| 1. |
- Rath, Emma M, et al.
(författare)
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BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.
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| 2. |
- Chao, Yashuan, et al.
(författare)
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In vitro and in vivo biofilm formation by pathogenic streptococci
- 2017
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Ingår i: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745. ; 1535, s. 285-299
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Bokkapitel (refereegranskat)abstract
- This manuscript presents novel approaches to grow and evaluate Streptococcal biofilm formation using the human respiratory pathogen Streptococcus pneumoniae (the pneumococcus) as the main model organism on biological surfaces in vitro and in vivo. Most biofilm models are based on growth on abiotic surfaces, which is relevant for many pathogens whose growth on surfaces or medical devices is a major cause of disease transmission and infections, especially in hospital environments. However, most infections with commensal organisms require biofilm formation on biological surfaces in the host at the site of colonization or infection. In vitro model systems incorporating biological components from the host and taking into account the host environment of the infectious site are not well described. In a series of publications, we have shown that S. pneumoniae form complex biofilms in the nasopharynx of mice and have devised methodology to evaluate the biofilm structure and function in this environment. We have also been able to recapitulate this biofilm phenotype in vitro by incorporating crucial factors associated with the host environment. Although the protocols presented in this manuscript are focused on S. pneumoniae, the same methodology can and has been used for other Streptococcal species that form biofilms on mucosal surfaces.
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| 3. |
- Dahlman, Disa, et al.
(författare)
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Behavioral characteristics and injection practices associated with skin and soft tissue infections among people who inject drugs : A community-based observational study
- 2017
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Ingår i: Substance Abuse. - : Informa UK Limited. - 0889-7077 .- 1547-0164. ; 38:1, s. 105-112
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Tidskriftsartikel (refereegranskat)abstract
- Background: People who inject drugs (PWID) are at increased risk for bacterial skin and soft tissue infections (SSTIs). Although SSTIs pose significant health risks, little is known about their prevalence and characteristics in the population of PWID in the United States. This study investigates whether behavioral factors related to skin and equipment hygiene and tissue-damaging injection practices are associated with recent SSTIs among PWID. Methods: Active PWID were recruited using targeted sampling in San Francisco in 2011–2013. Interviewers collected information on behavioral risk factors of past-month self-reported SSTIs. Inferential analyses used multivariate logistic regression methods (i.e., generalized linear model) to characterize risk factors for past-month SSTIs. Results: The self-reported prevalence of lifetime, past-year, and past-month SSTI was 70%, 29%, and 11%, respectively. Several factors were significantly associated with past-month SSTIs in bivariate analysis, including injecting nonpowder drugs (odds ratio [OR] = 3.57; 95% confidence interval [CI] = 1.23, 10.35; P = .01), needle-licking before injection (OR = 3.36; 95% CI = 1.28, 8.81; P = .01), injecting with someone else's preused syringe/needle (OR = 7.97; 95% CI = 2.46, 25.83; P < .001), being injected by another person (OR = 2.63; 95% CI = 1.02, 6.78; P = .04), infrequent skin cleaning before injection (OR = 2.47; 95% CI = 1.00, 6.10; P = .04), and frequent injections (P = .02). In multivariate analysis, only syringe/needle sharing (adjusted OR = 6.38; 95% CI = 1.90, 21.46) remained statistically significant. Conclusion: SSTIs are common among PWID. These data highlight the importance of clinical and public health screening efforts to reduce SSTIs. Needle exchange programs may be good venues for SSTIs screening and treatment.
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| 4. |
- Greene, Christopher J., et al.
(författare)
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A novel strategy to protect against influenza-induced pneumococcal disease without interfering with commensal colonization
- 2016
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Ingår i: Infection and Immunity. - 1098-5522. ; 84:6, s. 1693-1703
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae commonly inhabits the nasopharynx as a member of the commensal biofilm. Infection with respiratory viruses, such as influenza A virus, induces commensal S. pneumoniae to disseminate beyond the nasopharynx and to elicit severe infections of the middle ears, lungs, and blood that are associated with high rates of morbidity and mortality. Current preventive strategies, including the polysaccharide conjugate vaccines aim to eliminate asymptomatic carriage with vaccine-type pneumococci. However, this has resulted in serotype-replacement with, so-far, less fit pneumococcal strains, which has changed the nasopharyngeal flora, opening the niche for entry of other virulent pathogens (e.g., Streptococcus pyogenes, Staphylococcus aureus, and potentially Haemophilus influenzae). The long-term effects of these changes are unknown. Here, we present an attractive, alternative preventive approach where we subvert virally-induced pneumococcal disease without interfering with commensal colonization, thus specifically targeting disease-causing organisms. In that regard, pneumococcal surface protein A (PspA), a major surface protein of pneumococci, is a promising vaccine target. Intradermal (i.d.) immunization of mice with recombinant PspA in combination with LT-IIb(T13I), a novel i.d. adjuvant of the type II heat-labile enterotoxin family, elicited strong systemic PspA-specific IgG responses without inducing mucosal anti-PspA IgA responses. This response protected mice from otitis media, pneumonia, and septicemia and averted the cytokine storm associated with septic infection but had no effect on asymptomatic colonization. Our results firmly demonstrated that this immunization strategy against virally-induced, pneumococcal disease can be conferred without disturbing the desirable pre-existing commensal colonization of the nasopharynx.
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| 5. |
- Novak, Scott P., et al.
(författare)
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Nonmedical use of prescription drugs in the European Union
- 2016
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Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 16:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nonmedical prescription drug use (NMPDU) refers to the self-treatment of a medical condition using medication without a prescriber's authorization as well as use to achieve euphoric states. This article reports data from a cross-national investigation of NMPDU in five European Countries, with the aim to understand the prevalence and characteristics of those engaging in NMPDU across the EU. Methods: A parallel series of self-administered, cross-sectional, general population surveys were conducted in 2014. Data were collected using multi-stage quota sampling and then weighted using General Exponential Model. A total of 22,070 non-institutionalized participants, aged 12 to 49 years, in 5 countries: Denmark, Germany, Great Britain, Spain, and Sweden. Lifetime and past-year nonmedical use of prescription medications such as stimulants, opioids, and sedatives were ascertained via a modified version of the World Health Organization's Composite International Diagnostic Interview. Information about how the medications were acquired for NMPDU were also collected from the respondent. Results: Lifetime and past-year prevalence of nonmedical prescription drug use was estimated for opioids (13.5 and 5.0 %), sedatives (10.9 and 5.8 %), and stimulants (7.0 and 2.8 %). Germany exhibited the lowest levels of NMPDU, with Great Britain, Spain, and Sweden having the highest levels. Mental and sexual health risk factors were associated with an increased likelihood of past-year nonmedical prescription drug use. Among past-year users, about 32, 28, and 52 % of opioid, sedative, and stimulant nonmedical users, respectively, also consumed illicit drugs. Social sources (sharing by friends/family) were the most commonly endorsed methods of acquisition, ranging from 44 % (opioids) to 62 % (sedatives). Of interest is that Internet pharmacies were a common source of medications for opioids (4.1 %), stimulants (7.6 %), and sedatives (2.7 %). Conclusions: Nonmedical prescription drug use was reported across the five EU countries we studied, with opioids and sedatives being the most prevalent classes of prescription psychotherapeutics. International collaborations are needed for continued monitoring and intervention efforts to target population subgroups at greatest risk for NMDU.
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| 6. |
- Rath, Emma M., et al.
(författare)
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Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components
- 2015
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Ingår i: Journal of Pharmacy and Pharmaceutical Sciences. - 1482-1826. ; 18:4, s. 773-824
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Tidskriftsartikel (refereegranskat)abstract
- The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified.
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| 7. |
- van Roekel, Eline H., et al.
(författare)
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Circulating metabolites associated with alcohol intake in the european prospective investigation into cancer and nutrition cohort
- 2018
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTMp180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption withmetabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR q-value < 0.05) were further tested in the replication set (Bonferroni-corrected p-value < 0.05). Of the 72metabolites significantly related to alcohol intake in the discovery set, 34 were also significant in the replication analysis, including three acylcarnitines, the amino acid citrulline, four lysophosphatidylcholines, 13 diacylphosphatidylcholines, seven acyl-alkylphosphatidylcholines, and six sphingomyelins. Our results confirmed earlier findings that alcohol consumption was associated with several lipid metabolites, and possibly also with specific acylcarnitines and amino acids. This provides further leads for future research studies aiming at elucidating the mechanisms underlying the effects of alcohol in relation to morbid conditions.
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