tbuckley/cabot-search huggingface dataset:
Expression of HER2 and Estrogen Receptor α Depends upon Nuclear Localization of Y-Box Binding Protein-1 in Human Breast Cancers
Authors: Teruhiko Fujii, Akihiko Kawahara, Yuji Basaki, Satoshi Hattori, Kazutaka Nakashima, Kenji Nakano, Kazuo Shirouzu, Kimitoshi Kohno, Takashi Yanagawa, Hideaki Yamana, Kazuto Nishio, Mayumi Ono, Michihiko Kuwano, Masayoshi Kage
Journal: Cancer Research (2008)

Abstract In our present study, we examined whether nuclear localization of Y-box binding protein-1 (YB-1) is associated with the expression of epidermal growth factor receptors (EGFR), hormone receptors, and other molecules affecting breast cancer prognosis. The expression of nuclear YB-1, clinicopathologic findings, and molecular markers [EGFR, HER2, estrogen receptor (ER)α, ERβ, progesterone receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), phosphorylated Akt, and major vault protein/lung resistance protein] were immunohistochemically analyzed. The association of the expression of nuclear YB-1 and the molecular markers was examined in breast cancer cell lines using microarrays, quantitative real-time PCR, and Western blot analyses. Knockdown of YB-1 with siRNA significantly reduced EGFR, HER2, and ERα expression in ERα-positive, but not ERα-negative, breast cancer cell lines. Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ERα (P = 0.0122) and CXCR4 (P = 0.0166) in human breast cancer clinical specimens but was not correlated with EGFR expression. Nuclear YB-1 expression was an independent prognostic factor for overall (P = 0.0139) and progression-free (P = 0.0280) survival. In conclusion, nuclear YB-1 expression might be essential for the acquisition of malignant characteristics via HER2-Akt–dependent pathways in breast cancer patients. The nuclear localization of YB-1 could be an important therapeutic target against not only multidrug resistance but also tumor growth dependent on HER2 and ERα. [Cancer Res 2008;68(5):1504–12]
Signal Transducers and Activators of Transcription Mediate Fibroblast Growth Factor–Induced Vascular Endothelial Morphogenesis
Authors: Xinhai Yang, Dianhua Qiao, Kristy Meyer, Andreas Friedl
Journal: Cancer Research (2009)

The fibroblast growth factors (FGF) play diverse roles in development, wound healing, and angiogenesis. The intracellular signal transduction pathways, which mediate these pleiotropic activities, remain incompletely understood. We show here that the proangiogenic factors FGF2 and FGF8b can activate signal transducers and activators of transcription (STAT) in mouse microvascular endothelial cells (EC). Both FGF2 and FGF8b activate STAT5 and to a lesser extent STAT1, but not STAT3. The FGF2-dependent activation of endothelial STAT5 was confirmed in vivo with the Matrigel plug angiogenesis assay. In tissue samples of human gliomas, a tumor type wherein FGF-induced angiogenesis is important, STAT5 is detected in tumor vessel EC nuclei, consistent with STAT5 activation. By forced expression of constitutively active or dominant-negative mutant STAT5A in mouse brain ECs, we further show that STAT5 activation is both necessary and sufficient for FGF-induced cell migration, invasion, and tube formation, which are key events in vascular endothelial morphogenesis and angiogenesis. In contrast, STAT5 is not required for brain EC mitogenesis. The cytoplasmic tyrosine kinases Src and Janus kinase 2 (Jak2) both seem to be involved in the activation of STAT5, as their inhibition reduces FGF2- and FGF8b-induced STAT5 phosphorylation and EC tube formation. Constitutively active STAT5A partially restores tube formation in the presence of Src or Jak2 inhibitors. These observations show that FGFs use distinct signaling pathways to induce angiogenic phenotypes. Together, our findings implicate the FGF-Jak2/Src-STAT5 cascade as a critical angiogenic FGF signaling pathway.
Effects of ryanodine and caffeine on contractility, membrane voltage, and calcium exchange in cultured heart cells.
Authors: C A Rasmussen, J L Sutko, W H Barry
Journal: Circulation Research (1987)

To investigate the mechanisms of action of ryanodine and caffeine, changes in mechanical and electrical activity caused by these agents were correlated with alterations in 45Ca fluxes and cell Ca contents in chick embryo ventricular cell monolayer cultures. Ryanodine (10(-10)-10(-5) M) irreversibly decreased contraction amplitude by 10-70% relative to control in a concentration-dependent manner with minimal effects on electrical activity. Ryanodine caused a slight decrease in rapid 45Ca uptake, but no change in total exchangeable calcium content or rapid 45Ca efflux. Caffeine (1-20 mM) caused a transient (less than 10 seconds) 5-12% increase in contraction amplitude followed by a sustained 9-76% decrease in contraction amplitude and a 10 mV decrease in diastolic membrane voltage. Caffeine caused a decrease in rapid 45Ca uptake, a decrease in total exchangeable calcium content, and an increase in rapid 45Ca efflux. These results suggest that caffeine produces a decrease in sarcoplasmic reticulum (SR) Ca2+ uptake, and/or an increase in SR Ca2+ release that eventually depletes the SR of Ca2+, presumably accounting for the negative inotropic effect. The ryanodine effects on contraction are more difficult to account for solely in terms of alterations of transsarcolemmal Ca2+ fluxes and Ca2+ contents. Our data indicate an important role for the SR in excitation-contraction coupling in cultured chick embryo ventricular cells and suggest that SR Ca2+ is part of the rapidly exchanging Ca2+ compartment noted in 45Ca flux studies.
Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model1
Authors: Ryuta Saito, Michal T. Krauze, Charles O. Noble, Daryl C. Drummond, Dmitri B. Kirpotin, Mitchel S. Berger, John W. Park, Krystof S. Bankiewicz
Journal: Neuro-Oncology (2006)

Treatment of malignant gliomas represents one of the most formidable challenges in oncology. The combination of surgery, radiation, and chemotherapy yields median survivals of less than one year. Here we demonstrate the use of a minimally invasive surgical technique, convection-enhanced delivery (CED), for local administration of a novel nanoparticle liposome containing topotecan. CED of this liposomal topotecan (Ls-TPT) resulted in extended brain tissue retention (t½ = 1.5 days), whereas free topotecan was rapidly cleared (t½ = 0.1 days) after CED. The favorable pharmacokinetic profile of extended topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known topoisomerase I inhibition, an effective antiangiogenic therapy. In the rat intracranial U87MG tumor model, vascular targeting of Ls-TPT with CED was associated with reductions in laminin expression and vascular density compared to free topotecan or control treatments. A single CED treatment on day 7 showed that free topotecan conferred no survival benefit versus control. However, Ls-TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG tumors, where CED of Ls-TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire tumor with the infused therapeutic agent. CED of Ls-TPT was also efficacious in the intracranial U251MG tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-TPT and CED administration was very effective in treating experimental brain tumors.
Clinical Correlates and Familial Aggregation of Age at Onset in Bipolar Disorder
Authors: Ping-I Lin, Melvin G. McInnis, James B. Potash, Virginia Willour, Dean F. MacKinnon, J. Raymond DePaulo, Peter P. Zandi
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: To assess whether age at onset variation reflects underlying genetic heterogeneity in bipolar disorder, the authors examined the clinical and familial characteristics of age at onset in bipolar disorder subjects from families with multiple affected members. METHOD: A total of 211 families with 1,856 subjects were ascertained through bipolar I disorder probands. All the subjects were assessed with the Diagnostic Interview for Genetic Studies and assigned diagnoses by trained clinicians using best estimate procedures. Admixture analysis with the 211 bipolar disorder probands was used to decompose the age-at-onset distribution into a mixture of theoretical normal distributions. Logistic regression with general estimating equations was then used to examine clinical correlates and familial aggregation of age at onset in all 717 bipolar disorder subjects. RESULTS: The age-at-onset distribution consisted of a mixture of three normal distributions with means of 16.6 (SD=5.1), 26.0 (SD=1.4), and 34.7 (SD=6.6) years that comprised 79.7%, 7.2%, and 13.1% of the group, respectively. Cutoff points at ages 21 and 28 were derived from this analysis and used to define age-at-onset subgroups. Early-onset (age at onset ≤21) subjects had higher risks of drug abuse, alcohol abuse, rapid cycling, and suicide attempts. Affected subjects from a family with an early-onset proband were more likely than others to have an early onset (odds ratio=4.53, 95% CI=3.09–6.64). Subjects from a family with a proband whose age at onset was <28 were also more likely to have higher risks of drug abuse (odds ratio=11.62, 95% CI=2.16–62.66). CONCLUSIONS: Age at onset is associated with clinical heterogeneity in bipolar disorder and aggregates, possibly along with drug abuse, within families. These findings are consistent with the conclusion that age at onset reflects underlying genetic heterogeneity in bipolar disorder. Thus, age at onset may conceivably be used to identify more homogeneous groups of bipolar disorder families and thereby facilitate the mapping of bipolar disorder susceptibility genes.
Trends in pubertal development in Europe
Authors: S. M. P. F. de Muinck Keizer-Schrama
Journal: Human Reproduction Update (2001)

The secular changes in growth and maturation can be seen as indicators of socio-economic and health status. In most European countries the age of onset of puberty and of menarcheal age has been decreasing during the past few decades. The duration of puberty seems also to decrease, though few studies provide sufficient data to support this postulation. The four Dutch nationwide growth surveys are useful examples assessing the secular trend in pubertal development over the past 45 years. Genetic and environmental factors contribute to the secular changes. Environmental factors seem to be the most important. Recently, attention has been given to substances with oestrogen-like actions that are present in nutrients. The possible role of these substances in growth and maturation is discussed.
The complexity of NF-κB signaling in inflammation and cancer
Authors: Bastian Hoesel, Johannes A Schmid
Journal: Molecular Cancer (2013)

The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.
Bronchial provocation testing and collection of sputum with inhaled mannitol in children
Authors: Gerardo Vizmanos-Lamotte, Elisa Canturri Gispert, Victor Núñez Eroles, Mireia Martínez Abelló, Joan Martínez Benazet, Manuel Medina Rams
Journal: European Respiratory Journal (2014)

Introduction   Mannitol is used as an indirect challenge test to assess airway hyperresponsiveness in asthma. Recently, it has been tested in adults as an sputum inducer (Wood, L.G. et al. Clin Exp Allergy 2010; 40:232-41).  The aim of this preliminary study was to assess the feasibility and safety of the mannitol challenge test to obtain induced sputum in young children.   Methods   17 children (10 healthy and 7 asthmatics) aged 7-13 years were recruited. The mannitol challenge test (Osmohale®; Aldo-Union, Esplugues de Ll., Barcelona, Spain) was performed as previously published and induction sputum was done during the test. Sputum was processed using a slight modification of the method described by Pizzichini et al. (Pizzichini, E. et al. Eur Respir J 1996; 9:1174-80). Sputum eosinophlia was established when the percentage of eosinophils was ≥ 2.5%.   Results   Mannitol test was positive in 7 children (4 asthmatic and 3 healthy), provoking dose to induce a 15% fall in FEV 1  (PD15) ranged from 75 to 565.38 mg and the response-dose ratio (RDR: % fall in FEV 1 /cumulative dose) ranged from 0.03 to 0.14% fall in FEV 1 /mg. Sputum samples (viability > 50%; squamous cells    Conclusions   Mannitol can be used to induce good-quality sputum in young children.
Healthy Cities: Toward Worldwide Health Promotion
Authors: Beverly Collora Flynn
Journal: Annual Review of Public Health (1996)

Healthy Cities is a community problem-solving process for health promotion that began in Canada and Europe in the mid-1980s. Although Healthy Cities have expanded worldwide, there is limited scientific literature that documents the effects of these efforts. This review describes the dynamic status of Healthy Cities globally and summarizes what is known about these efforts. It is difficult to draw generalizations or clear differences between Healthy Cities and other efforts with similar objectives in the United States. There appears to be less variation among Healthy Cities in Europe, most likely because of the extensive technical support provided by the WHO European Regional Office to the Healthy Cities Project. Case descriptions present the diversity and types of activities of Healthy Cities. It is concluded that community participation and broad involvement from different sectors of the community are promising approaches to addressing urban problems.
Interleukin-4 Promoter Polymorphisms: A Genetic Prognostic Factor for Survival in Metastatic Renal Cell Carcinoma
Authors: Thomas Kleinrath, Christoph Gassner, Peter Lackner, Martin Thurnher, Reinhold Ramoner
Journal: Journal of Clinical Oncology (2007)

Purpose Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance. Patients and Methods A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors. Results Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype −589T−33T/−589C−33C as an independent prognostic risk factor (risk ratio, 3.1; P &lt; .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype −589T−33T and −589C−33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype −589T−33T (P &lt; .01) and an increase of IL4 haplotype −589C−33C frequency (P &lt; .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P &lt; .05) in heterozygote patients carrying IL4 haplotype −589T−33T and −589C−33C (3.78 months) compared with patients homozygote for IL4 haplotype −589C−33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected. Conclusion Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.
Hybrid-Versus-Parental Strain Reaction. III. Comparative Mortality in Parental Strain Mice of the H. k Genotype
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1976)

Lethally irradiated perental strain mice were inoculated with marrow from reciprocal hybrid donors. Hybrid cells could recognize the quantitatively greater antigenicity of parental strain recipients. The severity of the hybrid-versus-parental strain and parental strain-versus-hybrid reactions was compared. There was a significantly less severe reaction when DBA/2 mice were inoculated with (DBA/2female X C57BLmale)F1 arrow than with (C57BL X DBA/2)F1 marrow, which indicated a maternal influence on antigen recognition. The reaction of (DBA/2 X C57BL)F1 against DBA/2 recipients was significantly less severe than the DBA/2 reaction against (DBA/2 X C57BL)F1 recipients. All reactions involving C57BL were equally severe and more lethal than those involving DBA/2 mice. The strength of these reactions was a function of the relative tissue antigenicity and responsiveness of the parental strains of the hybrid cross. Both the expression of tissue antigens and the ability to recognize and respons to them are influenced by the maternal strain of the hybrid cross.
Toward an Antibody-Based HIV-1 Vaccine
Authors: James A. Hoxie
Journal: Annual Review of Medicine (2009)

Developing an HIV-1 vaccine that can elicit antibodies to prevent infection has been a formidable challenge. Although no single immunogen has generated antibodies that can neutralize diverse isolates, progress has been made in understanding (a) the structure of the HIV-1 envelope glycoprotein, which is targeted by neutralizing antibodies, (b) how HIV-1 evades antibodies made by an infected host, and (c) how rare monoclonal antibodies can exhibit broadly neutralizing activity. Advances in structural and molecular biology coupled with new approaches to isolate neutralizing antibodies from HIV-1-infected individuals are enhancing our understanding of what humoral immune responses will be required for a vaccine. This review summarizes progress in understanding the host antibody response to HIV-1 and current strategies for applying this information to develop an effective vaccine.
The Evolving Role of Cetuximab in Non–Small Cell Lung Cancer
Authors: Rogerio C. Lilenbaum
Journal: Clinical Cancer Research (2006)

Cetuximab is a monoclonal antibody directed against the ligand binding site in the extracellular domain of the epidermal growth factor receptor (EGFR). Cetuximab is currently approved for the treatment of patients with refractory colorectal cancer. In locally advanced head and neck carcinoma, cetuximab in combination with radiotherapy significantly improved survival compared with radiotherapy alone, and this treatment awaits Food and Drug Administration approval. In previously treated non-small cell lung cancer, single-agent cetuximab produced an objective response in 3 of 66 eligible patients and a median survival of 8.1 months. Treatment was well tolerated, with skin rash as the principal toxicity. The vast majority of patients (60 of 66) expressed EGFR by immunohistochemistry but no correlation existed between response and EGFR mutations. Two single-arm phase II trials testing cetuximab in combination with a platinum-based doublet in previously untreated patients showed responses in the range of 26% to 29%, with median survival times of 10 to 11 months. A European phase II randomized trial tested cisplatin/vinorelbine with or without cetuximab as first-line therapy in 86 patients with advanced non-small-cell lung cancer. Overall efficacy was slightly superior in the cetuximab arm and a phase III trial is currently ongoing to definitively determine the role of cetuximab in this setting.
Projecting the Number of Patients with End-Stage Renal Disease in the United States to the Year 2015
Authors: David T. Gilbertson, Jiannong Liu, Jay L. Xue, Thomas A. Louis, Craig A. Solid, James P. Ebben, Allan J. Collins
Journal: Journal of the American Society of Nephrology (2005)

The size of the prevalent ESRD population in the United States increased dramatically during the 1990s, from 196,000 in 1991 to 382,000 in 2000. Incidence also increased considerably during the same period, from 53,000 to 93,000 per year. If previous trends in ESRD incidence and prevalence continue, then current levels of health care resources that are devoted to the care of these patients will eventually be unable to meet the demand. This study discusses a Markov model developed to predict ESRD incidence, prevalence, and mortality to the year 2015 and incorporating expected changes in age/race distributions, diabetes prevalence, ESRD incidence, and probability of death. The model predicted that by 2015 there will be 136,166 incident ESRD patients per year (lower/upper limits 110,989 to 164,550), 712,290 prevalent patients (595,046 to 842,761), and 107,760 ESRD deaths annually (96,068 to 118,220). Incidence and prevalence counts are expected to increase by 44 and 85%, respectively, from 2000 to 2015 and incidence and prevalence rates per million population by 32 and 70%, respectively. The financial and human resources that will be needed to care for these patients in 2015 will be considerably greater than in 2005.
Undifferentiated nasopharyngeal carcinoma in children and adolescents: Comparison between staging systems
Authors: M. Casanova, A. Ferrari, L. Gandola, E. Orlandi, F. Spreafico, M. Terenziani, P. Navarria, R. Luksch, M. Massimino, G. Cefalo, F. Lombardi, F. Fossati-Bellani
Journal: Annals of Oncology (2001)