Prevention of Cancer Through Lifestyle Changes

Cancer is the second leading cause of death in the USA and an abundance of evidence suggests that lifestyle factors including smoking, the typical high-fat, refined-sugar diet and physical inactivity account for the majority of cancer. This review focuses on diet and inactivity as major factors for cancer promotion by inducing insulin resistance and hyperinsulinemia. Elevated levels of serum insulin impact on the liver primarily, increasing the production of insulin-like growth factor I (IGF-I) while reducing the production of insulin-like growth factor binding protein 1 (IGFBP-1) resulting in stimulation of tumor cell growth and inhibition of apoptosis (programmed cell death). Adopting a diet low in fat and high in fiber-rich starch foods, which would also include an abundance of antioxidants, combined with regular aerobic exercise might control insulin resistance, reduce the resulting serum factors and thus reduce the risk for many different cancers commonly seen in the USA

Protease inhibitors targeting coronavirus and filovirus entry.

In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics

Inhibition of adenovirus serotype 14 infection by octadecyloxyethyl esters of (S)-[(3-hydroxy-2-phosphonomethoxy)propyl]- nucleosides in vitro.

On September 22, 2008, a physician on Prince of Wales Island, Alaska, notified the Alaska Department of Health and Social Services (ADHSS) of an unusually high number of adult patients with recently diagnosed pneumonia (n = 10), including three persons who required hospitalization and one who died. ADHSS and CDC conducted an investigation to determine the cause and distribution of the outbreak, identify risk factors for hospitalization, and implement control measures. This report summarizes the results of that investigation, which found that the outbreak was caused by adenovirus 14 (Ad14), an emerging adenovirus serotype in the United States that is associated with a higher rate of severe illness compared with other adenoviruses. Among the 46 cases identified in the outbreak from September 1 through October 27, 2008, the most frequently observed characteristics included the following: male (70%), Alaska Native (61%), underlying pulmonary disease (44%), aged > or = 65 years (26%), and current smoker (48%). Patients aged > or = 65 years had a fivefold increased risk for hospitalization. The most commonly reported symptoms were cough (100%), shortness of breath (87%), and fever (74%). Of the 11 hospitalized patients, three required intensive care, and one required mechanical ventilation. One death was reported. Ad14 isolates obtained during the outbreak were identical genetically to those in recent community-acquired outbreaks in the United States which suggests the emergence of a new, and possibly more virulent Ad14 variant. Clinicians should consider Ad14 infection in the differential diagnosis for patients with community-acquired pneumonia, particularly when unexplained clusters of severe respiratory infections are detected

Analyzing Serum-Stimulated Prostate Cancer Cell Lines After Low-Fat, High-Fiber Diet and Exercise Intervention

Serum from men undergoing a low-fat, high-fiber diet and exercise intervention has previously been shown to decrease growth and increase apoptosis in serum-stimulated, androgen-dependent LNCaP cells associated with a reduction in serum IGF-I. Here we sought to determine the underlying mechanisms for these anticancer effects. Again, the intervention slowed growth and increased apoptosis in LNCaP cells; responses that were eliminated when IGF-I was added back to the post-intervention samples. The p53 protein content was increased and NFκB activation reduced in the post serum-stimulated LNCaP cells. Similar results were observed when the IGF-I receptor was blocked in the pre-intervention serum. In androgen-independent PC-3 cells, growth was reduced while none of the other factors were changed by the intervention. We conclude that diet and exercise intervention might help prevent clinical PCa as well as aid in the treatment of PCa during the early stages of development

Schizophrenia and the progression of emotional expression in relation to others

Gaining an improved understanding of people diagnosed with schizophrenia has the potential to influence priorities for therapy. Psychosis is commonly understood through the perspective of the medical model. However, the experience of social context surrounding psychosis is not well understood. In this research project we used a phenomenological methodology with a longitudinal design to interview 7 participants across a 12-month period to understand the social experiences surrounding psychosis. Eleven themes were explicated and divided into two phases of the illness experience: (a) transition into emotional shutdown included the experiences of not being acknowledged, relational confusion, not being expressive, detachment, reliving the past, and having no sense of direction; and (b) recovery from emotional shutdown included the experiences of being acknowledged, expression, resolution, independence, and a sense of direction. The experiential themes provide clinicians with new insights to better assess vulnerability, and have the potential to inform goals for therapy

Solitonic supersymmetry restoration

Q-balls are a possible feature of any model with a conserved, global U(1) symmetry and no massless, charged scalars. It is shown that for a broad class of models of metastable supersymmetry breaking they are extremely influential on the vacuum lifetime and make seemingly viable vacua catastrophically short lived. A net charge asymmetry is not required as there is often a significant range of parameter space where statistical fluctuations alone are sufficient. This effect is examined for two supersymmetry breaking scenarios. It is found that models of minimal gauge mediation (which necessarily have a messenger number U(1)) undergo a rapid, supersymmetry restoring phase transition unless the messenger mass is greater than 10^8 GeV. Similarly the ISS model, in the context of direct mediation, quickly decays unless the perturbative superpotential coupling is greater than the Standard Model gauge couplings.Comment: 17 pages, 3 figures, minor comments added, accepted for publication in JHE

A Synoptic Overview of Expert Opinion on Fisheries in a Post-Brexit World

Publisher PD

Condensate cosmology in O'Raifeartaigh models

Flat directions charged under an R-symmetry are a generic feature of O'Raifeartaigh models. Non-topological solitons associated with this symmetry, R-balls, are likely to form through the fragmentation of a condensate, itself created by soft terms induced during inflation. In gravity mediated SUSY breaking R-balls decay to gravitinos, reheating the universe. For gauge mediation R-balls can provide a good dark matter candidate. Alternatively they can decay, either reheating or cooling the universe. Conserved R-symmetry permits decay to gravitinos or gauginos, whereas spontaneously broken R-symmetry results in decay to visible sector gauge bosons.Comment: 29 pages, 5 figures. Comments and references added, accepted for publication in JHE

Platelet activation in cystic fibrosis

Cystic fibrosis (CF) is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). We examined platelet function in CF patients because lung inflammation is part of this disease and platelets contribute to inflammation. CF patients had increased circulating leukocyte-platelet aggregates and increased platelet responsiveness to agonists compared with healthy controls. CF plasma caused activation of normal and CF platelets; however, activation was greater in CF platelets. Furthermore, washed CF platelets also showed increased reactivity to agonists. CF platelet hyperreactivity was incompletely inhibited by prostaglandin E(1) (PGE(1)). As demonstrated by Western blotting and reverse-transcriptase-polymerase chain reaction (RT-PCR), there was neither CFTR nor CFTR-specific mRNA in normal platelets. There were abnormalities in the fatty acid composition of membrane fractions of CF platelets. In summary, CF patients have an increase in circulating activated platelets and platelet reactivity, as determined by monocyte-platelet aggregation, neutrophil-platelet aggregation, and platelet surface P-selectin. This increased platelet activation in CF is the result of both a plasma factor(s) and an intrinsic platelet mechanism via cyclic adenosine monophosphate (cAMP)/adenylate cyclase, but not via platelet CFTR. Our findings may account, at least in part, for the beneficial effects of ibuprofen in CF

Solution Focused brief therapy In post-stroke Aphasia (SOFIA): feasibility and acceptability results of a feasibility randomised wait-list controlled trial

Objectives: the SOlution Focused brief therapy In post-stroke Aphasia (SOFIA) feasibility trial had four primary aims: to assess (1) acceptability of the intervention to people with aphasia, including severe aphasia; (2) feasibility of recruitment and retention; (3) acceptability of research procedures and outcome measures; and (4) feasibility of delivering the intervention by Speech and Language Therapists. Design: two-group randomised controlled feasibility trial with wait-list design; blinded outcome assessors; nested qualitative research. Setting: participants identified via two community NHS Speech and Language Therapy London services and through community routes (e.g. voluntary-sector stroke groups). Participants: people with aphasia at least six months post stroke. Intervention: Solution Focused Brief Therapy, a psychological intervention, adapted to be linguistically accessible. Participants offered up to six sessions over three months, either immediately post randomisation or after a delay of six months. Outcome measures: primary endpoints related to feasibility and acceptability. Clinical outcomes were collected at baseline, three- and six-months post randomisation, and at nine months (wait-list group only). The candidate primary outcome measure was the Warwick Edinburgh Mental Wellbeing Scale. Participants and therapists also took part in in-depth interviews. Results: Thirty-two participants were recruited, including 44% with severe aphasia. Acceptability endpoints: therapy was perceived as valuable and acceptable by both participants (n=30 interviews) and therapists (n=3 interviews); 93.8% of participants received ≥2 therapy sessions (90.6% received 6/6 sessions). Feasibility endpoints: recruitment target was reached within the pre-specified 13-month recruitment window; 82.1% of eligible participants consented; 96.9% were followed up at six months; missing data <0.01%. All five pre-specified feasibility progression criteria were met. Conclusion: the high retention and adherence rates, alongside the qualitative data, suggest the study design was feasible and therapy approach acceptable even to people with severe aphasia. These results indicate a definitive RCT of the intervention would be feasible. Trial registration: ClinicalTrials.gov NCT03245060