Primary radiation as initial management in endometrial cancer: investigating EBRT, IMRT and HDR brachytherapy

For patients with endometrial cancer at increased risk of perioperative morbidity, primary radiation therapy is an effective alternative treatment option. However, there has been no consensus on radiation technique and little data on outcomes. Our aim was to identify factors which determine patient selection for primary radiation, investigate treatment efficacy of radiation compared to surgical management of endometrial cancer and to evaluate different radiation modalities including external beam radiation therapy alone or with a boost of either high dose rate brachytherapy or intensity-modulated radiation therapy for differences in toxicities, recurrence-free interval, cancer-specific survival and overall survival

Use of ITS‑1 to identify Bactrocera dorsalis and Bactrocera occipitalis (Diptera: Tephritidae): a case study using flies trapped in California from 2008 to 2018

Molecular methods are necessary to diagnose immature life stages of the agricultural pest fruit fly Bactrocera dorsalis (Hendel), and are useful to corroborate identifications based on adults because morphological variation within the species can overlap with congeners. DNA sequencing of the nuclear ribosomal internal transcribed spacer 1 (ITS‑1) has been adopted by the International Plant Protection Convention as an internationally accepted method to distinguish between the 2 pestiferous fruit fly species Bactrocera dorsalis and Bactrocera carambolae (Drew & Hancock). Reported ITS‑1 sequences also are distinct and diagnostically informative to distinguish several other Bactrocera species related to B. dorsalis. In this study, we applied DNA sequencing of ITS‑1 to a collection of 513 adult flies trapped in California, USA, in the yr 2008 to 2018. Internal transcribed spacer 1 sequences were successfully recovered from 504 (98%) of these flies. One fly had an ITS‑1 sequence that matched B. occipitalis (Bezzi) records. Re-examination of that fly using cytochrome c oxidase I, elongation factor 1‑alpha, and morphology supports it as the second record of B. occipitalis trapped in California. The other 503 flies had ITS‑1 sequences consistent with B. dorsalis. Six unique ITS‑1 sequences (or DNA types) were observed in the collection of 503 B. dorsalis. Three of the ITS‑1 sequences (types A, B, and C) were present in 84% of the 503 flies and match ITS‑1 records reported in prior publications on B. dorsalis. The other 3 sequences (types D, E, and F) observed in 4% of the 503 B. dorsalis have not been reported in publications. Ambiguous nucleotides were observed from 12% of the 503 B. dorsalis flies, precluding designation of a sequence type. Including the 3 new types from the current study, a total of 15 unique ITS‑1 sequences now are known for B. dorsalis. The study, therefore, documents additional intraspecific variation of ITS‑1 that aids in future applications for species identification. - Los métodos moleculares son necesarios para diagnosticar los estadios de vida inmaduras de la plaga agrícola mosca de la fruta Bactrocera dorsalis (Hendel) y son útiles para corroborar identificaciones basadas en adultos por la variación morfológica dentro de la especie puede superponerse con congéneres. La secuenciación del ADN del espaciador transcrito interno ribosómico nuclear 1 (ITS-1) ha sido adoptada por la Convención Internacional de Protección Fitosanitaria como un método aceptado internacionalmente para distinguir entre las dos especies de moscas de la fruta, Bactrocera dorsalis y Bactrocera carambolae (Drew & Hancock). Las secuencias de ITS-1 notificadas también son distintas y proporcionan información diagnóstica para distinguir varias otras especies de Bactrocera relacionadas con B. dorsalis. En este estudio, aplicamos la secuenciación de ADN de ITS-1 a una colección de 513 moscas adultas atrapadas en California, EE. UU. desde el 2008 hasta el 2018. Se recuperaron las secuencias espaciadoras transcritas internas1 con éxito de 504 (98%) de estas moscas. Una mosca tenía una secuencia ITS-1 que coincidía con los registros de B. occipitalis (Bezzi). El reexamen de esa mosca usando la citocromo c oxidasa I, el factor de elongación 1-alfa y la morfología lo respalda como el segundo registro de B. occipitalis atrapada en California. Las otras 503 moscas tenían secuencias de ITS-1 compatibles con B. dorsalis. Se observaron seis secuencias únicas de ITS-1 (o tipos de ADN) en la colección de 503 B. dorsalis. Tres de las secuencias de ITS-1 (tipos A, B, y C) estaban presentes en el 84% de las 503 moscas y coinciden con los registros de ITS-1 informados en publicaciones anteriores sobre B. dorsalis. Las otras 3 secuencias (tipos D, E, y F) observadas en el 4% de las 503 B. dorsalis no han sido reportadas en publicaciones. Se observaron nucleótidos ambiguos en el 12% de las 503 moscas B. dorsalis, lo que excluye la designación de un tipo de secuencia. Incluyendo los 3 nuevos tipos del estudio actual, ahora se conocen un total de 15 secuencias ITS-1 únicas para B. dorsalis. Por lo tanto, el estudio documenta una variación intraespecífica adicional de ITS-1 que ayuda en futuras aplicaciones para la identificación de especies

The impact of time and team on primary cytoreduction outcomes

The degree of cytoreduction at time of initial surgery for epithelial ovarian cancers is correlated with overall survival. Given that surgery can be physically and mentally taxing on the surgeon, we sought to examine if there were temporal and/or team relationships related to primary cytoreduction outcomes

Role of visual analytics in supporting mental healthcare systems research and policy: A systematic scoping review

The availability of healthcare data has exponentially grown, both in quantity and complexity. The speed of this evolution has generated new challenges for translating complex data into effective evidence-informed policy. Visual analytics offers new capacity to analyze healthcare systems and support better decision-making. We conducted a systematic scoping review to look for evidence of visual analytics approaches being applied to mental healthcare systems and their use in driving policy. We found 79 relevant studies and categorized them in two ways: by study purpose and by type of visualization. The majority (67.1%) of the studies used geographical maps, and 11% conducted highly complex studies requiring novel visualizations. Significantly, only 15% of the studies provided information indicating high levels of usability for policy and planning. Our findings suggest that while visual analytics continues to evolve rapidly, there is a need to ensure this evolution reflects the practical needs of policy makers

A predictive model for serous epithelial ovarian cancer chemo-response using clinical characteristics

One of the prognostic factors most highly associated with ovarian cancer survival is response to initial chemotherapy. Current prediction models of chemo-response built with comprehensive molecular datasets, like The Cancer Genome Atlas (TCGA), could be improved by including clinical and outcomes data designed to study response to treatment. The objective of this study was to create a prediction model of ovarian cancer chemo-response using clinical-pathological features, and to compare its performance with a similar TCGA clinical model

A protocol for custom CRISPR Cas9 donor vector construction to truncate genes in mammalian cells using pcDNA3 backbone

Background Clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided adaptive immune systems are found in prokaryotes to defend cells from foreign DNA. CRISPR Cas9 systems have been modified and employed as genome editing tools in wide ranging organisms. Here, we provide a detailed protocol to truncate genes in mammalian cells using CRISPR Cas9 editing. We describe custom donor vector construction using Gibson assembly with the commonly utilized pcDNA3 vector as the backbone. Results We describe a step-by-step method to truncate genes of interest in mammalian cell lines using custom-made donor vectors. Our method employs 2 guide RNAs, mutant Cas9D10A nickase (Cas9 = CRISPR associated sequence 9), and a custom-made donor vector for homologous recombination to precisely truncate a gene of interest with a selectable neomycin resistance cassette (NPTII: Neomycin Phosphotransferase II). We provide a detailed protocol on how to design and construct a custom donor vector using Gibson assembly (and the commonly utilized pcDNA3 vector as the backbone) allowing researchers to obtain specific gene modifications of interest (gene truncation, gene deletion, epitope tagging or knock-in mutation). Selection of mutants in mammalian cell lines with G418 (Geneticin) combined with several screening methods: western blot analysis, polymerase chain reaction, and Sanger sequencing resulted in streamlined mutant isolation. Proof of principle experiments were done in several mammalian cell lines. Conclusions Here we describe a detailed protocol to employ CRISPR Cas9 genome editing to truncate genes of interest using the commonly employed expression vector pcDNA3 as the backbone for the donor vector. Providing a detailed protocol for custom donor vector design and construction will enable researchers to develop unique genome editing tools. To date, detailed protocols for CRISPR Cas9 custom donor vector construction are limited (Lee et al. in Sci Rep 5:8572, 2015; Ma et al. in Sci Rep 4:4489, 2014). Custom donor vectors are commercially available, but can be expensive. Our goal is to share this protocol to aid researchers in performing genetic investigations that require custom donor vectors for specialized applications (specific gene truncations, knock-in mutations, and epitope tagging applications)

The PI3K pathway impacts stem gene expression in a set of glioblastoma cell lines

Background: The PI3K pathway controls diverse cellular processes including growth, survival, metabolism, and apoptosis. Nuclear FOXO factors were observed in cancers that harbor constitutively active PI3K pathway output and stem signatures. FOXO1 and FOXO3 were previously published to induce stem genes such as OCT4 in embryonic stem cells. Here, we investigated FOXO-driven stem gene expression in U87MG glioblastoma cells. Methods: PI3K-activated cancer cell lines were investigated for changes in gene expression, signal transduction, and clonogenicity under conditions with FOXO3 disruption or exogenous expression. The impact of PI3K pathway inhibition on stem gene expression was examined in a set of glioblastoma cell lines. Results: We found that CRISPR-Cas9-mediated FOXO3 disruption in U87MG cells caused decreased OCT4 and SOX2 gene expression, STAT3 phosphorylation on tyrosine 705 and clonogenicity. FOXO3 over expression led to increased OCT4 in numerous glioblastoma cancer cell lines. Strikingly, treatment of glioblastoma cells with NVP-BEZ235 (a dual inhibitor of PI3K and mTOR), which activates FOXO factors, led to robust increases OCT4 gene expression. Direct FOXO factor recruitment to the OCT4 promoter was detected by chromatin immunoprecipitation analyses using U87MG extracts. Discussion: We show for the first time that FOXO transcription factors promote stem gene expression glioblastoma cells. Treatment with PI3K inhibitor NVP-BEZ235 led to dramatic increases in stem genes in a set of glioblastoma cell lines. Conclusion: Given that, PI3K inhibitors are actively investigated as targeted cancer therapies, the FOXO-mediated induction of stem genes observed in this study highlights a potential hazard to PI3K inhibition. Understanding the molecular underpinnings of stem signatures in cancer will allow refinements to therapeutic strategies. Targeting FOXO factors to reduce stem cell characteristics in concert with PI3K inhibition may prove therapeutically efficacious

The C. elegans Opa1 Homologue EAT-3 Is Essential for Resistance to Free Radicals

The C. elegans eat-3 gene encodes a mitochondrial dynamin family member homologous to Opa1 in humans and Mgm1 in yeast. We find that mutations in the C. elegans eat-3 locus cause mitochondria to fragment in agreement with the mutant phenotypes observed in yeast and mammalian cells. Electron microscopy shows that the matrices of fragmented mitochondria in eat-3 mutants are divided by inner membrane septae, suggestive of a specific defect in fusion of the mitochondrial inner membrane. In addition, we find that C. elegans eat-3 mutant animals are smaller, grow slower, and have smaller broodsizes than C. elegans mutants with defects in other mitochondrial fission and fusion proteins. Although mammalian Opa1 is antiapoptotic, mutations in the canonical C. elegans cell death genes ced-3 and ced-4 do not suppress the slow growth and small broodsize phenotypes of eat-3 mutants. Instead, the phenotypes of eat-3 mutants are consistent with defects in oxidative phosphorylation. Moreover, eat-3 mutants are hypersensitive to paraquat, which promotes damage by free radicals, and they are sensitive to loss of the mitochondrial superoxide dismutase sod-2. We conclude that free radicals contribute to the pathology of C. elegans eat-3 mutants

BioMoon: a concept for a mission to advance space life sciences and astrobiology on the Moon

As humans advance their presence in space and seek to improve the quality of life on Earth, a variety of science questions in support of these two objectives can be answered using the Moon. In this paper, we present a concept for an integrated mission focused on answering fundamental and applied biological questions on the Moon: BioMoon. The mission was designed to investigate the effects of the lunar radiation, gravity, and regolith on biological systems ranging from biomolecules to systems with complex trophic interactions, spanning a range of model organisms. Using common analytical systems and data processing, BioMoon represents a systems-level integrated life sciences mission. It would provide fundamental insights into biological responses to the lunar environment, as well as applied knowledge for In-Situ Resource Utilisation (ISRU), closed-loop life support system development, planetary protection and human health care. The mission was conceived to test biotechnology and sensor technology for lunar and terrestrial application and provide education and outreach opportunities. Although BioMoon was considered in the context of the European Space Agency’s Argonaut (European Large Logistics Lander) concept, the mission design provides a template for any integrated life sciences experimental suite on the Moon and other celestial bodies, implemented either robotically or by human explorers.CSC acknowledges support from the Science and Technology Facilities Council (Grants ST/V000586/1 and ST/Y001788/1).Discover Spac

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer