epsilon-Polylysine-Capped Mesoporous Silica Nanoparticles as Carrier of the C9h Peptide to Induce Apoptosis in Cancer Cells

[EN] Apoptotic signaling pathways are altered in numerous pathologies such as cancer. In this scenario, caspase-9/PP2Ac alpha interaction constitutes a key target with pharmacological interest to re-establish apoptosis in tumor cells. Very recently, a short peptide (C9h) known to disrupt caspase-9/PP2Ac alpha interaction with subsequent apoptosis induction was described. Here, we prepared two sets of mesoporous silica nanoparticles loaded with safraninO (S2) or with C9h peptide (S4) and functionalized with epsilon-polylysine as capping unit. Aqueous suspensions of both nanoparticles showed negligible cargo release whereas in the presence of pronase, a marked delivery of safraninO or C9h was observed. Confocal microscopy studies carried out with HeLa cells indicated that both materials were internalized and were able to release their entrapped cargos. Besides, a marked decrease in HeLa cell viability (ca. 50%) was observed when treated with C9h-loaded S4 nanoparticles. Moreover, S4 provides peptide protection from degradation additionally allowing for a dose reduction to observe an apoptotic effect when compared with C9h alone or in combination with a cell-penetrating peptide (i.e., Mut3DPT-C9h). Flow cytometry studies, by means of Annexin V-FITC staining, showed the activation of apoptotic pathways in HeLa as a consequence of S4 internalization, release of C9h peptide and disruption of caspase-9/PP2Ac alpha interaction.The authors wish to express their gratitude to the Spanish government (Projects MAT2015-64139-C4-1, SAF2012-31405, SAF2015-67077-R, AGL2015-70235-C2-2-R (MINECO/FEDER)), the Generalitat Valencia (Projects PROMETEOII/2014/047, PROMETEO/2012/061) and the CIBER-BBN for their support. C.T. is grateful to the Spanish Ministry of Science and Innovation for her Ph.D. fellowship.De La Torre-Paredes, C.; Domínguez-Berrocal, L.; Murguía, JR.; Marcos Martínez, MD.; Martínez-Máñez, R.; Bravo, J.; Sancenón Galarza, F. 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Hospitalizations during the last months of life of nursing home residents: a retrospective cohort study from Germany

BACKGROUND: To describe hospitalisations of nursing home (NH) residents in Germany during their last months of life. METHODS: Retrospective cohort study on 792 NH residents in the Rhine-Neckar region in South-West Germany, newly institutionalized in the year 2000, who died until the study end (December 2001). Baseline variables were derived from a standardized medical examination routinely conducted by the medical service of the health care insurance plans in Germany. Information on hospitalisations and deaths was extracted form records of the pertinent health insurance plans. RESULTS: NH residents who died after NH stay of more than 1 year spent 5.8% of their last year of life in hospitals. Relative time spent in hospitals increased from 5.2% twelve months before death (N = 139 persons) to 24.1% in their last week of life (N = 769 persons). No major differences could be observed concerning age, gender or duration of stay in NH. Overall, 229 persons (28.9%) died in hospital. Among these, the last hospital stay lasted less than 3 days for 76 persons (31.9%). Another 25 persons (3.2%) died within three days after hospital discharge. CONCLUSION: Our study indicates that proximity of death is the most important driver of health care utilization among NH residents. The relation of age or gender to health care expenditures seem to be weak once time to death is controlled for. Duration of NH stay does not markedly change rates of hospitalisation during the last months of life

Are the pneumococcal polysaccharide vaccines effective? Meta-analysis of the prospective trials

The objective was to review the evidence of effectiveness of the polyvalent polysaccharide pneumococcal vaccine from prospective properly randomised controlled trials comparing pneumococcal vaccines with placebo in subjects who are immunocompetent and those likely to have an impaired immune system. Databases searched included the Cochrane Library, (issue 2, 2000), MEDLINE (1966-August 2000), PubMed (to August 2000) and EMBASE ( to August 2000). Reference lists of reports and reviews were also searched. To be included in the analysis, a study had to have been a prospective randomised comparison of a polysaccharide pneumococcal vaccine (any valency) and to have a placebo or no treatment comparison group. Papers had to report important clinical outcomes, such as rates of pneumonia, pneumococcal pneumonia, lower respiratory tract infections, pneumonia deaths or bacteraemia. Serological outcomes were not sought. Thirteen randomised comparisons with over 45,000 subjects were identified in an extensive literature review. Eight studies had a quality score of 3 or more on a scale of 1 to 5. In three comparisons with 21,152 immunocompetent subjects (South African gold miners, New Guinea highlanders) pneumococcal vaccination was effective in reducing the incidence of all-cause pneumonia (relative risk 0.56, 95% confidence interval 0.47 to 0.66), pneumococcal pneumonia (0.16; 0.11 to 0.23), pneumonia deaths (0.70; 0.50 to 0.96) and bacteraemia (0.18; 0.09 to 0.34). In ten comparisons in over 24,000 people who were elderly or likely to have impaired immune systems, pneumococcal vaccination was without effect for any outcome. Present guidelines recommend pneumococcal vaccination for "high-risk" groups. There is no evidence from randomised trials that this is of any benefit

Molecular Mechanisms of Microcystin Toxicity in Animal Cells

Microcystins (MC) are potent hepatotoxins produced by the cyanobacteria of the genera Planktothrix, Microcystis, Aphanizomenon, Nostoc and Anabaena. These cyclic heptapeptides have strong affinity to serine/threonine protein phosphatases (PPs) thereby acting as an inhibitor of this group of enzymes. Through this interaction a cascade of events responsible for the MC cytotoxic and genotoxic effects in animal cells may take place. Moreover MC induces oxidative stress in animal cells and together with the inhibition of PPs, this pathway is considered to be one of the main mechanisms of MC toxicity. In recent years new insights on the key enzymes involved in the signal-transduction and toxicity have been reported demonstrating the complexity of the interaction of these toxins with animal cells. Key proteins involved in MC up-take, biotransformation and excretion have been identified, demonstrating the ability of aquatic animals to metabolize and excrete the toxin. MC have shown to interact with the mitochondria. The consequences are the dysfunction of the organelle, induction of reactive oxygen species (ROS) and cell apoptosis. MC activity leads to the differential expression/activity of transcriptional factors and protein kinases involved in the pathways of cellular differentiation, proliferation and tumor promotion activity. This activity may result from the direct inhibition of the protein phosphatases PP1 and PP2A. This review aims to summarize the increasing data regarding the molecular mechanisms of MC toxicity in animal systems, reporting for direct MC interacting proteins and key enzymes in the process of toxicity biotransformation/excretion of these cyclic peptides

From recommendation to action: psychosocial factors influencing physician intention to use Health Technology Assessment (HTA) recommendations

BACKGROUND: Evaluating the impact of recommendations based upon health technology assessment (HTA) represents a challenge for both HTA agencies and healthcare policy-makers. Using a psychosocial theoretical framework, this study aimed at exploring the factors affecting physician intention to adopt HTA recommendations. The selected recommendations were prioritisation systems for patients on waiting lists for two surgical procedures: hip and knee replacement and cataract surgery. METHODS: Determinants of physician intention to use HTA recommendations for patient prioritisation were assessed by a questionnaire based upon the Theory of Interpersonal Behaviour. A total of 96 physicians from two medical specialties (ophthalmology and orthopaedic surgery) responded to the questionnaire (response rate 44.2%). A multiple analysis of variance (MANOVA) was performed to assess differences between medical specialties on the set of theoretical variables. Given the main effect difference between specialties, two regression models were tested separately to assess the psychosocial determinants of physician intention to use HTA recommendations for the prioritisation of patients on waiting lists for surgical procedures. RESULTS: Factors influencing physician intention to use HTA recommendations differ between groups of specialists. Intention to use the prioritisation system for patients on waiting lists for cataract surgery among ophthalmologists was related to attitude towards the behaviour, social norms, as well as personal normative beliefs. Intention to use HTA recommendations for patient prioritisation for hip and knee replacement among orthopaedic surgeons was explained by: perception of conditions that facilitated the realisation of the behaviour, personal normative beliefs, and habit of using HTA recommendations in clinical work. CONCLUSION: This study offers a model to assess factors influencing the intention to adopt recommendations from health technology assessment into professional practice. Results identify determinant factors that should be considered in the elaboration of strategies to support the implementation of evidence-based practice, with respect to emerging health technologies and modalities of practice. However, it is important to emphasise that behavioural determinants of evidence-based practice vary according to the specific technology considered. Evidence-based implementation of HTA recommendations, as well as other evidence-based practices, should build on a theoretical understanding of the complex forces that shape the practice of healthcare professionals

Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia

Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing proteins and the ataxia network. To begin to understand the biological relevance of these protein interactions within the ataxia network, we used OMIM to identify diseases associated with the expanded ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary ataxia. We found that patients with ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with ataxia is macular degeneration (MD). The ataxia network is significantly (P= 7.37 × 10−5) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7266Q/+ mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of ataxia, MD, and diseases comorbid with ataxia

Helminth immunomodulation in autoimmune disease

Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating "talents" of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases

Use of Biosensors as Alternatives to Current Regulatory Methods for Marine Biotoxins

Marine toxins are currently monitored by means of a bioassay that requires the use of many mice, which poses a technical and ethical problem in many countries. With the exception of domoic acid, there is a legal requirement for the presence of other toxins (yessotoxin, saxitoxin and analogs, okadaic acid and analogs, pectenotoxins and azaspiracids) in seafood to be controlled by bioassay, but other toxins, such as palytoxin, cyclic imines, ciguatera and tetrodotoxin are potentially present in European food and there are no legal requirements or technical approaches available to identify their presence. The need for alternative methods to the bioassay is clearly important, and biosensors have become in recent years a feasible alternative to animal sacrifice. This review will discuss the advantages and disadvantages of using biosensors as alternatives to animal assays for marine toxins, with particular focus on surface plasmon resonance (SPR) technology

CMS physics technical design report : Addendum on high density QCD with heavy ions

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