Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/ßc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/ßc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/ßc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. SIGNIFICANCE: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749.

Drug repurposing: Misconceptions, challenges, and opportunities for academic researchers.

Drug repurposing is promoted as a cost- and time-effective mechanism for providing new medicines. Often, however, there is insufficient consideration by academic researchers of the processes required to ensure that a repurposed drug can be used for a new indication. This may explain the inability of drug repurposing to fulfill its promise. Important aspects, often overlooked, include financial and intellectual property considerations, the clinical and regulatory path, and clinical equipoise, which provides ethical justification for randomized controlled trials. The goal of drug repurposing is to obtain a new regulator-approved label for an existing drug, and so, the trajectory for drug repurposing and traditional drug development is similar. Here, we discuss factors critical for a successful repurposed medicine to help academic investigators better identify drug repurposing opportunities.

Categorizing the characteristics of human carcinogens: a need for specificity.

The International Agency for Research on Cancer (IARC) has recently proposed employing "ten key characteristics of human carcinogens" (TKCs) to determine the potential of agents for harmful effects. The TKCs seem likely to confuse the unsatisfactory correlation from testing regimes that have ignored the differences evident when cellular changes are compared in short and long-lived species, with their very different stem cell and somatic cell phylogenies. The proposed characteristics are so broad that their use will lead to an increase in the current unacceptably high rate of false positives. It could be an informative experiment to take well-established approved therapeutics with well-known human safety profiles and test them against this new TKC paradigm. Cancers are initiated and driven by heritable and transient changes in gene expression, expand clonally, and progress via additional associated acquired mutations and epigenetic alterations that provide cells with an evolutionary advantage. The genotoxicity testing protocols currently employed and required by regulation, emphasize testing for the mutational potential of the test agent. Two-year, chronic rodent cancer bioassays are intended to test for the entire spectrum of carcinogenic transformation. The use of cytotoxic doses causing increased, sustained cell proliferation that facilitates accumulated genetic damage leads to a high false-positive rate of tumor induction. Current cancer hazard assessment protocols and weight-of-the-evidence analysis of agent-specific cancer risk align poorly with the pathogenesis of human carcinoma and so need modernization and improvement in ways suggested here.

Identifying and understanding factors that affect the translation of therapies from the laboratory to patients: a study protocol.

Background: The process of translating preclinical findings into a clinical setting takes decades. Previous studies have suggested that only 5-10% of the most promising preclinical studies are successfully translated into viable clinical applications. The underlying determinants of this low success rate (e.g. poor experimental design, suboptimal animal models, poor reporting) have not been examined in an empirical manner. Our study aims to determine the contemporary success rate of preclinical-to-clinical translation, and subsequently determine if an association between preclinical study design and translational success/failure exists. Methods: Established systematic review methodology will be used with regards to the literature search, article screening and study selection process. Preclinical, basic science studies published in high impact basic science journals between 1995 and 2015 will be included. Included studies will focus on publicly available interventions with potential clinical promise. The primary outcome will be successful clinical translation of promising therapies - defined as the conduct of at least one Phase II trial (or greater) with a positive finding. A case-control study will then be performed to evaluate the association between elements of preclinical study design and reporting and the likelihood of successful translation. Discussion: This study will provide a comprehensive analysis of the therapeutic translation from the laboratory bench to the bedside. Importantly, any association between factors of study design and the success of translation will be identified. These findings may inform future research teams attempting preclinical-to-clinical translation. Results will be disseminated to identified knowledge users that fund/support preclinical research.

The Antibody Society's antibody validation webinar series.

In the wake of the reproducibility crisis and numerous discussions on how commercially available antibodies as research tool contribute to it, The Antibody Society developed a series of 10 webinars to address the issues involved. The webinars were delivered by speakers with both academic and commercial backgrounds. This report highlights the problems, and offers solutions to help the scientific community appropriately identify the right antibodies and to validate them for their research and development projects. Despite the various solutions proposed here, they must be applied on a case-by-case basis. Each antibody must be verified based on the content of the product sheet, and subsequently through experimentation to confirm integrity, specificity and selectivity. Verification needs to focus on the precise application and tissue/cell type for which the antibody will be used, and all verification data must be reported openly. The various approaches discussed here all have caveats, so a combination of solutions must be considered.

Health economic analysis of a cluster-randomised trial (OptiBIRTH) designed to increase rates of vaginal birth after caesarean section.

OBJECTIVE: To perform a health economic analysis of an intervention designed to increase rates of vaginal birth after caesarean, compared with usual care. DESIGN: Economic analysis alongside the cluster-randomised OptiBIRTH trial (Optimising childbirth by increasing vaginal birth after caesarean section (VBAC) through enhanced women-centred care). SETTING: Fifteen maternity units in three European countries - Germany (five), Ireland (five), and Italy (five) - with relatively low VBAC rates. POPULATION: Pregnant women with a history of one previous lower-segment caesarean section; sites were randomised (3:2) to intervention or control. METHODS: A cost-utility analysis from both societal and health-services perspectives, using a decision tree. MAIN OUTCOME MEASURES: Costs and resource use per woman and infant were compared between the control and intervention group by country, from pregnancy recognition until 3 months postpartum. Based on the caesarean section rates, and maternal and neonatal morbidities and mortality, the incremental cost-utility ratios were calculated per country. RESULTS: The mean difference in costs per quality-adjusted life years (QALYs) gained from a societal perspective between the intervention and the control group, using a probabilistic sensitivity analysis, was: €263 (95% CI €258-268) and 0.008 QALYs (95% CI 0.008-0.009 QALYs) for Germany, €456 (95% CI €448-464) and 0.052 QALYs (95% CI 0.051-0.053 QALYs) for Ireland, and €1174 (95% CI €1170-1178) and 0.006 QALYs (95% CI 0.005-0.007 QALYs) for Italy. The incremental cost-utility ratios were €33,741/QALY for Germany, €8785/QALY for Ireland, and €214,318/QALY for Italy, with a 51% probability of being cost-effective for Germany, 92% for Ireland, and 15% for Italy. CONCLUSION: The OptiBIRTH intervention was likely to be cost-effective in Ireland and Germany. TWEETABLE ABSTRACT: The OptiBIRTH intervention (to increase VBAC rates) is likely to be cost-effective in Germany and Ireland.

A qualitative exploration of techniques used by expert midwives to preserve the perineum intact.

BACKGROUND: The perineum stretches during birth to allow passage of the baby, but 85% of women sustain some degree of perineal trauma during childbirth, which is painful post-partum. Episiotomy rates vary significantly, with some countries having rates of >60%. Recent Irish and New Zealand studies showed lower severe perineal trauma and episiotomy rates than other countries. AIM: To explore expert Irish and New Zealand midwives' views of the skills that they employ in preserving the perineum intact during spontaneous vaginal birth. METHODS: Following ethical approval a qualitative, descriptive study was undertaken. Semi-structured, recorded, interviews were transcribed and analysed using the constant comparative method. Expert midwives employed in New Zealand and one setting in Ireland, were invited to join the study. "Expert" was defined as achieving, in the preceding 3.5 years, an episiotomy rate for nulliparous women of <11.8%, a 'no suture' rate of 40% or greater, and a severe perineal tear rate of <3.2%. Twenty-one midwives consented to join the study. RESULTS: Four core themes emerged: 'Calm, controlled birth', 'Position and techniques in early second stage', 'Hands on or off?' and 'Slow, blow and breathe the baby out.' Using the techniques described enabled these midwives to achieve rates, in nulliparous women, of 3.91% for episiotomy, 59.24% for 'no sutures', and 1.08% for serious lacerations. CONCLUSIONS: This study provides further understanding of the techniques used by expert midwives at birth. These findings, combined with existing quantitative research, increases the evidence on how to preserve the perineum intact during spontaneous birth.

Admission cardiotocography versus intermittent auscultation of the fetal heart in low-risk pregnancy during evaluation for possible labour admission - a multicentre randomised trial: the ADCAR trial.

OBJECTIVE: To assess the effect of admission cardiotocography (ACTG) versus intermittent auscultation (IA) of the fetal heart (FH) in low-risk pregnancy during assessment for possible labour on caesarean section rates. DESIGN: A parallel multicentre randomised trial. SETTING: Three maternity units in the Republic of Ireland. POPULATION: Healthy, low-risk pregnant women, at term and ≥ 18 years old, who provided written informed consent. METHODS: Women were randomised to receive IA of the FH or 20 minutes ACTG on admission for possible labour onset, using remote telephone randomisation. Both groups received IA during labour, with conversion to continuous CTG as clinically indicated. MAIN OUTCOME MEASURES: Caesarean section (primary outcome), obstetric interventions (e.g. continuous CTG during labour, fetal blood sampling, augmentation of labour) and neonatal morbidity (e.g. metabolic acidosis, admission to the neonatal intensive care unit, neonatal death). RESULTS: Based on 3034 women (1513 and 1521 randomised to IA and ACTG, respectively), there was no statistical difference between the groups in caesarean section [130 (8.6%) and 105 (6.9%) for IA and ACTG groups, respectively; relative risk (RR) 1.24; 95% CI 0.97-1.58], or in any other outcome except for use of continuous CTG during labour, which was lower in the IA group (RR 0.90, 95% CI 0.86-0.93). CONCLUSION: Our study demonstrates no differences in obstetric or neonatal outcomes between IA and ACTG for women with possible labour onset, other than an increased risk for continuous CTG in women receiving ACTG. TWEETABLE ABSTRACT: No differences in outcomes between intermittent auscultation and admission cardiotocography for women with possible labour onset.

Mathematical modelling of glob-driven tear film breakup.

Evaporation is a recognized contributor to tear film thinning and tear breakup (TBU). Recently, a different type of TBU is observed, where TBU happens under or around a thick area of lipid within a second after a blink. The thick lipid corresponds to a glob. Evaporation alone is too slow to offer a complete explanation of this breakup. It has been argued that the major reason of this rapid tear film thinning is divergent flow driven by a lower surface tension of the glob (via the Marangoni effect). We examine the glob-driven TBU hypothesis in a 1D streak model and axisymmetric spot model. In the model, the streak or spot glob has a localized high surfactant concentration, which is assumed to lower the tear/air surface tension and also to have a fixed size. Both streak and spot models show that the Marangoni effect can lead to strong tangential flow away from the glob and may cause TBU. The models predict that smaller globs or thinner films will decrease TBU time (TBUT). TBU is located underneath small globs, but may occur outside larger globs. In addition to tangential flow, evaporation can also contribute to TBU. This study provides insights about mechanism of rapid thinning and TBU which occurs very rapidly after a blink and how the properties of the globs affect the TBUT.

Dynamics of Fluorescent Imaging for Rapid Tear Thinning.

A previous mathematical model has successfully simulated the rapid tear thinning caused by glob (thicker lipid) in the lipid layer. It captured a fast spreading of polar lipid and a corresponding strong tangential flow in the aqueous layer. With the simulated strong tangential flow, we now extend the model by adding equations for conservation of solutes, for osmolarity and fluorescein, in order to study their dynamics. We then compare our computed results for the resulting intensity distribution with fluorescence experiments on the tear film. We conclude that in rapid thinning, the fluorescent intensity can linearly approximate the tear film thickness well, when the initial fluorescein concentration is small. Thus, a dilute fluorescein is recommended for visualizing the rapid tear thinning during fluorescent imaging.

Definitions, measurements and prevalence of fear of childbirth: a systematic review.

BACKGROUND: Fear of Childbirth (FOC) is a common problem affecting women's health and wellbeing, and a common reason for requesting caesarean section. The aims of this review were to summarise published research on prevalence of FOC in childbearing women and how it is defined and measured during pregnancy and postpartum, and to search for useful measures of FOC, for research as well as for clinical settings. METHODS: Five bibliographic databases in March 2015 were searched for published research on FOC, using a protocol agreed a priori. The quality of selected studies was assessed independently by pairs of authors. Prevalence data, definitions and methods of measurement were extracted independently from each included study by pairs of authors. Finally, some of the country rates were combined and compared. RESULTS: In total, 12,188 citations were identified and screened by title and abstract; 11,698 were excluded and full-text of 490 assessed for analysis. Of these, 466 were excluded leaving 24 papers included in the review, presenting prevalence of FOC from nine countries in Europe, Australia, Canada and the United States. Various definitions and measurements of FOC were used. The most frequently-used scale was the W-DEQ with various cut-off points describing moderate, severe/intense and extreme/phobic fear. Different 3-, 4-, and 5/6 point scales and visual analogue scales were also used. Country rates (as measured by seven studies using W-DEQ with ≥85 cut-off point) varied from 6.3 to 14.8%, a significant difference (chi-square = 104.44, d.f. = 6, p < 0.0001). CONCLUSIONS: Rates of severe FOC, measured in the same way, varied in different countries. Reasons why FOC might differ are unknown, and further research is necessary. Future studies on FOC should use the W-DEQ tool with a cut-off point of ≥85, or a more thoroughly tested version of the FOBS scale, or a three-point scale measurement of FOC using a single question as 'Are you afraid about the birth?' In this way, valid comparisons in research can be made. Moreover, validation of a clinical tool that is more focussed on FOC alone, and easier than the longer W-DEQ, for women to fill in and clinicians to administer, is required.

Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-κB signaling by degrading TRAF2-associated cIAP1 in cancer cells.

The inhibitor of apoptosis (IAP) proteins have pivotal roles in cell proliferation and differentiation, and antagonizing IAPs in certain cancer cell lines results in induction of cell death. A variety of IAP antagonist compounds targeting the baculovirus IAP protein repeat 3 (BIR3) domain of cIAP1have advanced into clinical trials. Here we sought to compare and contrast the biochemical activities of selected monovalent and bivalent IAP antagonists with the intent of identifying functional differences between these two classes of IAP antagonist drug candidates. The anti-cellular IAP1 (cIAP1) and pro-apoptotic activities of monovalent IAP antagonists were increased by using a single covalent bond to combine the monovalent moieties at the P4 position. In addition, regardless of drug concentration, treatment with monovalent compounds resulted in consistently higher levels of residual cIAP1 compared with that seen following bivalent compound treatment. We found that the remaining residual cIAP1 following monovalent compound treatment was predominantly tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2)-associated cIAP1. As a consequence, bivalent compounds were more effective at inhibiting TNF-induced activation of p65/NF-κB compared with monovalent compounds. Moreover, extension of the linker chain at the P4 position of bivalent compounds resulted in a decreased ability to degrade TRAF2-associated cIAP1 in a manner similar to monovalent compounds. This result implied that specific bivalent IAP antagonists but not monovalent compounds were capable of inducing formation of a cIAP1 E3 ubiquitin ligase complex with the capacity to effectively degrade TRAF2-associated cIAP1. These results further suggested that only certain bivalent IAP antagonists are preferred for the targeting of TNF-dependent signaling for the treatment of cancer or infectious diseases.

Measures for screening for intimate partner violence: a systematic review.

WHAT IS KNOWN ON THE SUBJECT?: Intimate partner violence (IPV) has a significant impact on the onset, duration and recurrence of mental health problems. Prevalence rates of IPV are significantly higher in mental health services, but the studies are limited. Accurate assessment of IPV is important for decision making in risk assessment and safety planning within mental health nursing. Psychometrically tested tools are the most accurate way to identifying all areas of IPV abuse: physical, sexual and psychological. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Ten IPV screening tools were identified in healthcare and three tools; Women Abuse Screen Tool (WAST), Abuse Assessment Screen (AAS) and Humiliation, Afraid, Rape and Kick (HARK) were identified as having strong psychometric values as they assessed all areas of IPV and were validated against an appropriate reference standard. None of the three IPV tools identified (WAST, AAS, HARK) were tested on men or in mental health settings impacting the gender sensitivities of the tools and the reliability of the prevalence rates of IPV in mental healthcare. Over seventy percent of the studies reviewed were conducted in America this impacts the cultural sensitivities of the IPV tools. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: IPV screening needs to be incorporated as a priority in mental health services in order to reduce the morbidity and mortality issues associated with this abuse. Psychometric tools to screen for IPV need to be incorporated to assist mental health professionals in decision making in risk assessment and safety planning. Further research is needed to improve the psychometric properties of IPV tools in mental health settings, to ensure they are culturally and gender sensitive. ABSTRACT: Objective Intimate partner violence (IPV) is a public health priority due to the physical and mental impacts it has on health. No existing reviews have focused on the psychometric properties of IPV screening tools used to screen men and women within a mental health context. This review aimed to identify the best psychometrically tested screening tools available to assess all areas of IPV in men and women in mental health setting. Method Databases psycArticles, PsycINFO, Social Science, CINAHL, PubMed and Cochrane were searched from their starting date through to July 2015. Eligible studies were published in peer-reviewed publications in English. Results Thirty-six studies met the inclusion criteria. Ten IPV screening tools were identified. Three tools assessed all areas of IPV and were validated against an appropriate reference standard. One study tested IPV screening tool in a mental health setting. Conclusion Mental health nurses need to incorporate a psychometrically tested IPV tool as part of risk assessment and safety planning for clients. This review identified three tools that are suitable for identifying IPV in a mental health context. However, further research is necessary to validate IPV screening tools that are culturally sensitive and have been validated with men and women.

Determinants of breastfeeding initiation in Ireland.

BACKGROUND: Ireland continues to rank among countries with the lowest breastfeeding initiation rates. National and regional studies also show that few women in Ireland who initiate exclusive breastfeeding continue to breastfeed for the recommended 6 months. AIM: To assess the rate of exclusive and partial breastfeeding in Ireland at three time periods: birth to 48 h, 3-4 months following birth, and when the infant was 6-7 months old. METHODS: A longitudinal national cohort survey of 2527 mothers. RESULTS: Findings show that just 56 % (n = 1002) of mothers initiated breastfeeding at birth and, at 48 h, 42 % (n = 1064) of women were exclusively breastfeeding their babies. At 6-7 months, only 2.4 % of the 2527 mothers who took part, reported exclusive breastfeeding. Irish women were less likely to initiate breastfeeding (52.6 %) compared with Polish (82.2 %), British (64.5 %), and other nationalities (74.6 %). Multivariate analysis also revealed significant relationships between initiation and socio-economic variables, with mothers' health insurance status being of particular importance. CONCLUSION: The results highlight the necessity to support the initiation and maintenance of breastfeeding in Ireland, in order to reduce rates of infant morbidity.

Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.

Maternal obesity is linked with adverse outcomes for mothers and babies. To get an overview of risks related to obesity in pregnant women, a systematic review of reviews was conducted. For inclusion, reviews had to compare pregnant women of healthy weight with women with obesity, and measure a health outcome for mother and/or baby. Authors conducted full-text screening, quality assurance using the AMSTAR tool and data extraction steps in pairs. Narrative analysis of the 22 reviews included show gestational diabetes, pre-eclampsia, gestational hypertension, depression, instrumental and caesarean birth, and surgical site infection to be more likely to occur in pregnant women with obesity compared with women with a healthy weight. Maternal obesity is also linked to greater risk of preterm birth, large-for-gestational-age babies, foetal defects, congenital anomalies and perinatal death. Furthermore, breastfeeding initiation rates are lower and there is greater risk of early breastfeeding cessation in women with obesity compared with healthy weight women. These adverse outcomes may result in longer duration of hospital stay, with concomitant resource implications. It is crucial to reduce the burden of adverse maternal and foetal/child outcomes caused by maternal obesity. Women with obesity need support to lose weight before they conceive, and to minimize their weight gain in pregnancy.

Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus.

Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.

Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis.

We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4(+) T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.