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Reply to the 'Comment on "Towards a personalized approach to aromatase inhibitor therapy: a digital microfluidic platform for rapid analysis of estradiol in core-needle-biopsies"' by P. E. Lønning, Lab Chip, 2017, 17, DOI: 10.1039/C7LC00617A.

Reply to the 'Comment on "Towards a personalized approach to aromatase inhibitor therapy: a digital microfluidic platform for rapid analysis of estradiol in core-needle-biopsies"' by P. E. Lønning, Lab Chip, 2017, 17, DOI: 10.1039/C7LC00617A.

Lab Chip. 2017 Aug 17;:

Authors: Casper RF, Wheeler AR

Abstract
This article provides our response to a comment on our article that appeared in Lab on a Chip (S. Abdulwahab, A. H. C. Ng, M. D. Chamberlain, H. Ahmado, L.-A. Behan, H. Gomaa, R. F. Casper and A. R. Wheeler, Lab Chip, 2017, 17, 1594).

PMID: 28816309 [PubMed - as supplied by publisher]



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Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets.

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Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets.

Proc Natl Acad Sci U S A. 2017 Aug 16;:

Authors: Vlahos AE, Cober N, Sefton MV

Abstract
The transplantation of pancreatic islets, following the Edmonton Protocol, is a promising treatment for type I diabetics. However, the need for multiple donors to achieve insulin independence reflects the large loss of islets that occurs when islets are infused into the portal vein. Finding a less hostile transplantation site that is both minimally invasive and able to support a large transplant volume is necessary to advance this approach. Although the s.c. site satisfies both these criteria, the site is poorly vascularized, precluding its utility. To address this problem, we demonstrate that modular tissue engineering results in an s.c. vascularized bed that enables the transplantation of pancreatic islets. In streptozotocin-induced diabetic SCID/beige mice, the injection of 750 rat islet equivalents embedded in endothelialized collagen modules was sufficient to restore and maintain normoglycemia for 21 days; the same number of free islets was unable to affect glucose levels. Furthermore, using CLARITY, we showed that embedded islets became revascularized and integrated with the host's vasculature, a feature not seen in other s.c.
STUDIES: Collagen-embedded islets drove a small (albeit not significant) shift toward a proangiogenic CD206(+)MHCII(-)(M2-like) macrophage response, which was a feature of module-associated vascularization. While these results open the potential for using s.c. islet delivery as a treatment option for type I diabetes, the more immediate benefit may be for the exploration of revascularized islet biology.

PMID: 28814629 [PubMed - as supplied by publisher]



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Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth.

Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth.

Oncogene. 2017 Aug 14;:

Authors: Lustig LC, Dingar D, Tu WB, Lourenco C, Kalkat M, Inamoto I, Ponzielli R, Chan WCW, Shin JA, Penn LZ

Abstract
Developing therapeutics to effectively inhibit the MYC oncoprotein would mark a key advance towards cancer patient care as MYC is deregulated in over 50% of human cancers. MYC deregulation is correlated with aggressive disease and poor patient outcome. Despite strong evidence in mouse models that inhibiting MYC would significantly impact tumour cell growth and patient survival, traditional approaches have not yet yielded the urgently needed therapeutic agents that directly target MYC. MYC functions through its interaction with MAX to regulate gene transcription by binding to E-box DNA response elements of MYC target genes. Here we used a structure-based strategy to design ME47, a small minimalist hybrid protein (MHP) able to disrupt the MAX:E-box interaction/binding and block transcriptional MYC activity. We show that inducing ME47 expression in established tumour xenografts inhibits tumour growth and decreases cellular proliferation. Mechanistically, we show by chromatin immunoprecipitation that ME47 binds to E-box binding sites of MYC target genes. Moreover, ME47 occupancy decreases MYC:DNA interaction at its cognate E-box binding sites. Taken together, ME47 is a prototypic MHP inhibitor that antagonizes tumour cell growth in vitro and in vivo and inhibits the interaction of MYC with DNA E-box elements. These results support ME47's role as a MYC inhibitor and suggest that MHPs provide an alternative therapeutic targeting system that can be used to target transcription factors important in human diseases, including cancer.Oncogene advance online publication, 14 August 2017; doi:10.1038/onc.2017.275.

PMID: 28806396 [PubMed - as supplied by publisher]



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Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets.

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Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets.

Blood. 2017 Oct 19;130(16):1819-1831

Authors: Bouska A, Bi C, Lone W, Zhang W, Kedwaii A, Heavican T, Lachel CM, Yu J, Ferro R, Eldorghamy N, Greiner TC, Vose J, Weisenburger DD, Gascoyne RD, Rosenwald A, Ott G, Campo E, Rimsza LM, Jaffe ES, Braziel RM, Siebert R, Miles RR, Dave S, Reddy A, Delabie J, Staudt LM, Song JY, McKeithan TW, Fu K, Green M, Chan WC, Iqbal J

Abstract
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.

PMID: 28801451 [PubMed - indexed for MEDLINE]



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Home sweet home: the neural stem cell niche throughout development and after injury.

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Home sweet home: the neural stem cell niche throughout development and after injury.

Cell Tissue Res. 2017 Aug 03;:

Authors: Ruddy RM, Morshead CM

Abstract
Neural stem cells and their progeny reside in two distinct neurogenic niches within the mammalian brain: the subventricular zone and the dentate gyrus. The interplay between the neural stem cells and the niche in which they reside can have significant effects on cell kinetics and neurogenesis. A comprehensive understanding of the changes to the niche that occur through postnatal development and aging, as well as following injury, is relevant for developing therapeutics and interventions to promote neural repair. We discuss changes that occur within the neural stem and progenitor cell populations, the vasculature, extracellular matrix, microglia, and secreted proteins through aging which impact cell behavior within the neurogenic niches. We examine neural precursor cell and niche responses to injury in neonatal hypoxia-ischemia, juvenile cranial irradiation, and adult stroke. This review examines the interplay between the niche and stem cell behavior through aging and following injury as a means to understand intrinsic and extrinsic factors that regulate neurogenesis in vivo.

PMID: 28776186 [PubMed - as supplied by publisher]



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microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer.

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microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer.

JCI Insight. 2017 Aug 03;2(15):

Authors: Wang S, Liu JC, Ju Y, Pellecchia G, Voisin V, Wang DY, Leha L R, Ben-David Y, Bader GD, Zacksenhaus E

Abstract
The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce nonmalignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse pten in mammary epithelium are highly differentiated and lack transplantable tumor-initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbor transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations, and mutational landscape, as well as reduced expression of microRNA-143/145 (miR-143/145). Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR-145 deficiency significantly correlated with elevated RAS-pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/high RAS-pathway activity exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with RAS-pathway activation, either through miR-145 loss or other mechanisms, in basal-like breast cancer, and a need to identify and prioritize these tumors for aggressive therapy.

PMID: 28768903 [PubMed - as supplied by publisher]



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Ubiquitin Ligase WWP1 Interacts with Ebola Virus VP40 To Regulate Egress.

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Ubiquitin Ligase WWP1 Interacts with Ebola Virus VP40 To Regulate Egress.

J Virol. 2017 Oct 15;91(20):

Authors: Han Z, Sagum CA, Takizawa F, Ruthel G, Berry CT, Kong J, Sunyer JO, Freedman BD, Bedford MT, Sidhu SS, Sudol M, Harty RN

Abstract
Ebola virus (EBOV) is a member of the Filoviridae family and the cause of hemorrhagic fever outbreaks. The EBOV VP40 (eVP40) matrix protein is the main driving force for virion assembly and budding. Indeed, expression of eVP40 alone in mammalian cells results in the formation and budding of virus-like particles (VLPs) which mimic the budding process and morphology of authentic, infectious EBOV. To complete the budding process, eVP40 utilizes its PPXY L-domain motif to recruit a specific subset of host proteins containing one or more modular WW domains that then function to facilitate efficient production and release of eVP40 VLPs. In this report, we identified additional host WW-domain interactors by screening for potential interactions between mammalian proteins possessing one or more WW domains and WT or PPXY mutant peptides of eVP40. We identified the HECT family E3 ubiquitin ligase WWP1 and all four of its WW domains as strong interactors with the PPXY motif of eVP40. The eVP40-WWP1 interaction was confirmed by both peptide pulldown and coimmunoprecipitation assays, which also demonstrated that modular WW domain 1 of WWP1 was most critical for binding to eVP40. Importantly, the eVP40-WWP1 interaction was found to be biologically relevant for VLP budding since (i) small interfering RNA (siRNA) knockdown of endogenous WWP1 resulted in inhibition of eVP40 VLP egress, (ii) coexpression of WWP1 and eVP40 resulted in ubiquitination of eVP40 and a subsequent increase in eVP40 VLP egress, and (iii) an enzymatically inactive mutant of WWP1 (C890A) did not ubiquitinate eVP40 or enhance eVP40 VLP egress. Last, our data show that ubiquitination of eVP40 by WWP1 enhances egress of VLPs and concomitantly decreases cellular levels of higher-molecular-weight oligomers of eVP40. In sum, these findings contribute to our fundamental understanding of the functional interplay between host E3 ligases, ubiquitination, and regulation of EBOV VP40-mediated egress.IMPORTANCE Ebola virus (EBOV) is a high-priority, emerging human pathogen that can cause severe outbreaks of hemorrhagic fever with high mortality rates. As there are currently no approved vaccines or treatments for EBOV, a better understanding of the biology and functions of EBOV-host interactions that promote or inhibit viral budding is warranted. Here, we describe a physical and functional interaction between EBOV VP40 (eVP40) and WWP1, a host E3 ubiquitin ligase that ubiquitinates VP40 and regulates VLP egress. This viral PPXY-host WW domain-mediated interaction represents a potential new target for host-oriented inhibitors of EBOV egress.

PMID: 28768865 [PubMed - indexed for MEDLINE]



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Ubiquitin orchestrates proteasome dynamics between proliferation and quiescence in yeast.

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Ubiquitin orchestrates proteasome dynamics between proliferation and quiescence in yeast.

Mol Biol Cell. 2017 Aug 02;:

Authors: Gu ZC, Wu E, Sailer C, Jando J, Styles E, Eisenkolb I, Kuschel M, Bitschar K, Wang X, Huang L, Vissa A, Yip CM, Yedidi R, Friesen H, Enenkel C

Abstract
Proteasomes are essential for protein degradation in proliferating cells. Little is known about proteasome functions in quiescent cells. In non-dividing yeast, a eukaryotic model of quiescence, proteasomes are depleted from the nucleus and accumulate in motile cytosolic granules termed proteasome storage granules (PSG). PSG enhance resistance to genotoxic stress and confer fitness during aging. Upon exit from quiescence PSG dissolve and proteasomes are rapidly delivered into the nucleus. To identify key players in PSG organization, we performed high-throughput imaging of green fluorescent protein (GFP)-labeled proteasomes in the yeast null mutant collection. Mutants with reduced levels of ubiquitin are impaired in PSG formation. Co-localization studies of PSG with proteins of the yeast GFP collection, mass spectrometry and direct stochastic optical reconstitution microscopy (dSTORM) of cross-linked PSG revealed that PSG are densely packed with proteasomes and contain ubiquitin but no poly-ubiquitin chains. Our results provide insight into proteasome dynamics between proliferating and quiescent yeast in response to cellular requirements for ubiquitin-dependent degradation.

PMID: 28768827 [PubMed - as supplied by publisher]



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RNAi screen identifies essential regulators of human brain metastasis-initiating cells.

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RNAi screen identifies essential regulators of human brain metastasis-initiating cells.

Acta Neuropathol. 2017 Aug 01;:

Authors: Singh M, Venugopal C, Tokar T, Brown KR, McFarlane N, Bakhshinyan D, Vijayakumar T, Manoranjan B, Mahendram S, Vora P, Qazi M, Dhillon M, Tong A, Durrer K, Murty N, Hallet R, Hassell JA, Kaplan DR, Cutz JC, Jurisica I, Moffat J, Singh SK

Abstract
Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-β ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

PMID: 28766011 [PubMed - as supplied by publisher]



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Functional annotation of chemical libraries across diverse biological processes.

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Functional annotation of chemical libraries across diverse biological processes.

Nat Chem Biol. 2017 Sep;13(9):982-993

Authors: Piotrowski JS, Li SC, Deshpande R, Simpkins SW, Nelson J, Yashiroda Y, Barber JM, Safizadeh H, Wilson E, Okada H, Gebre AA, Kubo K, Torres NP, LeBlanc MA, Andrusiak K, Okamoto R, Yoshimura M, DeRango-Adem E, van Leeuwen J, Shirahige K, Baryshnikova A, Brown GW, Hirano H, Costanzo M, Andrews B, Ohya Y, Osada H, Yoshida M, Myers CL, Boone C

Abstract
Chemical-genetic approaches offer the potential for unbiased functional annotation of chemical libraries. Mutations can alter the response of cells in the presence of a compound, revealing chemical-genetic interactions that can elucidate a compound's mode of action. We developed a highly parallel, unbiased yeast chemical-genetic screening system involving three key components. First, in a drug-sensitive genetic background, we constructed an optimized diagnostic mutant collection that is predictive for all major yeast biological processes. Second, we implemented a multiplexed (768-plex) barcode-sequencing protocol, enabling the assembly of thousands of chemical-genetic profiles. Finally, based on comparison of the chemical-genetic profiles with a compendium of genome-wide genetic interaction profiles, we predicted compound functionality. Applying this high-throughput approach, we screened seven different compound libraries and annotated their functional diversity. We further validated biological process predictions, prioritized a diverse set of compounds, and identified compounds that appear to have dual modes of action.

PMID: 28759014 [PubMed - indexed for MEDLINE]



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