tbuckley/cabot-search huggingface dataset:
Outcomes in Children With Hemorrhagic Stroke
Authors: Warren D. Lo, Christine Hajek, Christopher Pappa, Wei Wang, Nicholas Zumberge
Journal: JAMA Neurology (2012)

Objectives: To determine if a specific intracerebral hemorrhage ratio predicts poor outcome; whether predictors of outcome in adults, specifically hemorrhage location, ventricular involvement, or initial Glasgow Coma Scale score, predict outcome in childhood hemorrhagic stroke; and whether the cause of hemorrhagic stroke predicts outcome.Design: Retrospective case study.Setting: A single tertiary care pediatric hospital.Participants: Fifty-nine cases who had nontraumatic hemorrhages. Main Outcome Measures:We examined whether hemorrhage volume, location, initial Glasgow Coma Scale score, or associated diagnoses predicted outcomes.We contacted survivors and parents and assessed outcomes using measures of neurological function, quality of life, and caregiver stress.Results: Twenty died of the hemorrhage or associated illnesses, and we obtained follow-up on 19 survivors.Most survivors had mild to moderate neurological deficits, but many reported impaired school or physical functioning.Increasing hemorrhage volume predicted poorer neurological outcomes and poorer quality-of-life ratings among survivors.Subjects who had intracranial vascular anomalies had the best outcomes of the group.Associated diagnoses strongly predicted scores on the parent-and child-rated quality-of-life measures.In contrast to what has been reported in adult studies, initial Glasgow Coma Scale score, primary location of the hemorrhage, and ventricular hemorrhage did not significantly predict outcomes, although ventricular hemorrhage was associated with trends toward poorer outcomes. Conclusions:The mortality of hemorrhagic stroke in children is lower than that in adults.Childhood survivors tend to have mild to moderate physical deficits, but they may have significant impairment in other domains such as school functioning.
Inherited genetic susceptibility to monoclonal gammopathy of unknown significance
Authors: Niels Weinhold, David C. Johnson, Andrew C. Rawstron, Asta Försti, Chi Doughty, Jayaram Vijayakrishnan, Peter Broderick, Nasrin B. Dahir, Dil B. Begum, Fay J. Hosking, Kwee Yong, Brian A. Walker, Per Hoffmann, Thomas W. Mühleisen, Christian Langer, Elisabeth Dörner, Karl-Heinz Jöckel, Lewin Eisele, Markus M. Nöthen, Dirk Hose, Faith E. Davies, Hartmut Goldschmidt, Gareth J. Morgan, Kari Hemminki, Richard S. Houlston
Journal: Blood (2014)
Cardiac-specific mindin overexpression attenuates cardiac hypertrophy via blocking AKT/GSK3β and TGF-β1–Smad signalling
Authors: Ling Yan, Xiang Wei, Qi-Zhu Tang, Jinghua Feng, Yan Zhang, Chen Liu, Zhou-Yan Bian, Lian-Feng Zhang, Manyin Chen, Xue Bai, Ai-Bing Wang, John Fassett, Yingjie Chen, You-Wen He, Qinglin Yang, Peter P. Liu, Hongliang Li
Journal: Cardiovascular Research (2011)

AimsMindin is a secreted extracellular matrix protein, an integrin ligand, and an angiogenesis inhibitor, other examples of which are all key players in the progression of cardiac hypertrophy.However, its function during cardiac hypertrophy remains unclear.This study was aimed to identify the effect of mindin on cardiac hypertrophy and the underlying mechanisms. Methods and resultsA significant down-regulation of mindin expression was observed in human failing hearts.To further investigate the role of mindin in cardiac hypertrophy, we used cultured neonatal rat cardiomyocytes with gain and loss of mindin function and cardiac-specific Mindin-overexpressing transgenic (TG) mice.In cultured cardiomyocytes, mindin negatively regulated angiotensin II (Ang II)-mediated hypertrophic growth, as detected by [ 3 H]-Leucine incorporation, cardiac myocyte area, and hypertrophic marker protein levels.Cardiac hypertrophy in vivo was produced by aortic banding (AB) or Ang II infusion in TG mice and their wild-type controls.The extent of cardiac hypertrophy was evaluated by echocardiography as well as by pathological and molecular analyses of heart samples.Mindin overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and left ventricular dysfunction in mice in response to AB or Ang II.Further analysis of the signalling events in vitro and in vivo indicated that these beneficial effects of mindin were associated with the interruption of AKT/glycogen synthase kinase 3b (GSK3b) and transforming growth factor (TGF)-b1-Smad signalling. ConclusionThe present study demonstrates for the first time that mindin serves as a novel mediator that protects against cardiac hypertrophy and the transition to heart failure by blocking AKT/GSK3b and TGF-b1 -Smad signalling.
One-Year Follow-Up of Secondary Versus Primary Mental Disorder in Persons With Comorbid Substance Use Disorders
Authors: Lisa Dixon, Scot McNary, Anthony Lehman
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: Service utilization and outcomes of dually diagnosed patients with independent mental disorders and those with substance-induced mental disorders were compared. METHOD: Diagnosis, service use, and severity of substance use problems at baseline and 1 year later were assessed in consecutively admitted inpatients with independent mental disorders plus substance use disorders (N=71), substance-induced mental disorders plus substance use disorders (N=38), and independent mental disorders only (N=59). RESULTS: At follow-up, patients with substance-induced mental disorders at baseline were more likely to have been rehospitalized than the other groups, were more likely to have used outpatient substance abuse services, were less likely to have an independent mental disorder, and had the most severe alcohol- and drug-related impairment. CONCLUSIONS: Treatment programs for both types of dual diagnosis patients must address mental health concerns. (Am J Psychiatry 1997; 154:1610–1612)
CARMA3 Represses Metastasis Suppressor NME2 to Promote Lung Cancer Stemness and Metastasis
Authors: Yi-Wen Chang, Ching-Feng Chiu, Kang-Yun Lee, Chih-Chen Hong, Yi-Yun Wang, Ching-Chia Cheng, Yi-Hua Jan, Ming-Shyan Huang, Michael Hsiao, Jui-Ti Ma, Jen-Liang Su
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

CARD-recruited membrane-associated protein 3 (CARMA3) is a novel scaffold protein that regulates nuclear factor (NF)-κB activation; however, the underlying mechanism of CARMA3 in lung cancer stemness and metastasis remains largely unknown.To investigate the molecular mechanisms underlying the involvement of CARMA3 in non-small cell lung cancer progression.The expression levels of CARMA3 and NME2 in a cohort of patients with lung cancer (n = 91) were examined by immunohistochemistry staining and assessed by Kaplan-Meier survival analysis. The effects of CARMA3, microRNA-182 (miR-182), and NME2 on cancer stemness and metastasis were measured in vitro and in vivo. Chromatin immunoprecipitation and luciferase reporter assays were performed to determine the mechanisms of NF-κB-driven miR-182 expression and NME2 regulation.We observed that CARMA3 inversely correlated with NME2 expression in patients with lung cancer (Pearson correlation coefficient: R = -0.24; P = 0.022). NME2 levels were significantly decreased in tumor tissues compared with adjacent normal lung tissues (P < 0.001), and patients with lung cancer with higher levels of NME2 had longer survival outcomes (overall survival, P < 0.01; disease-free survival, P < 0.01). Mechanistically, CARMA3 promoted cell motility by reducing the level of NME2 through the NF-κB/miR-182 pathway and by increasing cancer stem cell properties and metastasis in lung cancer.We identified a novel mechanism of CARMA3 in lung cancer stemness and metastasis through the negative regulation of NME2 by NF-κB-dependent induction of miR-182. Our findings provide an attractive strategy for targeting the CARMA3/NF-κB/miR-182 pathway as a potential treatment for lung cancer.
ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3
Authors: Yoko Mitsui, Satsuki Mochizuki, Takahide Kodama, Masayuki Shimoda, Takashi Ohtsuka, Takayuki Shiomi, Miyuki Chijiiwa, Tadashi Ikeda, Masaki Kitajima, Yasunori Okada
Journal: Cancer Research (2006)

A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas.
Phase I Study of Concurrent Weekly Docetaxel and Repeated Samarium-153 Lexidronam in Patients With Castration-Resistant Metastatic Prostate Cancer
Authors: Shi-Ming Tu, Paul Mathew, Franklin C. Wong, Donnah Jones, Marcella M. Johnson, Christopher J. Logothetis
Journal: Journal of Clinical Oncology (2009)

Samarium-153 ((153)Sm) lexidronam is a bone-targeting radiopharmaceutical with a short physical half-life and a favorable toxicity profile. We evaluated the safety and feasibility of a concurrent combination of weekly docetaxel with repeated (153)Sm-lexidronam in patients with castration-resistant prostate cancer (CRPC).A conventional 3 + 3 dose-escalation design was used for this study. Patients were treated in three cohorts comprising two cycles of weekly docetaxel at 25, 30, and 35 mg/m(2), respectively, on days 1, 8, and 15 of a 28-day cycle in combination with (153)Sm (1 mCi/kg) on day 1. Unacceptable hematologic toxicity (UHT) was defined as more than 7 days delay in therapy for inadequate counts: an absolute neutrophil count (ANC) more than 1,000/microL and platelets more than 70,000/microL were required at days 8 and 15 and ANC more than 1,500/microL and platelets more than 100,000/microL were required at cycle 2, day 1. If counts had not recovered by day 56 of either combination cycle, UHT was declared.Eighteen patients were treated in three cohorts. Two patients in separate cohorts experienced UHT; the maximum-tolerated dose for this regimen was not reached. The median interval between (153)Sm doses was 35 days (range, 27 to 57 days). The only significant toxicity was mild, transient myelosuppression. Five patients (28%) experienced grade 3 hematologic toxicity. There were no grade > or = 4 hematologic or nonhematologic toxicities.Two dosing cycles consisting of weekly docetaxel and monthly (153)Sm-lexidronam were well tolerated and feasible in this CRPC population.
Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK
Authors: Esperanza Fernández, David Torrents, Josep Chillarón, Rafael Martín del Río, Antonio Zorzano, Manuel Palacín
Journal: Journal of the American Society of Nephrology (2003)

During renal reabsorption, the amino acid transporters b(o,+) and y(+)L have a major role in the apical uptake of cystine and dibasic amino acids and in the basolateral efflux of dibasic amino acids, respectively. In contrast, the transporters responsible for the basolateral efflux of the apically transported cystine are unknown. This study shows the expression of system L and y(+)L transport activities in the basolateral domain of the proximal tubule-derived cell line OK and the cloning of the corresponding LAT-2 and y(+)LAT-1 cDNAs. Stable transfection with a LAT-2 antisense sequence demonstrated the specific role of LAT-2 in the basolateral system L amino acid exchange activity in OK cells. This partial reduction of LAT-2 expression decreased apical-to-basolateral trans-epithelial flux of cystine and resulted in a twofold to threefold increase in the intracellular content of cysteine. In contrast, the content of serine, threonine, and alanine showed a tendency to decrease, whereas other LAT-2 substrates were not affected. This demonstrates that LAT-2 plays a major specific role in the net basolateral efflux of cysteine and points to LAT-2 as a candidate gene to modulate cystine reabsorption.
Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials
Authors: G. De Berardis, M. Sacco, G. F M Strippoli, F. Pellegrini, G. Graziano, G. Tognoni, A. Nicolucci
Journal: BMJ (2009)

<b>Objective</b> To evaluate the benefits and harms of low dose aspirin in people with diabetes and no cardiovascular disease. <b>Design</b> Meta-analysis of randomised controlled trials. <b>Data sources</b> Medline (1966-November 2008), the Cochrane central register of controlled trials (<i>Cochrane Library</i> 2008;issue 4), and reference lists of retrieved articles. <b>Review methods</b> Randomised trials of aspirin compared with placebo or no aspirin in people with diabetes and no pre-existing cardiovascular disease were eligible for inclusion. Data on major cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, and all cause mortality) were extracted and pooled with a random effect model. Results are reported as relative risks with 95% confidence intervals. <b>Results</b> Of 157 studies in the literature searches, six were eligible (10 117 participants). When aspirin was compared with placebo there was no statistically significant reduction in the risk of major cardiovascular events (five studies, 9584 participants; relative risk 0.90, 95% confidence interval 0.81 to 1.00), cardiovascular mortality (four studies, n=8557, 0.94; 0.72 to 1.23), or all cause mortality (four studies, n=8557; 0.93, 0.82 to 1.05). Significant heterogeneity was found in the analysis for myocardial infarction (I<sup>2</sup>=62.2%; P=0.02) and stroke (I<sup>2</sup>=52.5%; P=0.08). Aspirin significantly reduced the risk of myocardial infarction in men (0.57, 0.34 to 0.94) but not in women (1.08, 0.71 to 1.65; P for interaction=0.056). Evidence relating to harms was inconsistent. <b>Conclusions</b> A clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved. Sex may be an important effect modifier. Toxicity is to be explored further.
Inhaled corticosteroids in COPD
Authors: S. HART;, M. CONFALONIERI, A. SPANEVELLO;, K. W TSANG;, M. CONFALONIERI, A. SPANEVELLO;, C E BRIGHTLING, I D PAVORD;, M. CONFALONIERI, A. SPANEVELLO
Journal: Thorax (1999)

Neuregulin 1 (NRG1) signaling is critical to various aspects of neuronal development and function. Among different NRG1 isoforms, the type III isoforms of NRG1 are unique in their ability to signal via the intracellular domain after γ-secretase-dependent intramembranous processing. However, the functional consequences of type III NRG1 signaling via its intracellular domain are mostly unknown. In this study, we have identified mutations within type III NRG1 that disrupt intramembranous proteolytic processing and abolish intracellular domain signaling. In particular, substitutions at valine 321, previously linked to schizophrenia risks, result in NRG1 proteins that fail to undergo γ-secretase-mediated nuclear localization and transcriptional activation. Using processing-defective mutants of type III NRG1, we demonstrate that the intracellular domain signaling is specifically required for NRG1 regulation of the growth and branching of cortical dendrites but not axons. Consistent with the role of type III NRG1 signaling via the intracellular domain in the initial patterning of cortical dendrites, our findings from pharmacological and genetic studies indicate that type III NRG1 functions in dendritic development independent of ERBB kinase activity. Together, these results support the proposal that aberrant intramembranous processing and defective signaling via the intracellular domain of type III NRG1 impair a subset of NRG1 functions in cortical development and contribute to abnormal neuroconnectivity implicated in schizophrenia.
Morphological study of vascular dissemination in a metastatic hepatocellular carcinoma model in the monkey
Authors: C K Lindsay, C C Sinha, U P Thorgeirsson
Journal: Hepatology (1997)

In this report we describe a metastatic monkey hepatocellular carcinoma (HCC) model in which intravascular metastatic development is clearly evident. The tumor-bearing livers contained intravenous tumor thrombi at different stages of progression within the small branches of the portal vein. These ranged from mural tumor thrombi lined with CD31-positive endothelial cells to tumor thrombi that had completely occluded the vascular lumen. Intravenous tumor expansion was frequently accompanied by the appearance of CD31-positive microvessels within the tumor thrombi and fibrous perivascular thickening, giving rise to isolated tumor nodules within the portal areas. Intravascular expansion of disseminating HCC was also evident within small branches of the pulmonary arteries in the lungs. These findings indicate that metastases of HCC can become established while still at an intravascular stage, suggesting that the direct interaction between tumor cells and parenchymal cells predicted from experimental rodent metastasis models is not a prerequisite for the metastatic development of these tumors.
Serum hepatitis C virus RNA quantity and histological features of hepatitis C virus carriers with persistently normal ALT levels
Authors: Masafumi Naito, Norio Hayashi, Hideki Hagiwara, Naoki Hiramatsu, Akinori Kasahara, Hideyuki Fusamoto, Takenobu Kamada
Journal: Hepatology (1994)

We studied hepatitis C virus carriers with normal liver function to evaluate the histological features of their livers and the replicative levels of hepatitis C virus. Liver biopsies were performed in 22 hepatitis C virus carriers with persistently normal ALT levels. Hepatitis C virus RNA in serum was quantified with a competitive assay that combined reverse transcription and the polymerase chain reaction, which is based on co-amplification of the target RNA with known amounts of synthetic mutated RNA. Three patients had normal livers on histological study, whereas the other 19 had chronic persistent hepatitis, with lymphoid infiltrates or aggregates in portal tracts commonly observed but intralobular inflammatory changes absent or minimal. The titer of hepatitis C virus RNA (logarithmic transformed copy number per milliliter of serum) varied from 4.0 to 8.0 (mean +/- S.D.: 6.3 +/- 1.1); it was significantly lower in the three patients with normal livers (4.3 +/- 0.2) than in those with chronic persistent hepatitis with mild (6.4 +/- 0.8, n = 11) or moderate (7.1 +/- 0.5, n = 8) portal inflammation. The titer of hepatitis C virus RNA was correlated with the total score (r = 0.68) and the score for portal inflammation (r = 0.68) in the histological activity index. These results indicated that there seem to be "healthy carriers" of hepatitis C virus with extremely low levels of viral replication. However, in most hepatitis C virus carriers with persistently normal ALT levels, there are inflammatory changes in the portal tracts, with severity depending on the replicative levels of hepatitis C virus.
Risk of Soft Tissue Sarcomas by Individual Subtype in Survivors of Hereditary Retinoblastoma
Authors: Ruth A. Kleinerman, Margaret A. Tucker, David H. Abramson, Johanna M. Seddon, Robert E. Tarone, Joseph F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (2007)

Survivors of hereditary retinoblastoma have an increased risk for second malignancies, especially soft tissue sarcomas. However, the risks of individual histologic subtypes of soft tissue sarcomas have not been evaluated.We estimated the risk for six subtypes of soft tissue sarcomas (fibrosarcoma, liposarcoma, histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and others) in a cohort of 963 one-year survivors of hereditary retinoblastoma among patients diagnosed at two US institutions from 1914 through 1984. We calculated standardized incidence ratios (SIRs) for specific subtypes of soft tissue sarcomas by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results database. We also calculated the cumulative risk for all soft tissue sarcomas combined.We observed 69 soft tissue sarcomas in 68 patients with hereditary retinoblastoma. Risks were elevated for soft tissue sarcomas overall (SIR = 184, 95% confidence interval [CI] = 143 to 233) and for individual subtypes. Leiomyosarcoma was the most frequent subtype (SIR = 390, 95% CI = 247 to 585), with 78% of leiomyosarcomas diagnosed 30 or more years after the retinoblastoma diagnosis (SIR = 435, 95% CI = 258 to 687). Among patients treated with radiotherapy for retinoblastoma, we found statistically significantly increased risks of soft tissue sarcomas in the field of radiation. Irradiated patients also had increased risks of soft tissue sarcomas, especially leiomyosarcomas, outside the field of radiation, and risks of soft tissue sarcomas were increased in nonirradiated patients as well, indicating a genetic predisposition to soft tissue sarcomas independent of radiation. The cumulative risk for any soft tissue sarcoma 50 years after radiotherapy for retinoblastoma was 13.1% (95% CI = 9.7% to 17.0%).Long-term follow-up of a cohort of survivors of hereditary retinoblastoma revealed a statistically significant excess of leiomyosarcoma and other soft tissue sarcomas that persists decades after the retinoblastoma diagnosis. Retinoblastoma survivors should undergo regular medical surveillance for sarcomas in their adult years.