Nearwork-induced transient myopia (NITM) in anisometropia

Objective: To assess the magnitude of nearwork-induced transient myopia (NITM) under binocular viewing conditions separately in each eye of individuals with mild to moderate anisometropia to determine the relationship between NITM and their interocular refractive error. Methods: Forty-three children and young adults with anisometropia [cycloplegic spherical equivalent (SE) difference >1.00 D] were tested (ages 9-28 years). NITM was measured with binocular viewing separately in each eye after binocularly performing a sustained near task (5 D) for 5 min incorporating a cognitive demand using an open-field, infrared autorefractor (Grand-Seiko, WAM-5500). Data were averaged over 10 s bins for 3 min in each eye. Initial NITM, its decay time (DT), and its decay area (DA) were determined. A-scan ultrasound ocular biometry was also performed to determine the axial length of each eye. Results: The more myopic eye exhibited increased initial NITM, DT, and DA as compared to the less myopic eye (0.21 ± 0.16 D vs 0.15 ± 0.13 D, p = 0.026; 108.4 ± 64.3 secs vs 87.0 ± 65.2 secs, p = 0.04; and 17.6 ± 18.7 D*secs vs 12.3 ± 15.7 D*secs, p = 0.064), respectively. The difference in DA and the difference in SE between the more versus less myopic eye were significantly correlated (r = 0.31, p = 0.044). Furthermore, 63% (27/43), 56% (24/43), and 70% (30/43) of the more myopic eyes exhibited increased initial NITM, longer DT, and larger DA, respectively, than found in the less myopic eye. Conclusions: In approximately two-thirds of the anisometropic individuals, the initial NITM and its decay area were significantly increased in the more myopic eye as compared to the less myopic eye. NITM may play an important role in the development of interocular differences in myopia, although a causal relationship is yet to be established. Furthermore, the findings have potentially important implications regarding accommodative control and interocular accommodative responsitivity in anisometropia, in particular for anisomyopia. © 2013 The College of Optometrists.

Oxidised LDL-lipids alter redox ratio, lipid raft formation and increase amyloid beta production by SHSY-5Y cells

Elevated cholesterol in mid-life has been associated with increased risk of dementia in later life. We have previously shown that low density lipoprotein (LDL) is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged [1]. We have investigated the hypothesis that amyloid beta production and neurodegeneration can be driven by oxidised lipids derived from LDL following the loss of blood brain barrier integrity with ageing. Therefore, we have investigated amyloid beta formation in SHSY5Y cells treated with LDL, minimally modified (ox) LDL, and lipids extracted from both forms of LDL. LDL-treated SHSY-5Y cell viability was not significantly decreased with up to 8 μg LDL/2 × 104 cells compared to untreated cells. However, 8 μg oxLDL protein/2 × 104 cells decreased the cell viability significantly by 33.7% (P < 0.05). A more significant decrease in cell viability was observed when treating cells with extracted lipids from 8 μg of LDL (by 32.7%; P < 0.01) and oxLDL (by 41%; P < 0.01). In parallel, the ratio of reduced to oxidised GSH was decreased; GSH concentrations were significantly decreased following treatment with 0.8 μg/ml oxLD-L (7.35 ± 0.58;P < 0.01), 1.6 μg/ml (5.27 ± 0.23; P < 0.001) and 4 μg/ml (5.31 ± 0.31; P < 0.001). This decrease in redox potential was associated with an increase acid sphingomyelinase activity and lipid raft formation which could be inhibited by desipramine; SHSY5Y cells treated with oxLDL, and lipids from LDL and oxLDL for 16 h showed significantly increased acid sphingomyelinase activity (5.32 ± 0.35; P < 0.05, 5.21 ± 0.6; P < 0.05, and 5.58 ± 0.44; P < 0.01, respectively) compared to control cells (2.96 ± 0.34). As amyloid beta production is driven by the activity of beta secretase and its association with lipid rafts, we investigated whether lipids from ox-LDL can influence amyloid beta by SHSY-5Y cells in the presence of oxLDL. Using ELISA and Western blot, we confirmed that secretion of amyloid beta oligomers is increased by SHSY-5Y cells in the presence of oxLDL lipids. These data suggest a mechanism whereby LDL, and more significantly oxLDL lipids, can drive amyloid beta production and cytotoxicity in neuronal cells. [1] Li L, Willets RS, Polidori MC, Stahl W, Nelles G, Sies H, Griffiths HR. Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance. Free Radic Res. 2010 Mar; 44(3): 241–8.

Monocyte subset counts associations with left ventricular systolic function post ST elevation myocardial infarction

Background: Monocytes are implicated in the initiation and progression of theatherosclerotic plaque contributing to plaque instability and rupture. Little is knownof the role played by the 3 phenotypically and functionally different monocytesubpopulations in determining ventricular remodeling following ST elevation my-ocardial infarction (STEMI). Mon1 are "classical" inflammatory monocytes, whilstMon3 are considered reparative with fibroblast deposition ability. The function ofthe newly described Mon2 is yet to be elucidated. Method: STEMI patients (n=196, mean age 62±13 years; 72% male) treatedwith percutaneous revascularization were recruited within the first 24 hours. Pe-ripheral blood monocyte subpopulations were enumerated and characterizedusing flow cytometry after staining for CD14, CD16 and CCR2. Phenotypi-cally, monocyte subpopulations are defined as: CD14+CD16-CCR2+ (Mon1),CD14+CD16+CCR+ (Mon2) and CD14lowCD16+CCR2- (Mon3) cells. Transtho-racic 2D echocardiography was performed within 7 days and 6 months post infarctto assess ventricular volumes, mass, systolic, and diastolic functions. Results: Using linear regression analysis higher counts for Mon1, and lowercounts for Mon2 and Mon3 were significantly associated with the baseline leftventricular ejection fraction (LVEF) within seven days post infarction. At 6 monthspost STEMI lower counts of Mon2 remained positively associated with decreasedLVEF (p value= 0.002).Monocyte subsets correlation with LVEFMonocytes mean florescence Baseline left ventricular Left ventricular ejectionintensity (cells/μl) ejection fraction (%) fraction (%) at 6 months post infarctβ-value P-valueβ-value P-valueTotal Mon0.31 P<0.001 0.360.009Mon 10.019 0.020.070.62Mon 2−0.28 0.001 −0.420.002Mon 3−0.27 0.001 −0.180.21 Conclusion: Peripheral monocytes of all three subsets correlate with LVEF af-ter a myocardial infarction. High counts of the inflammatory Mon1 are associatedwith reduction in the baseline LVEF. Post remodelling, the convalescent EF wasindependently predicted by monocyte subpopulation 2. As lower counts depictednegative ventricular remodeling, this suggests a reparative role for the newly de-scribed Mon2, possibly via myofibroblast deposition and angiogenesis, in contrastto an anticipated inflammatory role.

The effect of multimedia instruction on achievement of college history students

The purpose of this study was to investigate the effect of multimedia instruction on achievement of college students in AMR 2010 from exploration and discovery to 1865. A non-equivalent control group design was used. The dependent variable was achievement. The independent variables were learning styles, method of instruction, and visual clarifiers (notes). The study was conducted using two history sections from Palm Beach Community College, in Boca Raton, Florida, between August and December, 1998. Data were obtained by means of placement scores, posttests, the Productivity Environmental Preference Survey (PEPS), and a researcher-developed student survey. Statistical analysis of the data was done using SPSS statistical software. Demographic variables were compared using Chi square. T tests were run on the posttests to determine the equality of variances. The posttest scores of the groups were compared using the analysis of covariance (ANCOVA) at the .05 level of significance. The first hypothesis there is a significant difference in students' learning of U.S. History when students receive multimedia instruction was supported, F (1, 52) = 16.88, p < .0005, and F = (1, 53) = 8.52, p < .005 for Tests 2 and 3, respectively. The second hypothesis there is a significant difference on the effectiveness of multimedia instruction based on students' various learning preferences was not supported. The last hypotheses there is a significant difference on students' learning of U.S. History when students whose first language is other than English and students who need remediation receive visual clarifiers were not supported. Analysis of covariance (ANCOVA) indicated no difference between the groups on Test 1, Test 2, or Test 3: F (1, 45) = .01, p < .940, F (1, 52) = .77, p < .385, and F (1, 53) =.17, p < .678, respectively, for language. Analysis of covariance (ANCOVA) indicated no significant difference on Test 1, Test 2, or Test 3, between the groups on the variable remediation: F (1, 45) = .31, p < .580, F (1, 52) = 1.44, p < .236, and F (1, 53) = .21, p < .645, respectively. ^

Hispanic adolescents with severe substance abuse problems: Parental involvement, acculturation-related factors, and attachment

The main objective of the study was to investigate the relationship between parent-related, acculturation-related, and substance use-related variables found within individual, familial/parental, peer and school adolescent ecological domains, in a clinical sample (i.e. adolescents who met criteria for a Diagnostic Statistical Manual-IV [DSMIV] clinical diagnosis of substance abuse/dependence) of Hispanic adolescents from Miami, Florida. ^ The sample for this study consisted of 94 adolescent-mother pairs. The adolescent sample was 65% male, and 35% female, with a mean age of 15 years. More than half of the adolescents were born in the United States (60%) and had resided in the U.S. for an average of 12 years; 80% of the caregivers (primarily mothers) were foreign-born and lived in the U.S. for an average of 21 years. ^ Correlation and hierarchical regression were used to answer the research questions. The findings indicate that the hypothesized model and corresponding anticipated effect of the relationship between parental school and peer involvement on adolescents’ frequency of alcohol, marijuana and cocaine use was not supported by the data. Parental “acculturation-related” variables did not explain any of the variance in adolescent substance use frequency in this sample. Mediation and moderation models were not supported either. However, some interesting relationships were found: ^ The larger the acculturation gap, the lower the parental involvement in school tended to be (r = -.21, p < .05). Adolescents who experienced a greater acculturation gap with their parents (-.81, p >.01) had an earlier onset of marijuana (-.33, p < .01) and cocaine use (r = -.24, p <.01). The less acculturated parents experienced more parenting stress (r = -.31, p = < .01). Attachment was positively associated with parental peer involvement (r = .24, p < .05) and inversely associated with parenting acculturative stress (r = -.24, p < .05). Attachment was also positively associated with marijuana (r = .39, p < .01) and cocaine use (r = .33, p < .01). Adolescent males reported being more attached to their mothers when compared to adolescent females (r = .22, p >.05), they also reported using marijuana more frequently than females (.21, p >.05). ^

Social capital, HIV risk behavior and substance use among recent Latino immigrants in South Florida

Social capital, or social cohesion or group connectedness, can influence both HIV risk behavior and substance use. Because recent immigrants undergo a change in environment, one of the consequences can be a change in social capital. There may be an association among changes in social capital, and HIV risk behavior and substance use post immigration. The dissertation focused on the interface of these three variables among recent Latino immigrants (RLIs) in South Florida. The first manuscript is a systematic review of social capital and HIV risk behavior, and served as a partial background for the second and third manuscripts. Twelve papers with a measure of social capital as an independent variable and HIV risk as the dependent variable were included in the analysis. Eleven studies measured social capital at the individual level, and one study measured social capital at the group level. HIV risk was influenced by social capital, but the type of influence was dependent on the type of social capital and on the study population. Cognitive social capital, or levels of collective action, was protective against HIV in both men and women. The role of structural social capital, or levels of civic engagement/group participation, on HIV risk was dependent on the type of structural social capital and varied by gender. Microfinance programs and functional group participation were protective for women, while dysfunctional group participation and peer-level support may have increased HIV risk among men. The second manuscript was an original study assessing changes in social capital and HIV risk behavior pre to post immigration among RLIs in South Florida (n=527). HIV risk behavior was assessed through the frequency of vaginal-penile condom use, and the number of sexual partners. It was a longitudinal study using secondary data analysis to assess changes in social capital and HIV risk behavior pre immigration to two years post immigration, and to determine if there was a relationship between the two variables. There was an 8% decrease in total social capital (p < .05). Reporting of 'Never use' of condoms in the past 90 days increased in all subcategories (p < .05). Single men had a decrease in number of sexual partners (p < .05). Lower social capital measured on the dimension of 'friend and other' was marginally associated with fewer sexual partners. The third manuscript was another original study looking at the association between social capital and substance use among RLIs in South Florida (n=527). Substance use with measured by frequency of hazardous alcoholic drinking, and illicit drug use. It was a longitudinal study of social capital and substance-use from pre to two years post immigration. Post-immigration, social capital, hazardous drinking and illicit drug use decreased (p<.001). After adjusting for time, compared to males, females were less likely to engage in hazardous drinking (OR=.31, p<.001), and less likely to engage in illicit drug use (OR=.67, p=.01). Documentation status was a moderator between social capital and illicit drug use. 'Business' and 'Agency' social capital were associated with changes in illicit drug use for documented immigrants. After adjusting for gender and marital status, on average, documented immigrants with a one-unit increase in 'business' social capital were 1.2 times more likely to engage in illicit drug use (p<.01), and documented immigrants with one-unit increase in 'agency' social capital were 38% less likely to engage in illicit drug use (p<.01). 'Friend and other' social capital was associated with a decrease in illicit drug use among undocumented immigrants. After adjusting for gender and marital status, on average, undocumented immigrants with a one-unit increase in 'friend and other' social capital were 45% less likely to engage in hazardous drinking and 44% less likely to use illicit drugs (p<.01, p<.05). Studying these three domains is relevant because HIV continues to be a public health issue, particularly in Miami-Dade County, which is ranked among other U.S. regions with high rates of HIV/AIDS prevalence. Substance use is associated with HIV risk behavior; in most studies, increased substance use is associated with increased chances of HIV risk behavior. Immigration, which is the hypothesized catalyst for the change in social capital, has an impact on the dynamic of a society. Greater immigration can be burdensome on the host country's societal resources; however immigrants are also potentially a source of additional skilled labor for the workforce. Therefore, successful adaption of immigrants can have a positive influence on receiving communities. With Florida being a major receiver of immigrants to the U.S, this dissertation attempts to address an important public health issue for South Florida and the U.S. at large.

The effect of multimedia instruction on achievement of college history students

The purpose of this study was to investigate the effect of multimedia instruction on achievement of college students in AMH 2010 from exploration and discovery to1865. A non-equivalent control group design was used. The dependent variable was achievement. The independent variables were learning styles method of instruction, and visual clarifiers (notes). The study was conducted using two history sections from Palm Beach Community College, in Boca Raton, Florida, between August and December, 1998. Data were obtained by means of placement scores, posttests, the Productivity Environmental Preference Survey (PEPS), and a researcher-developed student survey. Statistical analysis of the data was done using SPSS statistical software. Demographic variables were compared using Chi square. T tests were run on the posttests to determine the equality of variances. The posttest scores of the groups were compared using the analysis of covariance (ANCOVA) at the .05 level of significance. The first hypothesis there is a significant difference in students' learning of U.S. History when students receive multimedia instruction was supported, F = (1, 52)= 688, p < .0005, and F = (1, 53) = 8.52, p < .005for Tests 2 and 3, respectively. The second hypothesis there is a significant difference on the effectiveness of multimedia instruction based on students' various learning preferences was not supported. The last hypotheses there is a significant difference on students' learning of U.S. History when students whose first language is other than English and students who need remediation receive visual clarifiers were not supported. Analysis of covariance (ANCOVA) indicated no difference between the groups on Test 1, Test 2, or Test 3: F (1, 4 5)= .01, p < .940, F (l, 52) = .77, p < .385, and F (1,53) =.17, p > .678, respectively, for language. Analysis of covariance (ANCOVA) indicated no significant difference on Test 1, Test 2, or Test 3, between the groups on the variable remediation: F (1, 45) = .31, p < .580, F (1, 52) = 1.44, p < .236, and F (1, 53) = .21, p < .645, respectively.

Estructura familiar no informativa y fenotipo tumoral triple-negativo como variables predictivas de mutaciones germinales en "BRCA1/2" en mujeres jóvenes con cáncer de mama esporádico

Un porcentaje no desdeñable de mujeres jóvenes con cáncer de mama esporádico son portadoras de mutaciones germinales en BRCA1/2. Esta prevalencia está estrechamente condicionada por otras variables como el tipo de población, fenotipo tumoral y edad de diagnóstico de cáncer de mama. La presencia de una estructura familiar no informativa es una variable predictiva de la presencia de mutaciones en BRCA1/2 en estas pacientes, pero este hallazgo no ha sido debidamente validado en cohortes independientes. Existe una fuerte asociación entre las mutaciones en BRCA1 y los tumores mamarios de tipo triple negativo (TN). En el presente trabajo analizamos la utilidad de las variables estructura familiar no informativa y fenotipo TN como variables predictivas de mutaciones germinales en BRCA1/2 en una cohorte de mujeres jóvenes ( 35 años) con cáncer de mama esporádico previamente remitidas (1998-2012) a unidades de asesoramiento genético españolas (n = 341). Retrospectivamente, la estructura familiar fue clasificada en informativa, no informativa o no clasificable mediante la revisión centralizada de los pedigrees disponibles en el momento de realizarse los respectivos estudios genéticos. Asimismo, los tumores de mama fueron clasificados en TN, no-TN y no clasificables mediante la revisión de las historias clínicas. Veinticuatro pacientes (7.12 %) fueron portadoras de mutaciones patogénicas, 14 en BRCA1 y 10 en BRCA2. Tanto la estructura familiar no informativa (OR = 3.61, p = 0.027) como el subtipo TN (OR = 3.14, p = 0.013) fueron variables independientes de la presencia de mutaciones germinales en BRCA1/2. La prevalencia de mutaciones en el subgrupo de mujeres con al menos un factor predictivo (estructura familiar no informativa, subtipo TN o ambos) fue del 13.5 %, frente al 2.8 % en aquellas mujeres con estrucutra familiar informativa y tumores no-TN (OR = 5.31, p = 0.006). Demostramos, con la información disponible en un contexto de práctica clínica rutinaria, la utilidad de la estructura familiar y el fenotipo TN como modelo predictivo de mutaciones germinales en BRCA1/2 en mujeres jóvenes con cáncer de mama esporádico. Nuestro estudio sugiere que restringir el análisis tan solo a aquellas mujeres con al menos un factor predicitivo podría ser una estrategia válida para optimizar la realización de estudios genéticos en este subgrupo de mujeres.

Usual medical treatments or levonorgestrel-IUS for women with heavy menstrual bleeding:long-term randomised pragmatic trial in primary care

Background: Heavy menstrual bleeding (HMB) is a common, chronic problem affecting women and health services. However, long-term evidence on treatment in primary care is lacking. Aim: To assess the effectiveness of commencing the levonorgestrel-releasing intrauterine system (LNG-IUS) or usual medical treatments for women presenting with HMB in general practice. Design and setting: A pragmatic, multicentre, parallel, open-label, long term, randomised controlled trial in 63 primary care practices across the English Midlands. Method: In total, 571 women aged 25–50 years, with HMB were randomised to LNG-IUS or usual medical treatment (tranexamic/mefenamic acid, combined oestrogen–progestogen, or progesterone alone). The primary outcome was the patient reported Menorrhagia Multi-Attribute Scale (MMAS, measuring effect of HMB on practical difficulties, social life, psychological and physical health, and work and family life; scores from 0 to 100). Secondary outcomes included surgical intervention (endometrial ablation/hysterectomy), general quality of life, sexual activity, and safety. Results: At 5 years post-randomisation, 424 (74%) women provided data. While the difference between LNG-IUS and usual treatment groups was not significant (3.9 points; 95% confidence interval = −0.6 to 8.3; P = 0.09), MMAS scores improved significantly in both groups from baseline (mean increase, 44.9 and 43.4 points, respectively; P<0.001 for both comparisons). Rates of surgical intervention were low in both groups (surgery-free survival was 80% and 77%; hazard ratio 0.90; 95% CI = 0.62 to 1.31; P = 0.6). There was no difference in generic quality of life, sexual activity scores, or serious adverse events. Conclusion: Large improvements in symptom relief across both groups show treatment for HMB can be successfully initiated with long-term benefit and with only modest need for surgery.

School and Community Screening Shows Malawi, Africa, to Have a High Prevalence of Latent Rheumatic Heart Disease

Rheumatic heart disease (RHD) is the largest cardiac cause of morbidity and mortality in the world's youth. Early detection of RHD through echocardiographic screening in asymptomatic children may identify an early stage of disease, when secondary prophylaxis has the greatest chance of stopping disease progression. Latent RHD signifies echocardiographic evidence of RHD with no known history of acute rheumatic fever and no clinical symptoms.

OBJECTIVE: Determine the prevalence of latent RHD among children ages 5-16 in Lilongwe, Malawi.

DESIGN: This is a cross-sectional study in which children ages 5 through 16 were screened for RHD using echocardiography.

SETTING: Screening was conducted in 3 schools and surrounding communities in the Lilongwe district of Malawi between February and April 2014.

OUTCOME MEASURES: Children were diagnosed as having no, borderline, or definite RHD as defined by World Heart Federation criteria. The primary reader completed offline reads of all studies. A second reader reviewed all of the studies diagnosed as RHD, plus a selection of normal studies. A third reader served as tiebreaker for discordant diagnoses. The distribution of results was compared between gender, location, and age categories using Fisher's exact test.

RESULTS: The prevalence of latent RHD was 3.4% (95% CI = 2.45, 4.31), with 0.7% definite RHD and 2.7% borderline RHD. There was no significant differences in prevalence between gender (P = .44), site (P = .6), urban vs. peri-urban (P = .75), or age (P = .79). Of those with definite RHD, all were diagnosed because of pathologic mitral regurgitation (MR) and 2 morphologic features of the mitral valve. Of those with borderline RHD, most met the criteria by having pathological MR (92.3%).

CONCLUSION: Malawi has a high rate of latent RHD, which is consistent with other results from sub-Saharan Africa. This study strongly supports the need for a RHD prevention and control program in Malawi.

Changes of 5-hydroxymethylcytosine distribution during myeloid and lymphoid differentiation of CD34+ cells

BACKGROUND: Hematopoietic stem cell renewal and differentiation are regulated through epigenetic processes. The conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) by ten-eleven-translocation enzymes provides new insights into the epigenetic regulation of gene expression during development. Here, we studied the potential gene regulatory role of 5hmC during human hematopoiesis.

RESULTS: We used reduced representation of 5-hydroxymethylcytosine profiling (RRHP) to characterize 5hmC distribution in CD34+ cells, CD4+ T cells, CD19+ B cells, CD14+ monocytes and granulocytes. In all analyzed blood cell types, the presence of 5hmC at gene bodies correlates positively with gene expression, and highest 5hmC levels are found around transcription start sites of highly expressed genes. In CD34+ cells, 5hmC primes for the expression of genes regulating myeloid and lymphoid lineage commitment. Throughout blood cell differentiation, intragenic 5hmC is maintained at genes that are highly expressed and required for acquisition of the mature blood cell phenotype. Moreover, in CD34+ cells, the presence of 5hmC at enhancers associates with increased binding of RUNX1 and FLI1, transcription factors essential for hematopoiesis.

CONCLUSIONS: Our study provides a comprehensive genome-wide overview of 5hmC distribution in human hematopoietic cells and new insights into the epigenetic regulation of gene expression during human hematopoiesis.

Marine inspired biosilica-filled hydrogels for hard tissue repair

• P.J Walsh, Susan Clarke, Iossif Strehin, Phillip Messersmith. “Marine inspired biosilica-filled hydrogels for hard tissue repair”. 26th European Conference on Biomaterials 2014, Liverpool, UK

Circulating miRNAs: Potential Novel Biomarkers for Hepatopathology Progression and Diagnosis of Schistosomiasis Japonica in Two Murine Models

BACKGROUND: Schistosomiasis remains a major public health issue, with an estimated 230 million people infected worldwide. Novel tools for early diagnosis and surveillance of schistosomiasis are currently needed. Elevated levels of circulating microRNAs (miRNAs) are commonly associated with the initiation and progression of human disease pathology. Hence, serum miRNAs are emerging as promising biomarkers for the diagnosis of a variety of human diseases. This study investigated circulating host miRNAs commonly associated with liver diseases and schistosome parasite-derived miRNAs during the progression of hepatic schistosomiasis japonica in two murine models.

METHODOLOGY/PRINCIPAL FINDINGS: Two mouse strains (C57BL/6 and BALB/c) were infected with a low dosage of Schistosoma japonicum cercariae. The dynamic patterns of hepatopathology, the serum levels of liver injury-related enzymes and the serum circulating miRNAs (both host and parasite-derived) levels were then assessed in the progression of schistosomiasis japonica. For the first time, an inverse correlation between the severity of hepatocyte necrosis and the level of liver fibrosis was revealed during S. japonicum infection in BALB/c, but not in C57BL/6 mice. The inconsistent levels of the host circulating miRNAs, miR-122, miR-21 and miR-34a in serum were confirmed in the two murine models during infection, which limits their potential value as individual diagnostic biomarkers for schistosomiasis. However, their serum levels in combination may serve as a novel biomarker to mirror the hepatic immune responses induced in the mammalian host during schistosome infection and the degree of hepatopathology. Further, two circulating parasite-specific miRNAs, sja-miR-277 and sja-miR-3479-3p, were shown to have potential as diagnostic markers for schistosomiasis japonica.

CONCLUSIONS/SIGNIFICANCE: We provide the first evidence for the potential of utilizing circulating host miRNAs to indicate different immune responses and the severity of hepatopathology outcomes induced in two murine strains infected with S. japonicum. This study also establishes a basis for the early and cell-free diagnosis of schistosomiasis by targeting circulating schistosome parasite-derived miRNAs.

FLIP: a targetable mediator of resistance to radiation in non-small cell lung cancer

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IR-induced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR.

Redox-dependent conformational switching of diphenylacetylenes

Herein we describe the design and synthesis of a redox-dependent single-molecule switch. Appending a ferrocene unit to a diphenylacetylene scaffold gives a redox-sensitive handle, which undergoes reversible one-electron oxidation, as demonstrated by cyclic voltammetry analysis. ¹H-NMR spectroscopy of the partially oxidized switch and control compounds suggests that oxidation to the ferrocenium cation induces a change in hydrogen bonding interactions that results in a conformational switch.