tbuckley/cabot-search huggingface dataset:
375. TDP-43 Interacts with Cannabinoid Type 1 Receptor Modulating Its Signaling Properties
Authors: Catalin Filipeanu, Matthew R. Deshotels, Peter Weed, Anastasia R. Robinson, Blessing Ongulade, Peter J. Winsauer, Jessie J. Guidry
Journal: Molecular Therapy (2016)

To identify new molecular chaperones of cannabinoid type-1 receptors (CB1R), we used a proteomic approach in HEK293T cells, transfected with two spicing variants of this receptor, CB1R and CB1AR. These two isoforms differ only in the composition of the N-terminus domain. Surprisingly, the only protein found to interact differently with CB1R and CB1AR was transactive response DNA-Binding Protein 43 (TDP-43), which is known to be involved in the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The specific interactions between CB1R and TDP-43 were also confirmed by co- immunoprecipitation not only in transfected HEK293 cells, as well at the endogenous level in rat crude spinal cord. TDP-43 overexpression decreased CB1R plasma membrane levels by stimulating receptor internalization, but it did not change the total receptor levels. Further, TDP-43 enhanced CB1R ubiquitination to similar levels, as induced by the full CB1R agonist, CP 55,940. Also, overexpression of TDP-43 resulted in reduced effects of CB1R stimulation on cAMP, P-ERK1/2, and P-CREB responses. Present results revealed TDP-43 as an unexpected molecular chaperone of CB1R and these findings may have significance in the regulation of CB1R intracellular trafficking and possibly in the treatment of ALS and FTLD.
Abstract 3709: Second cancers following Waldenström macroglobulinemia/lymphoplasmacytic lymphoma in the United States: analysis of Surveillance, Epidemiology and End Results (SEER) registry data, 1992 - 2011
Authors: Mary L. McMaster, Lynn R. Goldin, Neil E. Caporaso
Journal: Cancer Research (2015)

Abstract Waldenström macroglobulinemia (WM) is a subtype of lymphoplasmacytic lymphoma (LPL) that features secretion of monoclonal immunoglobulin type M (IgM) in the blood. WM/LPL occurs most commonly in elderly (median, 73 years) white males and is characterized by an indolent course and relatively long survival. Thus, WM/LPL patients may be at risk for development of subsequent cancers. We used data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) program to evaluate the risk of subsequent primary cancer in more than 3800 patients diagnosed with WM or LPL during the 20-year period, 1992 - 2011. We calculated observed-to-expected (O/E) standardized incidence ratios, together with 95% confidence intervals (95%CI), for invasive cancers occurring in these individuals. We found that the overall risk for second cancers was significantly increased among survivors of WM/LPL (O/E = 1.49; 95%CI 1.37-1.62) and risk increased with time since diagnosis. Increased risk was observed for both solid tumors (O/E = 1.21; 95%CI 1.09-1.33) and hematolymphoid cancers (O/E = 4.20; 95%CI 3.54-4.95). Significantly increased site-specific risks were seen for cancers of the lung and bronchus, melanoma, non-epithelial skin, and thyroid as well as for Hodgkin and non-Hodgkin lymphoma, multiple myeloma, and acute myeloid leukemia. Sample size limited subset analysis; however, overall increased risk was observed in all race (white, black, Asian/Pacific Islanders) and gender categories except for Asians/Pacific Islanders. Risk for second cancers appeared greater in younger patients (&amp;lt;65 vs. 65+) as well as in those diagnosed more recently, which may reflect changes in treatment regimens over time. We conclude that host factors, shared exposures and treatment effects may play a role in these observations. Citation Format: Mary L. McMaster, Lynn R. Goldin, Neil E. Caporaso. Second cancers following Waldenström macroglobulinemia/lymphoplasmacytic lymphoma in the United States: analysis of Surveillance, Epidemiology and End Results (SEER) registry data, 1992 - 2011. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3709. doi:10.1158/1538-7445.AM2015-3709
Abstract LB-022: Aptamer-mediated inhibition of EGFRvIII mutant in glioblastoma cells
Authors: Simona Camorani, Elvira Crescenzi, David Colecchia, Andrea Carpentieri, Angela Amoresano, Mario Chiariello, Laura Cerchia
Journal: Cancer Research (2015)

Abstract High-grade glioblastoma multiforme (GBM) is the most aggressive and common of gliomas in human populations, accounting for 55% of primary brain tumors. The prognosis of GBM is very poor and most patients die of tumor recurrence. The epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor β (PDGFRβ) are hallmarks in GBM since they influence multiple aspects of tumor biology including cell proliferation, migration, invasiveness and resistance to treatment. In approximately half of the tumors with amplified EGFR, the EGFRvIII truncated extracellular mutant is detected. EGFRvIII does not bind ligand, is highly oncogenic and appears to be relatively resistant to treatment with conventional anti-EGFR agents such as ligand blocking monoclonal antibodies or EGFR tyrosine kinase inhibitors (TKIs). Recently, it has been demonstrated that EGFRvIII-dependent cancers may escape targeted therapy by developing dependence on PDGFRβ signaling, thus providing a strong rationale for combination therapy aimed at blocking both EGFRvIII and PDGFRβ signaling. We have generated two nuclease resistant 2′F-Py RNA aptamers, CL4 and Gint4.T, as high affinity ligands and inhibitors of human wild-type EGFR (EGFRwt) and PDGFRβ, respectively. Thanks to their unique characteristics (low size, good target affinity, no immunogenicity, high stability) aptamers represent a new class of molecules with a great potential to rival monoclonal antibodies in both therapy and diagnosis. Herein, by different approaches we demonstrate that CL4 aptamer binds to the EGFRvIII mutant even though it lacks amino acids 6-273 in the extracellular domain. As a consequence of binding, the aptamer inhibits EGFRvIII activation by hampering receptor homodimerization and downstream STAT3 pathway, thus confirming the critical role of EGFRvIII dimerization for signaling. Further, we show that targeting EGFRvIII by CL4, as well as by erlotinib and gefitinib, causes upregulation of PDGFRβ as a compensatory response to support cancer cell survival. Importantly, CL4 and EGFRTKIs cooperate with the anti-PDGFRβ aptamer in inhibiting survival and proliferation of EGFRvIII-overexpressing glioblastoma cells. Given the paucity of selective inhibitors for receptor tyrosine kinases, this study could have impact in the fields of targeted molecular cancer therapeutics and may result in progress against GBM. Citation Format: Simona Camorani, Elvira Crescenzi, David Colecchia, Andrea Carpentieri, Angela Amoresano, Mario Chiariello, Laura Cerchia. Aptamer-mediated inhibition of EGFRvIII mutant in glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-022. doi:10.1158/1538-7445.AM2015-LB-022
Abstract 2478: A mAb within vivotherapeutic activity against spontaneous breast tumors in FVB-neuN mice recognizes SLP-2
Authors: Li-Xin Wang, Michael Berk, Gregory E. Plautz
Journal: Cancer Research (2015)

Abstract BCSC (breast cancer stem cells) derived from FVB-neuN mice bearing primary breast tumors were used to vaccinate mice and vaccine-draining lymph node T cells were adoptively transferred to mice with advanced primary tumors. Treated mice experienced tumor regression and importantly a concomitant serologic response was induced to an antigen that is expressed by BCSC even in Neu-antigen loss tumor cells. We generated a specific mAb (mAb2) reactive against a membrane antigen on BCSC tumorsphere cultures derived from NeuN spontaneous breast tumors but not the counterpart adherent cultures. In vivo administration of mAb2 inhibited progression of macroscopic primary tumors in Her-2/neu transgenic mice. We further observed that the molecule bound by mAb2 is expressed on proliferating but not growth-arrested C2D1-tumorspheres and this antigen is re-expressed when cells are digested into single cell suspension and re-fed with fresh medium. Similar results are observed with 4T1-tumorsphere cells, an additional breast cancer cell line arising initially in BALB/c mice. Interestingly, the target of mAb2 is also down-regulated following irradiation-induced growth arrest of tumor cells. To identify the antigen recognized by mAb2, cultured C2D1-tumorsphere or 4T1-tumorspheres were cells were lysed and the supernatant was immunoprecipitated with mAb2. The proteins captured by mAb2 were separated by 10% SDS-PAGE and visualized by silver staining. The bands of interest were excised then subjected to liquid chromatography-mass spectrometric (LC-MS/MS) analysis. A ∼40 KDa protein was detected in all five experiments from either C2D1-tumorsphere or 4T1-tumorsphere cells. Stomatin-like protein 2 (SLP-2) a 38.5 KDa protein was consistently identified whereas 14 other proteins were sporadically found. Western blots of mAb2 immunoprecipitates from C2D1 or 4T1-tumorsphere lysates were probed with two distinct commercial antibodies against SLP-2 and we confirmed its presence. To validate SLP-2 as the target, an expression vector was transfected into NIH 3T3 cells and FACS analysis demonstrated 19% positive cells versus 3.6% for un-transfected 3T3 cells. SLP-2 overexpression is associated with tumor metastasis and poor prognosis in several types of human tumors. Our results indicate that the antigen recognized by this auto-antibody might have immunodiagnostic or immunotherapeutic potential. Citation Format: Li-Xin Wang, Michael Berk, Gregory E. Plautz. A mAb with in vivo therapeutic activity against spontaneous breast tumors in FVB-neuN mice recognizes SLP-2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2478. doi:10.1158/1538-7445.AM2015-2478
The Prevalence of Anemia in Rio Grande Do Sul, Brazil: Is Iron Deficiency the Silent Burden Hidden Behind “Normal” Anemia?
Authors: Lucia Silla, Alice Zelmanowicz, Ingrid Mito, Liane Daudt, Carlos do Bem, Marta Alves, Denise Lehuguer, João Fridrisch, Christina Bittar, Gustavo Fisher, Laura Fogliatto, Alessandra Paz, Rosane Bittencourt, Gisele Bortolini, Larissa Brouwers, Marco Shilling, Mariana Michalowski, Tania Hellwig
Journal: Blood (2008)
Predictions of pathological response after preoperative chemotherapy plus trastuzumab in HER2-positive breast cancer
Authors: Masahiro Takada, Masahiro Sugimoto, Norikazu Masuda, Hiroji Iwata, Katsumasa Kuroi, Hiroyasu Yamashiro, Shinji Ohno, Hiroshi Ishiguro, Takashi Inamoto, Masakazu Toi
Journal: Annals of Oncology (2015)
Abstract B70: RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells
Authors: Matthias Ilmer, Jing Wang, Alejandro Recio, Jens Werner, Alexandr Bazhin, Eckhard Alt, Jody Vykoukal
Journal: Cancer Research (2016)

Abstract Cancer stem cells (CSC) in pancreatic ductal adenocarcinomas (PDAC) present formidable challenges in the treatment of patients by escaping therapeutic intervention and seeding tumors through processes that remain incompletely understood. Here, we describe subpopulations of pancreatic cancer cells with high susceptibility to the recently described group of Wnt enhancer molecules, in particular R-Spondin 2 (RSPO2), which seem to drive primary and secondary pancreatic neoplasms. PDAC cells responsive to RSPO2 stimuli upregulate canonical Wnt signaling activity as evidenced by Super-TOP/FOP luciferase assays and GFP-activity in cells transduced with a lentiviral Super-TOP-GFP reporter construct (7TGC). RSPO2-responsive cells (RSPO2pos) also possess properties indicative of CSCs, including tumor-initiating capacity and, more importantly, drug resistance in vivo. Cell populations with negligible Wnt activity preferentially express markers of differentiation. Furthermore, spontaneous response to extrinsic Wnt signals induced signaling networks comprising ERK1/2 and epithelial–mesenchymal transition (EMT) as shown by Western blot and RPPA analysis and led to a redistribution of Wnt enhancer receptors. In vivo, animals with RSPO2pos-derived tumors were bigger than RSPO2neg-derived tumors, harbored significantly more circulating tumor cells (CTCs), and higher number of exosomes in murine serum. In this context, the latter findings suggest that RSPO2pos-cells could prepare secondary sites via exosomal priming and subsequently seed CSC-enriched CTCs for metastatic outgrowth at distant organs. RSPO2 gradients in the CSC niche might induce EMT for the developing CTCs. Hence, RSPO2 seems to play a prominent upstream role in regulating these interplays in the tumor and metastatic microenvironment. In conclusion, our studies reveal adaptive aspects of pancreatic cancer stemness arising from populations of CSCs that misappropriate functional and responsive elements of archetypical self-renewal pathways. Blocking RSPO2-induced signaling pathways in conjunction with established chemotherapy could provide means to disrupt dynamic CSC processes and present novel therapeutic strategies for patients with PDAC. Citation Format: Matthias Ilmer, Jing Wang, Alejandro Recio, Jens Werner, Alexandr Bazhin, Eckhard Alt, Jody Vykoukal.{Authors}. RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B70.
Interpretation of surrogate endpoints in the era of the 21st Century Cures Act
Authors: Kevin Knopf, Michael Baum, William S Shimp, Charles L Bennett, Dinah Faith, Marc L Fishman, William J M Hrushesky
Journal: BMJ (2016)

<i>Surrogate endpoints are commonly used in clinical trials to get quicker results, but</i><b><i>Kevin Knopf and colleagues</i></b><i>show how they can lead to both medical and financial harm</i>
Skeletal related events in patients with metastatic renal cell carcinoma: A retrospective review
Authors: M. Secter, M. J. MacKenzie, P. O'Brien, F. Whiston
Journal: Journal of Clinical Oncology (2009)

e16118 Background: Approximately one third of patients with renal cell carcinoma (RCC) will develop bone metastases during the course of their disease. Previous studies suggest that the rate of skeletal related events (SREs) in patients with metastatic renal cell carcinoma is high, and that bisphosphonate therapy can lower the rate of SREs. We conducted a retrospective review of patients with metastatic renal cell carcinoma and bone metastases seen at our academic cancer centre. Methods: After approval by the Research Ethics Board, a retrospective review of all patients seen at the London Regional Cancer Centre with a diagnosis of RCC between January 2006 and December 2008 was performed. Data points collected included the number of patients with bone metastases, number of SREs, length of hospital stay, and treatments related to SREs. A SRE was defined as one of the following: pathologic fracture, spinal cord compression, radiotherapy or surgery to bone, or hypercalcemia in the presence of bone metastases. Results: 196 patients with metastatic RCC were identified. Of these, 63 (32%) had bone metastases. 75% of these patients with bone metastases received medical therapies including sunitinib, sorafenib or temsirolimus. 66% of patients received at least one dose of bisphosponate therapy. Common sites of metastases were vertebra (66%), pelvis (50%), and femur (42%). Of those with bone metastases, 61 (95%) experienced at least one SRE. 42% sustained a pathologic fracture; 28% suffered a spinal cord compression or cauda equina syndrome; 22% had surgery for bone metastases; 87.5% required radiotherapy and 27% had hypercalcemia. 40% of patients were hospitalized due to an SRE, and the mean length of hospital stay was 21 days (range 1–120 days). Conclusions: Despite significant recent improvements in the overall care of RCC, and expansion of the number of therapeutic options, bone metastases and consequent SREs continue to cause significant morbidity. These SREs come with frequent and prolonged hospitalizations. Our rate of SREs is actually higher than that documented in the placebo arm of a randomized trial of a bisphosphonate in RCC from the pre-tyrosine kinase era. Bone-related morbidity in mRCC remains a clinical problem with a significant unmet medical need. [Table: see text]
Abstract 4425: Multiple -omic analyses of a pair of primary HCC tumor cell lines with different drug response revealed the mechanisms of drug resistance
Authors: Gang Hu, Alicia Du, Yong Huang, Kunyan Liu, Fubo Xie, Xuzhen Tang, Xueyan Yang, Qi Gu, Yixin Zhang, Weikang Tao, Yingjia Zhang, Wei Tang, He Zhou
Journal: Cancer Research (2015)

Abstract Previously we reported the establishment of a pair of primary HCC cell lines from LIX-004, a patient-derived HCC xenograft model. LIXC004-NA was developed from an untreated PDX tumor; LIXC004-SR was generated from a PDX tumor progressed despite long term in vivo treatment with sorafenib. The two cell lines displayed similar response to sorafenib treatment in vitro. However, LIXC004-NA is sensitive and LIXC004-SR is resistant to sorafenib treatment in vivo. IHC and in vitro functional studies revealed activation of alternative angiogenic pathways as one of the potential reasons for the sorafenib resistance of LIXC004-SR. To fully explore different mechanisms/pathways, we performed a) micro-array analyses; b) whole exome sequencing; c) RNA-seq analyses of the two cell lines; d) metabolomic analyses of the cell lines in vitro culture in the presence and absence of different therapeutics; e) RNAseq analyses of the tumors derived from these two cell lines. The combination of different types of -omic analyses is our systematic approach to address the potential mechanisms of drug resistance without bias. The two cell lines shared a lot of the genetic mutation and expression profile for most genes. Differentially mutated or expressed genes were also identified at basal level. More changes were observed with the treatment of different therapeutics as well as analyses of the xenograft derived from the cell lines. Pathway analyses are performed to explore the underlying mechanisms for the development of drug resistance. Citation Format: Gang Hu, Alicia Du, Yong Huang, Kunyan Liu, Fubo Xie, Xuzhen Tang, Xueyan Yang, Qi Gu, Yixin Zhang, Weikang Tao, Yingjia Zhang, Wei Tang, He Zhou. Multiple -omic analyses of a pair of primary HCC tumor cell lines with different drug response revealed the mechanisms of drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4425. doi:10.1158/1538-7445.AM2015-4425
Abstract 3845: Smarce1 facilitates survival of metastatic breast cancer cells in circulation
Authors: Aarti Sethuraman, Meiyun Fan, Martin M. Brown, Zhaohui Wu
Journal: Cancer Research (2015)

Abstract Elevated BAF57/SMARCE1 protein expression has been linked to high metastatic potential of prostate cancer, while its relevance in metastatic breast cancer is not completely understood. The objective of this study is to investigate the role of SMARCE1 in regulating metastatic potential of basal-like breast tumor cells. SMARCE1 is a core subunit shared by all mammalian SWI/SNF complexes and is predicted to mediate the interaction between the SWI/SNF complex and transcriptional activators/repressors, as well as DNA binding. SWI/SNF are nucleosome modifying complexes that destabilize the histone-DNA interaction in an ATP-dependent manner to facilitate recruitment of transcription regulators to DNA. We found that SMARCE1 knockdown (SMARCE1-kd) in basal-like breast cancer cell line MDA-MB-231 reduced spontaneous lung metastasis in an orthotopic xenograft model, without affecting primary tumor growth. Through tail-vein injection of tumor cells we identified that SMARCE1-kd significantly reduced the number of metastatic foci in lungs of inoculated mice, implicating a role of SMARCE1 in promoting metastatic cell survival in later stages of metastasis occurring post-dissemination from primary tumors. In-vitro assays showed that SMARCE1-kd had no effect on cell migration and invasion, but substantially sensitized cells to anoikis. Consistently, we observed reduced activation/phosphorylation of the pro-survival proteins PTK2/FAK and MAPK/ERK and increased expression of apoptotic protein BCL2L11 in SMARCE1-kd cells compared to wild-type cells grown under suspension. We further confirmed using specific chemical inhibitors, that FAK and ERK phosphorylation are required for SMARCE1-mediated survival of tumor cells under suspension culture. Collectively, these results suggest a role for SMARCE1 in promoting metastasis by protecting cells against anoikis. The molecular mechanism underling SMARCE1-mediated regulation of FAK/ERK phosphorylation in response to loss of contact with extracellular matrix is under investigation. Citation Format: Aarti Sethuraman, Meiyun Fan, Martin M. Brown, Zhaohui Wu. Smarce1 facilitates survival of metastatic breast cancer cells in circulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2015-3845