A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities

Theory and practice of social norms interventions: eight common pitfalls.

BACKGROUND: Recently, Global Health practitioners, scholars, and donors have expressed increased interest in "changing social norms" as a strategy to promote health and well-being in low and mid-income countries (LMIC). Despite this burgeoning interest, the ability of practitioners to use social norm theory to inform health interventions varies widely. MAIN BODY: Here, we identify eight pitfalls that practitioners must avoid as they plan to integrate a social norms perspective in their interventions, as well as eight learnings. These learnings are: 1) Social norms and attitudes are different; 2) Social norms and attitudes can coincide; 3) Protective norms can offer important resources for achieving effective social improvement in people's health-related practices; 4) Harmful practices are sustained by a matrix of factors that need to be understood in their interactions; 5) The prevalence of a norm is not necessarily a sign of its strength; 6) Social norms can exert both direct and indirect influence; 7) Publicising the prevalence of a harmful practice can make things worse; 8) People-led social norm change is both the right and the smart thing to do. CONCLUSIONS: As the understanding of how norms evolve in LMIC advances, practitioners will develop greater understanding of what works to help people lead change in harmful norms within their contexts. Awareness of these pitfalls has helped several of them increase the effectiveness of their interventions addressing social norms in the field. We are confident that others will benefit from these reflections as well

Psychometric properties of two physical activity questionnaires, the AQuAA and the PASE, in cancer patients

Background: This study aimed to evaluate the reliability and validity of two self-report physical activity (PA) questionnaires - the AQuAA (Activity Questionnaire for Adults and Adolescents) and PASE (Physical Activity Scale for the Elderly) - in cancer patients. Methods: Test-retest reliability was determined by administering the questionnaires twice within 5 days. Intraclass correlation coefficient (ICC), standard error of measurement (SEM) and smallest detectable difference (SDD) were calculated. Construct validity was determined by comparing the questionnaire results with ActiGraph accelerometer scores using Spearman correlation coefficients (r(s)) and ICCs. Content validity was examined using the Three-Step Test-Interview (TSTI). Results: Reliability for the AQuAA scores were fair to excellent (ICC = 0.57 to 0.78). Reliability for the PASE scores ranged from good to excellent (ICC = 0.67 to 0.90). Correlations between the ActiGraph and the AQuAA and the PASE were low (r(s) = 0.05 and 0.16 respectively, and ICC = -0.001 to 0.44). The TSTI showed that participants experienced difficulties with the examples provided with the questions, the perceptions of intensity level of PA, and with recalling the time spent on PA. Conclusions: Both questionnaires showed good to excellent test-retest reliability for most scores. Construct validity of both questionnaires was low, as indicated by the low correlations with the ActiGraph. Except for a few difficulties that participants perceived when filling out the questionnaires, the content validity of both questionnaires was goo

A Two-Gene Balance Regulates Salmonella Typhimurium Tolerance in the Nematode Caenorhabditis elegans

Lysozymes are antimicrobial enzymes that perform a critical role in resisting infection in a wide-range of eukaryotes. However, using the nematode Caenorhabditis elegans as a model host we now demonstrate that deletion of the protist type lysozyme LYS-7 renders animals susceptible to killing by the fatal fungal human pathogen Cryptococcus neoformans, but, remarkably, enhances tolerance to the enteric bacteria Salmonella Typhimurium. This trade-off in immunological susceptibility in C. elegans is further mediated by the reciprocal activity of lys-7 and the tyrosine kinase abl-1. Together this implies a greater complexity in C. elegans innate immune function than previously thought

Prevalence of mental disorders from adolescence through early adulthood in American Indian and First Nations communities

Indigenous communities lack representation in psychiatric epidemiology despite disproportionate exposure to risk factors. We document the cumulative and 12-month prevalence of psychiatric disorders across the early life course among a sample of Indigenous young adults and compare prospective and retrospective reporting of lifetime mental disorders. This community-based participatory research includes data from 735 Indigenous people from 8 reservations/reserves. Personal interviews were conducted between 2002–2010 and 2017–2018 totaling 9 waves; diagnostic assessments of DSM-IV-TR alcohol abuse/dependence, marijuana use/dependence, other substance abuse/dependence, generalized anxiety disorder, major depressive disorder, dysthymic disorder, and attention deficit/hyperactivity disorder occurred at waves 1 (mean age = 11.1 years), 4 (mean age = 14.3 years), 6 (mean age = 16.2 years), 8 (mean age = 18.3 years), and 9 (mean age = 26.3 years). Cumulative lifetime psychiatric disorders reached 77.3% and lifetime comorbidity 56.4% by wave 9. Past-year prevalence and comorbidity at wave 9 were 28.7% and 6.7%, respectively. Substance use disorders (SUDs) were most common with peak past-year prevalence observed when participants were on average 16.3 years old then declining thereafter. Trends in early life course psychiatric disorders in this study with Indigenous participants highlight cultural variations in psychiatric epidemiology including surprisingly low rates of internalizing disorders in the face of risk factors, disproportionately high rates of early-onset and lifetime SUD, and lower rates of past-year SUD in early adulthood compared with prior research.Peer reviewedSociolog

Adaptive Contact Networks Change Effective Disease Infectiousness and Dynamics

Human societies are organized in complex webs that are constantly reshaped by a social dynamic which is influenced by the information individuals have about others. Similarly, epidemic spreading may be affected by local information that makes individuals aware of the health status of their social contacts, allowing them to avoid contact with those infected and to remain in touch with the healthy. Here we study disease dynamics in finite populations in which infection occurs along the links of a dynamical contact network whose reshaping may be biased based on each individual's health status. We adopt some of the most widely used epidemiological models, investigating the impact of the reshaping of the contact network on the disease dynamics. We derive analytical results in the limit where network reshaping occurs much faster than disease spreading and demonstrate numerically that this limit extends to a much wider range of time scales than one might anticipate. Specifically, we show that from a population-level description, disease propagation in a quickly adapting network can be formulated equivalently as disease spreading on a well-mixed population but with a rescaled infectiousness. We find that for all models studied here – SI, SIS and SIR – the effective infectiousness of a disease depends on the population size, the number of infected in the population, and the capacity of healthy individuals to sever contacts with the infected. Importantly, we indicate how the use of available information hinders disease progression, either by reducing the average time required to eradicate a disease (in case recovery is possible), or by increasing the average time needed for a disease to spread to the entire population (in case recovery or immunity is impossible)

A simulation analysis to characterize the dynamics of vaccinating behaviour on contact networks

<p>Abstract</p> <p>Background</p> <p>Human behavior influences infectious disease transmission, and numerous "prevalence-behavior" models have analyzed this interplay. These previous analyses assumed homogeneously mixing populations without spatial or social structure. However, spatial and social heterogeneity are known to significantly impact transmission dynamics and are particularly relevant for certain diseases. Previous work has demonstrated that social contact structure can change the individual incentive to vaccinate, thus enabling eradication of a disease under a voluntary vaccination policy when the corresponding homogeneous mixing model predicts that eradication is impossible due to free rider effects. Here, we extend this work and characterize the range of possible behavior-prevalence dynamics on a network.</p> <p>Methods</p> <p>We simulate transmission of a vaccine-prevetable infection through a random, static contact network. Individuals choose whether or not to vaccinate on any given day according to perceived risks of vaccination and infection.</p> <p>Results</p> <p>We find three possible outcomes for behavior-prevalence dynamics on this type of network: small final number vaccinated and final epidemic size (due to rapid control through voluntary ring vaccination); large final number vaccinated and significant final epidemic size (due to imperfect voluntary ring vaccination), and little or no vaccination and large final epidemic size (corresponding to little or no voluntary ring vaccination). We also show that the social contact structure enables eradication under a broad range of assumptions, except when vaccine risk is sufficiently high, the disease risk is sufficiently low, or individuals vaccinate too late for the vaccine to be effective.</p> <p>Conclusion</p> <p>For populations where infection can spread only through social contact network, relatively small differences in parameter values relating to perceived risk or vaccination behavior at the individual level can translate into large differences in population-level outcomes such as final size and final number vaccinated. The qualitative outcome of rational, self interested behaviour under a voluntary vaccination policy can vary substantially depending on interactions between social contact structure, perceived vaccine and disease risks, and the way that individual vaccination decision-making is modelled.</p

New targets for therapy in breast cancer: Small molecule tyrosine kinase inhibitors

Over the past several years many advances have been made in our understanding of critical pathways involved in carcinogenesis and tumor growth. These advances have led to the investigation of small molecule inhibitors of the ErbB family of receptor tyrosine kinases across a broad spectrum of malignancies. In this article we summarize the rationale for targeting members of the ErbB family in breast cancer, and review the preclinical and clinical data for the agents that are furthest in development. In addition, we highlight directions for future research, such as exploration of the potential crosstalk between the ErbB and hormone receptor signal transduction pathways, identification of predictive markers for tumor sensitivity, and development of rational combination regimens that include the tyrosine kinase inhibitors

Daptomycin antimicrobial activity tested against methicillin-resistant staphylococci and vancomycin-resistant enterococci isolated in European medical centers (2005)

BACKGROUND: Daptomycin is a cyclic lipopeptide with potent activity and broad spectrum against Gram-positive bacteria currently used for the treatment of complicated skin and skin structure infections and bacteremia, including right sided endocarditis. We evaluated the in vitro activity of this compound and selected comparator agents tested against clinical strains of staphylococci and enterococci collected in European medical centers in 2005. METHODS: A total of 4,640 strains from 23 medical centers located in 10 European countries, Turkey and Israel (SENTRY Program platform) were tested for susceptibility by reference broth microdilution methods according to Clinical and Laboratory Standards Institute guidelines and interpretative criteria. Mueller-Hinton broth was supplemented to 50 mg/L Ca(++ )for testing daptomycin. Results for oxacillin (methicillin)-resistant staphylococci and vancomycin-resistant enterococci were analyzed separately. RESULTS: Oxacillin resistance rates among Staphylococcus aureus varied from 2.1% in Sweden to 42.5% in the United Kingdom (UK) and 54.7% in Ireland (29.1% overall), while vancomycin resistance rates varied from 0.0% in France, Sweden and Switzerland to 66.7% in the UK and 71.4% in Ireland among Enterococcus faecium (17.9% overall). All S. aureus strains were inhibited at daptomycin MIC of 1 mg/L (MIC(50/90), 0.25/0.5 mg/L; 100.0% susceptible) and only one coagulase-negative staphylococci strain (0.1%) showed an elevated (>1 mg/L) daptomycin MIC value (4 mg/L). Among E. faecalis (MIC(50/90), 0.5/1 mg/L; 100% susceptible) the highest daptomycin MIC value was 2 mg/L; while among E. faecium (MIC(50/90), 2/4 mg/L; 100% susceptible) the highest MIC result was 4 mg/L. CONCLUSION: Daptomycin showed excellent in vitro activity against staphylococci and enterococci collected in European medical centers in 2005 and resistance to oxacillin, vancomycin or quinupristin/dalfopristin did not compromise its activity overall against these pathogens. Based on these results and those of previous publications, daptomycin appears to be an excellent therapeutic option for serious infections caused by oxacillin-resistant staphylococci and vancomycin-resistant enterococci in Europe

Rift Valley Fever Virus NSs Protein Promotes Post-Transcriptional Downregulation of Protein Kinase PKR and Inhibits eIF2α Phosphorylation

Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is a negative-stranded RNA virus with a tripartite genome. RVFV is transmitted by mosquitoes and causes fever and severe hemorrhagic illness among humans, and fever and high rates of abortions in livestock. A nonstructural RVFV NSs protein inhibits the transcription of host mRNAs, including interferon-β mRNA, and is a major virulence factor. The present study explored a novel function of the RVFV NSs protein by testing the replication of RVFV lacking the NSs gene in the presence of actinomycin D (ActD) or α-amanitin, both of which served as a surrogate of the host mRNA synthesis suppression function of the NSs. In the presence of the host-transcriptional inhibitors, the replication of RVFV lacking the NSs protein, but not that carrying NSs, induced double-stranded RNA-dependent protein kinase (PKR)–mediated eukaryotic initiation factor (eIF)2α phosphorylation, leading to the suppression of host and viral protein translation. RVFV NSs promoted post-transcriptional downregulation of PKR early in the course of the infection and suppressed the phosphorylated eIF2α accumulation. These data suggested that a combination of RVFV replication and NSs-induced host transcriptional suppression induces PKR-mediated eIF2α phosphorylation, while the NSs facilitates efficient viral translation by downregulating PKR and inhibiting PKR-mediated eIF2α phosphorylation. Thus, the two distinct functions of the NSs, i.e., the suppression of host transcription, including that of type I interferon mRNAs, and the downregulation of PKR, work together to prevent host innate antiviral functions, allowing efficient replication and survival of RVFV in infected mammalian hosts