The influence of membrane physical properties on microvesicle release in human erythrocytes

Exposure of human erythrocytes to elevated intracellular calcium causes fragments of the cell membrane to be shed as microvesicles. This study tested the hypothesis that microvesicle release depends on microscopic membrane physical properties such as lipid order, fluidity, and composition. Membrane properties were manipulated by varying the experimental temperature, membrane cholesterol content, and the activity of the trans-membrane phospholipid transporter, scramblase. Microvesicle release was enhanced by increasing the experimental temperature. Reduction in membrane cholesterol content by treatment with methyl-β-cyclodextrin also facilitated vesicle shedding. Inhibition of scramblase with R5421 impaired vesicle release. These data were interpreted in the context of membrane characteristics assessed previously by fluorescence spectroscopy with environment-sensitive probes such as laurdan, diphenylhexatriene, and merocyanine 540. The observations supported the following conclusions: 1) calcium-induced microvesicle shedding in erythrocytes relates more to membrane properties detected by diphenylhexatriene than by the other probes; 2) loss of trans-membrane phospholipid asymmetry is required for microvesicle release

Cetuximab in the treatment of metastatic mucoepidermoid carcinoma of the salivary glands: A case report and review of literature

<p>Abstract</p> <p>Introduction</p> <p>Patients with metastatic mucoepidermoid carcinoma of salivary glands have a poor outcome. The epidermal growth factor receptor protein is overexpressed in approximately 70% of mucoepidermoid carcinoma patients and may represent a therapeutic target. However, whether treatment with anti-epidermal growth factor receptor agents is effective is unclear and clinical trials are difficult due to the rarity of the disease. Here we assessed the activity of cetuximab in mucoepidermoid carcinoma on a molecular basis.</p> <p>Case presentation</p> <p>We present the case of a 40-year old Caucasian man with a mucoepidermoid carcinoma of the major salivary glands who developed distant bone and visceral metastases despite platinum-based chemotherapy. Epidermal growth factor receptor was overexpressed and fluorescence in situ hybridization analysis demonstrated a chromosome 7 polysomy. The patient was treated with the monoclonal antibody cetuximab in combination with cisplatin. After 11 doses of cetuximab, the patient developed brain metastases but evidence of response was documented at all extracranial metastatic sites.</p> <p>Conclusion</p> <p>This case report indicates that cetuximab can be active in mucoepidermoid carcinoma and may restore sensitivity to cisplatin in platinum-treated patients. Cetuximab does not cross the blood brain barrier and may select a metastatic clone to home the central nervous system while responding at other sites.</p

Ethics and biobanks

Biobank research has been the focus of great interest of scholars and regulatory bodies who have addressed different ethical issues. On the basis of a review of the literature it may be concluded that, regarding some major themes in this discussion, a consensus seems to emerge on the international scene after the regular exchange of arguments in scientific journals. Broad or general consent is emerging as the generally preferred solution for biobank studies and straightforward instructions for coding will optimise privacy while facilitating research that may result in new methods for the prevention of disease and for medical treatment. The difficult question regarding the return of information to research subjects is the focus of the current research, but a helpful analysis of some of the issues at stake and concrete recommendations have recently been suggested

Dysregulation of Cell Polarity Proteins Synergize with Oncogenes or the Microenvironment to Induce Invasive Behavior in Epithelial Cells

Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFα induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines

Long-Term Conditions Questionnaire (LTCQ): initial validation survey among primary care patients and social care recipients in England

Objective: The aim of this study was to validate a new generic patient-reported outcome measure, the Long-Term Conditions Questionnaire (LTCQ), among a diverse sample of health and social care users in England. Design: Cross-sectional validation survey. Data were collected through postal surveys (February 2016 - January 2017). The sample included a health care cohort of patients recruited through primary care practices, and a social care cohort recruited through local government bodies that provide social care services. Participants: 1,211 participants (24% confirmed social care recipients) took part in the study. Health care participants were recruited on the basis of having one of eleven specified LTCs, and social care participants were recruited on the basis of receiving social care support for at least one LTC. The sample exhibited high multi-morbidity, with 93% reporting two or more LTCs and 43% reporting a mental health condition. Outcome measures: The LTCQ’s construct validity was tested with reference to the EQ-5D (5-level version), the Self-efficacy for Managing Chronic Disease scale, an Activities of Daily Living scale, and the Bayliss burden of morbidity scale. Results: Low levels of missing data for each item indicate acceptability of the LTCQ across the sample. The LTCQ exhibits high internal consistency (Cronbach’s α = 0.95) across the scale’s 20 items and excellent test-retest reliability (ICC = 0.94, 95% CI 0.93 to 0.95). Associations between the LTCQ and all reference measures were moderate to strong and in the expected directions, indicating convergent construct validity. Conclusions: This study provides evidence for the reliability and validity of the Long-Term Conditions Questionnaire, which has potential for use in both health and social care settings. The LTCQ could meet a need for holistic outcome measurement that goes beyond symptoms and physical function, complementing existing measures to fully capture what it means to live well with LTCs

Nitride or Oxynitride? Elucidating the Composition–Activity Relationships in Molybdenum Nitride Electrocatalysts for the Oxygen Reduction Reaction

Molybdenum nitride (Mo−N) catalysts have shown promising activity and stability for the oxygen reduction reaction (ORR) in acid. However, the effect of oxygen (O) incorporation (from synthesis, catalysis, or exposure to air) on their activity remains elusive. Here, we use reactive sputtering to synthesize three compositions of thin-film catalysts and use extensive materials characterization to investigate the depth-dependent structure and incorporated O. We show that the as-deposited Mo−N films are highly oxidized both at the surface (>30% O) and in the bulk (3− 21% O) and that the ORR performance is strongly correlated with the bulk structure and composition. Activity for 4e− ORR is highest for compositions with the highest N/O and N/Mo ratio. Furthermore, H2O2 production for the films with moderate O content is comparable to or higher than the most H2O2-selective nonprecious metal catalysts in acidic electrolyte, on a moles per mass or surface area of catalyst basis. Density functional theory provides insight into the energetics of O incorporation and vacancy formation, and we hypothesize that activity trends with O/N ratios can be traced to the varying crystallite phases and their interactions with ORR adsorbates. This work demonstrates the prevalence and significance of O in metal nitride electrocatalysts and motivates further investigation into the role of O in other nonprecious metal materials

The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

Extent: 11 p.BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. CONCLUSION: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration: ClinicalTrials.gov NCT00448786Lee S. Rosen, Lara Lipton, Timothy J. Price, Neil D. Belman, Ralph V. Boccia, Herbert I. Hurwitz, Joe J. Stephenson Jr., Lori J. Wirth, Sheryl McCoy, Yong-jiang Hei, Cheng-Pang Hsu and Niall C. Tebbut

Antioxidants and breast cancer risk- a population-based case-control study in Canada

<p>Abstract</p> <p>Background</p> <p>The effect of antioxidants on breast cancer is still controversial. Our objective was to assess the association between antioxidants and breast cancer risk in a large population-based case-control study.</p> <p>Methods</p> <p>The study population included 2,362 cases with pathologically confirmed incident breast cancer (866 premenopausal and 1,496 postmenopausal) and 2,462 controls in Canada. Intakes of antioxidants from diet and from supplementation as well as other potential risk factors for breast cancer were collected by a self-reported questionnaire.</p> <p>Results</p> <p>Compared with subjects with no supplementation, 10 years or longer supplementation of zinc had multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) of 0.46 (0.25-0.85) for premenopausal women, while supplementation of 10 years or longer of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc had multivariable-adjusted ORs (95% CIs) of 0.74 (0.59, 0.92), 0.58 (0.36, 0.95), 0.79 (0.63-0.99), 0.75 (0.58, 0.97), and 0.47 (0.28-0.78), respectively, for postmenopausal women. No significant effect of antioxidants from dietary sources (including beta-carotene, alpha-carotene, lycopene, lutein and zeaxanthin, vitamin C, vitamin E, selenium and zinc) or from supplementation less than 10 years was observed.</p> <p>Conclusions</p> <p>This study suggests that supplementation of zinc in premenopausal women, and supplementation of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc in postmenopausal women for 10 or more years may protect women from developing breast cancer. However, we were unable to determine the overall effect of total dose or intake from both diet and supplement.</p