A Meta-Analysis of Bioelectric Data in Cancer, Embryogenesis, and Regeneration.

Developmental bioelectricity is the study of the endogenous role of bioelectrical signaling in all cell types. Resting potentials and other aspects of ionic cell physiology are known to be important regulatory parameters in embryogenesis, regeneration, and cancer. However, relevant quantitative measurement and genetic phenotyping data are distributed throughout wide-ranging literature, hampering experimental design and hypothesis generation. Here, we analyze published studies on bioelectrics and transcriptomic and genomic/phenotypic databases to provide a novel synthesis of what is known in three important aspects of bioelectrics research. First, we provide a comprehensive list of channelopathies-ion channel and pump gene mutations-in a range of important model systems with developmental patterning phenotypes, illustrating the breadth of channel types, tissues, and phyla (including man) in which bioelectric signaling is a critical endogenous aspect of embryogenesis. Second, we perform a novel bioinformatic analysis of transcriptomic data during regeneration in diverse taxa that reveals an electrogenic protein to be the one common factor specifically expressed in regeneration blastemas across Kingdoms. Finally, we analyze data on distinct Vmem signatures in normal and cancer cells, revealing a specific bioelectrical signature corresponding to some types of malignancies. These analyses shed light on fundamental questions in developmental bioelectricity and suggest new avenues for research in this exciting field.

An in vivo brain-bacteria interface: the developing brain as a key regulator of innate immunity.

Infections have numerous effects on the brain. However, possible roles of the brain in protecting against infection, and the developmental origin and role of brain signaling in immune response, are largely unknown. We exploited a unique Xenopus embryonic model to reveal control of innate immune response to pathogenic E. coli by the developing brain. Using survival assays, morphological analysis of innate immune cells and apoptosis, and RNA-seq, we analyzed combinations of infection, brain removal, and tail-regenerative response. Without a brain, survival of embryos injected with bacteria decreased significantly. The protective effect of the developing brain was mediated by decrease of the infection-induced damage and of apoptosis, and increase of macrophage migration, as well as suppression of the transcriptional consequences of the infection, all of which decrease susceptibility to pathogen. Functional and pharmacological assays implicated dopamine signaling in the bacteria-brain-immune crosstalk. Our data establish a model that reveals the very early brain to be a central player in innate immunity, identify the developmental origins of brain-immune interactions, and suggest several targets for immune therapies.

Brief Local Application of Progesterone via a Wearable Bioreactor Induces Long-Term Regenerative Response in Adult Xenopus Hindlimb.

The induction of limb repair in adult vertebrates is a pressing, unsolved problem. Here, we characterize the effects of an integrated device that delivers drugs to severed hindlimbs of adult Xenopus laevis, which normally regenerate cartilaginous spikes after amputation. A wearable bioreactor containing a silk protein-based hydrogel that delivered progesterone to the wound site immediately after hindlimb amputation for only 24 hr induced the regeneration of paddle-like structures in adult frogs. Molecular markers, morphometric analysis, X-ray imaging, immunofluorescence, and behavioral assays were used to characterize the differences between the paddle-like structures of successful regenerates and hypomorphic spikes that grew in untreated animals. Our experiments establish a model for testing therapeutic cocktails in vertebrate hindlimb regeneration, identify pro-regenerative activities of progesterone-containing bioreactors, and provide proof of principle of brief use of integrated device-based delivery of small-molecule drugs as a viable strategy to induce and maintain a long-term regenerative response.

Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding.

Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFκB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFκB regulatory functions. Inflammatory regulators thus also govern cancer cell growth-promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer.Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers. Mol Cancer Res; 16(1); 147-61. ©2017 AACR.

A qualitative evaluation of home-based contraceptive and sexual health care for teenage mothers.

AIM: This paper reports on the findings from a qualitative study exploring the experiences of teenage mothers using a nurse-led, home-based contraceptive service designed to prevent repeat unplanned pregnancies. The aim was to understand if, and how the service was effective in equipping teenage mothers to make informed choices about contraception, thus preventing a second pregnancy. BACKGROUND: Unplanned teenage pregnancy remains a significant focus of health and social policy in the United Kingdom (UK). Despite the long-term pattern of declining conception rates, the UK continues to report higher rates than comparable countries elsewhere in Europe. Current estimates suggest that approximately one fifth of births amongst under 18's are repeat pregnancies (Teenage Pregnancy Independent Advisory Group, 2009). Services that are designed to reduce second unplanned pregnancies are an important element in promoting teenage sexual health. However, there has been no UK research that explores this kind of service and the experiences of service users. METHODS: We conducted a qualitative interview study. From 2013-2014 we interviewed 40 teenage mothers who had engaged with the nurse-led, home-based contraceptive service. FINDINGS: The data demonstrates that the service was effective in preventing repeat pregnancies in a number of cases. Among the aspects of the service which were found to contribute to its effectiveness were privacy, convenience, flexibility, appropriately timed access, the non-judgemental attitude of staff and ongoing support.

Gendered attitudes towards sexual relationships among adolescents attending nurse led sexual health clinics in England: a qualitative study.

AIMS: This study aimed to explore gender differences in attitudes towards sexual relationships of adolescent attending nurse led sexual health clinics. BACKGROUND: Nurse led sexual health clinics are at the forefront of promoting adolescent sexual health. To provide sensitive, effective and non-judgemental care, nurses need to understand the complexities of adolescent sexual behaviour and the social factors that influence sexual relationships. Design. A qualitative, exploratory research design was used. METHODS: Ten focus groups (five male and five female) involving sexual health clinic attendees aged between 14-16 years were conducted. Focus groups were asked to comment on four sexual relationship 'case studies'. Group discussions were recorded and transcribed. Data were subject to thematic analysis. RESULTS: Three themes emerged from the data analysis. 'Empathy' reflected how young women were more likely to try to see their partner's point of view. 'Complexity' also reflected that young women were more aware of the complex nature of relationships than were the male participants. 'Language' related to how young males used aggressive language in the context of relationships - a feature absent from female participants' discourse. CONCLUSIONS: Male and female attitudes clearly differ. Female responses are more complex and empathic because of the more complex nature of the social pressures that sexualise young women. Young males are not as subject to these social forces. Young men are socialized into behaviour that can place females under pressure to have sex - this pressure can include the use of alcohol. RELEVANCE TO CLINICAL PRACTISE: Nurses working in sexual health should attempt to encourage empathic thinking in male clients. Females should be educated to deal with the social pressures they may face from their partners. Practitioners should also recognise the problematic role alcohol can play within sexual relationships.