The 'Melanoma-enriched' microRNA miR-4731-5p acts as a tumour suppressor

We previously identified miR-4731-5p (miR-4731) as a melanoma-enriched microRNA following comparison of melanoma with other cell lines from solid malignancies. Additionally, miR-4731 has been found in serum from melanoma patients and expressed less abundantly in metastatic melanoma tissues from stage IV patients relative to stage III patients. As miR-4731 has no known function, we used biotin-labelled miRNA duplex pull-down to identify binding targets of miR-4731 in three melanoma cell lines (HT144, MM96L and MM253). Using the miRanda miRNA binding algorithm, all pulled-down transcripts common to the three cell lines (n=1092) had potential to be targets of miR-4731 and gene-set enrichment analysis of these (via STRING v9.1) highlighted significantly associated genes related to the ‘cell cycle’ pathway and the ‘melanosome’. Following miR-4731 overexpression, a selection (n=81) of pull-down transcripts underwent validation using a custom qRT-PCR array. These data revealed that miR-4731 regulates multiple genes associated with the cell cycle (e.g. CCNA2, ORC5L, and PCNA) and the melanosome (e.g. RAB7A, CTSD, and GNA13). Furthermore, members of the synovial sarcoma X breakpoint family (SSX) (melanoma growth promoters) were also down-regulated (e.g. SSX2, SSX4, and SSX4B) as a result of miR-4731 overexpression. Moreover, this down-regulation of mRNA expression resulted in ablation or reduction of SSX4 protein, which, in keeping with previous studies, resulted in loss of 2D colony formation. We therefore speculate that loss of miR-4731 expression in stage IV patient tumours supports melanoma growth by, in part; reducing its regulatory control of SSX expression levels

Follicle size on day of trigger most likely to yield a mature oocyte

Funding: MRC, BBSRC and NIHR and supported by the NIHR/Wellcome Trust Imperial Clinical Research Facility and Imperial Biomedical Research Centre.Objective: To identify follicle sizes on the day of trigger most likely to yield a mature oocyte following hCG, GnRH agonist (GnRHa), or kisspeptin during IVF treatment. Design: Retrospective analysis to determine the size of follicles on day of trigger contributing most to the number of mature oocytes retrieved using generalized linear regression and random forest models applied to data from IVF cycles (2014–2017) in which either hCG, GnRHa, or kisspeptin trigger was used. Setting: HCG and GnRHa data were collected at My Duc Hospital, Ho Chi Minh City, Vietnam, and kisspeptin data were collected at Hammersmith Hospital, London, UK. Patients: Four hundred and forty nine women aged 18–38 years with antral follicle counts 4–87 were triggered with hCG (n = 161), GnRHa (n = 165), or kisspeptin (n = 173). Main outcome measure: Follicle sizes on the day of trigger most likely to yield a mature oocyte. Results: Follicles 12–19 mm on the day of trigger contributed the most to the number of oocytes and mature oocytes retrieved. Comparing the tertile of patients with the highest proportion of follicles on the day of trigger 12–19 mm, with the tertile of patients with the lowest proportion within this size range, revealed increases of 4.7 mature oocytes for hCG (P < 0.0001) and 4.9 mature oocytes for GnRHa triggering (P < 0.01). Using simulated follicle size profiles of patients with 20 follicles on the day of trigger, our model predicts that the number of oocytes retrieved would increase from a mean 9.8 (95% prediction limit 9.3–10.3) to 14.8 (95% prediction limit 13.3–16.3) oocytes due to the difference in follicle size profile alone. Conclusion: Follicles 12–19 mm on the morning of trigger administration were most likely to yield a mature oocyte following hCG, GnRHa, or kisspeptin.Publisher PDFPeer reviewe

Human Cortical Neural Stem Cells Expressing Insulin‐Like Growth Factor‐I: A Novel Cellular Therapy for Alzheimer’s Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135291/1/sct3201653379.pd

A systematic variation of the stellar initial mass function in early-type galaxies

Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars. It depends on the stellar initial mass function (IMF) describing the distribution of stellar masses when the population formed. Consequently knowledge of the IMF is critical to virtually every aspect of galaxy evolution. More than half a century after the first IMF determination, no consensus has emerged on whether it is universal in different galaxies. Previous studies indicated that the IMF and the dark matter fraction in galaxy centres cannot be both universal, but they could not break the degeneracy between the two effects. Only recently indications were found that massive elliptical galaxies may not have the same IMF as our Milky Way. Here we report unambiguous evidence for a strong systematic variation of the IMF in early-type galaxies as a function of their stellar mass-to-light ratio, producing differences up to a factor of three in mass. This was inferred from detailed dynamical models of the two-dimensional stellar kinematics for the large Atlas3D representative sample of nearby early-type galaxies spanning two orders of magnitude in stellar mass. Our finding indicates that the IMF depends intimately on a galaxy's formation history.Comment: 4 pages, 2 figures, LaTeX. Accepted for publication as a Nature Letter. More information about our Atlas3D project is available at http://purl.org/atlas3

Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ~7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity

MAS NMR investigation of molecular order in an ionic liquid crystal

The structure and molecular order in the thermotropic ionic liquid crystal (ILC), [choline][geranate(H)octanoate], an analogue of Choline And GEranate (CAGE), which has potential for use as a broad-spectrum antimicrobial and transdermal and oral delivery agent, were investigated by magic-angle spinning (MAS) nuclear magnetic resonance (NMR), polarizing optical microscopy, small-angle X-ray scattering (SAXS), and mass spectrometry. Mass spectrometry and the 1H NMR chemical shift reveal that CAGE-oct is a dynamic system, with metathesis (the exchange of interacting ions) and hydrogen exchange occurring between hydrogen-bonded/ionic complexes such as [(choline)(geranate)(H)(octanoate)], [(choline)(octanoate)2(H)], and [(choline)(geranate)2(H)]. These clusters, which are shown by mass spectrometry to be significantly more stable than expected for typical electrostatic ion clusters, involve hydrogen bonding between the carboxylic acid, carboxylate, and hydroxyl groups, with rapid hydrogen bond breaking and re-formation observed to average the 1H chemical shifts. The formation of a partial bilayer liquid crystal (LC) phase was identified by SAXS and polarizing optical microscopy at temperatures below ∼293 K. The occurrence of this transition close to room temperature could be utilized as a potential temperature-induced “switch” of the anisotropic properties for particular applications. The presence of an isotropic component of approximately 23% was observed to coexist with the LC phase, as detected by polarizing optical microscopy and quantified by both 1H–13C dipolar-chemical shift correlation (DIPSHIFT) and 1H double-quantum (DQ) MAS NMR experiments. At temperatures above the LC-to-isotropic transition, intermediate-range order (clustering of polar and nonpolar domains), a feature of many ILs, persists. Site-specific order parameters for the LC phase of CAGE-oct were obtained from the MAS NMR measurement of the partially averaged 13C–1H dipolar couplings (DCH) by cross-polarization (CP) build-up curves and DIPSHIFT experiments, and 1H–1H dipolar couplings (DHH) by double-quantum (DQ) build-up curves. The corresponding order parameters, SCH and SHH, are in the range 0–0.2 and are lower compared to those for smectic (i.e., layered) phases of conventional nonionic liquid crystals, resembling those of lamellar phases formed by lyotropic surfactant–solvent systems

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN