Evaluation of radiological and clinical efficacy of ^{90}Y-DOTATATE} therapy in patients with progressive metastatic midgut neuroendocrine carcinomas

Background: To evaluate the radiological and clinical therapeutic effectiveness of ^{90}Y-octreotate [DOTATATE] inpatients with progressive somatostatin receptor-positive midgut neuroendocrine carcinomas (GEPNETs). Material/Methods: The study group: 34 patients, with histological proven extensive non-resectable and progressive midgut GEP-NETs. Radionuclide therapy (^{90}Y-DOTATATE) was given i.v. with a mean activity per administration 3,82 GBq. Initial clinical tumor responses were assessed 6-7 weeks after therapy completion and then once 3-monthly. The objective tumor response was classified according to the RECIST, initially between 4-6 months and then after each of the 6 months interval. Results: At 6 months after treatment completion, radiological tumor response was observed in 6 subjects with PR (19%), 25 presented SD (78%) and single had PD (3%). Overall clinical response to therapy at 6 months follow-up was observed in 23 patients (68%), SD in 5 patients (15%) and PD in 6 (18%). A year after therapy radiological tumour response was seen in 11 patients (44%), SD had 12 subjects (44%) and DP was noted in 2 patients. Two years after completed therapy PR was seen in 6 patients (33%), SD in additional 11 subjects (61%), single patient had PD. Clinical response to treatment in terms of PR and SD were noted in 22 patients (88%) after 1 year and in 14 patients (87%) after 2 years. Median PFS was 20 months, while the median OS was 23 months. In the 6 patients with clinical PD within initial 6 months the median PFS was 6 months and OS 11 months, while in those with SD or PR PFS was 22 months and OS 26 months (P<0.05). Conclusions: Therapy with ^{90}Y-DOTATATE} is effective in terms of clinical response, however the radiological response measured by the RECIST criteria underestimates benefits of this type of therapy in patients with progressive somatostatin receptor-positive midgut neuroendocrine carcinomas

The Impact of Halogenated Phenylalanine Derivatives on NFGAIL Amyloid Formation

The hexapeptide hIAPP(22-27)(NFGAIL) is known as a crucial amyloid core sequence of the human islet amyloid polypeptide (hIAPP) whose aggregates can be used to better understand the wild-type hIAPP ' s toxicity to beta-cell death. In amyloid research, the role of hydrophobic and aromatic-aromatic interactions as potential driving forces during the aggregation process is controversially discussed not only in case of NFGAIL, but also for amyloidogenic peptides in general. We have used halogenation of the aromatic residue as a strategy to modulate hydrophobic and aromatic-aromatic interactions and prepared a library of NFGAIL variants containing fluorinated and iodinated phenylalanine analogues. We used thioflavin T staining, transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) to study the impact of side-chain halogenation on NFGAIL amyloid formation kinetics. Our data revealed a synergy between aggregation behavior and hydrophobicity of the phenylalanine residue. This study introduces systematic fluorination as a toolbox to further investigate the nature of the amyloid self-assembly process

Emotional intelligence buffers the effect of physiological arousal on dishonesty

We studied the emotional processes that allow people to balance two competing desires: benefitting from dishonesty and keeping a positive self-image. We recorded physiological arousal (skin conductance and heart rate) during a computer card game in which participants could cheat and fail to report a certain card when presented on the screen to avoid losing their money. We found that higher skin conductance corresponded to lower cheating rates. Importantly, emotional intelligence regulated this effect; participants with high emotional intelligence were less affected by their physiological reactions than those with low emotional intelligence. As a result, they were more likely to profit from dishonesty. However, no interaction emerged between heart rate and emotional intelligence. We suggest that the ability to manage and control emotions can allow people to overcome the tension between doing right or wrong and license them to bend the rules

The clinical effectiveness of individual behaviour change interventions to reduce risky sexual behaviour after a negative human immunodeficiency virus test in men who have sex with men: systematic and realist reviews and intervention development

Background: Men who have sex with men (MSM) experience significant inequalities in health and well-being. They are the group in the UK at the highest risk of acquiring a human immunodeficiency virus (HIV) infection. Guidance relating to both HIV infection prevention, in general, and individual-level behaviour change interventions, in particular, is very limited. Objectives: To conduct an evidence synthesis of the clinical effectiveness of behaviour change interventions to reduce risky sexual behaviour among MSM after a negative HIV infection test. To identify effective components within interventions in reducing HIV risk-related behaviours and develop a candidate intervention. To host expert events addressing the implementation and optimisation of a candidate intervention. Data sources: All major electronic databases (British Education Index, BioMed Central, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Educational Resource Index and Abstracts, Health and Medical Complete, MEDLINE, PsycARTICLES, PsycINFO, PubMed and Social Science Citation Index) were searched between January 2000 and December 2014. Review methods: A systematic review of the clinical effectiveness of individual behaviour change interventions was conducted. Interventions were examined using the behaviour change technique (BCT) taxonomy, theory coding assessment, mode of delivery and proximity to HIV infection testing. Data were summarised in narrative review and, when appropriate, meta-analysis was carried out. Supplemental analyses for the development of the candidate intervention focused on post hoc realist review method, the assessment of the sequential delivery and content of intervention components, and the social and historical context of primary studies. Expert panels reviewed the candidate intervention for issues of implementation and optimisation. Results: Overall, trials included in this review (n = 10) demonstrated that individual-level behaviour change interventions are effective in reducing key HIV infection risk-related behaviours. However, there was considerable clinical and methodological heterogeneity among the trials. Exploratory meta-analysis showed a statistically significant reduction in behaviours associated with high risk of HIV transmission (risk ratio 0.75, 95% confidence interval 0.62 to 0.91). Additional stratified analyses suggested that effectiveness may be enhanced through face-to-face contact immediately after testing, and that theory-based content and BCTs drawn from ‘goals and planning’ and ‘identity’ groups are important. All evidence collated in the review was synthesised to develop a candidate intervention. Experts highlighted overall acceptability of the intervention and outlined key ways that the candidate intervention could be optimised to enhance UK implementation. Limitations: There was a limited number of primary studies. All were from outside the UK and were subject to considerable clinical, methodological and statistical heterogeneity. The findings of the meta-analysis must therefore be treated with caution. The lack of detailed intervention manuals limited the assessment of intervention content, delivery and fidelity. Conclusions: Evidence regarding the effectiveness of behaviour change interventions suggests that they are effective in changing behaviour associated with HIV transmission. Exploratory stratified meta-analyses suggested that interventions should be delivered face to face and immediately after testing. There are uncertainties around the generalisability of these findings to the UK setting. However, UK experts found the intervention acceptable and provided ways of optimising the candidate intervention. Future work: There is a need for well-designed, UK-based trials of individual behaviour change interventions that clearly articulate intervention content and demonstrate intervention fidelity

Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with 111In-CP04 in medullary thyroid carcinoma patients

Introduction: From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methods: Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing do

Characterization of Plasmodium vivax Proteins in Plasma-Derived Exosomes From Malaria-Infected Liver-Chimeric Humanized Mice

Exosomes are extracellular vesicles of endocytic origin containing molecular signatures implying the cell of origin; thus, they offer a unique opportunity to discover biomarkers of disease. Plasmodium vivax, responsible for more than half of all malaria cases outside Africa, is a major obstacle in the goal of malaria elimination due to the presence of dormant liver stages (hypnozoites), which after the initial infection may reactivate to cause disease. Hypnozoite infection is asymptomatic and there are currently no diagnostic tools to detect their presence. The human liver-chimeric (FRG huHep) mouse is a robust P. vivax infection model for exo-erythrocytic development of liver stages, including hypnozoites. We studied the proteome of plasma-derived exosomes isolated from P. vivax infected FRG huHep mice with the objective of identifying liver-stage expressed parasite proteins indicative of infection. Proteomic analysis of these exosomes showed the presence of 290 and 234 proteins from mouse and human origin, respectively, including canonical exosomal markers. Human proteins include proteins previously detected in liver-derived exosomes, highlighting the potential of this chimeric mouse model to study plasma exosomes derived unequivocally from human hepatocytes. Noticeably, we identified 17 parasite proteins including enzymes, surface proteins, components of the endocytic pathway and translation machinery, as well as uncharacterized proteins. Western blot analysis validated the presence of human arginase-I and an uncharacterized P. vivax protein in plasma-derived exosomes. This study represents a proof-of-principle that plasma-derived exosomes from P. vivax infected FRG-huHep mice contain human hepatocyte and P. vivax proteins with the potential to unveil biological features of liver infection and identify biomarkers of hypnozoite infection

The Impact of Halogenated Phenylalanine Derivatives on NFGAIL Amyloid Formation

The hexapeptide hIAPP22–27 (NFGAIL) is known as a crucial amyloid core sequence of the human islet amyloid polypeptide (hIAPP) whose aggregates can be used to better understand the wild-type hIAPP’s toxicity to β-cell death. In amyloid research, the role of hydrophobic and aromatic-aromatic interactions as potential driving forces during the aggregation process is controversially discussed not only in case of NFGAIL, but also for amyloidogenic peptides in general. We have used halogenation of the aromatic residue as a strategy to modulate hydrophobic and aromatic-aromatic interactions and prepared a library of NFGAIL variants containing fluorinated and iodinated phenylalanine analogues. We used thioflavin T staining, transmission electron microscopy (TEM) and smallangle X-ray scattering (SAXS) to study the impact of side-chain halogenation on NFGAIL amyloid formation kinetics. Our data revealed a synergy between aggregation behavior and hydrophobicity of the phenylalanine residue. This study introduces systematic fluorination as a toolbox to further investigate the nature of the amyloid self-assembly process

An exploratory study of Muslim adolescents' views on sexuality: Implications for sex education and prevention

<p>Abstract</p> <p>Background</p> <p>This paper describes the results of an exploratory qualitative study on Muslim adolescents' views on sexuality in the Netherlands.</p> <p>Methods</p> <p>Data were gathered from an Internet forum on which 44 Muslim and 33 non-Muslim adolescents discussed sexuality as it relates to Islam. These discussions were subsequently analyzed for content using Nvivo 2.0.</p> <p>Results</p> <p>Our analysis revealed several issues that are relevant for the design of future sex education programs targeting Muslim youth. Apart from some expected outcomes regarding, for example, taboos on sexuality, sex outside marriage, abortion, homosexuality and conservative gender roles, our analyses showed that in cases of disputes 1) discussions were polarized, 2) opponents used the same Qur'anic passages to support their views, and 3) the authority of an Imam was questioned when his interpretation of Qur'anic passages was not in line with the views of participants.</p> <p>Conclusions</p> <p>Our findings show that current approaches to sex education among Muslim youth are likely to be unsuccessful given the rigidity of sexual norms in Muslim society. In addition, we also identified new barriers to sex education among Muslim youth (e.g. lack of respect for an Imam who opposes a youth's views on sexuality).</p

Environmental Constraints Guide Migration of Malaria Parasites during Transmission

Migrating cells are guided in complex environments mainly by chemotaxis or structural cues presented by the surrounding tissue. During transmission of malaria, parasite motility in the skin is important for Plasmodium sporozoites to reach the blood circulation. Here we show that sporozoite migration varies in different skin environments the parasite encounters at the arbitrary sites of the mosquito bite. In order to systematically examine how sporozoite migration depends on the structure of the environment, we studied it in micro-fabricated obstacle arrays. The trajectories observed in vivo and in vitro closely resemble each other suggesting that structural constraints can be sufficient to guide Plasmodium sporozoites in complex environments. Sporozoite speed in different environments is optimized for migration and correlates with persistence length and dispersal. However, this correlation breaks down in mutant sporozoites that show adhesion impairment due to the lack of TRAP-like protein (TLP) on their surfaces. This may explain their delay in infecting the host. The flexibility of sporozoite adaption to different environments and a favorable speed for optimal dispersal ensures efficient host switching during malaria transmission