A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.

Cancer cells are typically subject to profound metabolic alterations, including the Warburg effect wherein cancer cells oxidize a decreased fraction of the pyruvate generated from glycolysis. We show herein that the mitochondrial pyruvate carrier (MPC), composed of the products of the MPC1 and MPC2 genes, modulates fractional pyruvate oxidation. MPC1 is deleted or underexpressed in multiple cancers and correlates with poor prognosis. Cancer cells re-expressing MPC1 and MPC2 display increased mitochondrial pyruvate oxidation, with no changes in cell growth in adherent culture. MPC re-expression exerted profound effects in anchorage-independent growth conditions, however, including impaired colony formation in soft agar, spheroid formation, and xenograft growth. We also observed a decrease in markers of stemness and traced the growth effects of MPC expression to the stem cell compartment. We propose that reduced MPC activity is an important aspect of cancer metabolism, perhaps through altering the maintenance and fate of stem cells.

Sub-Regional Assessment of HPV Vaccination Among Female Adolescents in the Intermountain West and Implications for Intervention Opportunities.

Objectives We investigated the similarities and differences in the factors related to human papillomavirus (HPV) vaccination of female adolescents in three sub-regions of the Intermountain West (IW). Methods We analyzed 2011-2012 National Immunization Survey-Teen data. Respondents (parents) who were living in the IW and who had daughters aged 13-17 years old with provider-verified immunization records were included in our analyses. East, Central, and West sub-regions were defined based on geographic contiguity and similarity in HPV vaccination rates and sociodemographic characteristics. Survey-weighted Chi square tests and multivariable Poisson regressions were performed. Results In all three sub-regions, older teen age and receipt of other recommended adolescent vaccinations were significantly associated with HPV vaccination. In the East sub-region, providers' facility type and source of vaccines were significantly related to HPV vaccination. In the Central sub-region, teens with married parents were significantly less likely to be vaccinated than were those with unmarried parents. In the West sub-region, non-Hispanic teens were significantly less likely to be vaccinated than were Hispanic teens. Conclusions for Practice In order to improve HPV vaccine coverage in the IW, region-wide efforts to target younger teens and to promote the HPV vaccine with other recommended adolescent vaccinations should be supplemented with sub-regional attention to the health care system (East sub-region), to married parents (Central sub-region), and to non-Hispanic teens (West sub-region).

Genome Modeling System: A Knowledge Management Platform for Genomics.

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformatics development, allowing a large team to collaborate on data analysis, or an individual researcher to leverage the work of others effectively within its data management system. Rather than separating ad-hoc analysis from rigorous, reproducible pipelines, the GMS promotes systematic integration between the two. As a demonstration of the GMS, we performed an integrated analysis of whole genome, exome and transcriptome sequencing data from a breast cancer cell line (HCC1395) and matched lymphoblastoid line (HCC1395BL). These data are available for users to test the software, complete tutorials and develop novel GMS pipeline configurations. The GMS is available at https://github.com/genome/gms.

Episodic medication adherence in adolescents and young adults with perinatally acquired HIV: a within-participants approach.

Due to the success of antiretroviral (ART) medications, young people living with perinatally acquired HIV (PHIV+) are now surviving into adolescence and young adulthood. Understanding factors influencing ART non-adherence in this group is important in developing effective adherence interventions. Most studies of ART adherence in HIV-positive populations assess differences in adherence levels and adherence predictors between participants, over a period of time (global adherence). Many individuals living with HIV, however, including PHIV+ young people, take medication inconsistently. To investigate this pattern of adherence, a within-participants design, focussing on specific episodes of adherence and non-adherence, is suitable (episodic adherence). A within-participants design was used with 29 PHIV+ young people (17 female, median age 17 years, range 14-22 years), enrolled in the UK Adolescents and Adults Living with Perinatal HIV cohort study. Participants were eligible if they could identify one dose of medication taken and one dose they had missed in the previous two months. For each of the two episodes (one adherent, one non-adherent), behavioural factors (whom they were with, location, routine, day, reminders) and psychological factors at the time of the episode (information about medication, adherence motivation, perceived behavioural skills to adhere to medication - derived from the Information-Motivation-Behavioural Skills (IMB) Model - and affect) were assessed in a questionnaire. Non-adherence was significantly associated with weekend days (Friday to Sunday versus Monday to Thursday, p = .001), lack of routine (p = .004), and being out of the home (p = .003), but not with whom the young person was with or whether they were reminded to take medication. Non-adherence was associated with lower levels of behavioural skills (p < .001), and lower positive affect (p = .005). Non-adherence was not significantly associated with negative affect, information about ART, or ART motivation. The use of situationally specific strategies to enhance adherence in young people who take their medication inconsistently is proposed.

Internal working models and adjustment of physically abused children: the mediating role of self-regulatory abilities.

BACKGROUND: Abused children's internal working models (IWM) of relationships are known to relate to their socioemotional adjustment, but mechanisms through which negative representations increase vulnerability to maladjustment have not been explored. We sought to expand the understanding of individual differences in IWM of abused children and investigate the mediating role of self-regulation in links between IWM and adjustment. METHODS: Cluster analysis was used to subgroup 74 physically abused children based on their IWM. Internal working models were identified by children's representations, as measured by a narrative story stem task. Self-regulation was assessed by teacher report and a behavioral task, and adjustment was measured by teacher report. RESULTS: Cluster analyses indicated two subgroups of abused children with distinct patterns of IWMs. Cluster membership predicted internalizing and externalizing problems. Associations between cluster membership and adjustment were mediated by children's regulation, as measured by teacher reports of many aspects of regulation. There was no support for mediation when regulation was measured by a behavioral task that tapped more narrow facets of regulation. CONCLUSIONS: Abused children exhibit clinically relevant individual differences in their IWMs; these models are linked to adjustment in the school setting, possibly through children's self-regulation.

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.

Science Communication Training Imparts Confidence and Influences Public Engagement Activity.

The impacts of science are felt across all socio-ecological levels, ranging from the individual to societal. In order to adapt or respond to scientific discoveries, novel technologies, or biomedical or environmental challenges, a fundamental understanding of science is necessary. However, antiscientific rhetoric, mistrust in science, and the dissemination of misinformation hinder the promotion of science as a necessary and beneficial component of our world. Scientists can promote scientific literacy by establishing dialogues with nonexperts, but they may find a lack of formal training as a barrier to public engagement. To address this, the American Society for Biochemistry and Molecular Biology (ASBMB) launched the Art of Science Communication course in 2015 in order to provide scientists at all career stages with introductory science communication training. In 2020, we conducted a retrospective survey of former participants to evaluate how the course had impacted participants' science communication behaviors and their confidence engaging with nonexperts, as well as other benefits to their professional development. We found that scientists were significantly more likely to communicate with nonexpert audiences following the course compared to before (77% versus 51%; P < 0.0001). In addition, quantitative and qualitative data suggested that scientists were more confident in their ability to communicate science after completing the course (median of 8, standard deviation [SD] of 0.98 versus median of 5, SD of 1.57; P < 0.0001). Qualitative responses from participants supported quantitative findings. This suggested that the Art of Science Communication course is highly effective at improving the confidence of scientists to engage with the public and other nonexpert audiences regardless of career status. These data-driven perspectives provide a rationale for the implementation of broadly accessible science communication training programs that promote public engagement with science.

Management of pulmonary hypertension in Down syndrome.

UNLABELLED: Children with Down syndrome (DS) are at greater risk of pulmonary arterial hypertension (PAH) than the general population, partly due to upper airway obstruction and congenital heart disease. We wished to review our management of PAH and suggest a protocol for the systematic management of these children. Children with DS and PAH were included as referred for assessment from March 2005 to May 2010. Twenty-five patients (13 boys) met inclusion criteria. The median age was 385 days (range, 106 to 5,734); mean tricuspid regurgitation jet was 3.5 (range, 2.7-4.8) m/s. At cardiac catheterisation, mean pulmonary artery mean pressure was 26 mmHg (range, 12 to 46), and mean pulmonary vascular resistance (PVR) was 4.14 U.m² (range, 1.20 to 12.43) at baseline. PVR fell to a mean of 2.68 U.m² (range, 0.38 to 10.69) with 20 ppm inhaled nitric oxide and 100% oxygen. Respiratory assessment included polysomnography (18), bronchoscopy (16), showing malacia (eight), adenotonsillar hypertrophy (eight) and floppy aryepiglottic folds (four). One lung biopsy showed plexogenic arteriopathy, and one was diagnosed with tracheo-oesophageal fistula. CONCLUSION: In order to manage this complex group of patients, a combined cardiological, respiratory and surgical approach was required. A protocol with cardiac catheterisation, blood tests and respiratory assessment is suggested for the management of pulmonary hypertension in these children.

In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation.

A homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1) has been implicated in hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), an autosomal recessive neurodegenerative disease. However, it is uncertain how the H493R mutation elicits the specific pathologies of SCAN1. To address this question, and to further elucidate the role of TDP1 in repair of DNA end modifications and general physiology, we generated a Tdp1 knockout mouse and carried out detailed behavioral analyses as well as characterization of repair deficiencies in extracts of embryo fibroblasts from these animals. While Tdp1(-/-) mice appear phenotypically normal, extracts from Tdp1(-/-) fibroblasts exhibited deficiencies in processing 3'-phosphotyrosyl single-strand breaks and 3'-phosphoglycolate double-strand breaks (DSBs), but not 3'-phosphoglycolate single-strand breaks. Supplementing Tdp1(-/-) extracts with H493R TDP1 partially restored processing of 3'-phosphotyrosyl single-strand breaks, but with evidence of persistent covalent adducts between TDP1 and DNA, consistent with a proposed intermediate-stabilization effect of the SCAN1 mutation. However, H493R TDP1 supplementation had no effect on phosphoglycolate (PG) termini on 3' overhangs of double-strand breaks; these remained completely unprocessed. Altogether, these results suggest that for 3'-phosphoglycolate overhang lesions, the SCAN1 mutation confers loss of function, while for 3'-phosphotyrosyl lesions, the mutation uniquely stabilizes a reaction intermediate.

The Student-Teacher Relationship Quality of Abused Children.

Considering the association between children's quality of relationships with teachers and their academic adjustment, information pertaining to how abused children are functioning in their relationships with teachers could be useful in promoting their academic success- yet there has been limited research in this area. The purpose of this study was to use cluster analyses to explore within-group differences in relational schemas and quality of student-teacher relationships for 70 abused children. Two clusters of abused children emerged, and as hypothesized, there were significant differences in student-teacher relationships for the two clusters. The cluster with more positive relational schemas had less conflict and less dependency reported by their teachers compared to the cluster with negative relational schemas. However, there were no differences between the clusters in terms of closeness with teachers. Implications for practice in schools is discussed.

A Systematic Review of End-of-Life Care Communication Skills Training for Generalist Palliative Care Providers: Research Quality and Reporting Guidance.

CONTEXT: End-of-life care (EoLC) communication skills training for generalist palliative care providers is recommended in policy guidance globally. Although many training programs now exist, there has been no comprehensive evidence synthesis to inform future training delivery and evaluation. OBJECTIVES: To identify and appraise how EoLC communication skills training interventions for generalist palliative care providers are developed, delivered, evaluated, and reported. METHODS: Systematic review. Ten electronic databases (inception to December 2015) and five relevant journals (January 2004 to December 2015) were searched. Studies testing the effectiveness of EoLC communication skills training for generalists were included. Two independent authors assessed study quality. Descriptive statistics and narrative synthesis are used to summarize the findings. RESULTS: From 11,441 unique records, 170 reports were identified (157 published, 13 unpublished), representing 160 evaluation studies of 153 training interventions. Of published papers, eight were of low quality, 108 medium, and 41 high. Few interventions were developed with service user involvement (n = 7), and most were taught using a mixture of didactics (n = 123), reflection and discussion (n = 105), and role play (n = 86). Evaluation designs were weak: <30% were controlled, <15% randomized participants. Over half (n = 85) relied on staff self-reported outcomes to assess effectiveness, and 49% did not cite psychometrically validated measures. Key information (e.g., training duration, participant flow) was poorly reported. CONCLUSIONS: Despite a proliferation of EoLC communication skills training interventions in the literature, evidence is limited by poor reporting and weak methodology. Based on our findings, we present a CONSORT statement supplement to improve future reporting and encourage more rigorous testing.

The Effect of Communication Skills Training for Generalist Palliative Care Providers on Patient-Reported Outcomes and Clinician Behaviors: A Systematic Review and Meta-analysis.

CONTEXT: As most end-of-life care is provided by health care providers who are generalists rather than specialists in palliative care, effective communication skills training for generalists is essential. OBJECTIVES: To determine the effect of communication training interventions for generalist palliative care providers on patient-reported outcomes and trainee behaviors. METHODS: Systematic review from searches of 10 databases to December 2015 (MEDLINE, EMBASE, PsycINFO, ERIC, CINAHL, CENTRAL, Web of Science, ICTRP, CORDIS, and OpenGrey) plus hand searching. Randomized controlled trials of training interventions intended to enhance generalists' communication skills in end-of-life care were included. Two authors independently assessed eligibility after screening, extracted data, and graded quality. Data were pooled for meta-analysis using a random-effects model. PRISMA guidelines were followed. RESULTS: Nineteen of 11,441 articles were eligible, representing 14 trials. Eleven were included in meta-analyses (patients n = 3144, trainees n = 791). Meta-analysis showed no effect on patient outcomes (standardized mean difference [SMD] = 0.10, 95% CI -0.05 to 0.24) and high levels of heterogeneity (chi-square = 21.32, degrees of freedom [df] = 7, P = 0.003; I2 = 67%). The effect on trainee behaviors in simulated interactions (SMD = 0.50, 95% CI 0.19-0.81) was greater than in real patient interactions (SMD = 0.21, 95% CI -0.01 to 0.43) with moderate heterogeneity (chi-square = 8.90, df = 5, P = 0.11; I2 = 44%; chi-square = 5.96, df = 3, P = 0.11; I2 = 50%, respectively). Two interventions with medium effects on showing empathy in real patient interactions included personalized feedback on recorded interactions. CONCLUSIONS: The effect of communication skills training for generalists on patient-reported outcomes remains unclear. Training can improve clinicians' ability to show empathy and discuss emotions, at least in simulated consultations. Personalized feedback on recorded patient interactions may be beneficial. REGISTRATION NUMBER: CRD42014014777.

Factors associated with early adoption of the HPV vaccine in US male adolescents include Hispanic ethnicity and receipt of other vaccines.

Adolescent males' HPV vaccine initiation and completion in the United States is far below the Healthy People 2020 goal of 80% 3-dose completion among boys. In 2012, less than 7% of males ages 13-17 years had completed the 3-dose series. The Diffusion of Innovations framework guided this investigation of factors related to early adoption of HPV vaccination among male adolescents. Provider-validated data from the 2012 National Immunization Survey-Teen (NIS-Teen) for male adolescents ages 13-17 years were analyzed via a multivariable Poisson regression to estimate prevalence ratios for factors associated with HPV vaccine initiation and completion. Adolescent males who are Hispanic and those who are up to date on other recommended adolescent vaccinations were most likely to complete the HPV vaccine. Public health interventions are needed to improve low HPV vaccination rates among adolescent males in the United States. Description of early adopters of the HPV vaccine provides historical context of HPV vaccination acceptance that is needed to inform the design of targeted vaccination interventions to prevent negative HPV-associated outcomes.

An extended assistantship for final-year students.

BACKGROUND: Many students feel unprepared for clinical practice after completing their medical school training. There is evidence that a brief shadowing period improves student confidence and patient safety, but there is currently little evidence on the impact of a longer shadowing period. A 10-week student assistantship (SA) for final-year students was implemented for Year 5 undergraduates at the University of Bristol in 2011. This study investigated the impact of the SA on student confidence. METHODS: All final-year medical students at the University of Bristol in the academic year 2012-13 (n = 248) were contacted with an online questionnaire at the start of the SA. They were asked about confidence in a range of domains. Further questionnaires were sent at the end of the SA, and again once the students had qualified as foundation doctors. Descriptive statistical analysis was performed. Many students feel unprepared for clinical practice RESULTS: A total of 37 students responded to the pre-assistantship questionnaire, 62 to the post-assistantship questionnaire, and 13 to the questionnaire sent once students had qualified. Self-assessed confidence improved in all areas when the pre- and post-assistantship scores were compared, in particular prescribing, assessing and managing unwell patients, and aspects of death and dying. DISCUSSION: Our findings suggest that a prolonged assistantship period improves knowledge and skills in a range of domains relevant to becoming a junior doctor, and could be considered within medical schools as a way to address established areas of poor confidence in new graduates. Larger studies are needed to provide more robust evidence for these initial findings.

A mentorship programme for final-year students.

BACKGROUND: Current mentorship programmes in the UK tend to focus predominantly on junior medical students; however, final-year medical students may encounter significant academic and personal pressures. We established a mentoring scheme to provide individualised support for final-year students from a junior doctor mentor. The objectives of this study were to assess the benefits of the scheme and identify areas for future improvement. METHODS: Final-year students at Great Western Hospital in Swindon (n = 34) were allocated a junior doctor mentor at the start of their attachment. At the end of the 3-month placement, students and mentors provided feedback on their experiences of the mentoring scheme. In total, 24 students and eight doctors returned completed questionnaires. Qualitative analyses were performed using the constant comparison method, and descriptive statistical analyses were performed on the numerical data. RESULTS: Key benefits for students were improved confidence, academic support, increased enjoyment and sense of belonging during their final year. Mentors valued the opportunity to gain teaching experience. All doctors and 96 per cent of students would recommend the scheme to a friend. Possible improvements include an introductory lecture alongside the handbook and a bank of 'reserve' mentors to stand-in when a mentor is away. DISCUSSION: The mentorship programme was a valuable addition to the final-year experience, with benefits for students and mentors alike. We will be continuing this programme in the future, and would recommend the adoption of mentorship schemes for other final-year cohorts.

DNA double-strand break - induced pro-survival signaling.

Radiation and other types of DNA damaging agents induce a plethora of signaling events simultaneously originating from the nucleus, cytoplasm, and plasma membrane. As a result, this presents a dilemma when seeking to determine causal relationships and better insight into the intricacies of stress signaling. ATM plays critical roles in both nuclear and cytoplasmic signaling, of which, the DNA damage response (DDR) is the best characterized. We have recently created experimental conditions where the DNA damage signal alone can be studied while minimizing the influence from the extranuclear compartment. We have been able to document pro-survival and growth promoting signaling (via ATM-AKT-ERK) resulting from low levels of DSBs (equivalent to ≤2 Gy). More extensive DSBs (>2 Gy eq.) result in phosphatase-mediated ERK dephosphorylation, and thus shutdown of ERK signaling. In contrast, radiation does not result in such dephosphorylation even at very high doses. We propose that phosphatases are inactivated perhaps as a result of reactive oxygen species, which does not occur in response to 'pure' DNA damage. Our findings suggest that clinically relevant radiation doses, which are intended to halt tumor growth and induce cell death, are unable to inhibit tumor pro-survival signaling via ERK dephosphorylation.

SRSF1 regulates the alternative splicing of caspase 9 via a novel intronic splicing enhancer affecting the chemotherapeutic sensitivity of non-small cell lung cancer cells.

Increasing evidence points to the functional importance of alternative splice variations in cancer pathophysiology with the alternative pre-mRNA processing of caspase 9 as one example. In this study, we delve into the underlying molecular mechanisms that regulate the alternative splicing of caspase 9. Specifically, the pre-mRNA sequence of caspase 9 was analyzed for RNA cis-elements known to interact with SRSF1, a required enhancer for caspase 9 RNA splicing. This analysis revealed 13 possible RNA cis-elements for interaction with SRSF1 with mutagenesis of these RNA cis-elements identifying a strong intronic splicing enhancer located in intron 6 (C9-I6/ISE). SRSF1 specifically interacted with this sequence, which was required for SRSF1 to act as a splicing enhancer of the inclusion of the 4 exon cassette. To further determine the biological importance of this mechanism, we employed RNA oligonucleotides to redirect caspase 9 pre-mRNA splicing in favor of caspase 9b expression, which resulted in an increase in the IC(50) of non-small cell lung cancer (NSCLC) cells to daunorubicin, cisplatinum, and paclitaxel. In contrast, downregulation of caspase 9b induced a decrease in the IC(50) of these chemotherapeutic drugs. Finally, these studies showed that caspase 9 RNA splicing was a major mechanism for the synergistic effects of combination therapy with daunorubicin and erlotinib. Overall, we have identified a novel intronic splicing enhancer that regulates caspase 9 RNA splicing and specifically interacts with SRSF1. Furthermore, we showed that the alternative splicing of caspase 9 is an important molecular mechanism with therapeutic relevance to NSCLCs.