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The Global ETD Search service is a free service for researchers
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Showing 321 to 330 of 372 (0.185 seconds)| 321 |
Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumorsHochhauser, D., Meyer, T., Spanswick, V.J., Wu, J., Clingen, P.H., Loadman, Paul, Cobb, M., Gumbrell, L., Begent, R.H., Hartley, J.A., Jodrell, D. January 2009 (has links)
No / PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
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Stem cell factor/c-Kit signalling in normal and androgenetic alopecia hair folliclesRandall, Valerie A., Jenner, Tracey J., Hibberts, Nigel A., De Oliveira, Isabel O., Vafaee, Tayyebeh January 2008 (has links)
No / Androgens stimulate many hair follicles to alter hair colour and size via the hair growth cycle; in androgenetic alopecia tiny, pale hairs gradually replace large, pigmented ones. Since stem cell factor (SCF) is important in embryonic melanocyte migration and maintaining adult rodent pigmentation, we investigated SCF/c-Kit signalling in human hair follicles to determine whether this was altered in androgenetic alopecia. Quantitative immunohistochemistry detected three melanocyte-lineage markers and c-Kit in four focus areas: the epidermis, infundibulum, hair bulb (where pigment is formed) and mid-follicle outer root sheath (ORS). Colocalisation confirmed melanocyte c-Kit expression; cultured follicular melanocytes also exhibited c-Kit. Few ORS cells expressed differentiated melanocyte markers or c-Kit, but NKI/beteb antibody, which also recognises early melanocyte-lineage antigens, identified fourfold more cells, confirmed by colocalisation. Occasional similar bulbar cells were seen. Melanocyte distribution, concentration and c-Kit expression were unaltered in balding follicles. Androgenetic alopecia cultured dermal papilla cells secreted less SCF, measured by ELISA, than normal cells. This identifies three types of melanocyte-lineage cells in human follicles. The c-Kit expression by dendritic, pigmenting, bulbar melanocytes and rounded, differentiated, non-pigmenting ORS melanocytes implicate SCF in maintaining pigmentation and migration into regenerating hair bulbs. Less differentiated, c-Kit-independent cells in the mid-follicle ORS stem cell niche and occasionally in the bulb, presumably a local reserve for long scalp hair growth, implicate other factors in activating stem cells. Androgens appear to reduce alopecia hair colour by inhibiting dermal papilla SCF production, impeding bulbar melanocyte pigmentation. These results may facilitate new treatments for hair colour changes in hirsutism, alopecia or greying.
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Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathwaysSharov, A.A., Mardaryev, Andrei N., Sharova, T.Y., Grachtchouk, M., Atoyan, R., Byers, H.R., Seykora, J.T., Overbeek, P., Dlugosz, A., Botchkarev, Vladimir A. January 2009 (has links)
No / Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways.
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Specialized and independent processing of orientation and shape in visual field maps LO1 and LO2Silson, E.H., McKeefry, Declan J., Rodgers, J., Gouws, A.D., Hymers, M., Morland, A.B. January 2013 (has links)
No / We identified human visual field maps, LO1 and LO2, in object-selective lateral occipital cortex. Using transcranial magnetic stimulation (TMS), we assessed the functions of these maps in the perception of orientation and shape. TMS of LO1 disrupted orientation, but not shape, discrimination, whereas TMS of LO2 disrupted shape, but not orientation, discrimination. This double dissociation suggests that specialized and independent processing of different visual attributes occurs in LO1 and LO2.
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Melanin transfer in human skin cells is mediated by filopodia--a model for homotypic and heterotypic lysosome-related organelle transferSingh, Suman K., Kurfurst, R., Nizard, C., Schnebert, S., Perrier, E., Tobin, Desmond J. January 2010 (has links)
No / Transfer of the melanocyte-specific and lysosome-related organelle, the melanosome, from melanocytes to keratinocytes is crucial for the protection of the skin against harmful ultraviolet radiation (UVR)--our main physiological cutaneous stressor. However, this commonplace event remains a most enigmatic process despite several early hypotheses. Recently, we and others have proposed a role for filopodia in melanin transfer, although conclusive experimental proof remained elusive. Using known filopodial markers (MyoX/Cdc42) and the filopodial disrupter, low-dose cytochalasin-B, we demonstrate here a requirement for filopodia in melanosome transfer from melanocytes to keratinocytes and also, unexpectedly, between keratinocytes. Melanin distribution throughout the skin represents the key phenotypic event in skin pigmentation. Melanocyte filopodia were also necessary for UVR-stimulated melanosome transfer, as this was also inhibited by MyoX knockdown and low-dose cytochalasin-B. Knockdown of keratinocyte MyoX protein, in its capacity as a phagocytosis effector, resulted in the inhibition of melanin uptake by keratinocytes. This indicates a central role for phagocytosis by keratinocytes of melanocyte filopodia. In summary, we propose a new model for the regulation of pigmentation in human skin cells under both constitutive and facultative (post-UVR) conditions, which we call the "filopodial-phagocytosis model." This model also provides a unique and highly accessible way to study lysosome-related organelle movement between mammalian cells.
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Technical note: reliability of Suchey-Brooks and Buckberry-Chamberlain methods on 3D visualizations from CT and laser scans.Villa, C., Buckberry, Jo, Cattaneo, C., Lynnerup, N. January 2013 (has links)
Yes / Previous studies have reported that the ageing method of Suchey-Brooks (pubic bone) and some of the features applied by Lovejoy et al. and Buckberry-Chamberlain (auricular surface) can be confidently performed on 3D visualizations from CT-scans. In this study, seven observers applied the Suchey-Brooks and the Buckberry-Chamberlain methods on 3D visualizations based on CT-scans and, for the first time, on 3D visualizations from laser scans. We examined how the bone features can be evaluated on 3D visualizations and whether the different modalities (direct observations of bones, 3D visualization from CT-scan and from laser scans) are alike to different observers. We found the best inter-observer agreement for the bones versus 3D visualizations, with the highest values for the auricular surface. Between the 3D modalities, less variability was obtained for the 3D laser visualizations. Fair inter-observer agreement was obtained in the evaluation of the pubic bone in all modalities. In 3D visualizations of the auricular surfaces, transverse organization and apical changes could be evaluated, although with high inter-observer variability; micro-, macroporosity and surface texture were very difficult to score. In conclusion, these methods were developed for dry bones, where they perform best. The Suchey-Brooks method can be applied on 3D visualizations from CT or laser, but with less accuracy than on dry bone. The Buckberry-Chamberlain method should be modified before application on 3D visualizations. Future investigation should focus on a different approach and different features: 3D laser scans could be analyzed with mathematical approaches and sub-surface features should be explored on CT-scans
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Zinc oxide nanoparticles affect the expression of p53, Ras p21 and JNKs: an ex vivo/in vitro exposure study in respiratory disease patientsKumar, A., Najafzadeh, Mojgan, Jacob, B.K., Dhawan, A., Anderson, Diana January 2015 (has links)
No / Zinc oxide (ZnO) nanoparticles are the mostly used engineered metal oxide nanoparticles in consumer products. This has increased the likelihood of human exposure to this engineered nanoparticle (ENPs) through different routes. At present, the majority of the studies concerning ZnO ENPs toxicity have been conducted using in vitro and in vivo systems. In this study, for the first time we assessed the effect of ZnO ENPs on the major cellular pathways in the lymphocytes of healthy individuals as well as in susceptible patients suffering from lung cancer, chronic obstructive pulmonary disease (COPD) and asthma. Using the differential expression analysis, we observed a significant (P < 0.05) dose-dependent (10, 20 and 40 microg/ml for 6h) increase in the expression of tumour suppressor protein p53 (40, 60 and 110%); Ras p21 (30, 52 and 80%); c-Jun N-terminal kinases; JNKs) (28, 47 and 78%) in lung cancer patient samples treated with ZnO ENPs compared to healthy controls. A similar trend was also seen in COPD patient samples where a significant (P < 0.05) dose-dependent increase in the expression of tumour suppressor protein p53 (26, 45 and 84%), Ras p21 (21, 40 and 77%), JNKs (17, 32 and 69%) was observed after 6h of ZnO ENPs treatment at the aforesaid concentrations. However, the increase in the expression profile of tested protein was not significant in the asthma patients as compared to controls. Our results reiterate the concern about the safety of ZnO ENPs in consumer products and suggest the need for a complete risk assessment of any new ENPs before its use.
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Victims and survivors: stable isotopes used to identify migrants from the Great Irish Famine to 19th century LondonBeaumont, Julia, Geber, J., Powers, N., Wilson, Andrew S., Lee-Thorp, Julia A., Montgomery, Janet January 2013 (has links)
No / Historical evidence documents mass migration from Ireland to London during the period of the Great Irish Famine of 1845-52. The rural Irish were reliant on a restricted diet based on potatoes but maize, a C(4) plant, was imported from the United States of America in 1846-47 to mitigate against Famine. In London, Irish migrants joined a population with a more varied diet. To investigate and characterize their diet, carbon and nitrogen isotope ratios were obtained from bone collagen of 119 and hair keratin of six individuals from Lukin Street cemetery, Tower Hamlets (1843-54), and bone collagen of 20 individuals from the cemetery at Kilkenny Union Workhouse in Ireland (1847-51). A comparison of the results with other contemporaneous English populations suggests that Londoners may have elevated delta(15) N compared with their contemporaries in other cities. In comparison, the Irish group have lower delta(15) N. Hair analysis combined with bone collagen allows the reconstruction of perimortem dietary changes. Three children aged 5-15 years from Kilkenny have bone collagen delta(13) C values that indicate consumption of maize (C(4)). As maize was only imported into Ireland in quantity from late 1846 and 1847, these results demonstrate relatively rapid bone collagen turnover in children and highlight the importance of age-related bone turnover rates, and the impact the age of the individual can have on studies of short-term dietary change or recent migration. Stable light isotope data in this study are consistent with the epigraphic and documentary evidence for the presence of migrants within the London cemetery.
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Decreased brain venous vasculature visibility on susceptibility-weighted imaging venography in patients with multiple sclerosis is related to chronic cerebrospinal venous insufficiencyZivadinov, R., Poloni, G.U., Marr, K., Schirda, C.V., Magnano, C.R., Carl, E., Bergsland, N., Hojnacki, D., Kennedy, C., Beggs, Clive B., Dwyer, Michael G., Weinstock-Guttman, B. January 2011 (has links)
No / BACKGROUND: The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC). METHODS: 59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: < .3 mm, .3-.6 mm, .6-.9 mm and > .9 mm. RESULTS: CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p < .0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter < .3 mm, and increased DFV compared to HC (all p < .0001). Subjects diagnosed with CCSVI had significantly increased DFV (p < .0001), decreased overall ATVV and ATVV of veins with a diameter < .3 mm (p < .003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p < .0001) on pre- and post-contrast SWI, but not in HC. CONCLUSIONS: MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS.
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Changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: a case-control studyZivadinov, R., Magnano, C.R., Galeotti, R., Schirda, C.V., Menegatti, E., Weinstock-Guttman, B., Marr, K., Bartolomei, I., Hagemeier, J., Malagoni, A.M., Hojnacki, D., Kennedy, C., Carl, E., Beggs, Clive B., Salvi, F., Zamboni, P. January 2013 (has links)
No / The purpose of this article is to investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA). This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (>/=50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis. At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group. PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.
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