Visualization of membrane loss during the shrinkage of giant vesicles under electropulsation

We study the effect of permeabilizing electric fields applied to two different types of giant unilamellar vesicles, the first formed from EggPC lipids and the second formed from DOPC lipids. Experiments on vesicles of both lipid types show a decrease in vesicle radius which is interpreted as being due to lipid loss during the permeabilization process. We show that the decrease in size can be qualitatively explained as a loss of lipid area which is proportional to the area of the vesicle which is permeabilized. Three possible mechanisms responsible for lipid loss were directly observed: pore formation, vesicle formation and tubule formation.Comment: Final published versio

Retinol and Retinol Binding Protein 4 Levels and Cardiometabolic Disease Risk

Background: Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function. Methods: We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data. Results: The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVDP interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratio(per SD) [95% CI]: CVD, 0.71 [0.56-0.90]; T2D, 0.81 [0.70-0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06-1.64]; T2D, 1.15 [0.98-1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers\u27 interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III. Conclusions: Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer:The CVSS Study

BACKGROUND: The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. METHODS AND RESULTS: A total of 1002 CCSs (age range, 23– 48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age-and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4– 2.8) for HF stage A and 4.6 (95% CI, 4.1– 5.1) for the composite of HF stage B to D in an age-and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, −4.30 [95% CI, −5.70 to −2.80]), soft tissue sarcoma (β, −1.60 [95% CI, −2.90 to −0.30]), and renal tumors (β, −1.60 [95% CI, −2.80 to −0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. CONCLUSIONS: The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.</p

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer:The CVSS Study

BACKGROUND: The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. METHODS AND RESULTS: A total of 1002 CCSs (age range, 23– 48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age-and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4– 2.8) for HF stage A and 4.6 (95% CI, 4.1– 5.1) for the composite of HF stage B to D in an age-and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, −4.30 [95% CI, −5.70 to −2.80]), soft tissue sarcoma (β, −1.60 [95% CI, −2.90 to −0.30]), and renal tumors (β, −1.60 [95% CI, −2.80 to −0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. CONCLUSIONS: The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.</p

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer:The CVSS Study

BACKGROUND: The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. METHODS AND RESULTS: A total of 1002 CCSs (age range, 23– 48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age-and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4– 2.8) for HF stage A and 4.6 (95% CI, 4.1– 5.1) for the composite of HF stage B to D in an age-and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, −4.30 [95% CI, −5.70 to −2.80]), soft tissue sarcoma (β, −1.60 [95% CI, −2.90 to −0.30]), and renal tumors (β, −1.60 [95% CI, −2.80 to −0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. CONCLUSIONS: The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.</p

The ProPrems trial: investigating the effects of probiotics on late onset sepsis in very preterm infants

BACKGROUND: Late onset sepsis is a frequent complication of prematurity associated with increased mortality and morbidity. The commensal bacteria of the gastrointestinal tract play a key role in the development of healthy immune responses. Healthy term infants acquire these commensal organisms rapidly after birth. However, colonisation in preterm infants is adversely affected by delivery mode, antibiotic treatment and the intensive care environment. Altered microbiota composition may lead to increased colonisation with pathogenic bacteria, poor immune development and susceptibility to sepsis in the preterm infant.Probiotics are live microorganisms, which when administered in adequate amounts confer health benefits on the host. Amongst numerous bacteriocidal and nutritional roles, they may also favourably modulate host immune responses in local and remote tissues. Meta-analyses of probiotic supplementation in preterm infants report a reduction in mortality and necrotising enterocolitis. Studies with sepsis as an outcome have reported mixed results to date.Allergic diseases are increasing in incidence in "westernised" countries. There is evidence that probiotics may reduce the incidence of these diseases by altering the intestinal microbiota to influence immune function. METHODS/DESIGN: This is a multi-centre, randomised, double blinded, placebo controlled trial investigating supplementing preterm infants born at < 32 weeks' gestation weighing < 1500 g, with a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis). A total of 1,100 subjects are being recruited in Australia and New Zealand. Infants commence the allocated intervention from soon after the start of feeds until discharge home or term corrected age. The primary outcome is the incidence of at least one episode of definite (blood culture positive) late onset sepsis before 40 weeks corrected age or discharge home. Secondary outcomes include: Necrotising enterocolitis, mortality, antibiotic usage, time to establish full enteral feeds, duration of hospital stay, growth measurements at 6 and 12 months' corrected age and evidence of atopic conditions at 12 months' corrected age. DISCUSSION: Results from previous studies on the use of probiotics to prevent diseases in preterm infants are promising. However, a large clinical trial is required to address outstanding issues regarding safety and efficacy in this vulnerable population. This study will address these important issues. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN012607000144415The product "ABC Dophilus Probiotic Powder for Infants®", Solgar, USA has its 3 probiotics strains registered with the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ--German Collection of Microorganisms and Cell Cultures) as BB-12 15954, B-02 96579, Th-4 15957

Clostridia in Premature Neonates' Gut: Incidence, Antibiotic Susceptibility, and Perinatal Determinants Influencing Colonization

Although premature neonates (PN) gut microbiota has been studied, data about gut clostridial colonization in PN are scarce. Few studies have reported clostridia colonization in PN whereas Bacteroides and bifidobacteria have been seldom isolated. Such aberrant gut microbiota has been suggested to be a risk factor for the development of intestinal infections. Besides, PN are often treated by broad spectrum antibiotics, but little is known about how antibiotics can influence clostridial colonization based on their susceptibility patterns. The aim of this study was to report the distribution of Clostridium species isolated in feces from PN and to determine their antimicrobial susceptibility patterns. Additionally, clostridial colonization perinatal determinants were analyzed.Of the 76 PN followed until hospital discharge in three French neonatal intensive care units (NICUs), 79% were colonized by clostridia. Clostridium sp. colonization, with a high diversity of species, increased throughout the hospitalization. Antibiotic courses had no effect on the clostridial colonization incidence although strains were found susceptible (except C. difficile) to anti-anaerobe molecules tested. However, levels of colonization were decreased by either antenatal or neonatal (during more than 10 days) antibiotic courses (p = 0.006 and p = 0.001, respectively). Besides, incidence of colonization was depending on the NICU (p = 0.048).This study shows that clostridia are part of the PN gut microbiota. It provides for the first time information on the status of clostridia antimicrobial susceptibility in PN showing that strains were susceptible to most antibiotic molecules. Thus, the high prevalence of this genus is not linked to a high degree of resistance to antimicrobial agents or to the use of antibiotics in NICUs. The main perinatal determinant influencing PN clostridia colonization appears to be the NICU environment

Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician-(47,025 forms) and patient-(54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade >= 2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. Patient summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short-and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity