tbuckley/cabot-search huggingface dataset:
Large Deletions of the <i>PRKAR1A</i> Gene in Carney Complex
Authors: Anelia Horvath, Ioannis Bossis, Christoforos Giatzakis, Elizabeth Levine, Frank Weinberg, Elise Meoli, Audrey Robinson-White, Jennifer Siegel, Payal Soni, Lionel Groussin, Ludmila Matyakhina, Somya Verma, Elaine Remmers, Maria Nesterova, J. Aidan Carney, Jérôme Bertherat, Constantine A. Stratakis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found in ∼70% of the patients. To date, no germ-line PRKAR1A deletion and/or insertion exceeded a few base pairs (up to 15). Although a few families map to chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes in PRKAR1A–mutation-negative individuals with Carney complex. Experimental Design: To screen for gross alterations of the PRKAR1A gene, we applied Southern hybridization analysis on 36 unrelated Carney complex patients who did not have small intragenic mutations or large aberrations in PRKAR1A, including the probands from two kindreds mapping to chromosome 2. Results: We found large PRKAR1A deletions in the germ-line of two patients with Carney complex, both sporadic cases; no changes were identified in the remaining patients, including the two chromosome-2-mapping families. In the first patient, the deletion is expected to lead to decreased PRKAR1A mRNA levels but no other effects on the protein; the molecular phenotype is predicted to be PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing Carney complex. In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic protein kinase A subunit. In vitro transfection studies of the mutant PRKAR1A showed impaired ability to bind cyclic AMP and activation of the protein kinase A enzyme. The patient bearing this mutation had a more-severe-than-average Carney complex phenotype that included the relatively rare psammomatous melanotic schwannoma. Conclusions: Large PRKAR1A deletions may be responsible for Carney complex in patients that do not have PRKAR1A gene defects identifiable by sequencing. Preliminary data indicate that these patients may have a different phenotype especially if their defect results in an expressed, abnormal version of the PRKAR1A protein.
Psoriasis and risk of incident myocardial infarction, stroke or transient ischaemic attack: an inception cohort study with a nested case-control analysis
Authors: Y.B. Brauchli, S.S. Jick, M. Miret, C.R. Meier
Journal: British Journal of Dermatology (2009)

Background Systemic inflammation may increase the risk for cardiovascular diseases in patients with psoriasis, but data on this risk in patients with early psoriasis are scarce. Objectives To assess and compare the risk of developing incident myocardial infarction (MI), stroke or transient ischaemic attack (TIA) between an inception cohort of patients with psoriasis and a psoriasis‐free population. Methods We conducted an inception cohort study with a nested case–control analysis within the U.K.‐based General Practice Research Database. The study population encompassed 36 702 patients with a first‐time recorded diagnosis of psoriasis 1994–2005, matched 1 : 1 to psoriasis‐free patients. We assessed crude incidence rates (IRs) and applied conditional logistic regression to obtain odds ratios (ORs) with 95% confidence intervals (CIs). Results Overall, the IRs of MI (n =449), stroke (n =535) and TIA (n =402) were similar among patients with or without psoriasis. However, the adjusted OR of developing MI for patients with psoriasis aged < 60 years was 1·66 (95% CI 1·03–2·66) compared with patients without psoriasis, while the OR for patients aged ≥ 60 years was 0·99 (95% CI 0·77–1·26). The adjusted ORs of developing MI for patients of all ages with ≤ 2 or > 2 prescriptions/year for oral psoriasis treatment were 2·48 (95% CI 0·69–8·91) and 1·39 (95% CI 0·43–4·53), with a similar finding for stroke and TIA. Conclusions The risk of developing a cardiovascular outcome was not materially elevated for patients with early psoriasis overall. In subanalyses, however, there was a suggestion of an increased (but low absolute) MI risk for patients with psoriasis aged < 60 years, mainly with severe disease.
Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation
Authors: Beth A. Kaminski, Suzanne Kadereit, Robin E. Miller, Patrick Leahy, Kevin R. Stein, David A. Topa, Tomas Radivoyevitch, Martina L. Veigl, Mary J. Laughlin
Journal: Blood (2003)
Microenvironmental Regulation of Glioblastoma Radioresponse
Authors: Muhammad Jamal, Barbara H. Rath, Eli S. Williams, Kevin Camphausen, Philip J. Tofilon
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Brain tumor xenografts initiated from human glioblastoma (GBM) stem-like cells (TSC) simulate the biological characteristics of GBMs in situ. Therefore, to determine whether the brain microenvironment affects the intrinsic radiosensitivity of GBM cells, we compared the radioresponse of GBM TSCs grown in vitro and as brain tumor xenografts. Experimental Design: As indicators of DNA double-strand breaks (DSB), γH2AX, and 53BP1 foci were defined after irradiation of 2 GBM TSC lines grown in vitro and as orthotopic xenografts in nude mice. Microarray analysis was conducted to compare gene expression patterns under each growth condition. Results: Dispersal of radiation-induced γH2AX and 53BP1 foci was faster in the tumor cells grown as orthotopic xenografts compared with cells irradiated in vitro. In addition, cells irradiated in vivo were approximately 3-fold less susceptible to foci induction as compared with cells grown in vitro. Microarray analysis revealed a significant number of genes whose expression was commonly affected in the 2 GBM models by orthotopic growth conditions. Consistent with the decrease in sensitivity to foci induction, genes related to reactive oxygen species (ROS) metabolism were expressed at higher levels in the brain tumor xenografts. Conclusion: γH2AX and 53BP1 foci analyses indicate that GBM cells irradiated within orthotopic xenografts have a greater capacity to repair DSBs and are less susceptible to their induction than tumor cells irradiated under in vitro growth conditions. Because DSB induction and repair are critical determinants of radiosensitivity, these results imply that the brain microenvironment contributes to GBM radioresistance.Clin Cancer Res; 16(24); 6049–59. ©2010 AACR.
Phenotype at diagnosis predicts recurrence rates in Crohn's disease
Authors: F L Wolters
Journal: Gut (2005)

<b>Background:</b> In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. <b>Aims:</b> To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. <b>Methods:</b> A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non-surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. <b>Results:</b> A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13–2.10)) whereas age ⩾40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70–0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21–0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32–7.89)). <b>Conclusions:</b> A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North-South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres.
Medication Nonadherence in Diabetes
Authors: Leonard E. Egede, Mulugeta Gebregziabher, Clara E. Dismuke, Cheryl P. Lynch, R. Neal Axon, Yumin Zhao, Patrick D. Mauldin
Journal: Diabetes Care (2012)

OBJECTIVE To examine the longitudinal effects of medication nonadherence (MNA) on key costs and estimate potential savings from increased adherence using a novel methodology that accounts for shared correlation among cost categories. RESEARCH DESIGN AND METHODS Veterans with type 2 diabetes (740,195) were followed from January 2002 until death, loss to follow-up, or December 2006. A novel multivariate, generalized, linear, mixed modeling approach was used to assess the differential effect of MNA, defined as medication possession ratio (MPR) ≥0.8 on healthcare costs. A sensitivity analysis was performed to assess potential cost savings at different MNA levels using the Consumer Price Index to adjust estimates to 2012 dollar value. RESULTS Mean MPR for the full sample over 5 years was 0.78, with a mean of 0.93 for the adherent group and 0.58 for the MNA group. In fully adjusted models, all annual cost categories increased ∼3% per year (P = 0.001) during the 5-year study time period. MNA was associated with a 37% lower pharmacy cost, 7% lower outpatient cost, and 41% higher inpatient cost. Based on sensitivity analyses, improving adherence in the MNA group would result in annual estimated cost savings ranging from ∼$661 million (MPR &amp;lt;0.6 vs. ≥0.6) to ∼$1.16 billion (MPR &amp;lt;1 vs. 1). Maximal incremental annual savings would occur by raising MPR from &amp;lt;0.8 to ≥0.8 ($204,530,778) among MNA subjects. CONCLUSIONS Aggressive strategies and policies are needed to achieve optimal medication adherence in diabetes. Such approaches may further the so-called “triple aim” of achieving better health, better quality care, and lower cost.
Hepatic steatosis and altered very low density lipoprotein (VLDL) formation in apolipoprotein (APO) E3-Leiden transgenic mice
Authors: A.R. Mensenkamp, M.J.A. van Luyn, V. Bloks, J. Greeve, M.C. Jong, L.M. Havekes, F. Kuipers
Journal: Journal of Hepatology (2000)
Inclusion of Vasculature-Related Variables in the Dukes Staging System of Colon Cancer
Authors: Michael I. Koukourakis, Alexandra Giatromanolaki, Efthimios Sivridis, Kevin C. Gatter, Adrian L. Harris
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The Dukes stage is used to stratify colorectal cancer patients into groups of different prognosis and need of adjuvant radiotherapy and chemotherapy. However, ∼80% of patients with Dukes stage C colorectal cancer receive cytotoxic therapy without any expected benefit, for such patients would either not relapse without adjuvant therapy or they would inevitably do so because of tumor resistance to the available regimens. On the other hand, as 20% of Dukes stage B patients would relapse after surgery, adjuvant therapy could improve their survival. Improvement of the Dukes stage predictive accuracy is necessary to better assign patients for adjuvant therapies, especially nowadays when antiangiogenic agents are being incorporated in the clinical practice. Patients and Methods: In this study, we examined the prognostic role of Dukes staging system in parallel with three vasculature-related variables (vascular invasion, tumor angiogenic activity, and vascular survival ability) in a series of 130 stage B/C patients with colorectal cancer treated with surgery alone (without adjuvant radiotherapy or chemotherapy). Results: Inclusion of vasculature-related variables in the Dukes staging system significantly improved the prognostic categorization of patients, identifying subgroups of B-stage and C-stage patients with an up to 40% and 60% 5-year survival difference, respectively. Conclusions: Preliminary results show that the prognostic value of Dukes staging system is significantly improved after taking into account vasculature-related variables, which may be useful in stratifying patients for adjuvant therapies, highlighting also subgroups that may benefit the most from antiangiogenic agents.
A human lung mast cell chymotrypsin-like enzyme. Identification and partial characterization.
Authors: B U Wintroub, C E Kaempfer, N M Schechter, D Proud
Journal: Journal of Clinical Investigation (1986)

We have used a high performance liquid chromatography assay, which detects chymotryptic cleavage of the phe8-his9 bond of angiotensin I to yield angiotensin II, in order to examine human lung mast cells for the presence of chymotryptic activity. Mast cells, purified from human lung by enzymatic dispersion, countercurrent elutriation, and Percoll gradient centrifugation, were lysed or challenged with goat anti-human IgE. In multiple experiments angiotensin II-converting activity was detected in lysates of 10-99% pure mast cell preparations. Regression analysis of net percent release values of histamine and the angiotensin I-converting activity from dose-response experiments demonstrated a correlation between the two parameters, indicating that the chymotrypsin-like enzyme is a constituent of the mast cell secretory granule. The chymotryptic activity was completely inhibited by 10(-3) M phenylmethylsulfonylfluoride but not by 10(-3) M Captopril, and the pH optimum of activity was 7.5-9.5. Gel filtration of released material separated the activity from tryptase and demonstrated an approximate molecular weight of 30-35,000. The mast cell enzyme, like a human skin chymotrypsin-like proteinase, can be distinguished from leukocyte cathepsin G by lack of susceptibility to inhibition by bovine pancreatic trypsin inhibitor. Thus, an enzyme with limited chymotryptic specificity is present in human lung mast cells. The Michaelis constant of the enzyme for angiotensin I of 6.0 X 10(-5) M is similar to that of endothelial cell angiotensin-converting enzyme and is consistent with a reaction of physiologic importance.
Enhanced Macrophage Tumoricidal Activity and Tumor Suppression or Regression Caused by Heat-Killed &lt;italic&gt;Candida albicans&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J B Weinberg, J B Hibbs
Journal: JNCI Journal of the National Cancer Institute (1979)

The growth of line-10 hepatoma in male Sewall Wright strain 2 guinea pigs was totally suppressed when tumor cells were mixed with heat-killed Candida albicans. In a significant number of animals, injection of C. albicans into established tumors 10-12 mm in diameter caused complete, rapid tumor regression. Guinea pigs whose tumors regressed or were suppressed as a result of injection of C. albicans rejected subsequent challenges at distant sites with the line-10 hepatoma, which indicated the development of systemic immunity to the tumor. Untreated control guinea pigs had positive delayed hypersensitivity reactions to intradermally injected C. albicans, which suggested prior natural exposure of the animals to C. albicans antigens. Peritoneal macrophages from mice that had received ip injections of phosphate-buffered saline (PBS) or C. albicans were not cytocidal for mouse 3T12 tumor cells in vitro. However, macrophages from the mice given injections of C. albicans, unlike those from mice given PBS, were markedly tumoricidal in the presence of 1 ng or more endotoxin/ml in vitro. These results demonstrated that heat-killed C. albicans, when inoculated into the peritoneal cavity, increased the tumoricidal potential of peritoneal macrophages.
About ischaemic heart disease in inflammatory bowel disease: some considerations
Authors: Paolo Sossai, Baldovino Sponga
Journal: Gut (2013)

We have found the article by Rungoe et al about ischaemic heart disease (IHD) in inflammatory bowel disease (IBD) patients to be quite interesting since there are not many studies on this topic and they are mainly retrospective.1

As reported by the Authors, the high incidence of IHD observed in patients with IBD during the first year is probably due to bias, as considered in the study by Yarur et al in which heart disease cases in the 12 months following the diagnosis of IBD were excluded.2

The same methodological problem appears in the years following the first diagnosis of IBD, because these patients are more closely studied compared to the control general population.

Rungoe's table 2 does not show the concordance between Crohn's …
Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children
Authors: Daniel J. Jackson, Christine M. Virnig, Ronald E. Gangnon, Michael D. Evans, Kathy A. Roberg, Elizabeth L. Anderson, Ryan M. Burton, Lisa P. Salazar, Douglas F. DaSilva, Kathleen M. Shanovich, Christopher J. Tisler, James E. Gern, Robert F. Lemanske
Journal: Journal of Allergy and Clinical Immunology (2009)
Herpes simplex virus-2 (HSV-2) type-specific antibody correlates of protection in infants exposed to HSV-2 at birth.
Authors: R L Ashley, J Dalessio, S Burchett, Z Brown, S Berry, K Mohan, L Corey
Journal: Journal of Clinical Investigation (1992)

Western blot analysis was used to compare the herpes simplex virus (HSV)-2 antibody profiles of 40 infants less than 2 wk of age who had been exposed to maternal genital HSV-2 at birth. 4 mothers were HSV seronegative at delivery and seroconverted to HSV-2 ("primary infection"), 9 had HSV-1 antibodies and seroconverted to HSV-2 ("nonprimary first episode infection"), and 27 were HSV-2 seropositive ("recurrent infection"). Neonatal herpes infections developed in 1 of 4 infants of women with primary infection, in 3 of 9 infants of women with nonprimary first episode infection, and in none of the 27 infants of women with recurrent HSV-2. Antibodies to HSV-2 proteins gG-2, VP5, and ICP35 were detected in 83, 89, and 72% of the 36 uninfected infants, respectively. None of the four infected infants had detectable antibodies to gG-2 and only one (25%) had antibodies to VP5 or ICP35. The more limited profiles of the 13 infants born to mothers with first episodes of HSV-2 were then analyzed separately; these profiles were similar among infected and uninfected infants except for gG-2, which elicits antibodies that are type specific for HSV-2. None of the infected infants versus seven of nine (78%) uninfected infants were gG-2 seropositive. These comparisons suggest that maternal type-specific antibodies may play a role in preventing neonatal infection after exposure to HSV-2.
A History of Cancer Chemotherapy
Authors: Vincent T. DeVita, Edward Chu
Journal: Cancer Research (2008)

Abstract The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. It was, however, four World War II–related programs, and the effects of drugs that evolved from them, that provided the impetus to establish in 1955 the national drug development effort known as the Cancer Chemotherapy National Service Center. The ability of combination chemotherapy to cure acute childhood leukemia and advanced Hodgkin's disease in the 1960s and early 1970s overcame the prevailing pessimism about the ability of drugs to cure advanced cancers, facilitated the study of adjuvant chemotherapy, and helped foster the national cancer program. Today, chemotherapy has changed as important molecular abnormalities are being used to screen for potential new drugs as well as for targeted treatments. [Cancer Res 2008;68(21):8643–53]
Coexpression Network Analysis Identifies Transcriptional Modules Related to Proastrocytic Differentiation and Sprouty Signaling in Glioma
Authors: Alexander E. Ivliev, Peter A.C. 't Hoen, Marina G. Sergeeva
Journal: Cancer Research (2010)

Abstract Gliomas are primary brain tumors with high mortality and heterogeneous biology that is insufficiently understood. In this study, we performed a systematic analysis of the intrinsic organization of complex glioma transcriptome to gain deeper knowledge of the tumor biology. Gene coexpression relationships were explored in 790 glioma samples from 5 published patient cohorts treated at different institutions. We identified 20 coexpression modules that were common to all the data sets and associated with proliferation, angiogenesis, hypoxia, immune response, genomic alterations, cell differentiation phenotypes, and other features inherent to glial tumors. A collection of high-quality signatures for the respective processes was obtained using cross-data set summarization of the modules' gene composition. Individual modules were found to be organized into higher order coexpression groups, the two largest of them associated with glioblastoma and oligodendroglioma, respectively. We identified a novel prognostic gene expression signature (185 genes) linked to a proastrocytic pattern of tumor cell differentiation. This “proastrocytic” signature was associated with long survival and defined a subgroup of the previously established “proneural” class of gliomas. A strong negative correlation between proastrocytic and proneural markers across differentiated tumors underscored the distinction between these subtypes of glioma. Interestingly, one further novel signature in glioma was identified that was associated with EGFR (epidermal growth factor receptor) gene amplification and suggested that EGF signaling in glioma may be a subject to regulation by Sprouty family proteins. In summary, this integrated analysis of the glioma transcriptome provided several novel insights into molecular heterogeneity and pathogenesis of glial tumors. Cancer Res; 70(24); 10060–70. ©2010 AACR.
European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme
Authors: M.J. van den Bent, W. Grisold, D. Frappaz, R. Stupp, J.P. Desir, T. Lesimple, C. Dittrich, M.J.A. de Jonge, A. Brandes, M. Frenay, A.F. Carpentier, P. Chollet, J. Oliveira, B. Baron, D. Lacombe, M. Schuessler, P. Fumoleau
Journal: Annals of Oncology (2003)