Rational Drug Design: An Information Driven Approach to the Design of an Anthracycline Analog

Over the past fifty years anthracyclines have been used to treat a wide variety of cancers. Combination therapies with anthracyclines have the potential to greatly increase treatment success. Despite the great potential of anthracyclines in the treatment of cancer, their use has been limited due to the risk of chronic cardiotoxicity. The reduction of anthracyclines to an alcohol metabolite has been linked to the development of cardiotoxic side effects. One of the principal enzymes responsible for catalyzing the formation of the anthracycline alcohol metabolite is human carbonyl reductase 1(HCBR). Controlling the reduction of anthracyclines by HCBR may offer a means to reduce the risk of cardiotoxicity during treatment. The structure activity relationships responsible for the recognition and binding of the anthracycline substrates were investigated. Molecular modeling studies implicated Met 234 as a possible determinant of anthracycline specificity for HCBR. In order to test this, site directed mutagenesis was used to convert the methionine to a cysteine in a histidine expression system. The histidine tagged HCBR was found to have reduced enzyme activity and coenzyme binding compared to native enzyme. Further, the cysteine 234 mutant enzyme was found to be inactive, although it still appeared to possess coenzyme and anthracycline binding capability. It is clear that the addition of the histidine tag has impaired enzyme function and that such a modification may mask any effects introduced by mutating Met 234 to a cysteine (NIH-INBRE Grant# P20RR16454)

Salmonella in two gecko species on the island of Hawaii

Western Region, National Park Servic

Academic-Community Partnership to Explore High-Smoking Prevalence in Filipina Girls

Smoking prevalence for Asian-Americans (AA) is low compared to non-AAs; however in Hawai`, the prevalence of smoking among Filipina high school girls is more than double that of Japanese high school girls. This study explored socio-cultural factors facilitating or serving as barriers against tobacco use among Filipina girls. Representatives from four community organizations, recognized for their work with Filipinos, were engaged throughout the research to facilitate the project and to ensure cultural relevance. Eleven focus groups (n=88), led by peer facilitators, discussed smoking. Twelve cultural key informants interpreted results presented from the transcripts. Results: Self-reported reasons why Filipina girls may smoke included the need to cope and to fit in. School and family responsibilities were commonly stated as barriers to smoking among Filipina girls. Nonetheless, many girls said they were given cigarettes from family members who smoked. Cultural key informants recommended conducting research on a larger sample of Filipina girls and offering family and school-based tobacco prevention programs. Conclusion: Collaboration with a variety of community partners helped provide rich qualitative data and findings regarding socio-cultural factors associated with smoking and recommendations to prevent smoking among Filipina girls. The role of family in preventing and promoting tobacco use needs further exploration. Family appears to be a promising area to explore future interventions to prevent smoking among Filipina girls

Who will use pre-exposure prophylaxis (PrEP) and why?: Understanding PrEP awareness and acceptability amongst men who have sex with men in the UK – a mixed methods study

Background: Recent clinical trials suggest that pre-exposure prophylaxis (PrEP) may reduce HIV transmission by up to 86% for men who have sex with men (MSM), whilst relatively high levels of PrEP acceptability have been reported to date. This study examines PrEP awareness amongst sub-groups of MSM communities and acceptability amongst MSM in a low prevalence region (Scotland, UK), using a mixed methods design. Methods: Quantitative surveys of n = 690 MSM recruited online via social and sociosexual media were analysed using descriptive statistics and multivariate logistic regression. In addition, n = 10 in-depth qualitative interviews with MSM were analysed thematically. Results: Under one third (29.7%) of MSM had heard of PrEP, with awareness related to living in large cities, degree level education, commercial gay scene use and reporting an HIV test in the last year. Just under half of participants (47.8%) were likely to use PrEP if it were available but there was no relationship between PrEP acceptability and previous PrEP awareness. Younger men (18–25 years) and those who report higher risk UAI were significantly more likely to say they would use PrEP. Qualitative data described specific PrEP scenarios, illustrating how risk, patterns of sexual practice and social relationships could affect motivation for and nature of PrEP use. Conclusion: These findings suggest substantial interest PrEP amongst MSM reporting HIV risk behaviours in Scotland. Given the Proud results, there is a strong case to investigate PrEP implementation within the UK. However, it appears that disparities in awareness have already emerged along traditional indicators of inequality. Our research identifies the need for comprehensive support when PrEP is introduced, including a key online component, to ensure equity of awareness across diverse MSM communities (e.g. by geography, education, gay scene use and HIV proximity), as well as to responding to the diverse informational and sexual health needs of all MSM communities

Association of the Frequency of Respiratory Illness in Early Childhood with a Change in the Distribution of Blood Lymphocyte Subpopulations

Little is known about the distribution of lymphocyte phenotypes in young children and the association specific phenotypes may have with respiratory illnesses. The objective of this study was to describe lymphocyte distributions in children at approximately 2 years of age and to test for associations with the frequency of respiratory illness during the first 2 years of life. We hypothesized that an increased frequency of illness would be associated with those phenotypes that reflect previous antigen exposure and/or immune activation. Seventy-three children were followed during their first 2 years of life with daily symptom diaries and twice-monthly telephone calls to ascertain the incidence of respiratory illness. After the children reached 2 years of age, the phenotypes of circulating blood lymphocytes were measured by flow cytometry. Associations between illness and phenotypes were adjusted for education level of parents; hours per week in day care; hours per week exposed to environmental tobacco smoke, mould, or water damage in bedroom; and parental history of allergy and asthma. The resulting median lymphocyte count was 4.0 × 109 per litre (standard deviation, 1.3) with a CD4/CD8 count of 2.28, consistent with published values. Illness rates were positively associated with the percentage of CD8+ CD38+ T cells (unadjusted p = .03, adjusted p = .014), CD8+ CD45RO+ T cells (unadjusted p = .06, adjusted p = .036), and CD4+ CD45RO+ T cells (unadjusted p = .01, adjusted p = .005). Our conclusions is that there is an association between the distribution of lymphocyte phenotypes and the incidence of respiratory illness early in life. Future research is recommended to determine the directionality of this association

Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma

PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell-like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation

HIV infection of thymocytes inhibits IL-7 activity without altering CD127 expression

Abstract Background Thymic function is altered in HIV infection and characterized by dysregulation of the thymic epithelial network, reduced thymic output and ultimately an impaired naïve T-cell pool. The IL-7/IL-7 receptor (IL-7R) signalling pathway is critical for the maturation and differentiation of thymocytes. HIV infection is associated with a decrease in IL-7Rα (CD127) expression and impaired CD127 signalling in circulating CD8+ T-cells; however, little is known about the effect of HIV on CD127 expression and IL-7 activity in the thymus. Therefore, the effect of in vitro HIV infection on CD127 expression and IL-7-mediated function in thymocytes was investigated. Findings In vitro HIV infection of thymocytes did not affect CD127 expression on either total thymocytes or on single positive CD4 or single positive CD8 subsets. However, HIV infection resulted in a decrease in the level of IL-7-induced STAT-5 phosphorylation and Bcl-2 expression in unfractionated thymocytes. Conclusion These findings indicate that HIV infection alters IL-7 responsiveness of thymocytes by a mechanism other than CD127 downregulation and potentially explain the disruption in thymopoiesis observed in HIV infection

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group