1,724,249 research outputs found
Abstract 4498: O GlcNAcylation of SOX2 regulates its tumor initiation properties in pancreatic cancer
No full textAbstract Background: Pancreatic Cancer is an extremely aggressive disease with a bad outcome owing to its late detection, high rate of metastasis and self-renewal post-surgical and chemotherapeutic intervention. In cancer the balance between differentiation and self-renewal is tightly regulated by SOX2. Over expression of SOX2, as in pancreatic cancer, can tilt the balance towards self-renewal and thus increase the population of these undifferentiated “stem cells”. Methods: A CRISPR based OGT knockout kit was purchased from Origene and a knockout cell line was generated with S2VP10 cells. For the tumor initiation studies OGTi (OGT knockout cells) were implanted subcutaneously at a limiting dilution from 500,000 cells to 500 cells. Site directed mutagenesis was performed using theQuick-change Lightning from Agilent. Results: In the current study we show for the first time that SOX2 undergoes a type of post translational modification known as O GlcNAcylation. We also show for the first time that in humans this modification happens at Serine 246 and mutating this particular site via a side directed mutagenesis leads to a loss of O GlcNAcylation of SOX2.O GlcNAc modification of SOX2 further leads to its activation which then leads to its stabilization in the nucleus. A CRISPR-OGT knockout in pancreatic cancer cell line S2VP10 resulted in a delayed tumor initiation. We further showed that mutation of this site (S246A) prevents the modification of Sox2 and its downstream activity. Our study also demonstrated that targeting OGT in vivo with a small molecule inhibitor OSMI, results in decreased tumor burden, delayed tumor progression and a decreased expression of SOX2 in pancreatic cancer cells. Conclusion: Our study highlights for the first time that the O-GlcNAc transferase dependent SOX2 glycosylation has a profound effect on the transcriptional activity of SOX2 and is instrumental in determining self-renewal in pancreatic cancer which can be targeted therapeutically. Citation Format: Nikita S. Sharma, Vineet K. Gupta, Patricia Dauer, Roey Hadad, Kousik K. kesh, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. O GlcNAcylation of SOX2 regulates its tumor initiation properties in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4498
Linked collectors and determiners for: Three new species of entimine weevils in Early Miocene amber from the Dominican Republic (Coleoptera: Curculionidae).
No full textNatural history specimen data linked to collectors and determiners held within, "Three new species of entimine weevils in Early Miocene amber from the Dominican Republic (Coleoptera: Curculionidae)". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7">https://bionomia.net/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7">https://gbif.org/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7</a>. Formatted as a Frictionless Data package
Abstract 4498: Afatinib, an irreversible ErbB family inhibitor, demonstrates activity against HER2 mutated cervical cancer in vitro
No full textAbstract
Uterine cervical cancer (UCC) is the second leading cause of cancer deaths among women worldwide and results in 275,000 deaths annually. Functional characterization of cancer-associated genetic alterations may lead to new therapeutic approaches using molecularly targeted therapies which have the potential to improve patient outcomes. Consistent with this view, whole exome sequencing studies in a variety of human tumors including cervical cancer have recently identified somatic mutations in genes that encode for the ErbB family receptors. Importantly, some of these mutations have been shown to be “drivers” and to correlate with tumor sensitivity to the exposure to ErbB tyrosine kinase inhibitors in vitro as well as in vivo.
In this study we have evaluated whether genetic alterations in the c-erbB2 gene determine the sensitivity of UCC primary cell lines to Afatinib, an EGFR, HER2, and HER4 irreversible tyrosine kinase inhibitor.
Ten primary UCC cell lines, (two harboring c-erbB2 gene mutations in the extracellular HER2/neu domain [i.e., the S280F and E375D mutations-ref genome hg18] and eight harboring wild type c-erbB2), established as long term cultures in vitro, were analyzed in our study. The effect of Afatinib on cell growth, cell-cycle distribution and signaling were assessed using flow cytometry and western blot analysis following incubation of primary UCC cell lines with scalar concentrations of Afatinib for 72 hours in vitro.
We found that despite similar ErbB2 mRNA expression levels by qRT-PCR in the mutated versus the wild type c-erbB2 groups, IC50 values in response to Afatinib were significantly lower in the group of mutated cell lines than in the non-mutated control UCC (MEAN±SEM = 0.55±0.11 vs. 1.64±0.09 μM, P<0.05). Furthermore, Afatinib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells blocked in the G1 cell cycle phase as well as a dose-dependent dephosphorylation of HER2, S6, AKT and ERK in both c-erbB2 mutated and wild type UCC cell lines.
Our data suggests that Afatinib, a recently FDA approved drug, is highly effective against c-erbB2 mutated UCC in vitro and could represent a valid therapeutic option for patients harboring c-erbB2 mutated advanced/recurrent cervical cancers unresponsive to radiation and/or chemotherapy.
Citation Format: Salvatore Lopez, Emiliano Cocco, Bellone Stefania, Ileana Bortolomai, Elena Bonazzoli, Roberta Nicoletti, Carlton Schwab, Diana P. English, Corrado Terranova, Roberto Angioli, Alessandro D. Santin. Afatinib, an irreversible ErbB family inhibitor, demonstrates activity against HER2 mutated cervical cancer in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2014-449
Linked collectors and determiners for: Three new species of entimine weevils in Early Miocene amber from the Dominican Republic (Coleoptera: Curculionidae).
No full textNatural history specimen data linked to collectors and determiners held within, "Three new species of entimine weevils in Early Miocene amber from the Dominican Republic (Coleoptera: Curculionidae)". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7">https://bionomia.net/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7">https://gbif.org/dataset/5aa68ed2-0a6e-4498-97fc-928ffe0987a7</a>. Formatted as a Frictionless Data package
Linked collectors and determiners for: Downward flux of phytoplankton cells on the West Greenland continental shelf, July 2021.
No full textNatural history specimen data linked to collectors and determiners held within, "Downward flux of phytoplankton cells on the West Greenland continental shelf, July 2021". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/e053797e-1548-4498-af63-1f7fc1791d1d">https://bionomia.net/dataset/e053797e-1548-4498-af63-1f7fc1791d1d</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/e053797e-1548-4498-af63-1f7fc1791d1d">https://gbif.org/dataset/e053797e-1548-4498-af63-1f7fc1791d1d</a>. Formatted as a Frictionless Data package
Begonnen mit Zugangs-Nr. C 3359 am 23.12.55 : Abgeschlossen mit Zugangs-Nr. C 4498 am 19.3.56
No full textBEGONNEN MIT ZUGANGS-NR. C 3359 AM 23.12.55 : ABGESCHLOSSEN MIT ZUGANGS-NR. C 4498 AM 19.3.56
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
CircSLC7A2 protects against osteoarthritis through inhibition of the miR‐4498/TIMP3 axis
Get PDFObjectivesCircular RNAs (circRNAs) are noncoding RNAs that compete against other endogenous RNA species, such as microRNAs, and have been implicated in many diseases. In this study, we investigated the role of a new circRNA (circSLC7A2) in osteoarthritis (OA).Materials and methodsThe relative expression of circSLC7A2 was significantly lower in OA tissues than it was in matched controls, as shown by real-time quantitative polymerase chain reaction (RT-qPCR). Western blotting, RT-qPCR and immunofluorescence experiments were employed to evaluate the roles of circSLC7A2, miR-4498 and TIMP3. The in vivo role and mechanism of circSLC7A2 were also conformed in a mouse model.ResultscircSLC7A2 was decreased in OA model and the circularization of circSLC7A2 was regulated by FUS. Loss of circSLC7A2 reduced the sponge of miR-4498 and further inhibited the expression of TIMP3, subsequently leading to an inflammatory response. We further determined that miR-4498 inhibitor reversed circSLC7A2-knockdown-induced OA phenotypes. Intra-articular injection of circSLC7A2 alleviated in vivo OA progression in a mouse model of anterior cruciate ligament transection (ACLT).ConclusionsThe circSLC7A2/miR-4498/TIMP3 axis of chondrocytes catabolism and anabolism plays a critical role in OA development. Our results suggest that circSLC7A2 may serve as a new therapeutic target for osteoarthritis
LncRNA UCA1 regulates immune micro-environment in cisplatin-induced AKI by miRNA-4498/AKT3 pathway.
No full textAn increasing number of studies highlight the significance of long non-coding RNAs (lncRNAs) in the biological process of acute kidney injury (AKI). This study investigates the role and the mechanism of lncRNA UCA1 in cisplatin-induced AKI. Real-time quantitative PCR was used to measure lncRNA UCA1 expression in cisplatin-induced AKI mouse model, showing that lncRNA UCA1 was overexpressed. Knockdown of lncRNA UCA1 by shRNA significantly reduced inflammation caused by cisplatin treatment. A co-culture system demonstrated that lncRNA UCA1 upregulation in T cells induced apoptosis of tubular epithelial cells (TECs). A dual-luciferase reporter assay confirmed that lncRNA UCA1 acts as a miR-4498 sponge, binding to the 3'UTR of AKT3. Flow cytometry and ELISA results showed that reduced inflammation effect induced by lncRNA UCA1 knockdown was reversed by miR-4498 inhibition or AKT3 overexpression. Our findings suggest that lncRNA UCA1 functions as a miR-4498 sponge, upregulating AKT3 expression, and promoting inflammation in cisplatin-induced AKI
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