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Search Results: 1 - 10 of 325272 matches for " S. Alj "
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Can phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibition ERase them all?
Dominique S Meyer, Mohamed Bentires-Alj
Breast Cancer Research , 2010, DOI: 10.1186/bcr2718
Abstract: Tamoxifen, which interferes with estrogen for receptor binding, was the first successful targeted therapy and has been the treatment of choice for estrogen receptor (ER)-positive breast cancers for more than two decades. Unfortunately, resistance occurs in approximately 30% of patients and the mechanisms of resistance act directly on the ER pathway and/or activate parallel pathways that block the anti-proliferative and pro-apoptotic actions of tamoxifen [1,2]. For example, increased mitogen-activated protein kinase (MAPK) and phosphatidyl-inositol 3-kinase (PI3K) signaling downstream of growth factor receptors (for example, ERBB2 and Insulin-like growth factor 1 receptor (IGF-1R)) has been implicated in a crosstalk with ER and in resistance to endocrine therapy [1-3].The PI3K pathway, a central regulator of diverse normal cellular functions, is very often subverted during neoplastic transformation and contributes to several hallmarks of cancer that result in a competitive advantage for cancer cells [4-6]. Not surprisingly, the PI3K cascade is an attractive therapeutic target and several inhibitors are currently in phase I/II clinical trials. Preclinical studies have shown that PI3K inhibition circumvents resistance to trastuzumab in ERBB2-positive breast cancers and this has led to clinical trials combining anti-ERBB2 and anti-PI3K therapies [7]. Although PI3K has been implicated in resistance to endocrine therapy of ER-positive tumors, several questions remain unanswered. Is PI3K inhibition, alone or in combination with tamoxifen, effective in tamoxifen-resistant ER-positive cancer cells? Does PI3K inhibition block the emergence of tamoxifen resistance? Does a PI3K hyperactivation signature in human tumors predict tamoxifen sensitivity? Two recent papers now provide some answers to these outstanding questions.Creighton and colleagues [8] investigated the relationship between the PI3K pathway and ER levels and activity using breast cancer cell lines and data sets of
Unusual Cause of Trigeminal Neuralgia: Arachnoid Cyst of Petrous Apex  [PDF]
S. El Fakir, M. Ouha, Y. Zouine, L. El Assasse, S. Alj
Open Access Library Journal (OALib Journal) , 2019, DOI: 10.4236/oalib.1105807
Abstract:
Arachnoid cyst of petrous apex is an uncommon cyst lesion that herniates from the posterolateral portion of the Meckel’s cave into the petrous apex. It can be unilateral or bilateral, usually observed in female population. Its etiopathogenesis is still uncertain and many theories were reported in the literature. The characteristic imaging appearance, topography and benign behavior of the lesion allow to differentiate arachnoid cyst from other cyst-like lesions of petrous apex and prevent abusive surgery or unnecessary investigations. The purpose of this study is to illustrate through this observation the role of sectional imaging in the diagnosis of symptomatic arachnoid cyst of petrous apex.
Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion
Nicola Aceto, Stephan Duss, Gwen MacDonald, Dominique S Meyer, Tim-C Roloff, Nancy E Hynes, Mohamed Bentires-Alj
Breast Cancer Research , 2012, DOI: 10.1186/bcr3329
Abstract: Three-dimensional (3D) cultures, invasion and migration assays were used to determine the effects of HER2 and HER3 co-expression and activation. Gene expression analysis was performed to identify the gene network induced by HER2/HER3 in 3D cultures. Bioinformatic analysis and neutralizing antibodies were used to identify key mediators of HER2/HER3-evoked invasion.Co-expression of the tyrosine kinase receptors HER2 and HER3 induced migration and invasion of MCF10A cells. Microarray analysis of these cells revealed a specific "HER2/HER3 signature" comprising 80 upregulated transcripts, with IL8 being the highest (11-fold upregulation). Notably, examination of public datasets revealed high levels of IL8 transcripts in HER2-enriched as well as basal-like primary breast tumors, two subtypes characterized by a particularly poor prognosis. Moreover, IL8 expression correlated with high tumor grade and ER-negative status. Importantly, treatment with IL8-neutralizing antibodies prevented invasion of MCF10A-HER2/HER3 and BT474 cells in 3D cultures, highlighting the importance of IL8 autocrine signaling upon HER2/HER3 activation.Our findings demonstrate that HER2 and HER3 co-expression induces IL8 autocrine signaling, leading to the invasion of mammary cells. Agents targeting IL8 or its receptor CXCR1 may be useful for the treatment of HER2/HER3/IL8-positive breast cancers with invasive traits.HER2 (ErbB2) and HER3 (ErbB3) are members of a family of four receptor tyrosine kinases that also includes the epidermal growth factor receptor (HER1/EGFR) and HER4 (ErbB4) [1]. HER2 overexpression accounts for approximately 20% of all breast cancers and is commonly associated with a poor prognosis [2]. The importance of HER2 in cancer is highlighted by the clinical efficacy of the anti-HER2 humanized monoclonal antibody trastuzumab (Herceptin), especially when combined with chemotherapy, for the treatment of HER2-overexpressing breast cancers [3,4]. HER3 has been strongly implicated as a
Asymptotic properties of QML estimators for VARMA models with time-dependent coefficients: Part I
Abdelkamel Alj,Christophe Ley,Guy Mélard
Statistics , 2015,
Abstract: This paper is about vector autoregressive-moving average (VARMA) models with time-dependent coefficients to represent non-stationary time series. Contrarily to other papers in the univariate case, the coefficients depend on time but not on the length of the series $n$. Under appropriate assumptions, it is shown that a Gaussian quasi-maximum likelihood estimator is almost surely consistent and asymptotically normal. The theoretical results are illustrated by means of two examples of bivariate processes. It is shown that the assumptions underlying the theoretical results apply. In the second example the innovations are also marginally heteroscedastic with a correlation ranging from -0.8 to 0.8. In the two examples, the asymptotic information matrix is obtained in the Gaussian case. Finally, the finite-sample behaviour is checked via a Monte Carlo simulation study for $n$ going from 25 to 400. The results confirm the validity of the asymptotic properties even for short series and reveal that the asymptotic information matrix deduced from the theory is correct.
New methods in mammary gland development and cancer: proteomics, epigenetics, symmetric division and metastasis
Mohamed Bentires-Alj, Marina Glukhova, Nancy Hynes, Maria Vivanco
Breast Cancer Research , 2012, DOI: 10.1186/bcr3216
Abstract: Speaking of Weggis, where the European Network for Breast Development and Cancer (ENBDC) meeting is held, Mark Twain said 'Sunday in heaven is noisy compared to this quietness'. Indeed, people working on breast development and cancer took full advantage of this wonderfully quiet and beautiful place again this year for in-depth discussions. The meeting, held in April, started with an inspiring keynote lecture by Nancy Hynes and included the following sessions.The proteomics session consisted of two lectures, one by Bernd Bodenmiller (University of Zurich, Switzerland) and the other by Arzu Umar (Erasmus University Medical Center, Rotterdam, The Netherlands). Bodenmiller talked about mass cytometry, a new technology that combines flow cytometry and atomic mass spectrometry and that allows simultaneous measurement of up to 100 parameters [1]. This method allows the analysis of complex regulatory networks activated in response to various environmental signals at the single-cell level and can provide a system-wide picture of signaling events. Cellular signaling intermediates are recognized by antibodies, as used for other techniques, but become labeled with rare earth metals, non-radioactive and non-biological, instead of fluorochromes, and this generates a significantly larger range of reporter tags. In the mass cytometer, cells are introduced into the plasma, atomized, and analyzed by mass spectrometry. At present, a shortage of suitable antibodies against cellular signaling compounds is one of the limiting factors in mass cytometry. Nevertheless, the method significantly extends the capacities of currently used techniques and will play a central role in the analysis of complex cellular interactive networks [2].Umar presented a paper on the identification of a prognostic protein profile for triple-negative breast cancer. This group compared 25 triple-negative tumors that have a poor clinical prognosis with 38 tumors that have a more positive prognosis in order to defin
Hippo inactivation feeds tumor-initiating cells
Stephan Duss, Adrian Britschgi, Mohamed Bentires-Alj
Breast Cancer Research , 2012, DOI: 10.1186/bcr3190
Abstract: The Hippo signaling pathway was discovered more than 17 years ago in Drosophila mutant screens as a major regulator of organ size controlling proliferation and cell death [1]. This pathway is conserved and equally important in mammals and, not surprisingly, deregulation of the Hippo pathway plays fundamental roles in cancer [2,3]. Whereas the upstream components of the Hippo pathway (NF2, MST1/2, SAV1, LATS1/2, and MOB1A) are tumor suppressors, the downstream components (YAP1, TAZ and TEAD) are oncogenes [4]. The mammalian Hippo homolog kinases MST1/2 (macrophage stimulating 1/2) in complex with the scaffold protein SAV1 (salvador homolog 1), phosphorylate and activate the kinases LATS1/2 (large tumor suppressor homolog 1/2). LATS1/2 phosphorylate and inactivate the transcription co-activators YAP1 (Yes-associated protein 1) [5] and TAZ (transcriptional coactivator with PDZ-binding motif) [6]. Unphosphorylated YAP1/TAZ associate with TEAD (TEA domain family member 1) and activate their target genes [7] (Figure 1). TAZ binds heteromeric SMAD2/3-4, activates transforming growth factor-beta target genes and maintains human embryonic stem cell self-renewal [8]. Furthermore, TAZ enhances epithelial-to-mesenchymal transition (EMT), migration, invasion and tumorigenesis of breast cancer cell lines [6,9].Whereas many upstream components of the Hippo pathway in Drosophila [10] and zebrafish [11] have been identified, those in mammals remain poorly defined. The work of Cordenonsi and colleagues [12] indicates a role for EMT and the polarity gatekeeper Scribble upstream of the Hippo cascade in human breast tumor-initiating cells.To identify signaling pathways that drive breast tumorigenesis and heterogeneity, Cordenonsi and colleagues [12] analyzed a gene expression metadataset of breast tumors and found a TAZ/YAP signature to be correlated with high-grade (poorly differentiated) tumors. These tumors were previously shown to express embryonic and mammary stem cell signatures.
Polar POLICRYPS Diffractive Structures Generate Cylindrical Vector Beams
Domenico Alj,Sathyanarayana Paladugu,Giovanni Volpe,Roberto Caputo,Cesare Umeton
Physics , 2015,
Abstract: Local shaping of the polarization state of a light beam is appealing for a number of applications. This can be achieved by employing devices containing birefringent materials. In this article, we present one such device that permits one to convert a uniformly circularly polarized beam into a cylindrical vector beam (CVB). This device has been fabricated by exploiting the POLICRYPS photocuring technique. It is a liquid-crystal-based optical diffraction grating featuring polar symmetry of the director alignment. We have characterized the resulting CVB profile and polarization for the cases of left and right circularly polarized incoming beams.
The devil is in the methods: lineage tracing, functional screens and sequencing, hormones, tumour-stroma interactions, and expansion of human breast tumours as xenografts
María dM Vivanco, John Stingl, Robert B Clarke, Mohamed Bentires-Alj
Breast Cancer Research , 2011, DOI: 10.1186/bcr3021
Abstract: The third international meeting of the European Network for Breast Development and Cancer (ENBDC) again promoted the sharing of protocols and ideas between groups working on breast development and cancer. Graduate students, postdocs and research associates were encouraged to attend. The following topics were covered in depth: functional screens and sequencing, hormones, lineage tracing, the propagation of human breast tumours as xenografts and tumour-stroma interactions.Chris Lord from the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research in London presented examples of the power of genome-wide functional screens. First, his group combined tamoxifen treatment of breast cancer cells in vitro and a small interfering RNA (siRNA) screen for kinases in an approach to identify events leading to tamoxifen sensitivity and tamoxifen resistance. They identified low cyclin-dependent kinase (CDK)10 expression as an important mediator of resistance to endocrine therapy in breast cancer. Knockdown of CDK10 blocked its inhibitory effect on ETS2, which in turn induced transcription of c-Raf and led to activation of the ERK/mitogen-activated protein kinase (MAPK) pathway and resistance to tamoxifen [1]. They also used a pooled genome-wide small hairpin RNA (shRNA) screen in the presence or absence of tamoxifen, coupled with massively parallel sequencing, and identified groups of genes the silencing of which increased sensitivity (for example C10orf72, C15orf55/NUT, EDF1, ING5, KRAS) or resistance (for example, BAP1, CLPP, GPRC5D, NAE1, NF1) to tamoxifen [2]. Second, they used a synthetic lethal unbiased shRNA screen for identifying sensitizers to a poly (ADP-ribose) polymerase (PARP) inhibitor in BRCA1 wild-type breast cancer cells. Knockdown of RAD51D, a novel ovarian cancer susceptibility gene, dramatically increased cell death upon PARP inhibition [3]. Third, they used a kinome-wide siRNA screen to identify genetic dependencies of breast cancer cell l
It's all in the details: methods in breast development and cancer
Mohamed Bentires-Alj, Robert B Clarke, Jos Jonkers, Matthew Smalley, Torsten Stein
Breast Cancer Research , 2009, DOI: 10.1186/bcr2346
Abstract: There are several meetings devoted to breast cancer research, some of which include talks on normal breast development. In contrast, there is no meeting specifically dedicated to discussing methods used in breast development and cancer. A new group, the European Network for Breast Development and Cancer (ENBDC), has initiated an annual meeting specifically devoted to presenting and discussing methods in the mammary gland field. The first meeting was organised in Weggis, Switzerland last April. First-year graduate students as well as novices in the field of breast development and cancer were encouraged to attend. This inaugural meeting encompassed discussions on breast cancer histopathology, tumour-initiating cells, animal models and normal breast stem cells.The first session included David Robertson from the Breakthrough Breast Cancer Research Centre in London and Dr Kim Jensen from Cambridge University. Robertson presented the latest developments in multi-colour fluorescent imaging using formalin-fixed paraffin-embedded (FFPE) sections. FFPE archives around the world add up to a large database of tumour samples, but standard staining using chromogenic substrates has several limitations, especially the inability to target multiple proteins simultaneously and the limited intracellular resolution. Immunofluorescence potentially provides increased resolution and allows a multi-colour approach. However, FFPE material often displays a high level of auto-fluorescence. Using an optimised protocol and confocal laser microscopy, Robertson was able to dramatically reduce this background fluorescence, allowing the use of four-colour fluorescence for cellular and intracellular co-localisation studies on FFPE tissue microarrays [1]. His latest protocols will be published on the ENBDC website [2].Kim Jensen from Fiona Watt's laboratory also presented work on studying multiple genes in small samples. He has developed a technique for full genome microarray analysis on RNA amounts e
Methods in Mammary Gland Development and Cancer: the second ENDBC meeting - intravital imaging, genomics, modeling and metastasis
John Stingl, Matthew J Smalley, Marina A Glukhova, Mohamed Bentires-Alj
Breast Cancer Research , 2010, DOI: 10.1186/bcr2630
Abstract: The European Network for Breast Development and Cancer (ENBDC) organized its second meeting to foster interactions and the sharing of protocols between groups working on breast development and cancer. Graduate students, postdocs and research associates were encouraged to attend. The meeting included discussions on genomics, bioinformatics, intravital microscopy, disseminated tumor cells, ex vivo culture and in vivo models for studying breast cancer.Nuno Barbosa-Morais (Cancer Research UK, Cambridge Research Institute) discussed the importance of the correct annotation of microarray probes and of being sure that a probe truly maps to the gene of interest. Further problems to consider are probes that map to intron-exon boundaries, the presence of SNPs, and alternative splicing, which, as is becoming apparent, occurs on a far wider scale than previously appreciated. Splicing may lead to difficulties when summarizing data from multiple probes apparently mapping to the same gene but which in fact detect different splice variants. Overall, it is clear that whatever array platform is being used, application of the latest, most reliable annotation is important. In a test of annotation reliability, it was found that Refseq annotations are a more reliable guide to probe identity than GenBank/UniGene.Britta Weigelt (Cancer Research UK, London Research Institute) spoke on the design of gene expression microarray studies, which fall into three types. The first, class comparison, is a supervised analysis to define molecular differences between predefined groups. The second, class prediction, is a supervised analysis where, after identifying the transcriptional differences between predefined groups, a genomic classifier (signature) is defined to classify new samples. It has become clear that class prediction signatures mainly identify tumors with high proliferation, although they do perform well in identifying poor prognosis tumors of the estrogen receptor-positive type. The third
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