Fake Tales of San Francisco

Prose by Michelé Strachota

Session 1.3: Health Protection and Disease Prevention: A Critical Review of Experience

This is a summary of the presentations and discussion of Health Protection and Disease Prevention of the Conference, Health Aspects of the Tsunami Disaster in Asia, convened by the World Health Organization (WHO) in Phuket, Thailand, 04-06 May 2005. The topics discussed included issues related health protection and disease prevention as pertaining to the responses to the damage created by the Tsunami. It is presented in the following major sections:(1) key questions; (2) national perspectives; (3) an international perspective; (4) laboratory aspects in disease surveillance; and (5) partnershi

Eight-year-olds identified in infancy as at risk of harm: report of a prospective longitudinal study

Eight-year-olds identified in infancy as at risk of harm: report of a prospective longitudinal stud

Marine Natural Products with Activities against Prostate Cancer: Recent Discoveries

Prostate cancer is the most common cancer in men, with over 52,000 new cases diagnosed every year. Diagnostics and early treatment are potentially hindered by variations in screening protocols, still largely reliant on serum levels of acid phosphatase and prostate-specific antigen, with tumour diagnosis and grading relying on histopathological examination. Current treatment interventions vary in terms of efficacy, cost and severity of side effects, and relapse can be aggressive and resistant to the current standard of care. For these reasons, the scientific community is looking for new chemotherapeutic agents. This review reports compounds and extracts derived from marine organisms as a potential source of new drugs against prostate cancer. Whilst there are several marine-derived compounds against other cancers, such as multiple myeloma, leukemia, breast and lung cancer, already available in the market, the presently collated findings show how the marine environment can be considered to hold potential as a new drug source for prostate cancer, as well. This review presents information on compounds presently in clinical trials, as well as new compounds/extracts that may enter trials in the future. We summarise information regarding mechanisms of action and active concentrations

Modulation of tumour angiogenesis by targeting p38 MAPK signalling in tumour-associated macrophages

Cellular crosstalk between cancer cells and tumour-associated macrophages (TAMs) plays an important role in tumour growth and metastasis by promoting tumour angiogenesis. Western blot analyses of cell lysates from in vitro studies revealed that RAW macrophages co-cultured with Murine Lewis lung carcinoma (LLC) cells display elevated levels of p38 MAPK (p38) activation. To further investigate this signalling pathway we used the p38 inhibitor BIRB796. Exposure of cancer cells to macrophage-conditioned medium pre-incubated with BIRB796 showed a clear dose-dependent increase in apoptosis. By preparing liposomal formulations of BIRB796 (Lip-BIRB796) we can spare normal cells from the drug’s cytotoxic effects and specifically target p38 signalling in phagocytic macrophages. In vitro cytotoxicity studies revealed an increased chemosensitivity to doxorubicin treatment when macrophage/cancer cell co-cultures were treated with Lip-BIRB796 prior to doxorubicin exposure. Furthermore, in vivo CAM assays were able to demonstrate both a marked increase in angiogenesis in CAMs inoculated with RAW and LLC cell co-cultures as compared to the respective monocultures and a significant decrease where these co-cultures were treated with Lip-BIRB796. To conclude, our results suggest that p38 is a promising target in TAMs for cancer adjuvant therapy

Targeting Extracellular Domains D4 and D7 of Vascular Endothelial Growth Factor Receptor 2 Reveals Allosteric Receptor Regulatory Sites

Vascular endothelial growth factors (VEGFs) activate three receptor tyrosine kinases, VEGFR-1, -2, and -3, which regulate angiogenic and lymphangiogenic signaling. VEGFR-2 is the most prominent receptor in angiogenic signaling by VEGF ligands. The extracellular part of VEGF receptors consists of seven immunoglobulin homology domains (Ig domains). Earlier studies showed that domains 2 and 3 (D23) mediate ligand binding, while structural analysis of dimeric ligand/receptor complexes by electron microscopy and small-angle solution scattering revealed additional homotypic contacts in membrane-proximal Ig domains D4 and D7. Here we show that D4 and D7 are indispensable for receptor signaling. To confirm the essential role of these domains in signaling, we isolated VEGFR-2-inhibitory “designed ankyrin repeat proteins” (DARPins) that interact with D23, D4, or D7. DARPins that interact with D23 inhibited ligand binding, receptor dimerization, and receptor kinase activation, while DARPins specific for D4 or D7 did not prevent ligand binding or receptor dimerization but effectively blocked receptor signaling and functional output. These data show that D4 and D7 allosterically regulate VEGFR-2 activity. We propose that these extracellular-domain-specific DARPins represent a novel generation of receptor-inhibitory drugs for in vivo applications such as targeting of VEGFRs in medical diagnostics and for treating vascular pathologies

Recovery of forest canopy parameters by inversion of multispectral LiDAR data

We describe the use of Bayesian inference techniques, notably Markov chain Monte Carlo (MCMC) and reversible jump MCMC (RJMCMC) methods, to recover forest structural and biochemical parameters from multispectral LiDAR (Light Detection and Ranging) data. We use a variable dimension, multi-layered model to represent a forest canopy or tree, and discuss the recovery of structure and depth profiles that relate to photochemical properties. We first demonstrate how simple vegetation indices such as the Normalized Differential Vegetation Index (NDVI), which relates to canopy biomass and light absorption, and Photochemical Reflectance Index (PRI) which is a measure of vegetation light use efficiency, can be measured from multispectral data. We further describe and demonstrate our layered approach on single wavelength real data, and on simulated multispectral data derived from real, rather than simulated, data sets. This evaluation shows successful recovery of a subset of parameters, as the complete recovery problem is ill-posed with the available data. We conclude that the approach has promise, and suggest future developments to address the current difficulties in parameter inversion

Guidance for the Conduct and Reporting of Clinical Trials of Breast Milk Substitutes

Question What is the best way to ensure the validity of clinical trials of breast milk substitutes while protecting trial participants? Findings Through a Delphi consensus project, guidance was developed to address issues specific to trials of breast milk substitutes assessing growth and tolerance, as well as trials of breast milk substitutes with other objectives. This consensus guidance summarizes best practice for the design, conduct, analysis, and reporting of trials of breast milk substitutes. Meaning Use of this guidance, in conjunction with existing clinical trial regulations, should enhance the quality and validity of trials of breast milk substitutes, protect trial participants, and support the evidence base for infant nutrition recommendations. This consensus guidance summarizes best practice for the design, conduct, analysis, and reporting of trials of breast milk substitutes. Importance Breast milk substitutes (BMS) are important nutritional products evaluated in clinical trials. Concerns have been raised about the risk of bias in BMS trials, the reliability of claims that arise from such trials, and the potential for BMS trials to undermine breastfeeding in trial participants. Existing clinical trial guidance does not fully address issues specific to BMS trials. Objectives To establish new methodological criteria to guide the design, conduct, analysis, and reporting of BMS trials and to support clinical trialists designing and undertaking BMS trials, editors and peer reviewers assessing trial reports for publication, and regulators evaluating the safety, nutritional adequacy, and efficacy of BMS products. Design, Setting, and Participants A modified Delphi method was conducted, involving 3 rounds of anonymous questionnaires and a face-to-face consensus meeting between January 1 and October 24, 2018. Participants were 23 experts in BMS trials, BMS regulation, trial methods, breastfeeding support, infant feeding research, and medical publishing, and were affiliated with institutions across Europe, North America, and Australasia. Guidance development was supported by an industry consultation, analysis of methodological issues in a sample of published BMS trials, and consultations with BMS trial participants and a research ethics committee. Results An initial 73 criteria, derived from the literature, were sent to the experts. The final consensus guidance contains 54 essential criteria and 4 recommended criteria. An 18-point checklist summarizes the criteria that are specific to BMS trials. Key themes emphasized in the guidance are research integrity and transparency of reporting, supporting breastfeeding in trial participants, accurate description of trial interventions, and use of valid and meaningful outcome measures. Conclusions and Relevance Implementation of this guidance should enhance the quality and validity of BMS trials, protect BMS trial participants, and better inform the infant nutrition community about BMS products.Peer reviewe