tbuckley/cabot-search huggingface dataset:
Periodontitis: facts, fallacies and the future
Authors: Jørgen Slots
Journal: Periodontology 2000 (2017)

Abstract This volume of Periodontology 2000 represents the 25th anniversary of the Journal, and uses the occasion to assess important advancements in periodontology over the past quarter‐century as well as the hurdles that remain. Periodontitis is defined by pathologic loss of the periodontal ligament and alveolar bone. The disease involves complex dynamic interactions among active herpesviruses, specific bacterial pathogens and destructive immune responses. Periodontal diagnostics is currently based on clinical rather than etiologic criteria, and provides limited therapeutic guidance. Periodontal causative treatment consists of scaling, antiseptic rinses and occasionally systemic antibiotics, and surgical intervention has been de‐emphasized, except perhaps for the most advanced types of periodontitis. Plastic surgical therapy includes soft‐tissue grafting to cover exposed root surfaces and bone grafting to provide support for implants. Dental implants are used to replace severely diseased or missing teeth, but implant overuse is of concern. The utility of laser treatment for periodontitis remains unresolved. Host modulation and risk‐factor modification therapies may benefit select patient groups. Patient self‐care is a critical part of periodontal health care, and twice‐weekly oral rinsing with 0.10‐0.25% sodium hypochlorite constitutes a valuable adjunct to conventional anti‐plaque and anti‐gingivitis treatments. A link between periodontal herpesviruses and systemic diseases is a strong biological plausibility. In summary, research during the past 25 years has significantly changed our concepts of periodontitis pathobiology and has produced more‐effective and less‐costly therapeutic options.
Abstract 2054: Cerivastatin overcomes the acquired resistance to crizotinib in EML4-ALK positive non-small cell lung cancer by controlling YAP activation
Authors: Miran Yun, Hun Mi Choi, Kyoung Ho Pyo, Byoung Chul Cho
Journal: Cancer Research (2017)

Abstract Crizotinib is highly effective in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion. However, its efficacy has been limited by the development of acquired resistance, and the mechanisms of such resistance remain largely unknown. Herein, we investigated a possible candidate for circumventing the acquired resistance to crizotinib. We established a model of acquired resistance to crizotinib (H3122-CR) by exposing EML4-ALK-positive H3122 lung cancer cells to increasing doses of crizotinib, and performed MTT screening using a library of FDA (Food and Drug Administration)-approved drugs composed of a collection of 640 clinically used compounds. Our MTT screening identified that cerivastatin, a drug targeting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly inhibited the cell growth in H3122-CR cells, which was completely restored by addition of geranylgeranyl pyrophosphate (GGPP), a key metabolite of mevalonate pathway. We also found that yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, was robustly accumulated in nucleus with a concomitant decrement of YAP phosphorylation in H3122-CR cells compared to parental cells. Importantly, inhibition of geranylgeranylation (GGylation) by GGTI-298 or cerivastatin markedly increased YAP phosphorylation, led to cytoplasmic translocation of YAP, and subsequently induced YAP inactivation. Moreover, the enrichment of EGFR signaling pathway and cell cycle signature including transcriptional targets of YAP was enhanced in H3122-CR cells, whose induction contributed YAP-mediated resistance to crizotinib. Inhibition of YAP function with siRNA or verteporfin as a YAP inhibitor greatly abrogated cell growth of H3122-CR cells by modulating cell cycle regulators and EGFR activation. Finally, we confirmed up-regulation of nuclear YAP expression in crizotinib-acquired resistant patient derived tumor xenograft (PDTX) models established from EML4-ALK positive NSCLC patients. Collectively, our findings define the GGylation-mediated YAP transcriptional activation as a new mechanism of resistance to crizotinib, providing a rationale for further exploring statins as a possible anticancer agent to overcome the acquired resistance to crizotinib in EML4-ALK positive NSCLC cells. Citation Format: Miran Yun, Hun Mi Choi, Kyoung Ho Pyo, Byoung Chul Cho. Cerivastatin overcomes the acquired resistance to crizotinib in EML4-ALK positive non-small cell lung cancer by controlling YAP activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2054. doi:10.1158/1538-7445.AM2017-2054
Abstract 3816: Mutations of the lim protein ajuba mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell cycle inhibitors
Authors: Ming Zhang, Singh Ratnakar, Shaohua Peng, Mazumdar Tuhina, Shen Li, Pan Tong, Curtis Pickering, Jeffrey N. Myers, Jing Wang, Faye M. Johnson
Journal: Cancer Research (2017)

Abstract The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA,SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model. AJUBA protein expression was undetectable in most AJUBA-mutant HNSCC cell lines, and total PLK1 protein expression was increased in cell lines wild-type for AJUBA. Exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line partially rescued the phenotype of PLK1 inhibitor-induced apoptosis and decreased PLK1 substrate inhibition, suggesting a threshold effect in which higher drug doses are required to affect PLK1 substrate inhibition. PLK1 inhibition was an effective therapy for HNSCC in vitro and in vivo. However, biomarkers to guide such therapy are lacking. We identified AJUBA, SMAD4 and RAS mutations as potential candidate biomarkers of response of HNSCC to treatment with these mitotic inhibitors. Citation Format: Ming Zhang, Singh Ratnakar, Shaohua Peng, Mazumdar Tuhina, Shen Li, Pan Tong, Curtis Pickering, Jeffrey N. Myers, Jing Wang, Faye M. Johnson. Mutations of the lim protein ajuba mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell cycle inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3816. doi:10.1158/1538-7445.AM2017-3816
Abstract 2255: SMAD4 loss is associated with poor prognosis in Middle Eastern colorectal cancer
Authors: Maqbool Ahmed, Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2017)

Abstract Background: Colorectal cancer (CRC) is major cause of morbidity and mortality in cancer patients worldwide and it ranks as the most common cancer in males and the third most common among females in Saudi Arabia. Alteration in TGF-β pathway has been reported in many cancers. So In search for new molecular targets we analyzed the role of SMAD4, critical TGF-β pathway mediator, in Saudi colorectal cancers Methods: 426 CRC cases were analyzed for SMAD4 mutations by targeted capture sequencing and protein expression status by immunohistochemistry in a tissue microarray format. Results were analyzed for association with any clinico-pathological parameters and for prognostic significance. Results: SMAD4 mutations were detected in 11.9 %( 50/418) cases of Saudi colorectal cancers. CRC with SMAD4 mutations were significantly associated with NRAS mutations (p=0.0481). SMAD4 complete loss of expression by immunohistochemistry was seen in 12.8% (52/404) cases and this loss was associated with young age (p=0.0236) and inversely with MSI-high tumors (p=0.0005). SMAD4 expression loss by immunohistochemistry and mutation were significantly associated with each other (p=0.0028). In the multivariate analysis using the Cox proportional hazard model SMAD4 expression loss was an independent marker of poor prognosis (p=0.0119) Conclusion: SMAD4 alteration was found to be associated with a poor overall survival in the Saudi colorectal cancer patients. With the advent of targeted anticancer therapy, this study confirms the findings of other investigators and highlights a potential target which can be exploited to improve the survival of CRC patients in the Kingdom of Saudi Arabia Citation Format: Maqbool Ahmed, Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya. SMAD4 loss is associated with poor prognosis in Middle Eastern colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2255. doi:10.1158/1538-7445.AM2017-2255
Abstract 554: Accurately identifying neoantigens utilizing both DNA and RNA somatic variants in an enhanced platform
Authors: Sean M. Boyle, Jason Harris, Gabor Bartha, Ravi Alla, Mirian Karbelashvili, Steve Chervitz, Aldrin Montana, Craig Rowell, Patrick Jonganeel, Scott Kirk, Rena McClory, John West, Rich Chen
Journal: Cancer Research (2017)

Abstract The identification of neoantigens is a crucial step in the development of neoantigen-based personalized cancer vaccines and other immunotherapies. Accurately predicting which neoantigens are likely to be immunogenic remains a key challenge owing to the complex processes involved in determining neoantigen immunogenicity including the antigen presenting machinery, likelihood of MHC class I and II binding, similarity to self, and ability to interact with the TCR. We have developed a neoantigen detection pipeline built upon our analytically validated Accuracy and Content Enhanced (ACE) Exome and Transcriptome sequencing platform and somatic variants calling pipeline through combined DNA and RNA analysis. The analytical performance of these pipelines is greater than &amp;gt;97% sensitivity for small variants (RNA and DNA) with a specificity of &amp;gt;98% (DNA) and a fusion sensitivity of &amp;gt;99% (RNA). Within our neoantigen pipeline, variants that are detected by our DNA and RNA cancer analysis pipelines are processed for antigen identification, including SNVs, indels, and fusion events. Importantly, both in-frame and out-of-frame events are accurately considered by transcript, allowing for detection of a wealth of candidate neoantigens. Our pipeline includes assessment of important immunologic components including HLA prediction, MHC binding (class I and II), immunogenicity, similarity to self, and similarity to known antigens. Additionally, peptides are evaluated for variant allele frequency in both the RNA and DNA of the tumor sample and gene expression level is considered. Collectively, our ImmunoID product provides a comprehensive assessment of features that may be used for identifying and ranking potentially immunogenic neoantigens. To assess the effectiveness of this pipeline in predicting immunogenic neoantigens, we assembled a gold-set of 23 known, previously experimentally-validated immunogenic neoantigens from the literature. We spiked in these neoepitopes into exome data and assessed the ability of our neoantigen pipeline to find and rank these immunogenic known neoantigens. Preliminary results show our neoantigen pipeline is able to accurately identify 22 out of 23 (~96%) of the spiked in neoantigens as being potentially immunogenic. Citation Format: Sean M. Boyle, Jason Harris, Gabor Bartha, Ravi Alla, Mirian Karbelashvili, Steve Chervitz, Aldrin Montana, Craig Rowell, Patrick Jonganeel, Scott Kirk, Rena McClory, John West, Rich Chen. Accurately identifying neoantigens utilizing both DNA and RNA somatic variants in an enhanced platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 554. doi:10.1158/1538-7445.AM2017-554
Abstract 5872: Stat3 feedback activation-induced PTGIS expression is associated with acquired resistance to EGFR-TKI in lung cancer
Authors: Hsuan-Heng Yeh, Shang-Yin Wu, Chun-Hua Hung, Wu-Chou Su
Journal: Cancer Research (2017)

Abstract Targeted cancer therapies can effectively promote tumor regression in clinical responses. Eventually, most tumors develop resistance to these drugs. Stat3 activation has been suggested as one of the mechanisms that cause acquired resistance to EGFR-tyrosin kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are not well studied. In this study, we found that treatment of gefitinib (EGFR-TKI) in NSCLC cell lines harboring EGFR-TKI sensitive mutation induced feedback activation of Stat3 in a time- and dose-dependent manner. High levels of IL-6 were detected in the conditioned medium of gefitinib-treated cells by cytokine array and were confirmed by ELISA. We demonstrated that IL-6 treatment could induce Stat3 activation and conditioned medium treatment-induced Stat3 activation was suppressed by IL-6 neutralizing antibody. We also demonstrated that gefitinib treatment-induced IL-6 secretion could be inhibited by knockdown of Stat3 expression. Moreover, pharmacological inhibition and genetic inhibition of Stat3 activation increased cell cytotoxicity of gefitinib in both PC9 and HCC827 cells that harboring EGFR-TKI sensitive mutation. Our data suggested that gefitinib treatment could induce activation of IL-6/Stat3 signaling loop and modulate cell cytotoxicity of gefitinib. Microarray and Ingenuity Pathway Analysis (IPA) analysis revealed prostaglandin I2 synthase (PTGIS) as a downstream target gene of IL-6/Stat3 signaling and PTGIS was up-regulated by gefitinib treatment. The induction of PTGIS by gefitinib via Stat3 feedback activation was confirmed in vitro genetically and pharmacologically. Moreover, we showed that cotreatment with PTGIS inhibitor improves the efficacy of EGFR inhibition in PC9 and HCC827 cells. Importantly, high expression of PTGIS was found in gefitinib-resistant PC9 cells (PC9/gef) compared with gefitinib-sensitive PC9 cells. Targeting PTGIS was also effective in decreasing viability of cells with acquired resistance to gefitinib in PC9/gef cells. Taken together, our study indicated that Stat3 feedback activation-induced PTGIS expression participates in modulating gefitinib efficacy and Stat3/PTGIS inhibition could potentially overcome acquired resistance to gefitinib in NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Hsuan-Heng Yeh, Shang-Yin Wu, Chun-Hua Hung, Wu-Chou Su. Stat3 feedback activation-induced PTGIS expression is associated with acquired resistance to EGFR-TKI in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5872. doi:10.1158/1538-7445.AM2017-5872
Abstract 14: Anticancer activities of terpenoid compounds isolated from the plant <i>centipeda minma</i> against nasopharyngeal carcinoma cells
Authors: Bei-bei Liu, Kui-yuan Zhu, Chi-on Chan, Ling-Hua Zhang, Daniel Kam-Wah Mok, Si-bao Chen
Journal: Cancer Research (2017)

Abstract Nasopharyngeal carcinoma (NPC) is one of common cancers throughout south-east Asia, southern China and other regions. Radiotherapy and chemotherapy are the standard treatments for NPC with severe adverse effects, multi-drug resistance, and insensitivity to advanced NPC. Complementary and novel treatments for NPC gain considerable interest around the world. The medicinal plant Centipeda minma is traditionally used in China for the treatment of various nasal diseases such as allergy, rhinitis, sinusitis and nasopharyngeal carcinoma. In the current study, we studied the anticancer potential of an ethanol extract (CME) and 3 pure sesquiterpenoids (A1, A2, A3) extracts from Centipeda minma against NPC cells in vitro and some underlying mechanisms of actions. The NPC cell lines CNE-1 and CNE-2 cells were treated with either CME or 3 pure compounds (A1, A2, A3). Proliferation of NPC cells was inhibited in a concentration- and time-dependent manner. For 48 h treatment, the IC50 values were 41.57 to 24.98 μg/mL for CME, and 2.3 to 7.5 μM for A1 to A3. While these extracts showed no appreciable effect on normal human LO2 hepatocytes, significant numbers of NPC cells underwent apoptotic morphological changes following treatments. Cytometric analysis demonstrated that treatments with CME and compounds results in NPC cell cycle arrest at the G2/M phase and eventually apoptosis in a concentration and time-dependent manner. Western blot analysis showed that these extracts could down-regulate Bcl-2 expression, up-regulate Bax expression and caspase-8, 9, 3 activities. In addition, the potential anti-NPC actions might be also associated with the marked inhibition of multiple signal transduction pathways including EGFR, VEGFR, HER2, FGFR, IGF-1R, PI3K/AKT/mTOR, MAP/ERK and Jan/Stat3 pathways. In summary, the Centipeda minma extract and terpenoids are potential apoptosis inducing agents to kill NPC cells and may be promising anti-cancer drug leads against nasopharyngeal carcinoma. The exact mechanism of actions remains further study. Note: This abstract was not presented at the meeting. Citation Format: Bei-bei Liu, Kui-yuan Zhu, Chi-on Chan, Ling-Hua Zhang, Daniel Kam-Wah Mok, Si-bao Chen. Anticancer activities of terpenoid compounds isolated from the plant centipeda minma against nasopharyngeal carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 14. doi:10.1158/1538-7445.AM2017-14
Abstract 3559: Functional characterization of HNF4α in gastric cancer
Authors: Chang Xu, Wen Fong Ooi, Aditi Qamra, Patrick Tan
Journal: Cancer Research (2017)

Abstract Gastric cancer (GC) is a leading cause of cancer mortality worldwide and particularly common in East Asia. Transcription factors are frequently amplified or overexpressed in GC and might contribute to tumorgenesis, however the underlying mechanisms largely remain unknown. Our previous data indicates that HNF4α is a common target of three amplified transcription factors (GATA4, GATA6 and KLF5) in gastric cancer. HNF4α had also been found to be related to diverse aspects of tumorigenesis. In liver and colon cancers, there are reports indicating that the targets of HNF4α are mainly involved in intermediary metabolism, however, its tissue-specific downstream targets and pathways have not been systemically studied yet. Therefore, a comprehensive functional characterization of HNF4α is required to identify its tissue-specific role in gastric cancer. In this study, we analyzed the expression features of HNF4α in GC, and found the expression level of HNF4α is significantly higher in early stage tumor and in CIN and MSI compared to GS and EBV subtypes of GC according to TCGA classification method. In addition, we performed the HNF4α ChIP in GC cell lines, and the results revealed a number of HNF4α binding sites in GC. Comparison with the published ChIP-seq data of Caco2 and HepG2 cell lines indicated the existence of GC-exclusive targets. Furthermore, functional annotation analysis revealed that the GC-exclusive targets are significantly related to the negative regulation of cellular metabolic process compared to the common targets. These preliminary data suggests that HNF4α might play a tissue specific role in GC, especially in metabolic related processes. Through further target validation and biological function studies, this study hopes to systemically investigate of HNF4α’s role in GC tumorigenesis, especially in metabolism related pathways. Citation Format: Chang Xu, Wen Fong Ooi, Aditi Qamra, Patrick Tan. Functional characterization of HNF4α in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3559. doi:10.1158/1538-7445.AM2017-3559
Abstract 3218: Molecular function of PARP inhibition in glioblastoma
Authors: Christopher Aldrighetti, Barbara Huebert, Delphine Quenet
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor, whose major biomarkers are the DNA methylation status of the promoter for O6-methylguanine-DNA-methyltransferase (MGMT) and the loss/mutation of the tumor suppressor phosphatase and tensin homolog (PTEN). Despite treatment combining surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ), patient survival remains poor and recurrence is virtually inevitable, due to TMZ resistance. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. This enzyme catalyses the transfer and polymerization of ADP ribose units from NAD+ to form branched polymers of ADP-ribose, called poly(ADP-ribose) (PAR), covalently attached to heterologous acceptor proteins or PARP-1 itself. There is a growing interest in PARP inhibitors (PARPi) for their clinical potential in cancer treatment. Because of the importance of PARP-1 activity in the maintenance of genomic integrity and DNA repair, treatment with PARPi as adjuvant to TMZ chemotherapy can be beneficial in GBM. PARPi are currently in clinical trials for patients with GBM (NCT02152982, NCT01390571, NCT01514201), and one of them is a phase II/III study of the PARPi veliparib for patients with newly-diagnosed GBM (NCT02152982). However, the molecular role of PARP-1 and its activity in GBM remains elusive. Using cellular and molecular approach, we are assessing the effectiveness of the PARPi veliparib compared to standard treatment with TMZ in PTEN-mutated GBM and TMZ-resistant GBM cell lines. By understanding the biology of PARP inhibition in GBM, we will establish a specific molecular signature that predicts the efficacy of PARPi treatment in patients diagnosed with GBM. Citation Format: Christopher Aldrighetti, Barbara Huebert, Delphine Quenet. Molecular function of PARP inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3218. doi:10.1158/1538-7445.AM2017-3218