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Background: Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown., Methods: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort., Results: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort., Conclusion: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Intra-tumoral CD8 + T-cell infiltration in squamous cell carcinoma of the head and neck (HNSCC) has previously been linked to the efficacy of cisplatin-based chemoradiation (CDDP-CRTX) and immune checkpoint inhibitor (ICI) monotherapy. Further detailed characterization of the tumor immune-micromilieu and its influence on outcome may guide the development of CRTX-ICI combinations., Methods: Comprehensive immune transcriptome analysis was applied to a training set of tumor specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients treated with CDDP-CRTX in the ARO-0401 phase III study (n = 33). A composite immune signature risk score (ISRS) for survival prediction was developed, and subsequently validated in two independent OPSCC cohorts treated with either CDDP-CRTX (n = 36) or mitomycin-based CRTX (MMC-CRTX, n = 31). Further validation of the ISRS was performed in the OPSCC subset (n = 79) of the TCGA HNSCC cohort. Potential interference between immune signatures and HPV status was evaluated in multivariate Cox regression models., Results: Significant differences according to the 3-y OS status in the abundance of tumor-infiltrating T- and B-cells, and the expression levels of 51 immune-related genes were observed. A risk score based on 13 differentially expressed genes involved in cytokine signaling, T-cell effector functions and the TNFR pathway was established as robust predictive factor of OS. Its predictive power was superior to the 6-gene interferon-gamma signature of ICI efficacy and independent of the HPV status., Conclusions: This study further elucidates the complex interaction of the tumor immune microenvironment with the efficacy of CDDP-CRTX in OPSCC. The results suggest immune markers for selection of patients treated with CRTX-ICI combinations.

Background: Family planning is an effective tool for preventing death among women who do not want to become pregnant and has been shown to improve newborn health outcomes, advance women's empowerment, and bring socioeconomic benefits through reductions in fertility and population growth. Yet among the populations that would benefit the most from family planning, uptake remains too low. The emergence of digital health tools has created new opportunities to strengthen health systems and promote behavior change. In this study, women with an unmet need for family planning in Western Kenya were randomized to receive an encouragement to try an automated investigational digital health intervention that promoted the uptake of family planning., Objective: The objectives of the pilot study were to explore the feasibility of a full-scale trial-in particular, the recruitment, encouragement, and follow-up data collection procedures-and to examine the preliminary effect of the intervention on contraception uptake., Methods: This pilot study tested the procedures for a randomized encouragement trial. We recruited 112 women with an unmet need for family planning from local markets in Western Kenya, conducted an eligibility screening, and randomized half of the women to receive an encouragement to try the investigational intervention. Four months after encouraging the treatment group, we conducted a follow-up survey with enrolled participants via short message service (SMS) text message., Results: The encouragement sent via SMS text messages to the treatment group led to differential rates of intervention uptake between the treatment and control groups; however, uptake by the treatment group was lower than anticipated (19/56, 33.9% vs 1/56, 1.8%, in the control group). Study attrition was also substantial. We obtained follow-up data from 44.6% (50/112) of enrolled participants. Among those in the treatment group who tried the intervention, the instrumental variables estimate of the local average treatment effect was an increase in the probability of contraceptive uptake of 41.0 percentage points (95% uncertainty interval -0.03 to 0.85)., Conclusions: This randomized encouragement design and study protocol is feasible but requires modifications to the recruitment, encouragement, and follow-up data collection procedures., Trial Registration: ClinicalTrials.gov NCT03224390; https://clinicaltrials.gov/ct2/show/NCT03224390 (Archived by WebCite at http://www.webcitation.org/70yitdJu8)., (©Eric P Green, Arun Augustine, Violet Naanyu, Anna-Karin Hess, Lulla Kiwinda. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 31.07.2018.)

Background: The predictive value of microRNAs (miRNAs) in tumour cells and infiltrating immune cells for the efficacy of chemoradiation (CRTX) in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated., Methods: Formalin-fixed, paraffin-embedded tumour material was collected from patients with locally advanced HNSCC treated within the ARO-0401 phase III trial with radiotherapy in combination with either 5-fluorouracil/cisplatin (CDDP-CRTX) or 5-fluorouracil/mitomycin C (MMC-CRTX). MiRNA and immune profiles were established in a test cohort of 48 oropharyngeal carcinoma (OPSCC) cases by Affymetrix miRNA microarrays and the nanoString PanCancer Immune Panel, respectively. Expression of miRNA candidates was measured in 149 HNSCC patients by real-time PCR. Interference of miRNA profiles with CRTX efficacy was determined by Kaplan-Meier and Cox regression analysis., Results: Expression levels of five miRNAs (miR-27b, -130b, -200b, -451 and -532-5p) were significantly associated with overall survival after MMC-CRTX. Six different miRNAs (miR-125b, -146a, -150, -155, -187 and -342-5p) were correlated with overall survival after CDDP-CRTX. Validation by real-time PCR confirmed the predictive value of miR-200b and miR-155 in OPSCC, which was absent in hypopharyngeal carcinomas. MiR-146a was revealed as a prognostic marker for both CRTX regimens. MiR-200b expression was mainly associated with distant metastasis, whereas miR-155 correlated with local recurrence. MiR-155 and miR-146a were identified as surrogate markers for tumour-infiltrating lymphocytes., Conclusions: MiR-200b and miR-155 were established as potential markers for personalised treatment selection of two standard regimens of CRTX. The predictive role of miR-155 deserves further investigation, especially within the framework of clinical trials of CRTX/immune checkpoint inhibitor combinations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite recent advances in radiochemotherapy, treatment of locally advanced head and neck squamous cell carcinoma is still challenging, and survival rates have improved only slightly. This is due to the high frequency of metastases and local and/or regional tumor recurrences that have acquired radio- or chemoresistance. MiRNAs regulate diverse processes in tumorigenesis, metastasis, and therapy resistance in head and neck squamous cell carcinoma. Hence, miRNAs are highly valued in biomarker studies. Establishment of the miRNA profiles of oropharyngeal tumors enables personalized treatment selection, since expression of distinct miRNAs can predict the response to two different radiochemotherapy regimens. Development of novel miRNA therapeutics has a high clinical potential for further improving treatment of cancerous disease. The use of nanoparticles with distinct surface modifications as miRNA vectors permits prolonged bioavailability, high efficacy in tumor targeting, and low toxicity. Nevertheless, the efficacy of miRNA therapy has only been shown in animal models to date.

mRNA is translated with a non-uniform speed that actively coordinates co-translational folding of protein domains. Using structure-based homology we identified the structural domains in epoxide hydrolases (EHs) and introduced slow-translating codons to delineate the translation of single domains. These changes in translation speed dramatically improved the solubility of two EHs of metagenomic origin in Escherichia coli. Conversely, the importance of transient attenuation for the folding, and consequently solubility, of EH was evidenced with a member of the EH family from Agrobacterium radiobacter, which partitions in the soluble fraction when expressed in E. coli. Synonymous substitutions of codons shaping the slow-transiting regions to fast-translating codons render this protein insoluble. Furthermore, we show that low protein yield can be enhanced by decreasing the free folding energy of the initial 5'-coding region, which can disrupt mRNA secondary structure and enhance ribosomal loading. This study provides direct experimental evidence that mRNA is not a mere messenger for translation of codons into amino acids but bears an additional layer of information for folding, solubility and expression level of the encoded protein. Furthermore, it provides a general frame on how to modulate and fine-tune gene expression of a target protein.

Sperm proteins of marine sessile invertebrates have been extensively studied to understand the molecular basis of reproductive isolation. Apart from molecules such as bindin of sea urchins or lysin of abalone species, the acrosomal protein M7 lysin of Mytilus edulis has been analyzed. M7 lysin was found to be under positive selection, but mechanisms driving the evolution of this protein are not fully understood. To explore functional aspects, this study investigated the protein expression pattern of M7 and M6 lysin in gametes and somatic tissue of male and female M. edulis. The study employs a previously published monoclonal antibody (G26-AG8) to investigate M6 and M7 lysin protein expression, and explores expression of both genes. It is shown that these proteins and their encoding genes are expressed in gametes and somatic tissue of both sexes. This is in contrast to sea urchin bindin and abalone lysin, in which gene expression is strictly limited to males. Although future studies need to clarify the functional importance of both acrosomal proteins in male and female somatic tissue, new insights into the evolution of sperm proteins in marine sessile invertebrates are possible. This is because proteins with male-specific expression (bindin, lysin) might evolve differently than proteins with expression in both sexes (M6/M7 lysin), and the putative function of both proteins in females opens the possibility that the evolution of M6/M7 lysin is under sexual antagonistic selection, for example, mutations beneficial to the acrosomal function that are less beneficial the function in somatic tissue of females., (Copyright © 2012 Wiley Periodicals, Inc.)

Two experiments were conducted to assess the degree to which violent media stimulate violent fantasy as depicted on inkblot responses. In Experiment I, 41 gifted high school students were exposed to a bucolic or violent film clip and then were asked to produce inkblot responses. In Experiment II, a second sample of 43 additional students were exposed to a verbal description of the bucolic or violent scene to assess whether the "hot" or "cooler" media (McLuhan, 1964) had different effects on the inkblot responses. In both experiments, the media exposure led to increased levels of violent responses, and in both cases males produced more violent responses. There was no sex by media interaction effect. Implications for clinical and forensic assessments are presented.

The intelligence levels of three groups of mothers were ascertained by the vocabulary test of the Stanford-Binet Intelligence Scale. Eight mothers having children diagnosed as failure-to-thrive due to non-organic reasons (FTT-E), eight mothers with children diagnosed as failure-to-thrive due to physically traceable reasons (FTT-O), and eight mothers with children hospitalized due to reasons other than failure-to-thrive (C), were contrasted on intelligence, age, education and the presence or absence of the father in the home. Hypotheses regarding a disadvantage of FTT-E mothers on the four variables were supported. Implications of the results were discussed regarding programmes dealing with failure-to-thrive children and mothers. Further investigation in this area was proposed.

The assumption is presented of the test-taker as a hypothesis-generating organism who can become "testwise." Testwiseness is defined as a stable skill, acquired by test-taking experiences, by which an individual can make test responses conform to a desired response pattern. Forty-three college students completed two forms of The Personality Research Form (PRF) and a rank ordering of their predicted personality need pattern. Results show significantly higher correlations of PRF predictions in the second administration. Analyses show PRF profiles, not predictions, to have been modified. Furthermore, high testwise subjects had higher needs for Understanding and Nurturance, and lower needs for Aggression and Defendence than low testwise persons. The importance of considering testwiseness, given trends in society encouraging access to psychological records, is discussed.

Fifty-eight adult male felons were given the Minnesota Multiphasic Personality Inventory (MMPI), the Buss - Durkee Hostility Inventory ( BDHI ), and the Draw-a-Person Test (DAP) to test the relative sensitivity of subtlety or obviousness of items to response sets. The inmates were randomly assigned to three response set groups: a fake-aggressive group, a fake-nonaggressive group, and a standard-instruction control group. The MMPIs were scored for five obvious and five subtle aggression or hostility research scales. The BDHI is a totally obvious test, whereas the DAP is a very subtle measure. A paradoxical relationship between response set and subtlety of the scales was hypothesized, such that the obvious scales could be successfully faked , but the subtle scales would show scores in the opposite from the intended direction. It was found that the inmates did correctly manipulate the obvious scales, but the subtle scales did not consistently show the hypothesized trend. Possible reasons for this are discussed, including the nature of the scales used and characteristics of the population.

The effects of aggressive and nonaggressive response sets on the MMPI subtle and obvious clinical subscales were investigated. Fifty-eight male prison inmates answered the MMPI as if they were either highly aggressive or highly nonaggressive. The clinical scales with sufficient items in each category were scored for subtle, neutral, and obvious subscales. Inmates successfully feigned aggressiveness on several of the obvious subscales (p = .0056) and one neutral scale; the subtle subscales were not significantly different across groups, consistent with previous research on this population in terms of the resistance of subtle items to these response sets.

The relationship of the WISC-R Arithmetic and WRAT Arithmetic scales to grades was determined for a sample of 8 female and 14 male juvenile delinquents. The WISC-R correlated .538 with grades and .302 with the WRAT, while the WRAT correlated .289 with grades. The WISC-R also correlated .508 with sex (females scoring higher). While WRAT Arithmetic is questioned as an indicator of academic achievement, WISC-R accounts for 29% of grades variance and may be a useful correlate.