tbuckley/cabot-search huggingface dataset:
Younger Age of Cancer Initiation Is Associated with Shorter Telomere Length in Li-Fraumeni Syndrome
Authors: Uri Tabori, Sonia Nanda, Harriet Druker, Jodi Lees, David Malkin
Journal: Cancer Research (2007)

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown. We speculated that telomere attrition will increase genomic instability and cause earlier tumor onset in successive generations. We analyzed mean telomere length and MDM2-SNP309 polymorphism status in individuals from multiple LFS families and controls. A total of 45 peripheral blood lymphocyte samples were analyzed from 9 LFS families and 15 controls. High rate of MDM2-SNP309 was found in TP53 carriers (P = 0.0003). In children, telomere length was shorter in carriers affected with cancer than in nonaffected carriers and wild-type controls (P < 0.0001). The same pattern was seen in adults (P = 0.002). Within each family, telomere length was shorter in children with cancer than in their nonaffected siblings and their noncarrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Our results support the role of MDM2-SNP309 as a genetic modifier in LFS. The novel finding of accelerated telomere attrition in LFS suggests that telomere length could explain earlier age of onset in successive generations of the same family with identical TP53/MDM2-SNP309 genotypes. Furthermore, telomere shortening could predict genetic anticipation observed in LFS and may serve as the first rational biological marker for clinical monitoring of these patients.
Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis
Authors: Carlo Vancheri, Claudio Mastruzzo, Ferdinando Armato, Valerio Tomaselli, Salvatore Magrì, Maria Provvidenza Pistorio, Maria LaMicela, Leda D'Amico, Nunzio Crimi
Journal: Journal of Allergy and Clinical Immunology (2001)
Anti-heparin platelet factor 4 antibodies in systemic lupus erythaematosus are associated with IgM antiphospholipid antibodies and the antiphospholipid syndrome
Authors: D Alpert, L A Mandl, D Erkan, W Yin, E I Peerschke, J E Salmon
Journal: Annals of the Rheumatic Diseases (2007)

To investigate the prevalence and clinical correlates of anti-heparin platelet factor 4 antibodies (anti-HPF4) in systemic lupus erythematosus (SLE) patients with and without antiphospholipid antibodies (aPL).Sera and clinical data were obtained from the Hospital for Special Surgery Autoimmune Disease Registry for 78 aPL-positive and 91 aPL-negative SLE patients without heparin-induced thrombocytopenia (HIT). Controls were 90 blood donors of comparable age and sex. Sera were assayed for anti-HPF4, IgG/IgM antiphospholipid antibodies (APhL), and IgG/IgM anti-beta2-glycoprotein 1 antibodies (anti-beta 2GP1). Serotonin release assays (SRAs) were performed for subjects with positive anti-HPF4.Positive anti-HPF4 was seen in 9% of aPL-positive SLE patients, 4% of aPL-negative SLE patients and 1% of controls (p = 0.026, aPL-positive SLE vs controls). Two of 12 subjects with positive anti-HPF4 had reactive SRAs. In SLE patients, anti-HPF4 significantly correlated with IgM APhL, IgM anti-beta2GP1, and inversely with complement C4. In immunoabsorption experiments, there was partial cross-reactivity of IgM anti-HPF4 with IgM APhL, but not with IgM anti-beta 2GP1. SLE patients with positive anti-HPF4 had increased odds of the antiphospholipid syndrome (APS; odds ratio (OR) 4.5, p = 0.019), and APS with arterial thrombosis (OR 6.1, p = 0.007). In multivariate linear regression analyses, APS and IgM APhL were independently associated with anti-HPF4.Anti-HPF4 is detectable in SLE patients with and without aPL in the absence of HIT, and is most prevalent in aPL-positive SLE patients. In this SLE cohort, anti-HPF4 correlates with IgM APhL, IgM anti-beta 2GP1 and inversely with C4, and is associated with manifestations of APS.
The Training of Physician Assistants: Status and Issues
Authors: Joseph Kadish
Journal: JAMA (1970)

The idea of having assistants for the physician is not new. The concept of the division of responsibilities and the stratification of functions among the various types of health professionals has been endorsed for many decades— in some instances, for centuries. Today heightened interest and concern about health and medical care in the nation are forcing a reexamination of interpretations of this concept by the medical community and the public. It is too early to seek a consensus about the descriptions and roles of such personnel in the United States. However, there is an identifiable interest in both the medical and the nonmedical sectors of US society. The goal is to develop means to make adequate health care available to more people. One consideration is the rational delegation of the physician's traditional functions to nonphysicians in the delivery of health care. If some of the physician's responsibilities and duties are
Human lymphokine-activated killer cells are cytotoxic against cells infected with Toxoplasma gondii.
Authors: C S Subauste, L Dawson, J S Remington
Journal: The Journal of Experimental Medicine (1992)

Experiments were conducted to determine whether human lymphokine-activated killer (LAK) cells are cytotoxic against cells infected with Toxoplasma gondii. Nylon wool nonadherent (NWNA) peripheral blood lymphocytes, as well as purified natural killer cell (NK) (CD3- CD16+ CD56+) and T (CD3+ CD16- CD56-) cells obtained from five healthy T. gondii seronegative volunteers exhibited minimal cytotoxic activity against T. gondii-infected cells. When standard LAK (S-LAK) cell preparations were induced by incubation of NWNA cells with recombinant interleukin 2, induction of remarkable cytotoxic activity against T. gondii-infected cells. When standard in LAK cell preparations from each of the volunteers. The phenotype of the LAK precursor and effector cells varied depending on the target cell used. Whereas the precursor and the effector cells of most of the LAK activity against K562 and Daudi cells were cells with NK phenotype, when T. gondii-infected cells were used as targets, both cells with NK and T cell phenotypes were precursors and effectors of the lysis. When cytotoxic activity of S-LAK cells was compared with the activity of adherent LAK (A-LAK) cells, A-LAK cells displayed higher cytotoxic activity against T. gondii-infected cells, as well as against K562 and Daudi cells. Cold target inhibition experiments suggested that there is a subset of LAK effector cells capable of lysing both T. gondii-infected cells and Daudi cells, whereas other subsets preferentially or exclusively lyse one of these target cells.
Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis
Authors: Keith Syson Chan, Steve Carbajal, Kaoru Kiguchi, John Clifford, Shigetoshi Sano, John DiGiovanni
Journal: Cancer Research (2004)

Abstract In the present study, we have investigated the possible role of signal transducers and activators of transcription (STATs), particularly Stat3, in mouse skin tumor promotion and multistage carcinogenesis. Stat1, Stat3, and Stat5 were activated in mouse epidermis after treatment with different classes of tumor promoters, including 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid, and chrysarobin. In addition, Stat1, Stat3, and Stat5 were constitutively activated in skin tumors generated by the two-stage carcinogenesis regimen using 7,12-dimethylbenz(a)anthracene as initiator and TPA as promoter. Several approaches were used to examine the possible role of epidermal growth factor receptor (EGFR) in modulating Stat3 activity during tumor promotion. In primary cultures of mouse keratinocytes, addition of exogenous EGF led to activation of Stat3 as shown by an elevation in tyrosine phosphorylation and nuclear translocation. In epidermis of transgenic mice expressing transforming growth factor α under control of the keratin 14 promoter, Stat3 was constitutively activated. Abrogation of EGFR function in mouse epidermis using an EGFR kinase inhibitor or by overexpressing a dominant negative form of EGFR led to a reduction in Stat3 activation in response to TPA treatment. Immunoprecipitation analyses using lysates from TPA-treated epidermis and skin papillomas showed enhanced interaction between the EGFR and Stat3. Finally, Stat3 deficiency in mouse epidermis significantly reduced the proliferative response after TPA treatment. Collectively, the current results suggest that Stat3 activation may be a critical event during mouse skin tumor promotion, possibly through regulation of keratinocyte proliferation. In addition, Stat3 activation in tumor promoter-treated epidermis and in skin papillomas may occur, at least in part, via interaction with and phosphorylation by the EGFR. Finally, constitutive activation of Stat3 in both papillomas and squamous cell carcinomas suggest a role in both the development of autonomous growth and the progression of epithelial tumors in mouse skin.
O4.04 * 'FROM THE CORE TO BEYOND THE MARGIN': A GENOMIC PICTURE OF GLIOBLASTOMA INTRATUMOR HETEROGENEITY
Authors: M. Aubry, M. de Tayrac, A. Etcheverry, A. Clavreul, S. Saikali, P. Menei, J. Mosser
Journal: Neuro-Oncology (2014)

INTRODUCTION: Glioblastoma (GB) is a very agressive brain tumor that almost systematically recurs. This recurrence is linked to the highly invasive behavior of this tumor. Major challenges in therapy of GB are therefore associated with controlling this infiltration sustained by a strong heterogeneous biology of GB tumors. In the past decade, molecular studies of GB have been focused on inter-individual heterogeneity. These studies have identified gene mutations and molecular signatures with putative prognostic or predictive significance. However, accumulating evidence suggests that intratumor heterogeneity is the key to understanding treatment failure. MATERIAL AND METHOD: To explore GB intratumor heterogeneity we developed a surgical multisampling scheme to collect tumor fragments from 10 GB patients in four spatially distinct areas defined on 3D MRI ‘from the core to beyond the margin’: necrotic zone, tumor zone, interface, and peripheral brain zone. These samples were studied genome-wide at three molecular levels: genome, transcriptome and methylome. We used Principal Component Analysis (PCA) to classify the samples and to select genes. We constructed a co-expression network on the basis of the expression data of the most informative genes related to the data structure revealed by PCA. RESULTS AND DISCUSSION: At the genome level, we identified common GB alterations (loss/partial loss of chromosome 10, polysomy of chromosome 7, focal deletion of the CDKN2A/B and focal high-level amplifications of EGFR) and a strong inter-individual molecular heterogeneity. Transcriptome analysis highlighted a pronounced intratumor architecture reflecting the surgical sampling plan of the study and identified gene modules associated with hallmarks of cancer. We provide a master gene signature highly correlated with the intratumor gradient and associated with the tumor infiltrative behavior. In this signature, the percentage of genes presenting an anti-correlation between expression and methylation levels was significantly higher than in the whole genome. This indicated that their abnormal expression might be linked to cis-acting epimutations in their promoter. We also evidenced that a single tumor can harbor different transcriptional GB subtypes depending on its spatial architecture. Results were validated on published data (Sottoriva et al., PNAS, 2013). CONCLUSION: Our study confirms that GBs are highly diverse at the three molecular levels, but not randomly so. GB intratumor heterogeneity is an important issue for the potential use of GB molecular subclasses in predictive algorithms and clinical trial stratification. We also evidenced a strong epigenetic determination of GB intratumor heterogeneity.
Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth
Authors: Lucy Cassar, He Li, Alexander Ruvantha Pinto, Craig Nicholls, Sharyn Bayne, Jun-Ping Liu
Journal: Cancer Research (2008)

Abstract Telomere maintenance is critical in tumor cell immortalization. Here, we report that the cytokine bone morphogenetic protein-7 (BMP7) inhibits telomerase activity that is required for telomere maintenance in cervical cancer cells. Application of human recombinant BMP7 triggers a repression of the human telomerase reverse transcriptase (hTERT) gene, shortening of telomeres, and hTERT repression–dependent cervical cancer cell death. Continuous treatment of mouse xenograft tumors with BMP7, or silencing the hTERT gene, results in sustained inhibition of telomerase activity, shortening of telomeres, and tumor growth arrest. Overexpression of hTERT lengthens telomeres and blocks BMP7-induced tumor growth arrest. Thus, BMP7 negatively regulates telomere maintenance, inducing cervical tumor growth arrest by a mechanism of inducing hTERT gene repression. [Cancer Res 2008;68(22):9157–66]
Maturational changes of endothelial vasoactive factors and pulmonary vascular tone at birth
Authors: M Levy, E Souil, S Sabry, F Favatier, P Vaugelade, JC Mercier, J Dall'Ava-Santucci, AT Dinh-Xuan
Journal: European Respiratory Journal (2000)

The aim of this study was to determine which endothelial factors were involved in the decrease of pulmonary vascular resistance at birth, and how they changed with maturation. Response of intrapulmonary artery rings precontracted with prostaglandin F2alpha were studied from piglets aged <2 h, 2-3 day, 10 day and adult pigs for pharmacological responses to acetylcholine (ACh) and cromakalim (CMK) in the presence and the absence of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NA), the adenosine triphosphate sensitive potassium (K(ATP)) channel blocker, glibenclamide and the endothelin (ET)-A receptor antagonist, BQ123. In situ hybridization and immunochemistry studies were performed in lung tissues of the same animals in order to determine the expression of NOS and ET. There was a small contractile effect of ACh in the newborn. Relaxation to ACh, which was blocked by L-NA and reduced by glibenclamide, only appeared from the age of 3 days. The significantly greater relaxation to CMK in rings without endothelium (p<0.05) was abolished by BQ123 in the newborn, and then disappeared by 2 days of age. Glibenclamide had a greater inhibitory effect on relaxation induced by CMK at 10 days than in the newborn and 2 days old piglets. NOS expression was low in pulmonary arteries of the newborn and increased by 2 days of age whereas the converse was seen with ET expression. It is concluded that: 1) relaxant response to acetylcholine was absent at birth and appeared at 2 days; 2) the reduced relaxant response to cromakalin in rings with endothelium at birth could be blocked by BQ123; and 3) the expression of endothelin decreased whereas the expression of nitric oxide synthase increased from birth to 2 days of age.
Anti-chromatin antibodies in systemic lupus erythematosus: a useful marker for lupus nephropathy
Authors: R Cervera
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Anti-chromatin antibodies have recently been described in patients with systemic lupus erythematosus (SLE) and it has been suggested that their presence is associated with lupus nephritis. <b>Objective:</b> To assess the prevalence and clinical associations of these antibodies in SLE. <b>Methods:</b> The presence of anti-chromatin antibodies in 100 patients with SLE was investigated by an enzyme linked immunosorbent assay (ELISA). To determine the specificity of these antibodies, 100 patients with primary Sjögren's syndrome, 30 with primary antiphospholipid syndrome (APS), 10 with systemic sclerosis, and 100 normal controls were also tested. <b>Results:</b> Positive levels were detected in 69/100 (69%) patients with SLE. In contrast, they were found in only 8/100 (8%) of those with primary Sjögren's syndrome, in 1/10 (10%) with systemic sclerosis, in 2/30 (7%) with primary APS, and in none of the 100 healthy controls. Patients with anti-chromatin antibodies had a twofold higher prevalence of lupus nephropathy than those without these antibodies (58% <i>v</i> 29%, p&lt;0.01). A significant correlation was found between the levels of anti-chromatin antibodies and disease activity score as measured by the European Consensus Lupus Activity Measurement (ECLAM; p=0.011). <b>Conclusions:</b> The measurement of anti-chromatin antibodies appears to be a useful addition to the laboratory tests that can help in the diagnosis and treatment of SLE. These antibodies are both sensitive and specific for SLE, and are a useful marker for an increased risk of lupus nephritis.
AMOUNT AND DURATION OF IMMUNITY INDUCED BY INTRADERMAL INOCULATION OF CULTURED VACCINE VIRUS
Authors: Thomas M. Rivers, S. M. Ward, R. D. Baird
Journal: The Journal of Experimental Medicine (1939)

Continued cultivation of vaccine virus in a medium consisting of minced chick embryo tissue and Tyrode's solution has resulted in a virus qualitatively changed to such an extent that considerable amounts of it can be injected intradermally into human beings without danger or inconvenience. Individuals who are vaccinated intradermally with the cultured virus should be revaccinated dermally six months to a year later with a potent calf lymph virus in order to obtain a satisfactory immunity to smallpox without being subjected to the dangers and inconvenience associated with primary vaccinations with calf lymph virus.
Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers
Authors: Johnathan Watkins, Daniel Weekes, Vandna Shah, Patrycja Gazinska, Shalaka Joshi, Bhavna Sidhu, Cheryl Gillett, Sarah Pinder, Fabio Vanoli, Maria Jasin, Markus Mayrhofer, Anders Isaksson, Maggie C.U. Cheang, Hasan Mirza, Jessica Frankum, Christopher J. Lord, Alan Ashworth, Shaveta Vinayak, James M. Ford, Melinda L. Telli, Anita Grigoriadis, Andrew N.J. Tutt
Journal: Cancer Discovery (2015)

Triple-negative breast cancers (TNBC) are characterized by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that allelic-imbalanced copy-number aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene, HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs, as well as sensitizing cancer cells to HR-targeting therapies. Our data therefore provide a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability, and an association with response to platinum-based chemotherapy in TNBC.
The Diagnostic Interview Schedule for Deaf Patients on Interactive Video: A Preliminary Investigation
Authors: Annie G. Steinberg, Douglas S. Lipton, Elizabeth A. Eckhardt, Marjorie Goldstein, Vicki Joy Sullivan
Journal: American Journal of Psychiatry (1998)

The authors investigated the feasibility of translating the National Institute of Mental Health Quick Diagnostic Interview Schedule-III, Revised, computer version, for deaf individuals.The study involved translation of selected scales into American Sign Language, Signed English, and speech reading; review by an advisory panel and back translator; and collection and analysis of deaf individuals' reactions to translations.Focus groups responded favorably, translation problems were revealed, and solutions were suggested.The findings support the feasibility of translation of the Quick Diagnostic Interview Schedule-III, Revised, into American Sign Language, Signed English, and speech reading for deaf patients.
Simple Risk Stratification at Admission to Identify Patients With Reduced Mortality From Primary Angioplasty
Authors: Jens Jakob Thune, Dan Eik Hoefsten, Matias Greve Lindholm, Leif Spange Mortensen, Henning Rud Andersen, Torsten Toftegaard Nielsen, Lars Kober, Henning Kelbaek
Journal: Circulation (2005)

Randomized trials comparing fibrinolysis with primary angioplasty for acute ST-elevation myocardial infarction have demonstrated a beneficial effect of primary angioplasty on the combined end point of death, reinfarction, and disabling stroke but not on all-cause death. Identifying a patient group with reduced mortality from an invasive strategy would be important for early triage. The Thrombolysis in Myocardial Infarction (TIMI) risk score is a simple validated integer score that makes it possible to identify high-risk patients on admission to hospital. We hypothesized that a high-risk group might have a reduced mortality with an invasive strategy.We classified 1527 patients from the Danish Multicenter Randomized Study on Fibrinolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction (DANAMI-2) trial with information for all variables necessary for calculating the TIMI risk score as low risk (TIMI risk score, 0 to 4) or high risk (TIMI risk score > or =5) and investigated the effect of primary angioplasty versus fibrinolysis on mortality and morbidity in the 2 groups. Follow-up was 3 years. We classified 1134 patients as low risk and 393 as high risk. There was a significant interaction between risk status and effect of primary angioplasty (P=0.008). In the low-risk group, there was no difference in mortality (primary angioplasty, 8.0%; fibrinolysis, 5.6%; P=0.11); in the high-risk group, there was a significant reduction in mortality with primary angioplasty (25.3% versus 36.2%; P=0.02).Risk stratification at admission based on the TIMI risk score identifies a group of high-risk patients who have a significantly reduced mortality with an invasive strategy of primary angioplasty.