tbuckley/cabot-search huggingface dataset:
Human Carcinoma Cell Growth and Invasiveness Is Impaired by the Propeptide of the Ubiquitous Proprotein Convertase Furin
Authors: Ricardo López de Cicco, Daniel E. Bassi, Stanley Zucker, Nabil G. Seidah, Andrés J.P. Klein-Szanto
Journal: Cancer Research (2005)

Abstract Furin, a potent proprotein convertase involved in activation of several cancer-related substrates, is synthesized as an inactive zymogen, thus minimizing the occurrence of premature enzymatic activity that would lead to inappropriate protein activation or degradation. This natural inhibitory mechanism is based on the presence of an inactivating prosegment at the NH2 terminal of the zymogen. After initial autocatalytic cleavage, the prosegment remains tightly associated with the convertase until it reaches the trans-Golgi network where the dissociation of the prosegment and activation of furin occurs. We hypothesized that the inhibitory properties of the preprosegment of furin (ppFur) could be beneficial if ectopically expressed in tumor cells. Transfection of four human head and neck squamous cell carcinoma cell lines with the complete ppFur cDNA sequence (pIRES-EGFP-ppFur) or with the empty expression vector (pIRES-EGFP) was done. The inhibitory effect was evaluated using in vivo tumorigenicity, invasion, anchorage-independent growth in soft agar, and proliferation assays, as well as by investigating impairment of furin substrates processing. Following transfection of ppFur, a significant reduction in cell proliferation, tumorigenicity, and invasiveness was observed in vitro and in vivo. These biological changes are directly related to the inhibition of furin-mediated activation of crucial cancer-related substrates, such as membrane type 1 matrix metalloproteinase, transforming growth factor-β, insulin-like growth factor-1 receptor, and vascular endothelial growth factor-C. PpFur expression in head and neck squamous cell carcinoma cell lines showed a mechanistic link between furin inhibition, decreased substrate processing, cell proliferation, and invasive ability. These findings suggest that furin inhibition is a feasible approach to ameliorate and even abolish the malignant phenotype of various malignancies.
Rapid method for measurement of bronchial responsiveness.
Authors: K Yan, C Salome, A J Woolcock
Journal: Thorax (1983)

A rapid, simple method for measuring bronchial responsiveness to inhaled histamine is described. The method was used to obtain dose response curves in 50 atopic subjects with varying respiratory and nasal symptoms. The cumulative dose of histamine which caused a 20% fall in the one second forced expiratory volume (PD20-FEV1) varied between 0.046 and greater than 3.9 mumol and correlated with the severity of symptoms. The reproducibility of the PD20-FEV1, determined from duplicate measurements in 15 subjects with varying degrees of bronchial responsiveness was found to be satisfactory. When the PD20-FEV1 from this rapid method was compared with that obtained from the dosimeter method no significant difference was found. The dose delivered by this method was shown to be cumulative.
Efficacy of cytisine in helping smokers quit: systematic review and meta-analysis
Authors: Peter Hajek, Hayden McRobbie, Katie Myers
Journal: Thorax (2013)

<h3>Background</h3> A recent rigorous study has shown that cytisine, a low-cost drug, is effective for smoking cessation. A number of earlier studies exist, mostly from former communist countries where cytisine has been used since the 1960s. The key question now is whether there is sufficient evidence to warrant licensing cytisine or whether more work is needed. A systematic review was undertaken to assess the efficacy of cytisine in smoking cessation. <h3>Methods</h3> The Cochrane Library, CINAHL, Embase, Medline and PsycINFO databases were searched for relevant data. Data from controlled trials were entered into two separate meta-analyses. The first considered the strictest definition of outcome and longest follow-up from all available studies and the second pooled outcomes from studies with biochemically validated abstinence and follow-up of 6 months or longer. <h3>Results</h3> Eight controlled trials were identified. Seven trials provided extractable data and, when pooled (first meta-analysis), produced a risk ratio (RR) of 1.57 (95% CI 1.42 to 1.74). Data from two high-quality studies (second meta-analysis) produced a pooled RR of 3.29 (95% CI 1.84 to 5.90). Patients on cytisine reported more gastrointestinal symptoms than patients on placebo (RR=1.76, 95% CI 1.28 to 2.42). There was no difference in overall reports of adverse events and no specific safety concerns emerged. <h3>Conclusions</h3> Cytisine is an effective treatment for smoking cessation with efficacy comparable to that of other currently licensed treatments. Given its low cost and potential for public health benefit, expedited licensing of cytisine for smoking cessation is warranted.
Targeted Disruption of the Scavenger Receptor and Chemokine CXCL16 Accelerates Atherosclerosis
Authors: Ara M. Aslanian, Israel F. Charo
Journal: Circulation (2006)

The uptake of oxidized low-density lipoprotein (OxLDL) by macrophage scavenger receptors is thought to be a key process in the formation of foam cells, the hallmark of early atherosclerotic lesions. CXCL16/scavenger receptor for phosphatidylserine and OxLDL is a multifunctional chemokine that exhibits scavenger receptor activity toward oxidized lipids in a membrane-bound configuration and may be shed to serve as a chemoattractant for T helper 1-polarized T lymphocytes. These properties, as well as the expression of CXCL16 in human and mouse atheroma, suggest that CXCL16 plays a role in atherosclerosis.To examine the role of CXCL16 in plaque formation, we created CXCL16-deficient mice (CXCL16-/-) and bred them with mice deficient in the LDL receptor (LDLR-/-). In vitro, macrophages from CXCL16-/- mice have a significant reduction in the capacity to bind and internalize OxLDL. We found that CXCL16-/-/LDLR-/- mice have accelerated atherosclerosis, enhanced macrophage recruitment to the aortic arch, and more abundant mRNA for monocyte chemotactic protein-1 and tumor necrosis factor-alpha.These data suggest that scavenger receptor activity mediated by CXCL16 in vivo is atheroprotective, and they contrast with studies that document protection from atherosclerosis in scavenger receptor class A- and CD36-deficient mice.
Inhibition of endothelial progenitor cell glycogen synthase kinase-3β results in attenuated neointima formation and enhanced re-endothelialization after arterial injury
Authors: Benjamin Hibbert, Xiaoli Ma, Ali Pourdjabbar, Erik Holm, Katey Rayner, Yong-Xiang Chen, Jiangfeng Sun, Lionel Filion, Edward R. O'Brien
Journal: Cardiovascular Research (2009)

Endothelial progenitor cells (EPCs) are circulating pluripotent vascular cells capable of enhancing re-endothelialization and diminishing neointima formation following arterial injury. Glycogen synthase kinase (GSK)-3beta is a protein kinase that has been implicated in the regulation of progenitor cell biology. We hypothesized that EPC abundance and function could be enhanced with the use of an inhibitor of GSK-3beta (GSKi), thereby resulting in improved arterial repair.Human EPCs were expanded ex vivo, treated with a specific GSKi, and then assessed for both yield and functional characteristics by in vitro assays for adherence, apoptosis, and survival. In vivo functionality of treated human EPCs was assessed in immune-tolerant mice subjected to femoral artery wire injury. Re-endothelialization was assessed at 72 h and neointima formation at 7 and 14 days following injury. GSKi treatment resulted in an improvement in the yield of EPCs and a reduction in apoptosis in cells derived from both healthy controls and patients with coronary artery disease. Treatment also increased vascular endothelial growth factor secretion, up-regulated expression of mRNA for the alpha-4 integrin subunit, and improved adhesion, an effect which could be abrogated with an alpha-4 integrin blocking antibody. EPCs without or with ex vivo GSKi treatment enhanced re-endothelialization 72 h following injury as well as reduced neointima formation at 7 days (e.g. endothelial coverage: 7.2 +/- 1.7% vs. 70.7 +/- 5.8% vs. 87.2 +/- 4.1%; intima to media ratios: 1.05 +/- 0.19 vs. 0.39 +/- 0.08 vs. 0.14 +/- 0.02; P < 0.05 for all comparisons), an effect that was persistent at 14 days.GSKi improves the functional profile of EPCs and is associated with improved re-endothelialization and reduced neointima formation following injury.
Abstract P4-06-05: Transcriptional heterogeneity correlates with chemotherapy sensitivity in triple negative breast cancer and varies by molecular subtype
Authors: T Jiang, W Shi, S Ononye, G Han, V Wali, L Pusztai, C Hatzis
Journal: Cancer Research (2013)

Abstract Purpose: Different molecular subtypes of breast cancer are believed to have different degrees of molecular heterogeneity. However, the heterogeneity of breast cancer subtypes has not been formally compared. The goal of this analysis was to develop metrics of global transcriptional heterogeneity, compare heterogeneity across breast cancer subtypes and assess whether heterogeneity metrics correlate with sensitivity to chemotherapy in basal-like cancers. Methods: Affymetrix U133A gene expression data from 836 breast cancers (basal n = 219, HER2-like n = 147, luminal A n = 343, luminal B n = 127) were analyzed. Among the basal-like cancers, 128 received neoadjuvant chemotherapy (pathologic complete response, pCR, n = 44; residual disease, RD, n = 94). Molecular class was assigned by the PAM50 classifier. We used the average pairwise Pearson distance, the sum of eigenvalues of the correlation matrix and multi-dimensional scaling dispersions of the probe set expression values to quantify heterogeneity. Distribution of each metric within the different subtypes was estimated from 500 bootstrapped cohorts of 80 cases in each subtype. We used analysis of variance (ANOVA) to evaluate the significance of the differences in heterogeneity between subtypes. Results: All three heterogeneity metrics yielded concordant results. Within subtypes, heterogeneity was greatest in basal-like cancers followed by HER2-like, luminal B and luminal A (see figure). Luminal A cancers were distinctly less heterogeneous than the rest. Basal-like cancers with RD were more heterogeneous than those with pCR. The best metric to separate basal tumors with pCR versus RD was the sum of eigenvalues shown below. Conclusion: Breast cancer molecular subtypes differ in transcriptional heterogeneity. Luminal A cancers have the lowest within group heterogeneity while basal like cancers have the highest. Among the basal-like cancers, those with high chemotherapy sensitivity (pCR) are more homogeneous than those with RD suggesting that transcriptional heterogeneity might be contributing to increased resistance to therapy in this subgroup. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-05.
Virus-induced diabetes mellitus. VI. Genetically determined host differences in the replicating of encephalomyocarditis virus in pancreatic beta cells.
Authors: J W Yoon, A L Notkins
Journal: The Journal of Experimental Medicine (1976)

Beta cells were isolated from strains of mice that were susceptible and resistant to encephalomyocarditis (EMC) viral-induced diabetes mellitus. Beta cells from susceptible mice that were infected in vivo with EMC virus showed higher viral titers, more severe degranulation, and lower concentrations of immunoreactive insulin than beta cells from resistant mice. Immunofluorescence and infectious center assays revealed that pancreas from susceptible mice contained at least 10 times more infected cells than pancreas from resistant mice. Beta cell cultures prepared from susceptible mice and infected in vitro also showed higher viral titers and more severe cytopathologic changes than beta cell cultures from resistant mice. In contrast to beta cell cultures, virus replicated equally well in primary embryo and kidney cell cultures from susceptible and resistant strains of mice. It is concluded that the development of EMC virus-induced diabetes is related to genetically determined host differences in the capacity of the virus to infect beta cells.
MicroRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma
Authors: Meir Preis, Timothy B. Gardner, Stuart R. Gordon, J. Marc Pipas, Todd A. Mackenzie, Erin E. Klein, Daniel S. Longnecker, Edward J. Gutmann, Lorenzo F. Sempere, Murray Korc
Journal: Clinical Cancer Research (2011)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC. Experimental Design: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid–modified DNA probes against miR-10b, miR-21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)–positive epithelial cells using optical intensity analysis. Results: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells (P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR-10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19-positive epithelial cells in benign lesions (P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival. Conclusion: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease. Clin Cancer Res; 17(17); 5812–21. ©2011 AACR.
Tumor induction by azoxymethane (AOM) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in F344 rat gastric mucosa featuring intestinal metaplasia caused by X-irradiation.
Authors: S Kashiwabara, N Kashimoto, T Uesaka, K Wakabayashi, K Kamiya, H Watanabe
Journal: Journal of experimental & clinical cancer research (2005)

Male F344 5-week-old rats were X-irradiated, and 16 weeks after the first dose, azoxymethane (AOM) was injected or 2-amino-1 -methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) was given by intragastric intubation. Tumors in the pylorus of the glandular stomach were observed in 4 out of the 29 animals receiving X-rays + AOM and in 4 out of the 25 animals receiving X-rays + PhIP, 12 months after administration. No such lesions were found in the chemical or X-ray alone groups. Intestinal metaplasia and some induced tumors were positive for CDX2. It was concluded that the presence of intestinal metaplasia may increase sensitivity to the induction of gastric tumors by colon carcinogens.
The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice
Authors: Matthew B. Greenblatt, Jae-Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger Davis, Laurie H. Glimcher
Journal: Journal of Clinical Investigation (2010)

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member–encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β–activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.
Validation of the accuracy of both right and left ventricular outflow volume determinations and semiautomated calculation of shunt volumes through atrial septal defects by digital color Doppler flow mapping in a chronic animal model
Authors: Takahiro Shiota, Michael Jones, Satoshi Aida, Masahide Chikada, Hiroyuki Tsujino, Taher El-Kadi, David J Sahn
Journal: Journal of the American College of Cardiology (1999)
Clinical Practice Guidelines in End-Stage Renal Disease
Authors: ALAN S. KLIGER, WILLIAM E. HALEY
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Clinical practice guidelines (CPGs) for end-stage renal failure (ESRD) were recently published, and represent a comprehensive review of available literature and the considered judgment of experts in ESRD. To prioritize and implement these guidelines, the evidence underlying each guideline should be ranked and the attributes of each should be defined. Strategies to improve practice patterns should be tested. Focused information for each high priority guideline should be disseminated, including a synopsis and assessment of the underlying evidence, the evidence model used to develop that guideline, and suggested strategies for CPG implementation. Clinical performance measures should be developed and used to measure current practice, and the success of changing practice patterns on clinical outcomes. Individual practitioners and dialysis facilities should be encouraged to utilize continuous quality improvement techniques to put the guidelines into effect. Local implementation should proceed at the same time as a national project to convert high priority CPGs into clinical performance measures proceeds. Patients and patient care organizations should participate in this process, and professional organizations must make a strong commitment to educate clinicians in the methodology of CPG and performance measure development and the techniques of continuous quality improvement. Health care regulators should understand that CPGs are not standards, but are statements that assist practitioners and patients in making decisions.
Evidence of White Matter Pathology in Bipolar Disorder Adolescents Experiencing Their First Episode of Mania: A Diffusion Tensor Imaging Study
Authors: Caleb M. Adler, John Adams, Melissa P. DelBello, Scott K. Holland, Vince Schmithorst, Ari Levine, Kelly Jarvis, Stephen M. Strakowski
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: Previous diffusion tensor imaging findings have supported suggestions that bipolar disorder is characterized by subtle white matter changes. The chronic nature of the study population, however, has limited interpretation of these findings. In this study the authors utilized diffusion tensor imaging to study white matter tracts of adolescents in their first episode of mania to address whether abnormalities are present in early bipolar disorder. METHOD: Eleven medication-naive adolescents in their first episode of mania and 17 healthy subjects underwent diffusion tensor imaging scans. Fractional anisotropy and trace apparent diffusion coefficients of prefrontal and posterior regions of interest were compared between groups. RESULTS: Bipolar adolescents showed significantly decreased fractional anisotropy only in superior-frontal white matter tracts. Trace apparent diffusion coefficients did not significantly differ in any regions examined. CONCLUSIONS: These findings suggest that prefrontal white matter abnormalities are present early in bipolar disorder and may consist largely of axonal disorganization. The presence of changes in young first-episode patients also suggests that white matter pathology may represent an early marker of bipolar disorder.
The Multifaceted Role of MTDH/AEG-1 in Cancer Progression
Authors: Guohong Hu, Yong Wei, Yibin Kang
Journal: Clinical Cancer Research (2009)

Cancer is the result of the progressive acquisition of multiple malignant traits through the accumulation of genetic or epigenetic alterations. Recent studies have established a functional role of MTDH (Metadherin)/AEG-1 (Astrocyte Elevated Gene 1) in several crucial aspects of tumor progression, including transformation, evasion of apoptosis, invasion, metastasis, and chemoresistance. Overexpression of MTDH/AEG-1 is frequently observed in melanoma, glioma, neuroblastoma, and carcinomas of breast, prostate, liver, and esophagus and is correlated with poor clinical outcomes. MTDH/AEG-1 functions as a downstream mediator of the transforming activity of oncogenic Ha-Ras and c-Myc. Furthermore, MTDH/AEG-1 overexpression activates the PI3K/Akt, nuclear factor kappaB (NFkappaB), and Wnt/beta-catenin signaling pathways to stimulate proliferation, invasion, cell survival, and chemoresistance. The lung-homing domain of MTDH/AEG-1 also mediates the adhesion of tumor cells to the vasculature of distant organs and promotes metastasis. These findings suggest that therapeutic targeting of MTDH/AEG-1 may simultaneously suppress tumor growth, block metastasis, and enhance the efficacy of chemotherapeutic treatments.
Leukotriene D4 activates 2-integrin adhesion in human polymorphonuclear leukocytes
Authors: A. Y. Meliton, N. M. Muñoz, C. M. Osan, L. N. Meliton, A. R. Leff
Journal: European Respiratory Journal (2009)

We examined the functional role and mechanisms by which activation of cysteinyl leukotriene-1 receptor (cysLT(1)R) regulates beta(2)-integrin adhesion to intercellular adhesion molecule (ICAM)-1 in human polymorphonuclear leukocytes (PMNs) in vitro. Human peripheral blood PMNs and eosinophils were isolated separately from the same mildly atopic donors. Surface expression of cysLT(1)R was identified both in PMNs and in eosinophils by immunofluorescence analysis. Total cysLT(1)R protein was substantially greater in eosinophils than in PMNs as determined by Western blot analysis. However, leukotriene D(4) (LTD(4)) upregulated beta(2)-integrin adhesion of PMNs to ICAM-1 with high efficacy in a time- and concentration-dependent manner. Upregulated beta(2)-integrin adhesion of PMNs was related temporally and quantitatively to phosphorylation of 85-kDa cytosolic group IVa phospholipase A2 (gIVaPLA2). Augmented LTD(4)-induced adhesion was blocked significantly by montelukast, a cysLT(1)R antagonist. Trifluoromethylketone (a gIVaPLA2 inhibitor) blocked beta(2)-integrin adhesion caused by LTD(4) activation, as did anti-CD18 monoclonal antibody directed against beta(2)-integrin on the PMN surface. Our data demonstrate that LTD(4) causes phosphorylation of gIVaPLA2 and upregulation of beta(2)-integrin adhesion to ICAM-1 or ICAM-1 surrogate through cysLT(1)R activation. Activation of gIVaPLA2 is a critical step through which beta(2)-integrin adhesion is upregulated by the cysLT(1)R expressed on the surface membrane of human PMN.