tbuckley/cabot-search huggingface dataset:
Abstract 2714: Effects of endosulfan on COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways
Authors: Eun Hee Han, Sang Mi Jun, Young Ho Chung
Journal: Cancer Research (2015)

Abstract Endosulfan is correlated with endocrine disruption, reproductive, and immune dysfunctions. Recently, endosulfan was shown to have an effect on inflammatory pathways, but its influence on cyclooxygenase-2(COX-2) expression is unclear. This study investigated the effects of COX-2 and molecular mechanisms by endosulfan in murine macrophage RAW 264.7 cells. Endosulfan significantly induced COX-2 protein and mRNA levels, as well as COX-2 promoter-driven luciferase activity and the production of prostaglandin E2, a major COX-2 metabolite. Transfection experiments with several human COX-2 promoter constructs revealed that endosulfan activated NF-KB, C/EBP, AP-1, and CREB. Moreover, Akt and mitogen-activated protein kinases (MAPK) were significantly activated by endosulfan. Moreover, endosulfan increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2, and NOX3. These results demonstrate that endosulfan induces COX-2 expression via NADPH oxidase, ROS, and Akt/MAPK pathways. These findings provide further insight into the signal transduction pathways involved in the inflammatory effects of endosulfan. Citation Format: Eun Hee Han, Sang Mi Jun, Young Ho Chung. Effects of endosulfan on COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways. [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 2714. doi:10.1158/1538-7445.AM2015-2714
Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival
Authors: Tal Shahar, Uri Rozovski, Kenneth R. Hess, Anwar Hossain, Joy Gumin, Feng Gao, Gregory N. Fuller, Lindsey Goodman, Erik P. Sulman, Frederick F. Lang
Journal: Neuro-Oncology (2016)

Human mesenchymal stem cells (hMSCs) have been shown to reside as stromal cells in human gliomas as glioma-associated hMSCs (GA-hMSCs), but their biological role remains unclear. Because recent evidence indicates that GA-hMSCs drive tumor cell proliferation and stemness, we hypothesized that a higher percentage of GA-hMSCs in tumors predicts poor patient prognosis.We determined the percentage of cells coexpressing GA-hMSC markers CD105+/CD73+/CD90+ from patients with newly diagnosed high-grade glioma and analyzed the association between this percentage and overall survival (OS) in 3 independent cohorts: fresh surgical glioblastoma specimens (cohort 1, N = 9), cultured tumor specimens at passage 3 (cohort 2, N = 28), and The Cancer Genome Atlas (TCGA) database.In all cohorts, patient OS correlated with the percentages of GA-hMSCs in tumors. For cohort 1, the median OS of patients with tumors with a low percentage of triple-positive cells was 46 months, and for tumors with a high percentage of triple-positive cells, it was 12 months (hazard ratio [HR] = 0.24; 95% CI: 0.02-0.5, P = .02). For cohort 2, the median OS of patients with tumors with a low percentage of GA-hMSCs was 66 months, and for tumors with a high percentage, it was 11 months (HR = 0.38; 95% CI: 0.13-0.9, P = .04). In the database of TCGA, the median OS times in patients with high and low coexpression levels of CD105/CD73/CD90 were 8.4 months and 13.1 months (HR = 0.4; 95% CI: 0.1-0.88; P = .04), respectively.The percentage of GA-MSCs inversely correlates with OS, suggesting a role for GA-MSCs in promoting aggressive behavior of gliomas.
Bortezomib as Front-Line Therapy in Primary Plasma Cell Leukemia
Authors: Giuseppe Pietrantuono, Roberto Guariglia, Oreste Villani, Maria Carmen Martorelli, Fiorella D’Auria, Antonia Zonno, Rosa Lerose, Giuseppe Fioritoni, Elena Zamagni, Fausto Rossini, Nunzio Filardi, Livio Pagano, Gerardo Musuraca, Vincenzo Pitini, Gerlando Quintini, Antonietta Falcone, Sara Bringhen, Antonio Palumbo, Pellegrino Musto
Journal: Blood (2008)
Racial disparities in colon cancer: Retrospective analysis of VACCR database.
Authors: N. Didwaniya, W. Gonsalves, P. T. Silberstein, S. Subbiah
Journal: Journal of Clinical Oncology (2011)

528 Background: A racial/ethnic difference in colon cancer survival has been described in literature. However the reasons for this are unclear and access to health care is one of the factors that have been implicated. We plan to examine the clinicopathologic factors of Caucasians (CA) and African Americans (AA) in an equal to access health care system. Methods: 21,992 patients from 1995 to 2009 were identified from the VA Central Cancer Registry database. Age, race, stage, histology, lymph node status, and type of treatment received data were collected. Results: Out of 21,992 patients, 17,924 were CA and 4,068 were AA. 98.07% of CA and 97.83% of all AA were males. Pathological T stages were as follows: T1 = 15.58% vs. 16.13%, T2 = 18.81% vs. 17.56%, T3 = 55.48% vs. 56.03%, T4 = 10.13% vs. 10.28% for CA and AA respectively. Stage-specific incidence, histological grades, and lymph nodal involvement rates were similar in both groups. 77.16% of CA and 77.03% of all AA received chemotherapy. 82.07% of CA and 78.78% of all AA underwent surgery. Median overall survival in CA was 30.73 months and in AA it was 27 months (p &lt; 0.0001). Stage-specific survival (in months) was significantly better for CA in early-stage disease (p &lt; 0.0001) but is similar for both races in metastatic disease (see Table). Median survival in male and female sex irrespective of race was 29.867 months and 35.667 months respectively. Conclusions: Overall survival is better in CA when compared to AA in an equal to access health care system. This survival difference was present only in early-stage disease while in metastatic disease the survival was uniformly poor. Incidence as per stage, lymph node status,and grade were not significantly different among AA and CA. Tumor biology and post-treatment surveillance are potential factors and this needs to be investigated further. [Table: see text] No significant financial relationships to disclose.
617. Identification of Novel AAV Capsid Variants with Enhanced Tropism for the Canine Outer Retina Following Intravitreal Delivery
Authors: Leah C. Byrne, Meike Visel, Valerie Dufour, Felipe Pompeo Marinho, Gustavo D. Aguirre, William A. Beltran, John G. Flannery, David V. Schaffer
Journal: Molecular Therapy (2016)

The delivery of AAV vectors across physical barriers to target the outer retina is key to the success of retinal gene therapies. Subretinal injection of AAV vectors is the most common approach to deliver genes to photoreceptors and RPE; however, this route of administration presents surgical challenges and potential complications, as well as mediates transfer to only a limited region of the retinal surface. Intravitreal administration may represent a safer way of targeting larger areas of the outer retina; physical barriers such as the internal limiting membrane significantly limit efficiency of natural AAVs through this route. In a prior murine proof of concept study, we showed that directed evolution is promising method for engineering new AAV capsid variants with enhanced permissivity for the outer retina. Here, we show results from a screen performed in the canine retina, a large animal model with eye structure and size similar to the human eye. A library of >107 distinct capsid variant AAV vectors was injected intravitreally into the eye of a wildtype dog. A subset of the AAV vectors injected was recovered from samples of outer retina by PCR amplification. Isolated variants were then pooled and re-injected in additional wildtype canine eyes, and following 5 total rounds of selection the pool had converged to a relatively small number of variants. High throughput sequencing was used to characterize the convergence of variants over all rounds of selection. The final candidate variants were then evaluated by packaging a GFP reporter controlled by a ubiquitous CAG promoter. Retinal distribution and cellular tropism of the variants was examined by cSLO (AF mode) imaging, histology and immunocytochemistry. Nineteen variants were identified as candidate vectors for targeting the canine outer retina. Intravitreal injection of a mixture of equal amounts of these variants carrying GFP fused to a barcode resulted in efficient targeting of all retinal layers including photoreceptors and RPE in 6 eyes of 3 wildtype dogs. Thus, directed evolution performed in a large animal model, with an eye structure similar to that of humans, resulted in new AAV capsid variants with improved abilities to bypass significant structural barriers and efficiently transduce the outer retina. High throughput sequencing allowed for identification of promising variants and monitoring of convergence. These vectors show promise for gene therapy delivery via the intravitreal route of administration, potentially providing a safer approach for targeting a larger area of outer retina than currently achieved by the more traumatic and focal subretinal injection method.
Abstract LB-192: A single catastrophic genomic event is required for the development of osteosarcoma
Authors: Sven Bilke, Paul Meltzer
Journal: Cancer Research (2015)

Abstract Over sixty years ago, the groundbreaking works by Nordling1, Armitage and Doll2 found a deep connection between the age dependent incidence rates of cancer with elementary mutational processes in cancer. However, their method to estimate the number of driver mutations from the characteristic increase of adult cancer risk with patient age implicitly assumes tissue homeostasis. It can therefore not be used for developmental cancers emerging from growing tissues. Osteosarcoma (OS), a bone cancer most frequently occurring during adolescence, is one prominent example. Here we combine a model of bone growth and maintenance with somatic mutation theory. Based on age dependent stature3` and morphometric data, we find that our model accurately reproduces epidemiological OS incidence rates4`. We conclude that the OS risk can be explained by the cell cycle rate in the osteoblast lineage. Other risk factors, such as endocrine and paracrine signaling have only a weak, if any, impact. The strict association with the cell cycle rate, as opposed to wall clock time, suggests that environmental factors play no dominant role either. In other words, with few exceptions such as genetic syndromes or unusually strong environmental factors such as radiation in cancer treatment, the OS risk is dominated by pure chance. We find that the OS incidence rate is strictly proportional to the age dependent cell cycle rate. This result implies that there is only a single rate limiting factor in the etiology of the disease. This result is a remarkable as it suggests that the disease is not necessarily initiated within a stem cell because the Hayflick limit set by telomere shortening can not suppress single-hit-malignancies. Our results are not only important for a better understanding of the disease and the design of future sequencing efforts. But they also inform development of treatment strategies to reduce the mortality caused by this still deadly disease. 1. Nordling, C. O. C. A New Theory on the Cancer-inducing Mechanism. Br. J. Cancer 7, 68¨C72 (1953). 2. Armitage, P. &amp; Doll, R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer VIII, 1¨C12 (1954). 3. CDC Height Data. at 4. Cancer incidence in five continents, vol. I to VIII. CancerBase No. 7. (Lyon: IARC). at Citation Format: Sven Bilke, Paul Meltzer. A single catastrophic genomic event is required for the development of osteosarcoma. [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-192. doi:10.1158/1538-7445.AM2015-LB-192
PSMA Expression in Tumor Neovasculature Endothelial Cells of Follicular Thyroid Adenoma as Identified by Molecular Imaging Using 68Ga-PSMA Ligand PET/CT
Authors: Thorsten Derlin, Hans-Heinrich Kreipe, Udo Schumacher, Bisharah Soudah
Journal: Clinical Nuclear Medicine (2016)

The prostate-specific membrane antigen (PSMA) is expressed by both prostate cancer and other neoplasms. We report the case of a 65-year-old man with castration-resistant metastatic prostate cancer who underwent 68Ga-PSMA ligand PET/CT for restaging of disease. 68Ga-PSMA ligand accumulation was noted in a thyroid lesion, suspicious for thyroid malignancy on complementary ultrasound. Subsequent resection and histopathological analysis showed follicular thyroid adenoma with PSMA expression in tumor neovasculature endothelial cells, but not in thyroid epithelial cells. It is important to be aware that both malignant and benign thyroid neoplasms may show PSMA expression to avoid misinterpretation.
Abstract POSTER-BIOL-1331: Nucleotide excision repair mutations confer sensitivity to platinum but not PARP-inhibitors in epithelial ovarian cancer
Authors: Raphael Ceccaldi, Kevin O'Connor, Kent W. Mouw, Adam Y. Li, Ursula A. Matulonis, Alan D. D'Andrea, Panagiotis A. Konstantinopoulos
Journal: Clinical Cancer Research (2015)

Abstract The marked platinum sensitivity of epithelial ovarian cancer (EOC) is thought to be related to underlying defects in the homologous recombination (HR) DNA repair pathway, which are present in approximately 50% of tumors with high-grade serous histology. However, repair of platinum-induced DNA damage does not always involve the HR pathway. More than 90% of platinum-DNA lesions are intrastrand cross-links which are repaired by the nucleotide excision repair (NER) pathway. We curated the TCGA ovarian cancer dataset and identified 22 tumors (7%) with nonsynonymous or splice site NER gene mutations among the 316 sequenced high grade serous ovarian tumors. All NER mutations were mutually exclusive and 8 (36%) were accompanied by heterozygous loss of the respective NER gene. In 12 (55%) of the 22 cases, there were no concomitant HR alterations identified. In vitro functional evaluation of two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in patients with advanced stage tumors and extreme response to first-line platinum therapy, showed that both mutations conferred platinum, but not PARPi, or doxorubicin sensitivity, and did not affect HR activity. Interestingly, ERCC6-Q524* was not associated with heterozygous loss but sensitized cells to platinum in a dominant negative fashion. Our findings suggest a novel mechanism of platinum sensitivity in EOC that involves NER gene mutations, which may occur independently of HR alterations. Unlike tumors with defective HR, tumors harboring only NER mutations may be sensitive to platinum but not PARP inhibition. Dissociation of platinum and PARPi sensitivity in this setting may have important implications for PARPi trials for both HR-proficient and HR-deficient EOCs. Citation Format: Raphael Ceccaldi, Kevin O’Connor, Kent W. Mouw, Adam Y. Li, Ursula A. Matulonis, Alan D. D’Andrea, Panagiotis A. Konstantinopoulos. Nucleotide excision repair mutations confer sensitivity to platinum but not PARP-inhibitors in epithelial ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1331.
Abstract 4532: Functional evaluation of novel Tubulysin analogs as payloads for antibody-drug conjugates
Authors: Junxiang Jia, Xiaomai Zhou, Yuanyuan Huang, Hongsheng Xie, Huihui Guo, Shun Gai, Lan Qu, Wenjun Li, Lin Chen, Xing Li, Sanxing Sun, Qingliang Yang, Xiaotao Zhuo, Hangbo Ye, Robert Zhao
Journal: Cancer Research (2015)

Abstract Antibody-drug conjugates (ADCs) couple tumor cell targeting specificity of monoclonal antibodies with potency of small molecule cytotoxic payloads to overcome the limitations of antibody's moderate cytotoxicity and narrow therapeutic window /poor pharmacokinetics of chemotherapeutic agents[1]. Most of the small molecule drugs used in ADCs now target either microtubules or DNA. Since the highly cytotoxic drugs linked to antibodies may be partially released, which leads to side-effects before they are delivered into the target cancer cells [2], it is important to choose appropriate cytotoxic molecules, linkage structures and conjugation strategies, in order to achieve maximal therapeutic window. To this end, we have designed and synthesized a series of Tubulysin B analogs and then conjugated these articles to anti-Her2 antibodies using different conjugation techniques. Functional assays in vitro based on Her2+ cancer cells showed that some of these novel molecules had significantly lower cytotoxicities as free drugs due to their favorable physiochemical and biological properties, in comparisons with the maytansinoid DM1derivatives, but were more potent than DM1 conjugates in killing the target cells when linked to identical anti-Her2 antibodies. Consistently, in comparisons with T-DM1, our novel ADCs demonstrated improved efficacy as well as reduced systemic side toxicities in Her2-positive xenograft tumor models. The conjugate structures and results from functional assays at both cellular and animal model levels are detailed in the presentation. References: 1. Goldmacher, V.S. and Y.V. Kovtun, Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. 2011 2(3):. 397-416.. 2. Xie, H., et al., Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J Pharmacol Exp Ther, 2004. 308(3): 1073-1082. Citation Format: Junxiang Jia, Xiaomai Zhou, Yuanyuan Huang, Hongsheng Xie, Huihui Guo, Shun Gai, Lan Qu, Wenjun Li, Lin Chen, Xing Li, Sanxing Sun, Qingliang Yang, Xiaotao Zhuo, Hangbo Ye, Robert Zhao. Functional evaluation of novel Tubulysin analogs as payloads for antibody-drug conjugates. [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 4532. doi:10.1158/1538-7445.AM2015-4532
Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis
Authors: Stephen L. Hauser, Amit Bar-Or, Giancarlo Comi, Gavin Giovannoni, Hans-Peter Hartung, Bernhard Hemmer, Fred Lublin, Xavier Montalban, Kottil W. Rammohan, Krzysztof Selmaj, Anthony Traboulsee, Jerry S. Wolinsky, Douglas L. Arnold, Gaelle Klingelschmitt, Donna Masterman, Paulo Fontoura, Shibeshih Belachew, Peter Chin, Nicole Mairon, Hideki Garren, Ludwig Kappos
Journal: New England Journal of Medicine (2016)

B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.
Does Highly Active Anti-Retroviral Therapy (HAART) Delay Myeloid Engraftment after Autologous Stem Cell Transplant (ASCT) in HIV Associated Lymphoma (HIV+Ly) Patients?.
Authors: Jose L. Diez-Martin, Rafael Carrion, Javier Anguita, Pascual Balsalobre, Pilar Miralles, Juan Berenguer, Ismael Buno, Alfonso Gomez-Pineda, Eulogio Conde, Rosario Varela, Jose M. Ribera, Ildefonso Espigado, Lourdes Escoda, Javier Loscertales, David Serrano
Journal: Blood (2005)
Fatigue as a symptom in psoriasis and psoriatic arthritis: an observational study
Authors: A.M. Tobin, M. Sadlier, P. Collins, S. Rogers, O. FitzGerald, B. Kirby
Journal: British Journal of Dermatology (2016)

Fatigue is a common, debilitating symptom associated with chronic disease such as inflammatory disorders, heart disease, and cancer1. Fatigue is described in patients with psoriatic arthritis (PsA) where higher levels have been shown to correlate with pain, physical disability and psychological distress2-5. Less is known about this important symptom in patients with psoriasis without joint involvement.

This article is protected by copyright. All rights reserved.
Nilotinib in advanced GIST: A retrospective analysis of nilotinib in compassionate use
Authors: M. Montemurro, P. Schöffski, P. Reichardt, H. Gelderblom, H. Joensuu, J. Schütte, C. M. Wendtner, J. T. Hartmann, V. Elsig, S. Leyvraz
Journal: Journal of Clinical Oncology (2008)

10523 Background: Tyrosine kinase inhibitors (TKI) have considerably improved outcome of advanced GIST. First-line imatinib treatment achieves an excellent mOS of 5 years, yet, a mPFS of approximately 2 years with first-line imatinib and 24 weeks with second-line sunitinib calls for treatment alternatives. Nilotinib is a second-generation TKI with at least similar inhibitory activity as imatinib, but reaching 7–10 fold higher intracellular concentrations. A Phase I study has shown that nilotinib monotherapy has clinical activity in GIST. Methods: Patients (pts) failing all available therapeutic options had access to nilotinib on a compassionate use (CU) programm. Nilotinib starting dose was 400 mg bid, with an allowed dose reduction to 400 mg qd for toxicity. 94 pts were approved for nilotinib CU in 10 European countries. We herein present retrospective data of 36 pts from 5 European countries treated in 8 centers. Results: Median age at nilotinib treatment start was 59 years (median; range 24–79 y), and 70% of pts were male. Most pts had metastatic disease of gastric origin at initial diagnosis. KIT exon 11 mutations were most frequent. The median number of surgical resections was 1 (range 0–8). All pts had failed both imatinib and sunitinib before nilotinib, and 8% had also received additional investigational treatments. Nilotinib was well tolerated, as only 14% discontinued nilotinib due to toxicity. Median follow-up is 156 days (range 15–765 d). Nilotinib treatment duration is 60 days (median; range 3–727 d) and one third of pts were treated for longer than 3 months. Partial remission with nilotinib treatment was seen in 6% of pts. Median OS was 211 days (Kaplan-Meier). Conclusions: This is the largest series assessing efficacy of nilotinib for imatinib- and sunitinib-refractory GIST reported yet. Nilotinib displays significant clinical activity in this heavily pretreated group of pts. One third of pts have disease control on nilotinib for longer than three months. These results warrant further investigation of nilotinib in GIST, including its use in first or second-line treatment. Patient and data collection is ongoing, updated results will be presented at ASCO 2008. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Pfizer Oncology