, we show that gp91phox-deficient T (T−/−) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase–dependent Bax activation and apoptosis. Activated T−/− cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.
Economic evaluation of human papillomavirus vaccination in the United Kingdom
Authors: M. Jit, Y. H. Choi, W J. Edmunds
Journal: BMJ (2008)

<b>Objective</b> To assess the cost effectiveness of routine vaccination of 12 year old schoolgirls against human papillomavirus infection in the United Kingdom. <b>Design</b> Economic evaluation. <b>Setting</b> UK. <b>Population</b> Schoolgirls aged 12 or older. <b>Main outcome measures</b> Costs, quality adjusted life years (QALYs), and incremental cost effectiveness ratios for a range of vaccination options. <b>Results</b> Vaccinating 12 year old schoolgirls with a quadrivalent vaccine at 80% coverage is likely to be cost effective at a willingness to pay threshold of £30 000 (€37 700; $59 163) per QALY gained, if the average duration of protection from the vaccine is more than 10 years. Implementing a catch-up campaign of girls up to age 18 is likely to be cost effective. Vaccination of boys is unlikely to be cost effective. A bivalent vaccine with the same efficacy against human papillomavirus types 16 and 18 costing £13-£21 less per dose (depending on the duration of vaccine protection) may be as cost effective as the quadrivalent vaccine although less effective as it does not prevent anogenital warts. <b>Conclusions</b> Routine vaccination of 12 year old schoolgirls combined with an initial catch-up campaign up to age 18 is likely to be cost effective in the UK. The results are robust to uncertainty in many parameters and processes. A key influential variable is the duration of vaccine protection.
Transmural Heterogeneity of Na <sup>+</sup> –Ca <sup>2+</sup> Exchange
Authors: Wei Xiong, Yanli Tian, Deborah DiSilvestre, Gordon F. Tomaselli
Journal: Circulation Research (2005)

Spatial electrical heterogeneity has a profound effect on normal cardiac electrophysiology and genesis of cardiac arrhythmias in diseased hearts. The Na + –Ca 2+ exchanger (NCX) is a key linker, through Ca 2+ signaling, between contractility and arrhythmias. Here we characterize the differential transmural expression of NCX in normal and rapid pacing-induced failing canine hearts. Significant transmural heterogeneity of NCX was present in normal hearts, as NCX current density measured at +80 mV was significantly ( P &lt;0.05) greater in epicardial (EPI) (5.49 pA/pF) than mid-myocardial (MID) (2.84 pA/pF) and endocardial (ENDO) (2.21 pA/pF) cells. Interestingly, heart failure caused a selective increase in NCX current density ( P &lt;0.05) limited to ENDO (by 202%) and MID (by 76%) but not EPI myocytes ( P =not significant). The differences in functional expression were associated with changes in both mRNA and protein levels. The normal EPI layer exhibited the greatest NCX mRNA and protein levels compared with MID and ENDO layers, whereas the ENDO layer underwent the most pronounced increase in mRNA (by 185%) and protein (by 207%) levels in heart failure. The transmural NCX gradient, from EPI (greatest) to ENDO (least), is disrupted in heart failure. A selective upregulation of NCX expression in MID and ENDO in heart failure markedly redirects the orientation of the transmural functional gradient of NCX and may lead to enhanced vulnerability to cardiac arrhythmias.
<i>PTCH1</i> gene haplotype association with basal cell carcinoma after transplantation
Authors: A. Begnini, G. Tessari, A. Turco, G. Malerba, L. Naldi, E. Gotti, L. Boschiero, A. Forni, C. Rugiu, S. Piaserico, A.B. Fortina, A. Brunello, C. Cascone, G. Girolomoni, M. Gomez Lira
Journal: British Journal of Dermatology (2010)

Background Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals. Objectives To search for novel common polymorphisms in the proximal 5′ regulatory region upstream of PTCH1 gene exon 1B, and to investigate the possible association of PTCH1 polymorphisms and haplotypes with BCC risk after organ transplantation. Methods Three PTCH1 single nucleotide polymorphisms (rs2297086, rs2066836 and rs357564) were analysed by restriction fragment length polymorphism analysis in 161 northern Italian OTRs (56 BCC cases and 105 controls). Two regions of the PTCH1 gene promoter were screened by heteroduplex analysis in 30 cases and 30 controls. Results Single locus analysis showed no significant association. Haplotype T1686–T3944 appeared to confer a significantly higher risk for BCC development (odds ratio 2·98, 95% confidence interval 2·55–3·48; P =0·001). Two novel rare polymorphisms were identified at positions 176 and 179 of the 5′UTR. Two novel alleles of the ‐4 (CGG)n microsatellite were identified. No association of this microsatellite with BCC was observed. Conclusions Haplotypes containing T1686–T3944 alleles were shown to be associated with an increased BCC risk in our study population. These data appear to be of great interest for further investigations in a larger group of transplant individuals. Our results do not support the hypothesis that common polymorphisms in the proximal 5′ regulatory region of the PTCH1 gene could represent an important risk factor for BCC after organ transplantation.
Downstaging or Downsizing: Time for a New Staging System in Advanced Colorectal Cancer?
Authors: Graeme Poston, Rene Adam, Jean-Nicolas Vauthey
Journal: Journal of Clinical Oncology (2006)

Ten years ago, the management of advanced colorectal cancer was relatively straightforward. For the fortunate few with liveronly disease who managed to find their way to a liver surgeon and who met the stringent criteria of the day for hepatectomy (one to three unilobar metastases, preferably presenting metachronously, and resectable with a generous margin of healthy liver tissue), there was the chance of surgery with curative intent. If they survived the surgery, the patients had a 30% to 40% chance of being alive 5 years later. However, these patients accounted for less than 10% of all patients with advanced liver-only disease, and for patients with nonresectable disease, the chance of being alive 5 years after diagnosis was less than 1%. Palliative chemotherapy using fluorouracil and leucovorin achieved a measurable response in barely 20% of patients and improved median survival time from 8 months with best supportive care to little over 12 months. At that time, the American Joint Committee on Cancer staging system for advanced colorectal cancer was equally straightforward; all patients with metastatic disease beyond the immediate lymph node basin of the primary tumor had stage IV disease, and their prognosis was grim. The situation in 2006 has changed completely for both resectable and unresectable patients. Over the last 10 years, the definition of resectability has evolved, overcoming the morphologic limitation used in the past as selection criteria. Now the definition of resectability with curative intent is the ability of the surgeon to clear, with negative margin, all measurable disease from the liver while leaving a healthy future remnant liver of 20% of the total liver volume. Factors that determine the extent of safe liver resection include performance status and concurrent parenchymal liver disease. Liver resection is now considered selectively in some subsets of patients with limited resectable extrahepatic disease. Hilar lymph node metastases; lung, ovarian, and adrenal metastases; and local or regional recurrence are no longer formal contraindications.
Validation of the stop bang questionnaire in a sleep clinic in Greece for the prediction of obstructive sleep apnea
Authors: Athanasia Pataka, Nikolaos Chavouzis, Katalin Fekete Passa, Vasilios Bagalas, Georgia Pitsiou, Ioannis Stanopoulos, George Kalamaras, Asimina Paspala, Evdokia Sourla, Eleni Vaitsi, Paraskevi Argyropoulou
Journal: European Respiratory Journal (2013)

Background: Stop Bang(S-B) is a simple questionnaire effective to identify patients at risk for postoperative complications because of obstructive sleep apnea syndrome(OSAS).  Aim: To evaluate S-B as a screening tool for OSAS in a European (Greek) population visiting a sleep clinic.  Methods: Patients with possible OSAS answered a Greek translation of STOP questionnaire and underwent polysomnography (PSG). BMI, age, neck circumference,and gender (BANG) were documented.  Results: Over 4 yr, 1520 patients (75.2%males) had PSG study and compled S-B. Their mean age was 52±14 yr, BMI 32.7±6.96 kg/ m2, neck circumference 41.8±4.3 cm, Epworth Sleepiness Scale (ESS) 11.2±5, Apnea Hypopnea Index (AHI) 33±26.5/h, Oxygen Desaturation Index (ODI) 37.5±29.5 and S-B score 5±1.5. OSAS was diagnosed in 80.9% of patients: 13.5% mild, 18.8% moderate, and 48.5% severe. By S-B scoring 94.3%(1434) of patients were classified as being at high risk of OSAS. For a S-B≥3, the odds ratio (OR) for OSAS (AHI≥5) was 4.1. The sensitivities of S-B model for AHI ≥5, ≥ 15 and ≥ 30 were 96.2%, 92.5% and 98.6%, respectively; the specificities 13.9%,12.6%,10%, the positive predictive values 83.2%, 70.6%, 52.7% and the negative predictive values 45.3%, 70.9% and 88.3%. The area under the ROC curve at AHI≥ 5 was 0.735. S-B had good correlation with Berlin questionnaire (p  Conclusions: In a sleep clinic S-B is an easy-to-use screening tool that can be used to evaluate patients with high risk of OSAS.
Breast-feeding and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
Authors: H. Jernstrom, J. Lubinski, H. T. Lynch, P. Ghadirian, S. Neuhausen, C. Isaacs, B. L. Weber, D. Horsman, B. Rosen, W. D. Foulkes, E. Friedman, R. Gershoni-Baruch, P. Ainsworth, M. Daly, J. Garber, H. Olsson, P. Sun, S. A. Narod
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. Methods: We conducted a case–control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 280]), year of birth (±2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. Results: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P <.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; Ptrend <.001). Women with BRCA1 mutations who breast-fed for more than 1 year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P = .001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P = .83). Conclusions: Women with deleterious BRCA1 mutations who breast-fed for a cumulative total of more than 1 year had a statistically significantly reduced risk of breast cancer.
Immunohistochemical demonstration of fibronectin in the most superficial layer of normal rabbit articular cartilage.
Authors: K Nishida, H Inoue, T Murakami
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To locate fibronectin ultrastructurally in the most superficial layer of normal articular cartilage of rabbits, in order to clarify its role in joint physiology. METHODS--Articular cartilage was obtained from the femoral condyle of seven normal adult rabbits and prepared by a method that included tannic acid fixation. Polyclonal antibodies against rabbit fibronectin were used in an immunohistochemical electron microscopic study, without any enzymic digestion but with a pre-embedding method for the transmission electron microscopy. RESULTS--The cartilage surface was successfully preserved by tannic acid fixation. The most superficial layer in electron photomicrographs was approximately 200-300 nm thick, cell free, and appeared to have two parallel components: the more superficial lamina and the deeper lamina. Gold labelled fibronectin lined this layer in immunohistochemical electron photomicrographs. CONCLUSIONS--Fibronectin covering the surface of the articular cartilage may have a role in joint lubrication and protection of the cartilage by binding with the collagenous matrix and hyaluronic acid in synovial fluid. Chondroitin sulphates may act as a charge barrier in close relationship with the collagen fibrils in the deeper lamina. Significant alteration in these functions may be one of the first causal steps leading to destruction of the articular cartilage.