tbuckley/cabot-search huggingface dataset:
Elevated Expression of Wnt Antagonists Is a Common Event in Hepatoblastomas
Authors: Arend Koch, Andreas Waha, Wolfgang Hartmann, Aksana Hrychyk, Ulrich Schüller, Anke Waha, Keith A. Wharton, Serge Y. Fuchs, Dietrich von Schweinitz, Torsten Pietsch
Journal: Clinical Cancer Research (2005)

Abstract Hepatoblastomas are the most frequent malignant liver tumors of childhood. A high frequency of activating β-catenin mutations in hepatoblastomas indicates that the Wnt signaling pathway plays an important role in the development of this embryonic neoplasm. Stabilization of β-catenin leads to an increased formation of nuclear β-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes. In this study, we analyzed the mRNA expression levels of nine Wnt genes, including c-JUN, c-MYC, CYCLIN D1, FRA-1, NKD-1, ITF-2, MMP-7, uPAR, and β-TRCP, by competitive reverse transcription-PCR. We analyzed 23 hepatoblastoma biopsies for which matching liver tissue was available, 6 hepatoblastoma cell lines, and 3 human fetal liver samples. β-TRCP and NKD-1 were highly expressed in all hepatoblastoma samples, independent of the β-catenin mutational status, in comparison with their nontumorous counterparts. β-TRCP mRNA overexpression was associated with accumulation of intracytoplasmic and nuclear β-TrCP protein. In human liver tumor cells without β-catenin mutations, Nkd-1 inhibited the Wnt-3a-activated Tcf-responsive-luciferase reporter activity, whereas Nkd-1 in hepatoblastomas with β-catenin mutations had no antagonistic effect. Our data emphasize the inhibitory effect of β-TrCP and Nkd-1 on the Wnt signaling pathway in a manner analogous to Conductin (AXIN2) and Dkk-1, inhibitors shown previously to be up-regulated in hepatoblastomas. Our findings indicate that overexpression of the Wnt antagonists Nkd-1 and β-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas. We propose that Nkd-1 and β-TrCP may be used as possible diagnostic markers for the activated Wnt signaling pathway in hepatoblastomas.
C-Reactive Protein in Type 1 Diabetes and Its Relationship to Coronary Artery Calcification
Authors: Helen M. Colhoun, Casper Schalkwijk, Michael B. Rubens, Coen D.A. Stehouwer
Journal: Diabetes Care (2002)

OBJECTIVE—In 196 type 1 diabetic subjects and 195 nondiabetic subjects aged 30–55 years, we examined whether C-reactive protein (CRP) is elevated in diabetes and whether CRP is associated with coronary artery calcification (CAC). RESEARCH DESIGN AND METHODS—CRP was measured with a highly sensitive immunoassay. CAC was measured using electron beam computed tomography. RESULTS—CRP was elevated in diabetic women compared with nondiabetic women (median 1.62 vs. 0.85 mg/l, P &amp;lt; 0.001) independently of other factors, but was similar in diabetic and nondiabetic men (median 0.82 vs. 0.81 mg/l). Insulin dose per day was positively correlated with CRP in diabetic women (Spearman’s ρ = 0.36, P = 0.0003) but much less so in men (ρ = 0.16, P = 0.09). Being in the top tertile for CRP was associated with CAC in diabetic and nondiabetic men even after adjustment for other risk factors (adjusted odds ratio [OR] = 4.6 and 4.3, respectively, P = 0.02 for both). In nondiabetic women, being in the top tertile for CRP was associated with CAC (OR 3.1, P = 0.04), but not independently of BMI (OR = 1 after adjustment). Among diabetic women the association was not significant even before adjustment for BMI (OR = 2.6, P = 0.07). CONCLUSIONS—Elevated CRP in diabetic women might reflect a particular sensitivity to insulin levels or might reflect insulin resistance. In general, CRP is an important marker of subclinical atherosclerosis, but the clinical significance of elevated CRP in diabetic women needs to be addressed in prospective studies, since CRP was not clearly associated with CAC in this group.
Computed Tomographic Virtual Colonoscopy to Screen for Colorectal Neoplasia in Asymptomatic Adults
Authors: Perry J. Pickhardt, J. Richard Choi, Inku Hwang, James A. Butler, Michael L. Puckett, Hans A. Hildebrandt, Roy K. Wong, Pamela A. Nugent, Pauline A. Mysliwiec, William R. Schindler
Journal: New England Journal of Medicine (2003)

We evaluated the performance characteristics of computed tomographic (CT) virtual colonoscopy for the detection of colorectal neoplasia in an average-risk screening population.A total of 1233 asymptomatic adults (mean age, 57.8 years) underwent same-day virtual and optical colonoscopy. Radiologists used the three-dimensional endoluminal display for the initial detection of polyps on CT virtual colonoscopy. For the initial examination of each colonic segment, the colonoscopists were unaware of the findings on virtual colonoscopy, which were revealed to them before any subsequent reexamination. The sensitivity and specificity of virtual colonoscopy and the sensitivity of optical colonoscopy were calculated with the use of the findings of the final, unblinded optical colonoscopy as the reference standard.The sensitivity of virtual colonoscopy for adenomatous polyps was 93.8 percent for polyps at least 10 mm in diameter, 93.9 percent for polyps at least 8 mm in diameter, and 88.7 percent for polyps at least 6 mm in diameter. The sensitivity of optical colonoscopy for adenomatous polyps was 87.5 percent, 91.5 percent, and 92.3 percent for the three sizes of polyps, respectively. The specificity of virtual colonoscopy for adenomatous polyps was 96.0 percent for polyps at least 10 mm in diameter, 92.2 percent for polyps at least 8 mm in diameter, and 79.6 percent for polyps at least 6 mm in diameter. Two polyps were malignant; both were detected on virtual colonoscopy, and one of them was missed on optical colonoscopy before the results on virtual colonoscopy were revealed.CT virtual colonoscopy with the use of a three-dimensional approach is an accurate screening method for the detection of colorectal neoplasia in asymptomatic average-risk adults and compares favorably with optical colonoscopy in terms of the detection of clinically relevant lesions.
Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium.
Authors: C Ventura, R Miller, H P Wolf, N Beier, R Jonas, M Klockow, I Lues, O Hano, H A Spurgeon, E G Lakatta
Journal: Circulation Research (1992)

The inotropic state of the myocardium can be enhanced via an increase in cell Ca2+ loading or in myofilament responsiveness to Ca2+. Although different pharmacological agents combine these properties, no presently available drug acts predominantly as a myofilament sensitizer in situ. We have investigated the effects and the mechanism of action of novel diazinone derivatives, EMD 54622, EMD 53998, and EMD 54650 (developed by E. Merck, Darmstadt), on guinea pig myocardial preparations. Force- and ATPase-pCa relations in skinned fibers show differing potencies of these agents on myofilament sensitization: EMD 54622 greater than EMD 53998 much greater than EMD 54650. This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622. In isolated hearts studied at constant coronary flow, each of the three diazinone derivatives had a positive inotropic effect. In enzymatically dissociated left ventricular myocytes loaded with the Ca2+ probe indo-1, the positive inotropic effect of EMD 54622 occurred with no change in the amplitude of the cytosolic [Ca2+] (Cai) transient. In contrast, both EMD 53998 and EMD 54650 enhanced Cai transient and twitch contraction amplitudes. Length-indo-1 fluorescence relations were analyzed to determine the effects of the three substances on myofilament responsiveness to Ca2+. EMD 54622 enhanced and EMD 54650 had no effect on myofilament responsiveness to Ca2+. Less uniform results were obtained with EMD 53998 (in two of five cells the myofilament responsiveness to Ca2+ was increased, whereas in three other cells it was unaltered). Our results indicate that structural changes in the diazinone molecule shift the mechanism of action for the positive inotropic effect of the diazinone derivatives in the intact cell from a predominant myofilament sensitization (EMD 54622) to an enhancement in cell Ca2+ loading and an augmentation in the Cai transient (EMD 54650).
Growth of the bronchial tree in man.
Authors: K Horsfield, W I Gordon, W Kemp, S Phillips
Journal: Thorax (1987)

Bronchial tree casts were made from one or both lungs from nine children aged from five weeks to 17 years. The branches of the casts were ordered by the method of Strahler, and diameter ratio, length ratio, and branching ratio were determined. From five to 12 weeks the diameter ratio is about 1.35, but by 13 months it has risen to 1.45, indicating a faster rate of growth in the larger airways over the period; thereafter it stays at or above this level. The data show that the peripheral conducting airways are relatively large in diameter at 1-3 months, attaining their adult proportion after one year. In contrast, length ratio shows no trend with age. On the assumption of 25,000 terminal bronchioles, the mean number of orders between terminal bronchiole and trachea was estimated to be about 12.
THE TRANSFORMATION OF PNEUMOCOCCAL TYPES
Authors: Martin H. Dawson
Journal: The Journal of Experimental Medicine (1930)

1. Type-specific S pneumococci may be transformed from one specific S type into other specific S types through the intermediate stage of the R form. 2. R forms of pneumococi, derived from any specific S type, may be transformed into S organisms of other specific types by the following procedure:-The subcutaneous injection, in white mice, of small amounts of living R forms together with vaccines of heterologous S cultures. (i) S vaccines heated for 15' at temperatures between 60 degrees and 80 degrees C., are effective in causing R forms, derived from heterologous S types, to revert to the type of the vaccine. (ii) S vaccines heated for 15' at temperatures between 80 degrees and 100 degrees C., are not effective in causing R forms, derived from heterologous S types, to revert to the type of the vaccine. (iii) S vaccines heated for 15' at temperatures between 80 degrees and 100 degrees C., may cause 2 R and 3 R cultures to revert to their original S type. (iv) S vaccines of any type, including Type I, heated for 15' at temperatures between 80 degrees and 100 degrees C., are not effective in causing 1 R cultures to revert to their original S type. (v) S vaccines heated for periods as long as two hours at 60 degrees C. are effective in causing R forms, derived from heterologous types, to revert to the type of the vaccine. 3. A single cell R strain, derived from a Type II S pneumococcus, has been successively transformed into a Type III S, a Type I S and a Group IV S culture. 4. Corresponding with the various degrees of "degradation" of the R form there are varying degrees of "development" of the S form. 5. The nature of the conditions responsible for alteration of type as induced by these procedures has been investigated and the causes responsible for the transformations are discussed. 6. All attempts to produce transformation of type in vitro have been unsuccessful. 7. The rô1e which the phenomenon of transformation of type may play in problems of infection and epidemiology is indicated.
BCR/ABL and Other Kinases from Chronic Myeloproliferative Disorders Stimulate Single-Strand Annealing, an Unfaithful DNA Double-Strand Break Repair
Authors: Kimberly Cramer, Margaret Nieborowska-Skorska, Mateusz Koptyra, Artur Slupianek, Emir Tyrone P. Penserga, Connie J. Eaves, Walter Aulitzky, Tomasz Skorski
Journal: Cancer Research (2008)

Abstract Myeloproliferative disorders (MPD) are stem cell–derived clonal diseases arising as a consequence of acquired aberrations in c-ABL, Janus-activated kinase 2 (JAK2), and platelet-derived growth factor receptor (PDGFR) that generate oncogenic fusion tyrosine kinases (FTK), including BCR/ABL, TEL/ABL, TEL/JAK2, and TEL/PDGFβR. Here, we show that FTKs stimulate the formation of reactive oxygen species and DNA double-strand breaks (DSB) both in hematopoietic cell lines and in CD34+ leukemic stem/progenitor cells from patients with chronic myelogenous leukemia (CML). Single-strand annealing (SSA) represents a relatively rare but very unfaithful DSB repair mechanism causing chromosomal aberrations. Using a specific reporter cassette integrated into genomic DNA, we found that BCR/ABL and other FTKs stimulated SSA activity. Imatinib-mediated inhibition of BCR/ABL abrogated this effect, implicating a kinase-dependent mechanism. Y253F, E255K, T315I, and H396P mutants of BCR/ABL that confer imatinib resistance also stimulated SSA. Increased expression of either nonmutated or mutated BCR/ABL kinase, as is typical of blast phase cells and very primitive chronic phase CML cells, was associated with higher SSA activity. BCR/ABL-mediated stimulation of SSA was accompanied by enhanced nuclear colocalization of RAD52 and ERCC1, which play a key role in the repair. Taken together, these findings suggest a role of FTKs in causing disease progression in MPDs by inducing chromosomal instability through the production of DSBs and stimulation of SSA repair. [Cancer Res 2008;68(17):6884–8]
Molecular interplay between leptin, insulin-like growth factor-1, and β-amyloid in organotypic slices from rabbit hippocampus
Authors: Gurdeep Marwarha, Jaya RP Prasanthi, Jared Schommer, Bhanu Dasari, Othman Ghribi
Journal: Molecular Neurodegeneration (2011)

Evidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce β-amyloid (Aβ) production and tau phosphorylation, two major hallmarks of Alzheimer's disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that Aβ reduces leptin by inhibiting the mTORC1 pathway and Aβ was also suggested to inhibit the JAK/STAT pathway, potentially attenuating IGF-1 expression. As IGF-1 can activate mTORC1 and leptin can modulate JAK/STAT pathway, we determined the extent to which IGF-1 and leptin can upregulate the expression of one another and protect against Aβ-induced downregulation.We demonstrate that incubation of organotypic slices from adult rabbit hippocampus with Aβ42 downregulates IGF-1 expression by inhibiting JAK2/STAT5 pathway. Leptin treatment reverses these Aβ42 effects on IGF-1 and treatment with the STAT5 inhibitor completely abrogated the leptin-induced increase in IGF-1. Furthermore, EMSA and ChIP analyses revealed that leptin increases the STAT5 binding to the IGF-1 promoter. We also show that IGF-1 increases the expression of leptin and reverses the Aβ42-induced attenuation in leptin expression via the activation of mTORC1 signaling as the mTORC1 inhibitor rapamycin completely precluded the IGF-1-induced increase in leptin expression.Our results demonstrate for the first time that Aβ42 downregulates IGF-1 expression and that leptin and IGF-1 rescue one another from downregulation by Aβ42. Our study provides a valuable insight into the leptin/IGF-1/Aβ interplay that may be relevant to the pathophysiology of AD.
Clinical Model to Predict Survival in Chemonaive Patients With Advanced Non–Small-Cell Lung Cancer Treated With Third-Generation Chemotherapy Regimens Based on Eastern Cooperative Oncology Group Data
Authors: Tien Hoang, Ronghui Xu, Joan H. Schiller, Philip Bonomi, David H. Johnson
Journal: Journal of Clinical Oncology (2004)

(1) Identify clinical factors that can be used to predict survival in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy regimens, and (2) build a clinical model to predict survival in this patient population.Using data from two randomized, phase III Eastern Cooperative Oncology Group (ECOG) trials (E5592/E1594), we performed univariate and multivariate stepwise Cox regression analyses to identify survival prognostic factors. We used 75% of randomly sampled data to build a prediction model for survival, and the remaining 25% of data to validate the model.From 1993 to 1999, 1,436 patients with stage IV or IIIB NSCLC with effusion were treated with platinum-based doublets (involving either paclitaxel, docetaxel, or gemcitabine). The response rate and median survival time were 20% and 8.2 months, respectively. One- and 2-year survivals were 33% and 11%, respectively. In multivariate analysis, six independent poor prognostic factors were identified: skin metastasis (hazard ratio [HR], 1.88), lower performance status (ECOG 1 or 2; HR, 1.46), loss of appetite (HR, 1.62), liver metastasis (HR, 1.32), >/= four metastatic sites (HR, 1.20), and no prior surgery (HR, 1.16). A nomogram using six pretreatment prognostic factors was built to predict 1- and 2-year survival.Six pretreatment factors can be used to predict survival in chemotherapy-naive NSCLC patients treated with standard chemotherapy. Using our prognostic nomogram, 1- and 2-year survival probability of NSCLC patients can be estimated before treatment. This prognostic model may help clinicians and patients in clinical decision making, as well as investigators in research planning.
DISPLACEMENT AND MIGRATION
Authors: LIBUSE TYHURST
Journal: American Journal of Psychiatry (1951)

1. Clinical findings in the psychiatric study and treatment of 48 displaced persons have been described. 2. The two phases of the psychological reactions following arrival have been outlined. Common features in the symptomatology of these reactions have been described: suspiciousness and paranoid trends; co-existence of anxiety and depression; somatic reactions. 3. These findings have been discussed briefly with an emphasis upon the psychosocial dynamics of mobility. A concluding statement of the differences between the displaced persons and the ordinary prewar immigrant has been made.
Differentiating the Mood and Anxiety Disorders: A Quadripartite Model
Authors: David Watson
Journal: Annual Review of Clinical Psychology (2009)

Recent work has focused on explicating the relations among the current mood and anxiety disorders. This research has yielded some important findings (e.g., the very strong link between generalized anxiety disorder and the unipolar mood disorders). I discuss problems associated with disorder-based analyses, however, and I argue that they need to be supplemented by examining relations among the specific symptom dimensions within these diagnostic classes. I demonstrate that two quantitative elements need to be considered when analyzing the properties of symptoms—the level of specificity and the magnitude of the general distress variance. These quantitative elements can be used to organize relevant symptoms into four groups (i.e., a quadripartite model) that reflect varying combinations of distress and specificity. I illustrate the value of this approach by reviewing the properties of the major symptom dimensions within posttraumatic stress disorder, obsessive-compulsive disorder, and major depression.
Exposure to Infant Siblings During Early Life and Risk of Multiple Sclerosis
Authors: Anne-Louise Ponsonby
Journal: JAMA (2005)

ContextThe "hygiene hypothesis" has implicated sibship as a marker of infection load during early life and suggests that exposure or reexposure to infections can influence the developing immune system.Viral infection has also been implicated in the pathogenesis of multiple sclerosis (MS).Objectives To evaluate whether exposure to infant siblings in early life is associated with the risk of MS, and to explore the possible mechanism for any apparent protective effect, including altered Epstein-Barr virus (EBV) infection patterns. Design, Setting, and PatientsPopulation-based case-control study in Tasmania, Australia, from 1999 to 2001 based on 136 cases of magnetic resonance imagingconfirmed MS and 272 community controls, matched on sex and year of birth.Main Outcome Measure Risk of MS by duration of contact with younger siblings aged less than 2 years in the first 6 years of life. ResultsIncreasing duration of contact with a younger sibling aged less than 2 years in the first 6 years of life was associated with reduced MS risk (adjusted odds ratios [AORs]: Ͻ1 infant-year, 1.00 [reference]; 1 to Ͻ3 infant-years, 0.57 [95% confidence interval {CI}, 0.33-0.98]; 3 to Ͻ5 infant-years, 0.40 [95% CI, 0.19-0.92];Ն5 infant-years, 0.12 [95% CI, 0.02-0.88];test for trend, P=.002).A history of exposure to infant siblings was associated with a reduced IgG response to EBV among controls.Controls with at least 1 infant-year contact had a reduced risk of infectious mononucleosis and a reduced risk of very high composite EBV IgG titers (AOR, 0.33; 95% CI, 0.11-0.98)compared with other controls.The inverse association between higher infant contact and MS was independent of EBV IgG titer. ConclusionHigher infant sibling exposure in the first 6 years of life was associated with a reduced risk of MS, possibly by altering childhood infection patterns and related immune responses.
Oxidative Stress and Insulin Resistance
Authors: Kyong Park, Myron Gross, Duk-Hee Lee, Paul Holvoet, John H. Himes, James M. Shikany, David R. Jacobs
Journal: Diabetes Care (2009)

OBJECTIVE Although cumulative evidence suggests that increased oxidative stress may lead to insulin resistance in vivo or in vitro, community-based studies are scarce. This study examined the longitudinal relationships of oxidative stress biomarkers with the development of insulin resistance and whether these relationships were independent of obesity in nondiabetic young adults. RESEARCH DESIGN AND METHODS Biomarkers of oxidative stress (F2-isoprostanes [F2Isop] and oxidized LDL [oxLDL]), insulin resistance (the homeostasis model assessment of insulin resistance [HOMA-IR]), and various fatness measures (BMI, waist circumference, and estimated percent fat) were obtained in a population-based observational study (Coronary Artery Risk Development in Young Adults) and its ancillary study (Young Adult Longitudinal Trends in Antioxidants) during 2000–2006. RESULTS There were substantial increases in estimated mean HOMA-IR over time. OxLDL and F2Isop showed little association with each other. Mean evolving HOMA-IR increased with increasing levels of oxidative stress markers (P &amp;lt; 0.001 for oxLDL and P = 0.06 for F2Isop), measured in 2000–2001. After additional adjustment for adiposity, a positive association between oxLDL and HOMA-IR was strongly evident, whereas the association between F2Isop and HOMA-IR was not. CONCLUSIONS We observed positive associations between each of two oxidative stress markers and insulin resistance. The association with oxidized LDL was independent of obesity, but that with F2Isop was not.