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#32376470   2020/05/04 To Up

Transcriptomics analysis of pericytes from retinas of diabetic animals reveals novel genes and molecular pathways relevant to blood-retinal barrier alterations in diabetic retinopathy.

Selective pericyte loss, the histological hallmark of early diabetic retinopathy (DR), enhances the breakdown of the blood-retinal barrier (BRB) in diabetes. However, the role of pericytes on BRB alteration in diabetes and the signaling pathways involved in their effects are currently unknown. To understand the role of diabetes-induced molecular alteration of pericytes, we performed transcriptomic analysis of sorted retinal pericytes from mice model of diabetes. Retinal tissue from non-diabetic and diabetic (duration 3 months) mouse eyes (n = 10 in each group) were used to isolate pericytes through fluorescent activated cell sorting (FACS) using pericyte specific fluorescent antibodies, PDGFRb-APC. For RNA sequencing and qPCR analysis, a cDNA library was generated using template switching oligo and the resulting libraries were sequenced using paired-end Illumina sequencing. Molecular functional pathways were analyzed using differentially expressed genes (DEGs). Differential expression analysis revealed 217 genes significantly upregulated and 495 genes downregulated, in pericytes isolated from diabetic animals. These analyses revealed a core set of differentially expressed genes that could potentially contribute to the pericyte dysfunction in diabetes and highlighted the pattern of functional connectivity between key candidate genes and blood retinal barrier alteration mechanisms. The top up-regulated gene list included: Ext2, B3gat3, Gpc6, Pip5k1c and Pten and down-regulated genes included: Notch3, Xbp1, Gpc4, Atp1a2 and AKT3. Out of these genes, we further validated one of the down regulated genes, Notch 3 and its role in BRB alteration in diabetic retinopathy. We confirmed the downregulation of Notch3 expression in human retinal pericytes exposed to Advanced Glycation End-products (AGEs) treatment mimicking the chronic hyperglycemia effect. Exploration of pericyte-conditioned media demonstrated that loss of NOTCH3 in pericyte led to increased permeability of endothelial cell monolayers. Collectively, we identify a role for NOTCH3 in pericyte dysfunction in diabetes. Further validation of other DEGs to identify cell specific molecular change through whole transcriptomic approach in diabetic retina will provide novel insight into the pathogenesis of DR and novel therapeutic targets.
Sampathkumar Rangasamy, Finny Monickaraj, Christophe Legendre, Andrea P Cabrera, Lorida Llaci, Cherae Bilagody, Paul McGuire, Arup Das

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#30819916   2019/02/28 To Up

A B-cell receptor-related gene signature predicts response to ibrutinib treatment in mantle cell lymphoma cell lines.


Tiziana D'Agaro, Antonella Zucchetto, Filippo Vit, Tamara Bittolo, Erika Tissino, Francesca Maria Rossi, Massimo Degan, Francesco Zaja, Pietro Bulian, Michele Dal Bo, Simone Ferrero, Marco Ladetto, Alberto Zamò, Valter Gattei, Riccardo Bomben

2006 related Products with: A B-cell receptor-related gene signature predicts response to ibrutinib treatment in mantle cell lymphoma cell lines.

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#30343280   // To Up

Evaluation of the Insulin-like Growth Factor Receptor Pathway in Patients with Advanced Breast Cancer Treated with Trastuzumab.

Trastuzumab is a monoclonal antibody against HER2-positive breast cancer. Despite improving the natural history of the disease, there is a number of patients who are resistant to it, whereas all patients will eventually develop resistance and disease will progress. Inconsistent preclinical data show that the IGF-R pathway may contribute to either de novo or acquired resistance to trastuzumab.
Christos Christodoulou, Georgios Oikonomopoulos, Georgia Angeliki Koliou, Ioannis Kostopoulos, Vassiliki Kotoula, Mattheos Bobos, George Pentheroudakis, George Lazaridis, Maria Skondra, Sofia Chrisafi, Angelos Koutras, Dimitrios Bafaloukos, Evangelia Razis, Kyriaki Papadopoulou, Pavlos Papakostas, Haralambos P Kalofonos, Dimitrios Pectasides, Pantelis Skarlos, Konstantine T Kalogeras, George Fountzilas

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#29595878   // To Up

AKT2 is the predominant AKT isoform expressed in human skeletal muscle.

Skeletal muscle physiology and metabolism are regulated by complex networks of intracellular signaling pathways. Among many of these pathways, the protein kinase AKT plays a prominent role. While three AKT isoforms have been identified (AKT1, AKT2, and AKT3), surprisingly little is known regarding isoform-specific expression of AKT in human skeletal muscle. To address this, we examined the expressions of each AKT isoform in muscle biopsy samples collected from the vastus lateralis of healthy male adults at rest. In muscle, AKT2 was the most highly expressed AKT transcript, exhibiting a 15.4-fold increase over AKT1 and AKT3 transcripts. Next, the abundance of AKT protein isoforms was determined using antibody immunoprecipitation followed by Liquid Chromatography-Parallel Reaction Monitoring/Mass Spectrometry. Immunoprecipitation was performed using either mouse or rabbit pan AKT antibodies that were immunoreactive with all three AKT isoforms. We found that AKT2 was the most abundant AKT isoform in human skeletal muscle (4.2-fold greater than AKT1 using the rabbit antibody and 1.6-fold greater than AKT1 using the mouse antibody). AKT3 was virtually undetectable. Next, cultured primary human myoblasts were virally-transduced with cDNAs encoding either wild-type (WT) or kinase-inactive AKT1 (AKT1-K179M) or AKT2 (AKT2-K181M) and allowed to terminally differentiate. Myotubes expressing WT-AKT1 or WT-AKT2 showed enhanced fusion compared to control myotubes, while myotubes expressing AKT1-K179M showed a 14% reduction in fusion. Myotubes expressing AKT2-K181M displayed 63% decreased fusion compared to control. Together, these data identify AKT2 as the most highly-expressed AKT isoform in human skeletal muscle and as the principal AKT isoform regulating human myoblast differentiation.
Ronald W Matheny, Alyssa V Geddis, Mary N Abdalla, Luis A Leandry, Michael Ford, Holly L McClung, Stefan M Pasiakos

1806 related Products with: AKT2 is the predominant AKT isoform expressed in human skeletal muscle.

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#29472356   2018/02/22 To Up

A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial.

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptor and B-cell receptor) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (, and ), was used to classify the 83 cases (43 B-cell receptor and 40 B-cell receptor). The B-cell receptor signature associated with shorter progression-free survival (=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (=0.0014 and =0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. ().
Riccardo Bomben, Simone Ferrero, Tiziana D'Agaro, Michele Dal Bo, Alessandro Re, Andrea Evangelista, Angelo Michele Carella, Alberto Zamò, Umberto Vitolo, Paola Omedè, Chiara Rusconi, Luca Arcaini, Luigi Rigacci, Stefano Luminari, Andrea Piccin, Delong Liu, Adrian Wiestner, Gianluca Gaidano, Sergio Cortelazzo, Marco Ladetto, Valter Gattei

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#28376174   // To Up

Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.

The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K.
Rebecca A Previs, Guillermo N Armaiz-Pena, Cristina Ivan, Heather J Dalton, Rajesha Rupaimoole, Jean M Hansen, Yasmin Lyons, Jie Huang, Monika Haemmerle, Michael J Wagner, Kshipra M Gharpure, Archana S Nagaraja, Justyna Filant, Michael H McGuire, Kyunghee Noh, Piotr L Dorniak, Sarah L Linesch, Lingegowda S Mangala, Sunila Pradeep, Sherry Y Wu, Anil K Sood

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#28005260   2016/12/22 To Up

High early growth response 1 (EGR1) expression correlates with resistance to anti-EGFR treatment in vitro and with poorer outcome in metastatic colorectal cancer patients treated with cetuximab.

Biomarkers, such as mutant RAS, predict resistance to anti-EGFR therapy in only a proportion of patients, and hence, other predictive biomarkers are needed. The aims were to identify candidate genes upregulated in colorectal cancer cell lines resistant to anti-EGFR monoclonal antibody treatment, to knockdown (KD) these genes in the resistant cell lines to determine if sensitivity to anti-EGFR antibody was restored, and finally to perform a pilot correlative study of EGR1 expression and outcomes in a cohort of metastatic colorectal cancer (mCRC) patients given cetuximab therapy.
S S Kumar, Y Tomita, J Wrin, M Bruhn, A Swalling, M Mohammed, T J Price, J E Hardingham

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#27708223   // To Up

Differential effects of peptidoglycan on colorectal tumors and intestinal tissue post-pelvic radiotherapy.

Immediate medical intervention is required after pelvic tumor radiotherapy to protect the radiosensitive intestine and also to mitigate tumor growth. Toll-like receptors (TLRs) have been shown to promote tissue repair processes. Here, we analyzed the effect observed upon combining the TLR2 agonist, peptidoglycan (PGN), with radiation therapy on tumors as well as intestinal tissue, both in vitro and in vivo. In contrast to radiotherapy alone, PGN when combined with ionizing radiation (IR) elicited enhanced antitumor effects and also reduced the IR-induced intestinal damage. Mechanistic studies showed that PGN first induced an IL13 response in the irradiated intestine, but was decreased in tumor cell models screened by Th1/Th2 FlowCytomix assay and validated by the application of IL13 and anti-IL13 neutralizing antibodies. Next, PGN stimulated Akt3, but not Akt1/2, as was verified by AKT1/2/3 plasmid transfection assay and in AKT1/2/3 knockout mice in vivo. Akt3 expression was inhibited in 20 μg/mL PGN-treated tumor cells and in 1.5 mg/kg PGN-treated mouse tumor models. However, Akt3 was raised via IL13 in the irradiated intestine and human intestinal cell line after the same treatment. Finally, PGN activated mTOR via IL13/AKT3 in the intestine and restored intestinal structure and function. As an adjuvant to radiotherapy, PGN inhibited tumorigenesis by suppression of mTOR activity. To summarize, the IL13/AKT3/mTOR pathway was lessened in PGN-treated irradiated tumors but was raised in the normal intestine tissue. This distinct effect of PGN on normal and tumor tissues during pelvic radiotherapy suggests that PGN may be a promising adjuvant therapy to radiation.
Gen Li, Anqing Wu, Dandan Qi, Fengmei Cui, Yanan Zeng, Fang Xie, Hongya Wu, Yongping Gu, Qiu Chen, Xueguang Zhang

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#26909918   2016/01/22 To Up

Gene expression profiling of epithelial ovarian cancer reveals key genes and pathways associated with chemotherapy resistance.

The aim of this study is to analyze gene expression data to identify key genes and pathways associated with resistance to platinum-based chemotherapy in epithelial ovarian cancer (EOC) and to improve clinical treatment strategies. The gene expression data set was downloaded from Gene Expression Omnibus and included 12 chemotherapy-resistant EOC samples and 16 chemotherapy-sensitive EOC samples. A differential analysis was performed to screen out differentially expressed genes (DEGs). A functional enrichment analysis was conducted for the DEGs using the database for annotation, visualization, and integration discovery. A protein-protein interaction (PPI) network was constructed with information from the human protein reference database. Pathway-pathway interactions were determined with a test based on the hypergeometric distribution. A total of 1564 DEGs were identified in chemotherapy-sensitive EOC, including 654 upregulated genes and 910 downregulated genes. The top three upregulated genes were HIST1H3G, AKT3, and RTN3, while the top three downregulated genes were NBLA00301, TRIM62, and EPHA5. A Gene Ontology enrichment analysis showed that cell adhesion, biological adhesion, and intracellular signaling cascades were significantly enriched in the DEGs. A KEGG pathway enrichment analysis revealed that the calcium, mitogen-activated protein kinase, and B cell receptor signaling pathways were significantly over-represented in the DEGs. A PPI network containing 101 interactions was acquired. The top three hub genes were RAC1, CAV1, and BCL2. Five modules were identified from the PPI network. Taken together, these findings could advance the understanding of the molecular mechanisms underlying intrinsic chemotherapy resistance in EOC.
M Zhang, S C Luo

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