SWAN pathway-network identification of common aneuploidy-based oncogenic drivers.

Haploinsufficiency drives Darwinian evolution. Siblings, while alike in many aspects, differ due to monoallelic differences inherited from each parent. In cancer, solid tumors exhibit aneuploid genetics resulting in hundreds to thousands of monoallelic gene-level copy-number alterations (CNAs) in each tumor. Aneuploidy patterns are heterogeneous, posing a challenge to identify drivers in this high-noise genetic environment. Here, we developed Shifted Weighted Annotation Network (SWAN) analysis to assess biology impacted by cumulative monoallelic changes. SWAN enables an integrated pathway-network analysis of CNAs, RNA expression, and mutations via a simple web platform. SWAN is optimized to best prioritize known and novel tumor suppressors and oncogenes, thereby identifying drivers and potential druggable vulnerabilities within cancer CNAs. Protein homeostasis, phospholipid dephosphorylation, and ion transport pathways are commonly suppressed. An atlas of CNA pathways altered in each cancer type is released. These CNA network shifts highlight new, attractive targets to exploit in solid tumors.

Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.

Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.

Autophagy modulating therapeutics inhibit ovarian cancer colony generation by polyploid giant cancer cells (PGCCs).

BACKGROUND: Genomic instability and chemoresistance can arise in cancer due to a unique form of plasticity: that of polyploid giant cancer cells (PGCCs). These cells form under the stress of chemotherapy and have higher than diploid chromosome content. PGCCs are able to then repopulate tumors through an asymmetric daughter cell budding process. PGCCs have been observed in ovarian cancer histology, including the deadly and common form high-grade serous ovarian carcinoma (HGSC). We previously discovered that drugs which disrupt the cellular recycling process of autophagy are uniquely efficacious in pre-clinical HGSC models. While autophagy induction has been associated with PGCCs, it has never been previously investigated if autophagy modulation interacts with the PGCC life cycle and this form of tumor cell plasticity. METHODS: CAOV3 and OVCAR3 ovarian cancer cell lines were treated with carboplatin or docetaxel to induce PGCC formation. Microscopy was used to characterize and quantify PGCCs formed by chemotherapy. Two clinically available drugs that inhibit autophagy, hydroxychloroquine and nelfinavir, and a clinically available activator of autophagy, rapamycin, were employed to test the effect of these autophagy modulators on PGCC induction and subsequent colony formation from PGCCs. Crystal violet-stained colony formation assays were used to quantify the tumor-repopulating stage of the PGCC life cycle. RESULTS: Autophagy inhibitors did not prevent PGCC formation in OVCAR3 or CAOV3 cells. Rapamycin did not induce PGCC formation on its own nor did it exacerbate PGCC formation by chemotherapy. However, hydroxychloroquine prevented efficient colony formation in CAOV3 PGCCs induced by carboplatin (27% inhibition) or docetaxel (41% inhibition), as well as in OVCAR3 cells (95% and 77%, respectively). Nelfinavir similarly prevented colony formation in CAOV3 PGCCs induced by carboplatin (64% inhibition) or docetaxel (94% inhibition) as well as in OVCAR3 cells (89% and 80%, respectively). Rapamycin surprisingly also prevented PGCC colony outgrowth (52-84% inhibition). CONCLUSIONS: While the autophagy previously observed to correlate with PGCC formation is unlikely necessary for PGCCs to form, autophagy modulating drugs severely impair the ability of HGSC PGCCs to form colonies. Clinical trials which utilize hydroxychloroquine, nelfinavir, and/or rapamycin after chemotherapy may be of future interest.

Genetic evidence supports a range extension for the Brazilian cownose ray Rhinoptera brasiliensis in the western North Atlantic.

We report 24 new records of the Brazilian cownose ray Rhinoptera brasiliensis outside its accepted geographic range. Sequencing of a 442-base pair portion of the mitochondrial NADH dehydrogenase subunit 2 gene for 282 Rhinoptera samples revealed eight records off the east coast of the USA and 16 from the eastern Gulf of Mexico. Both sexes of all life stages were documented in all seasons over multiple years in the Indian River and Lake Worth lagoons, Florida, indicating that their range extends further in the western North Atlantic than previously described.

MYC is sufficient to generate mid-life high-grade serous ovarian and uterine serous carcinomas in a p53-R270H mouse model.

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse. MYC, an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the fallopian tube epithelium.

Cybersickness and postural stability of first time VR users playing VR videogames.

This study investigated symptoms of cybersickness and postural instability experienced by new users of head-mounted display virtual reality (HMD-VR), playing VR videogames over long and repeated sessions, and moderation of these symptoms by previous videogame experience and intensity of videogame stimulus. Cybersickness (SSQ) and postural stability (anterior-posterior path-velocity) of new users of VR (n = 80) was collected PRE-VR, POST-VR and 10 min after completing (POST-RECOVERY) a VR gaming experience. Users comprised of videogamers (n = 40) and non-videogamers (n = 40), who were randomly assigned to play either action (high-intensity stimuli) or adventure (low-intensity stimuli) games in VR for 30 min and repeated twice, one week apart. All participants, irrespective of gaming status and genre of game, experienced significant cybersickness after 30 min in VR using current-generation HMD-VR technology, and did not adapt (POST-VR) after two sessions. However videogamers were able to recover (POST-RECOVERY) from cybersickness induced in VR significantly better than non-videogamers. All participants experienced significantly better postural stability after 30 min in VR, irrespective of gaming experience or genre of game. Developers should create VR experiences that minimise negative symptoms of cybersickness and postural instability experience by new users of VR.

It takes a virtual village: Childbearing women's experience of a closed Facebook support group for mothers.

BACKGROUND: Childbearing women engage in large public pregnancy and parenting forums, primarily for the purpose of seeking information and advice. There is an absence of research related to women's engagement in closed and private online mothers' groups. AIM: The aim of this study was to explore the experiences of participation and support for members within a closed online mothers' group. METHOD: A qualitative study using in-depth interviews. Reflexive thematic analysis was used to analyse the data. FINDINGS: This study demonstrated that a closed online mothers' group enabled a group of childbearing women to overcome isolation and form sustained, evolving and supportive friendships within a small, private and trusted group. The technology allowed women to engage and share at a level much deeper than what they would in "real life". The depth of sharing was enhanced in a closed online mothers' group due to a smaller, private audience of trusted friends. Virtual support felt safer than face-to-face support as information could not impact one's real world reputation, and communication was able to be controlled. This was particularly helpful to women experiencing social difficulties or isolation. CONCLUSION: This study has provided a unique and rare insight into the private world of closed online mothers' groups. As a virtual village, this closed group enabled childbearing women to form a small community with members sharing responsibility and working for the wellbeing and benefit of all. By encouraging, locating and establishing similar groups, maternity health professionals may assist women to access their own 'virtual village'.

Steps towards empowerment: an examination of colleges, health services and universities.

In Australia, nursing educators work across three main contexts - training colleges, health services and universities. Because the pace of change for nursing has increased dramatically and the curriculum is becoming even more crowded, educators in these contexts are likely to be experiencing work-related stress. This study investigated this issue utilising a purposive sampling strategy to interview a cross section of nurse educators and those supporting educators. Eighteen in-depth interviews were completed, which included fourteen nurse educators and four key stakeholders. Qualitative analysis revealed that regardless of context, nurse educators found their role rewarding but there are common challenges. These included: Work role pressures, a non-validating culture, the pace of change, isolation and concern for the profession. There are also differences amongst the cohorts. Finally, participants elaborated on specific solutions to these problems and there is strong support for the establishment of a national community of practice to bring diverse educators together to share, support, extend and evaluate each others' work.

An annotated checklist of the chondrichthyan fishes inhabiting the northern Gulf of Mexico Part 1: Batoidea.

Herein we consolidate the information available concerning the biodiversity of batoid fishes in the northern Gulf of Mexico, including nearly 70 years of survey data collected by the National Marine Fisheries Service, Mississippi Laboratories and their predecessors. We document 41 species proposed to occur in the northern Gulf of Mexico. However, the validity of several of these reports and their associated data is questioned. In addition, we provide information and remarks concerning the distribution, conservation status, taxonomy and recorded history for each species covered.

Tamoxifen is a candidate first-in-class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells-Unrecognized players in tumorigenesis.

Polyploid giant cancer cells (PGCC) represent a poorly understood, small subpopulation of tumor cells that are increasingly being recognized for their critical role in therapy resistance, metastasis, and cancer recurrence. PGCC have the potential to generate progeny through primitive or cleavage-like division, which allows them to evade antimitotic insults. We recently demonstrated that the sphingolipid enzyme acid ceramidase (ASAH1) is required for this process. Since specific ASAH1 inhibitors are not clinically available, we investigated whether tamoxifen, which interferes with ASAH1 function via off-target effects, has a potential clinical benefit independent of estrogen signaling. Our results show that tamoxifen inhibits generation of PGCC offspring in prostate cancer, glioblastoma, and melanoma cells. Analysis of two state-level cancer registries revealed that tamoxifen improves survival outcomes for second, nonbreast cancers that develop in women with early stage breast cancer. Our results suggest that tamoxifen may have a clinical benefit in a variety of cancers that is independent of estrogen signaling and could be due to its inhibition of acid ceramidase. Thus the distinct application of tamoxifen as potentially a first-in-class therapeutic that inhibits the generation of PGCC offspring should be considered in future clinical trials.

Women's use of social networking sites related to childbearing: An integrative review.

BACKGROUND: Social support is essential in both the transition to motherhood and maternal role development. With diminishing access to traditional communities of motherhood wisdom, women struggle to access this information in their tangible worlds. AIM: This paper presents a review of the research literature investigating childbearing women's use of social networking sites related to pregnancy and parenting and how these may influence women's experiences of the childbearing period. METHOD: An integrative review. FINDINGS: Today's women are increasingly drawn to the online environment, particularly social media groups, to connect with other childbearing women. Their online interactions influence their childbearing decisions and empower them to challenge expert narratives. Social networking presents a mechanism for mothers to build bonding and bridging social capital through the formation of virtual networks. DISCUSSION: The value of emotional and instrumental support gained in online environments should not be underestimated and has benefits for childbearing women. While childbearing women are far from gullible in trusting online sources, health professionals may have a role in educating women in the evaluation information gained through online interactions. Insight into mothers' experiences of using closed online groups over longer periods would also be valuable. CONCLUSION: Mother's understandings of childbearing norms are being shaped through digital, mother to mother interactions. Maternity care disciplines should work toward establishing a better understanding of the meaning and worth that mothers receive from ongoing participation in online groups. This knowledge has the potential to identify and address shortcomings to better meet the needs of new mothers.

Examining key design decisions involved in developing a serious game for child sexual abuse prevention.

This paper presents a case study of the key decisions made in the design of Orbit, a child sexual abuse prevention computer game targeted at school students between 8 and 10 years of age. Key decisions include providing supported delivery for the target age group, featuring adults in the program, not over-sanitizing game content, having a focus on building healthy self-concept of players, making the game engaging and relatable for all players and evaluating the program. This case study has implications for the design of Serious Games more generally, including that research should underpin game design decisions, game designers should consider ways of bridging the game to real life, the learning that arises from the game should go beyond rote-learning, designers should consider how the player can make the game-world their own and comprehensive evaluations of Serious Games should be undertaken.

Gaming well: links between videogames and flourishing mental health.

This paper is a review of the state of play of research linking videogaming and flourishing, and explores the role of videogames and technology to improve mental health and well-being. Its purpose is to develop understandings about the positive intersection of gaming and well-being, to document evidence regarding links between videogames and positive mental health, and to provide guidelines for use by other researchers as they design and use tools and games to improve mental health and well-being. Using Huppert's (Huppert and So, 2013) proposition that to flourish is more than the absence of mental disorder but rather a combination of feeling good and functioning effectively, resulting in high levels of mental well-being, and Seligman's (Seligman, 2011) PERMA theory of well-being, the paper identifies strengths in existing games that generate positive affect, positive functioning, and positive social functioning, contributing to, and supporting mental health and well-being.