tbuckley/cabot-search huggingface dataset:
Abstract 1100: Synergistic interaction between gemcitabine and PD-0325901 in C-33A cervical carcinoma cell line
Authors: Macarena Irigoyen, Gonzalo Castillo
Journal: Cancer Research (2017)

Abstract Cervical cancer affects over half a million women worldwide, and is one of the most common causes of death in women. Treatment of cervical cancers consists of surgery, radiation, chemotherapy, or combination of therapies. However, about half of patients with advance cancer will show recurrent tumors. Signaling cascades are often dysregulated in human cancer cells making them attractive targets for combination drug therapies. PD-0325901, an inhibitor of the mitogen-activated protein kinase, is a promising target for metastatic cancer. Another drug used to treat cervical carcinoma is gemcitabine, a nucleoside analog inhibitor of the ribonucleotide reductase and DNA damage inducible protein 45a (Gadd45a). This drug is generally used in combination with other drugs, after reoccurrence of the disease state. We decided to evaluate the efficacy of gemcitabine in combination with PD-0325901 in C-33A, a metastatic cervical cancer-derived cell line. We evaluated the potency of gemcitabine and PD-0325901 alone and in combination. Cell viability after incubation with the drugs was determined at 72 hours and at 7 days by measuring ATP content. Synergy was determined assessed utilizing BIOENSIS’s suite of drug combination analysis tools including: isobologram, combination index (CI) and Bliss analysis. Isobologram analysis at 72 hours of incubation revealed that the mean values of the observed data were significantly smaller than those of the predicted maximum additive values, indicating synergy. Bliss and combination index analysis confirmed the observation, showing a synergistic effect at concentrations between 2 - 200 nM PD-0325901 and 0.3 - 3 nM gemcitabine. Similar patterns of synergy were observed with 7 day incubations of C-33A with gemcitabine and PD-0325901. These results indicate that gemcitabine and PD-0325901 showed significantly more growth inhibition than either drug alone in the C-33A tumor cell line, suggesting that the combination of gemcitabine - PD-0325901 could be used in cervical cancer therapy. Citation Format: Macarena Irigoyen, Gonzalo Castillo. Synergistic interaction between gemcitabine and PD-0325901 in C-33A cervical carcinoma cell line [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 1100. doi:10.1158/1538-7445.AM2017-1100
Abstract 2085: Development of a novel targeted therapy for malignant mesothelioma carcinoma by a midkine inhibitor
Authors: Takuya Fukazawa, Yuitaka Maeda, Tomoki Yamatsuji, Munenori Takaoka, Masakazu Yoshida, Naomasa Ishida, Miki Iwai, Etsuko Yokota, Takuro Yukawa, Minoru Haisa, Noriko Miyake, Tomoko Ikeda, Nagio Takigawa, Jeffery Whitsett, Yoshio Naomoto
Journal: Cancer Research (2017)

Abstract Malignant pleural mesothelioma is an aggressive tumor of mesenchymal origin and is increasing worldwide as a result of widespread exposure to asbestos. The median survival of patients with mesothelioma from time of diagnosis ranges between 1 and 2 years. The mortality is expected to increase, at least until 2020, which is mainly due to the long latency (30-50 years) of the disease. Despite considerable advances in the understanding of its pathogenesis and etiology, malignant mesothelioma remains largely unresponsive to standard modalities of cancer therapy. Thus, there is an urgent need for new therapeutic options for mesothelioma.Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. We have previously reported that a MDK inhibitor, iMDK, suppresses non-small cell lung cancer expressing MDK without harming normal cells. Importantly, iMDK inhibits the PI3 kinase / Akt pathway and induces apoptosis in MDK expressing non-small cell lung cancer cells. In the present study, we have investigated the antitumor effect of iMDK against malignant mesothelioma both in vitro and in vivo. 48 hours after treatment, iMDK dose-dependently inhibited cell growth of MDK expressing malignant mesothelioma cells. iMDK also suppressed colony formation of MSTO-211H mesothelioma cells. TUNEL positive cells were significantly increased in MSTO-211H cells 48 hours after iMDK treatment in a dose-dependent manner, confirming the induction of apoptosis in mesothelioma cells by iMDK. Combination treatment of iMDK and Bcl-2 inhibitor ABT-263 is more effective than each drug alone in MSTO-211H mesothelioma cells. Moreover, systemic administration of iMDK significantly inhibited tumor growth in a mesothelioma xenograft tumor in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of malignant mesothelioma that is driven by MDK. Citation Format: Takuya Fukazawa, Yuitaka Maeda, Tomoki Yamatsuji, Munenori Takaoka, Masakazu Yoshida, Naomasa Ishida, Miki Iwai, Etsuko Yokota, Takuro Yukawa, Minoru Haisa, Noriko Miyake, Tomoko Ikeda, Nagio Takigawa, Jeffery Whitsett, Yoshio Naomoto. Development of a novel targeted therapy for malignant mesothelioma carcinoma by a midkine inhibitor [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 2085. doi:10.1158/1538-7445.AM2017-2085
Abstract 208: Proteomic measurements of protein abundance and phosphorylation identify novel kinase-substrate relationships in ovarian cancer
Authors: Jason E. McDermott, Tao Liu, Samuel Payne, Vladislav Petyuk, Hui Zhang, Zhen Zhang, Daniel Chan, Richard Smith, Karin Rodland
Journal: Cancer Research (2017)

Abstract As part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we have recently published the first large-scale proteomic and phosphoproteomic analysis of high-grade serous ovarian tumors. We observed that phosphorylation status was an excellent indicator of pathway activity and could discriminate between patient survival times. This dataset covers tumor samples from 69 patients with deep phosphoproteomic depth (&amp;gt;20,000 phosphopeptides confidently identified). Our continuing analysis of this dataset, reported here, has revealed that the correlation between kinase protein abundance and abundance of phosphorylated target peptides is very low, indicating that kinase abundance is not a good proxy for phosphorylation status overall. However, highly correlated kinase-substrate pairs are significantly more likely to be true relationships (from existing knowledge), demonstrating that this method could be used to predict novel kinase targets in some cases. Using this approach we predicted novel kinase-target relationships and constructed a kinase activity network of ovarian cancer. To better analyze cancer-relevant pathway activity we developed a novel approach that characterizes correlation, differential abundance, and statistical interactions between components to analyze multiple omics types in the context of signaling and functional pathways. We used this approach, called the Layered Enrichment Analysis of Pathways (LEAP), to identify active pathways in molecular subtypes of ovarian cancer, contrasting observations in patients stratified for short versus long overall survival. This analysis resulted in a pre-treatment protein-based signature that is significantly predictive of overall survival. Our results show that integration of multiple omics types has the ability to inform our understanding of novel kinase-substrate interactions, and potentially identify novel interactions associated with patient survival. Note: This abstract was not presented at the meeting. Citation Format: Jason E. McDermott, Tao Liu, Samuel Payne, Vladislav Petyuk, Hui Zhang, Zhen Zhang, Daniel Chan, Richard Smith, Karin Rodland, Clinical Proteomic Tumor Analysis Consortium. Proteomic measurements of protein abundance and phosphorylation identify novel kinase-substrate relationships in ovarian 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 208. doi:10.1158/1538-7445.AM2017-208
Abstract 1890: PLEK2 contributes to lung cancer progression through upregulation of NDRG1 expression
Authors: Yi-Pin Hsieh, Hui-Chia Liu, Hao-Yu Huang, Wan-Jiun Tang, Tai-Lin Lee, Meng-Feng Tsai
Journal: Cancer Research (2017)

Abstract PLEK2 is one of the pleckstrin homology domain (PH domain) proteins. Recently studies suggested that PLEK2 may play a critical role in T lymphocyte migration through by PI3K/AKT dependent and independent pathways. However, the biological functions of PLEK2 in lung cancer is not clear. We detected the expression of PLEK2 in various lung adenocarcinoma cell lines using quantitative RT-PCR methods. The results indicated that PLEK2 expression significantly positive correction with cancer cell migration and invasion ability. Forced expression of PLEK2 in lung cancer cells exhibited markedly promoting in the proliferation rate, anchorage independent growth, cell motility and invasion, whereas knockdown of PLEK2 was found to suppress lung cancer cell progression. In addition, we also reported that PLEK2 expression induce lung cancer cell epithelial-mesenchymal transition (EMT) phenomenon, and involve in chemotherapeutic drug resistance through upregulation NDRG1 gene expression. Overexpression of NDRG1 in PLEK2-knockdown cell line restored cancer cell proliferation, migration, and invasion. These results will provide information and help us to understand the roles of NDRG1 in lung cancer cells. Citation Format: Yi-Pin Hsieh, Hui-Chia Liu, Hao-Yu Huang, Wan-Jiun Tang, Tai-Lin Lee, Meng-Feng Tsai. PLEK2 contributes to lung cancer progression through upregulation of NDRG1 expression [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 1890. doi:10.1158/1538-7445.AM2017-1890
Michael Jackson’s Skin
Authors: Michael Collins
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 2809: Role of c-Met in the development and progression of Tpl2-related skin cancer
Authors: Nicole F. Bonan, David Kowalski, Kaitlin Kudlac, Lauren G. Falkenberg, Erik Maradiaga, Kira Flaherty, Jonathan S. Wiest, Katie L. DeCicco-Skinner
Journal: Cancer Research (2017)

Abstract Cutaneous squamous cell carcinoma (cSCC), a form of non-melanoma skin cancer, is the second most common form of cancer in the United States, with over one million cases diagnosed annually. Tpl2 (MAP3K8) is a serine threonine protein kinase in the mitogen-activated protein kinase (MAPK) signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressive function in skin carcinogenesis, with Tpl2 knockout mice developing significantly more papillomas and squamous cell carcinomas than matched wildtype (WT) controls. Cellular mesenchymal to epithelial transition factor (c-Met) is a receptor heightened in malignant skin cancers and involved in Tpl2 signaling. When bound to its ligand, hepatocyte growth factor (HGF), c-Met can regulate cell proliferation, survival, angiogenesis and invasion. The aim of this study was to ascertain whether c-Met signaling contributes to the heightened skin tumorigenesis in Tpl2-/- mice. Forty-four WT and Tpl2 -/- mice were subjected to a two-stage chemical carcinogenesis protocol for one year to induce skin tumors. Starting at the time of promotion, half of the WT and Tpl2 -/- mice were placed on normal diet and half received diet plus 30mg/kg Capmatinib, a pharmacological inihibitor of c-Met. This diet continued for the duration of the study. No adverse health effects were found in Capmatinib-treated mice. Similar to what we previously reported, Tpl2 -/- mice developed tumors earlier than WT controls and had statistically higher tumor incidence and overall tumor burden than WT mice. The number of tumor bearing Tpl2 -/- and Tpl2 -/- + Capmatinib fed mice was similar, although Capmatinib fed mice had a 60% reduction in overall tumor burden. Studies are underway to determine if Capmatinib affected the frequency of malignant conversion in Tpl2 -/- mice. In summary, our studies demonstrate that heightened c-Met signaling contributes to the higher tumor formation in Tpl2-/- mice and should be evaluated further as a possible therapeutic target in Tpl2-related skin cancers. Citation Format: Nicole F. Bonan, David Kowalski, Kaitlin Kudlac, Lauren G. Falkenberg, Erik Maradiaga, Kira Flaherty, Jonathan S. Wiest, Katie L. DeCicco-Skinner. Role of c-Met in the development and progression of Tpl2-related skin 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 2809. doi:10.1158/1538-7445.AM2017-2809
Dexmedetomidine in Patients With Sepsis Requiring Mechanical Ventilation—Reply
Authors: Hitoshi Yamamura, Yu Kawazoe, Takeshi Morimoto
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 4204: ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models
Authors: Sanjeeva P. Reddy, Niranjan Rao, David Zammit, Scott K. Thompson, Roger A. Smith, Louis Denis
Journal: Cancer Research (2017)

Abstract Spleen tyrosine kinase (SYK) and Janus kinase (JAK) play important roles in the pathogenesis of various types of lymphomas, solid tumors, and myeloproliferative and inflammation disorders. Inhibition of both SYK and JAK kinases has been shown to suppress tumor growth in various preclinical and/or clinical studies. ASN002 is a novel and potent dual inhibitor of SYK and JAK kinases with IC50 values of 4-46 nM in biochemical assays. In mechanistic cell-based studies, ASN002 strongly suppressed the SYK and JAK family kinase signaling pathways as measured in pLAT and pSTAT assays, respectively. When profiled in a panel of 178 cell lines, the compound showed strong anti-proliferative activity in many lymphoid/leukemia cell lines, including SU-DHL-6, SU-DHL-4, OCI-LY10, H929 and Pfeiffer. The proliferation of many solid tumor cell lines representing bladder, lung and colorectal cancer tumor types was also potently inhibited. Importantly, it also strongly inhibited the growth of ibrutinib and idelalisib resistant cell lines. ASN002 was highly efficacious in inhibiting the tumor growth in several tumor xenograft models which include Pfeiffer (diffuse large B-cell lymphoma, DLBCL), SU-DHL-6 (DLBCL), H929 (myeloma), HEL (erythroleukemia), and RT112 (bladder). ASN002 shows little to no inhibition of CYP450 isozymes suggesting low potential for drug-drug interactions. ASN002 is currently being evaluated in a Phase I/II clinical study in patients with lymphomas (DLBCL, mantle cell lymphoma and follicular lymphoma) and solid tumors. Citation Format: Sanjeeva P. Reddy, Niranjan Rao, David Zammit, Scott K. Thompson, Roger A. Smith, Louis Denis. ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models [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 4204. doi:10.1158/1538-7445.AM2017-4204
Abstract 5234: Expression of cytochrome P450 in head and neck cancer cell lines
Authors: Daniela F. Presa, Goreti Ribeiro Morais, Mark Sutherland, Jim McCaul, Jacques Robert, Laurence Patterson, Klaus Pors
Journal: Cancer Research (2017)

Abstract Background: The high expression of cytochrome P450 (CYP) enzymes including isoforms CYP1A1, 1B1 and 2W1 in some tumor types compared to normal tissue make these potential targets for targeted drug discovery. Our efforts in this space have resulted in the discovery of duocarmycin bioprecursors that are bioactivated by CYP1A1 and CYP2W1 expressed in malignant tissues1-2. Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including CYPs to detoxify or activate such carcinogens. Here, we report on the expression of CYP1A1, CYP1B1 and CYP2W1 in HNC cell lines and human primary tissues. Materials and methods: A panel of HNC cell lines (FaDu, Detroit-562, A253, OSC19) was characterized for CYP1A1, CYP1B1 and CYP2W1 gene expression using real time PCR. Furthermore, immunofluorescence (IF) was used to detect protein expression in HNC cell lines and immunohistochemistry (IHC) in xenografts, paraffin-embedded and snap-frozen human HNC tissue. Anti-proliferative activity was measured using the MTT assay and DNA damage was measured using the comet assay. Results: In the HNC cell lines significant expression (5-10 fold) was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit xenografts and in a small cohort of 10 human HNC samples as measured by IF and IHC, respectively. In agreement with CYP1 expression, the cytotoxicity results of ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines suggesting bioactivation of these two lead duocarmycin bioprecursors. Conclusion: Accordingly, from these data we can conclude that CYP1A1, CYP1B1 and CYP2W1 are expressed in selected HNC cell lines and tumor tissue. In addition, early evidence suggests that CYP2W1 expression is stimulated by the presence of an in vivo microenvironment. However a larger cohort (≥ 60) of clinical HNC samples will be used to confirm this observation and will be reported at the annual AACR meeting. [1] Sheldrake et al.Reengineering of the duocarmycin structural architecture enables bioprecursors development targeting CYP1A1 and CYP2W1 for biological activity. J Med Chem. 2013, 56, 62737. [2] Travica et al. Colon cancer-specific cytochrome P450 2W1 converts duocarmycin analogues into potent tumor cytotoxins. Clin Cancer Res. 2013, 19, 295261. Citation Format: Daniela F. Presa, Goreti Ribeiro Morais, Mark Sutherland, Jim McCaul, Jacques Robert, Laurence Patterson, Klaus Pors. Expression of cytochrome P450 in head and neck cancer cell lines [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 5234. doi:10.1158/1538-7445.AM2017-5234
Abstract 646: Targeting MHC class I molecules and immune checkpoints as key immune evasion strategies in EBV-associated nasopharyngeal carcinoma
Authors: Sharie Pui-Kei Siu, Ka Fai To, Grace Tin-Yun Chung, Vivian W.Y. Lui, Yvonne Y. Li, Peter S. Hammerman, Kwok Wai Lo
Journal: Cancer Research (2017)

Abstract Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that is consistently associated with intensive lymphocytes infiltration and Epstein-Barr virus infection. This study aims at elucidating the mechanism contributing to immune evasion in NPC. During NPC tumorigenesis, multiple intrinsic mechanisms are acquired to escape cellular immune response for the tumor and viral antigens. By genome sequencing, somatic alterations of multiple MHC class I genes including NLRC5, HLA-A, HLA-B, HLA-C and B2M were detected in 30% of primary NPC. Significant correlation of MHC class I gene alterations and poor survival rate in the patients was also shown. The finding suggested that the deficiency of antigen presentation mechanism represents a common strategy for immune evasion in NPC and favors rapid tumor progression. Losses of HLA-A, HLA-B and NLRC5 expression were validated in a panel of NPC tumor lines and selected primary tumors. The role of NLRC5 as key transcription regulator of HLA-A and HLA-B expression was demonstrated in the nasopharyngeal epithelial cells. To further evaluate the mechanisms contributed to immune evasion in NPC, we have elucidated immunosuppressive molecules involved in immune surveillance in Epstein Barr Virus (EBV)-associated NPC and its association with EBV-encoded LMP1 in an independent cohort of primary NPCs. By immunohistochemistry, the expression of EBV-encoded LMP1, MHC class I genes and various immunosuppressive molecules including PDL1, PDL2 and IDO1 was examined in 98 primary tumors. PDL1 and PDL2 were found to be over-expressed in 50% and 33.7% of NPC cases while IDO1 was found to be expressed in 28.8% of cases. Primary NPC cases expressing either PDL1 or PDL2 accounted for 64.3%. A significant association between LMP1 and PDL1 and PDL2 expression was also found. The correlation of PDL1, PDL2 and/or MHC class I molecule expression with the outcome of the patients was determined. The high incidence of MHC class I deficiencies and PDL1/PDL2 overexpression imply that EBV-associated NPC escape from the host immune response by targeting both antigen presentation mechanisms and immune checkpoints. Our findings also suggested that the expression of MHC class I molecules and PDL1/PDL2 is a potential biomarker for immunotherapy in NPC patients. Citation Format: Sharie Pui-Kei Siu, Ka Fai To, Grace Tin-Yun Chung, Vivian W.Y. Lui, Yvonne Y. Li, Peter S. Hammerman, Kwok Wai Lo. Targeting MHC class I molecules and immune checkpoints as key immune evasion strategies in EBV-associated nasopharyngeal carcinoma [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 646. doi:10.1158/1538-7445.AM2017-646