tbuckley/cabot-search huggingface dataset:
A novel inflammatory-based prognostic score in hepatocellular carcinoma.
Authors: D. J. Pinato, H. S. Wasan, L. Maslen, B. North, R. Sharma
Journal: Journal of Clinical Oncology (2011)

10581 Background: In the management of hepatocellular cancer (HCC) several prognostic systems exist however these are inconsistent. Inflammation is associated with both pathogenesis and prognosis of HCC. We therefore explored the prognostic impact of 3 inflammation based prognostic scores; the Glasgow Prognostic Score (GPS), neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR), and compared their accuracy with the conventional BCLC and CLIP scores in order to identify a more adequate prognostic model for HCC. Methods: Patients had a diagnosis of HCC either on radiological or histological criteria as per American Association for the Study of the Liver guidelines. Patients with a history of inflammatory disease or infection were excluded. Clinical variables including demographic data, CBP, albumin, CRP, AFP, liver function tests, tumour stage including number and diameter of hepatic lesions, Child-Turcotte Pugh class, CLIP and BCLC scores were collected. GPS, NLR and PLR scoring systems were generated. Kaplan Meier statistics and log rank test were used to assess OS with each prognostic score. C-index was used to rank different staging systems. Results were then validated in an independent data set. Results: 112 consecutive patients presenting between 1993 and 2010 were included (mean age 62, range 20-83), Child Turcotte Pugh Class A 65%, intermediate/advanced BCLC Staging Algorithm 81%. Median overall survival 6.3 months. On univariate analysis GPS (p<0.001), NLR (p=0.006), PLR (p=0.01), CLIP (p<0.001) and BCLC score (p=0.002) were significant predictors of overall survival. Multivariate analysis: GPS (p=0.01) and CLIP scores (p=0.006) independent predictors of survival. CLIP score and GPS ranked as most informative staging systems, with a respective c-index score of 0.685 (95% CI 0.549-0.820) and 0.640 (95% CI 0.532-0.747). The predictive accuracy of the combined GPS and CLIP score was superior to that of the CLIP score alone, combined c-index score 0.711 (CI 95% 0.579-0.842). Results from independent validation set will be presented. Conclusions: GPS allows for risk stratification of advanced HCC patients and independently predicts overall survival. Combination of CLIP score and GPS may represent more accurate staging system for HCC.
689. Defining Genome-Wide Off-Target Cleavage Profiles of CRISPR-Cas RNA-Guided Nucleases Using GUIDE-Seq
Authors: Shengdar Q. Tsai, Zongli Zheng, Nhu T. Nguyen, Matthew Liebers, Ved V. Topkar, Vishal Thapar, Nicolas Wyvekens, Cyd Khayter
Journal: Molecular Therapy (2015)

Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated (Cas) RNA-guided nucleases (RGNs) have been broadly adopted by the scientific community for use as robust genome editing tools. However, CRISPR-Cas RGNs have been demonstrated to exhibit high-frequency off-targets at sites with up to 5 mismatches from the intended target site, raising questions about their global specificity. We have developed a novel method called GUIDE-seq (for Genome-wide Unbiased Identification of DSBs enabled by Sequencing), based on the efficient integration of a double-stranded oligodeoxynucleotide (dsODN) tag followed by tag-specific amplification and high-throughput sequencing. We performed GUIDE-seq on 10 RGNs in 2 human cell lines and identified all known off-target cleavage sites of these RGNs as well as hundreds of additional novel sites. The number of off-target cleavage sites identified varied widely among these RGNs, and the majority of identified sites were not predicted by existing computational methods or ChIP-seq. GUIDE-seq provides a robust method for evaluating the genome-wide specificities of RGNs that will be useful for the clinical translation of these important and widely applicable genome editing reagents.
405. Enhanced Chondrogenic Potential of Human Bone Marrow Aspirates Upon rAAV-Mediated Overexpression of IGF-I
Authors: Janina Frisch, Ana Rey-Rico, Jagadeesh K. Venkatesan, Henning Madry, Magali Cucchiarini
Journal: Molecular Therapy (2015)

Genetic modification of human bone marrow aspirates is an attractive strategy as a convenient, one-step treatment of articular cartilage defects. Here, we tested whether overexpression of the mitogenic and pro-anabolic IGF-I factor via rAAV vectors enhances the reparative activities of human bone marrow aspirates. Aspirates obtained from the distal femurs of patients undergoing total knee arthroplasty were directly transduced with an rAAV-hIGF-I vector vs. control rAAV-lacZ transduction and maintained in chondrogenic medium for up to 21 days. Transgene expression was monitored by immunohistochemistry on paraffin-embedded sections of aspirates also stained with toluidine blue and for type-II collagen immunoreactivity. The DNA and proteoglycan contents were monitored by Hoechst 22358 assay and binding to DMMB, respectively. Real-time RT-PCR was performed using the 2-ΔΔCt method to monitor the expression of SOX9, ACAN, COL2A1, COL1A1, and COL10A1, with GAPDH as a control for normalization, by measuring the fold inductions in IGF-I vs. lacZ conditions. Each condition was performed in duplicate in three experiments. The t-test was employed with P ≤ 0.05 considered statistically significant. Effective production of IGF-I was achieved in IGF-I- vs. lacZ-treated aspirates. Enhanced chondrogenic differentiation was observed after 21 days in the aspirates with rAAV-hIGF-I, as noted by more robust toluidine blue staining and stronger type-II collagen immunostaining compared with rAAV-lacZ. IGF-I treatment also increased the DNA and proteoglycan contents in the aspirates vs. lacZ. These findings were corroborated by real-time RT-PCR analysis showing higher levels of SOX9, ACAN, and COL2A1 expression with IGF-I that also increased the levels of COL1A1 and COL10A1. Overexpression of IGF-I via rAAV is thus capable of stimulating the metabolic and chondrogenic activities in human bone marrow aspirates. Regulation of growth factor expression will be necessary to contain terminal differentiation and hypertrophy for translation of the approach in cartilage defects.
Abstract 4642: Quercetin inhibits prostate cancer by modulating molecules involved in apoptosis and cell proliferation
Authors: Ashely B. Ward, Hina Mir, Neeraj Kapur, Shailesh Singh
Journal: Cancer Research (2015)

Abstract Prostate cancer (PCa) remains the second leading cause of death in men, despite the multimodal options offered in the clinics. Long latency and indolent nature of PCa provides window of opportunity for preventive interventions using natural and synthetic agents. Quercetin, a bioflavonoid abundant in fruits and vegetables, has been reported to inhibit growth in cancer and reduce inflammation in conditions like prostatitis. Considering this, we investigated the chemo-preventive effects of Quercetin on PCa. The effects of Quercetin on apoptosis and associated proteins on both RNA and protein levels were determined using apoptosis assay, real-time qPCR and western blot, respectively. Furthermore, an antibody microarray was performed to observe changes induced by Quercetin on signaling molecules and possible mechanism of cell survival/apoptosis in PCa. PCa cells treated with Quercetin showed decreased cell proliferation in a time and dose dependent manner, while no significant effect was seen on normal prostate cells. Quercetin treatment also significantly induced apoptosis in PCa cells, as compared with untreated controls. Different phosphorylation status of key molecules (Bcl-2, Akt-1 and NF-k B) was observed following Quercetin treatment in PCa cell lines, as compared with untreated controls, which are known to be involved in supporting PCa progression. These results suggest that Quercetin could be a potential chemo-preventative agent capable of slowing down the progression of PCa, by increasing apoptosis and decreasing cell proliferation. Note: This abstract was not presented at the meeting. Citation Format: Ashely B. Ward, Hina Mir, Neeraj Kapur, Shailesh Singh. Quercetin inhibits prostate cancer by modulating molecules involved in apoptosis and cell proliferation. [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 4642. doi:10.1158/1538-7445.AM2015-4642
IMST-37. SYSTEMIC LYMPHOCYTE DEPLETION FOLLOWING FOCAL BRAIN RADIATION IN A MOUSE MODEL
Authors: Anna F. Piotrowski, Thomas Nirschl
Journal: Neuro-Oncology (2016)

Severe lymphopenia following radiation is common, long-lasting, and associated with inferior survival in patients with brain, pancreatic and lung cancers. An animal model was developed to study the effects of focal brain radiation on systemic lymphocytes, lymph nodes and cytokines. The brains of C57BL/6 and BALB/c mice were treated using 4 Gy x 10 or 2 Gy x 30 fractions via the small animal radiation research platform (SARRP). Blood was drawn weekly and blood counts and lymphocyte subsets were assessed. Lymph nodes from outside the radiated field were resected before, during, and after radiation and examined by immunohistochemistry. Blood and lymph node cytokines were assessed using an array. Fifty-two mice received focal brain irradiation which resulted in a rapid decrease in systemic lymphocyte counts in both strains (42% reduction in C57BL/6 and 75% in BALB/c with 2 weeks of radiation) and with both treatment plans (70% reduction and 49% with 6 weeks). Similar trends were seen in total T cells, CD4+, regulatory T and CD8+ cells. Changes in nodal cellularity and architecture and the appearance of macrophages correlated with lymphopenia. Three weeks after radiation, lymphocyte counts returned to >60% of baseline which was preceded by increased IL-7 levels in lymph nodes and blood. Focal brain radiation in mice without cancer results in severe systemic lymphoid depletion which differs from humans in that there is spontaneous recovery. All lymphocyte subtypes appeared to be affected. Compensatory increased IL-7 levels in lymph nodes and blood likely play a role in recovery. Understanding the mechanisms underlying this systemic lymphopenia is critical to improving responses to immunologic interventions and survival in cancer patients.
Possible Role of Impaired Erk1,2 Phosphorilation and Increased sIL2r Alpha Plasma Levels in the Reduced Frequency of Circulating T Regulatory Cells of Patients with Primary Myelofibrosis
Authors: Rita Campanelli, Gabriela Fois, Carlotta Abbà, Mara De Amici, Laura Villani, Elisa Bonetti, Paolo Catarsi, Valentina Poletto, Giovanni Barosi, Vittorio Rosti, Margherita Massa
Journal: Blood (2015)
Abstract 2740: Familial Hodgkin lymphoma by relationship, sex, age and histology: a joint study from five Nordic countries
Authors: Mahdi Fallah, Elham Kharazmi, Eero Pukkala, Jørgen H. Olsen, Laufey Tryggvadottir, Kristina Sundquist, Steinar Tretli, Kari Hemminki
Journal: Cancer Research (2015)

Abstract Background: We aimed to estimate lifetime (0-79 years) cumulative risk (CR) of Hodgkin lymphoma (HL) in relatives of patients with HL by relationship, sex, age and histology. Design: A population-based cohort of 57,475 first-degree relatives of 13,922 HL patients diagnosed in 1955-2009 in Nordic countries was followed for cancer incidence. Standardized incidence ratios (SIRs) were calculated using histology-, age-, sex-, period-, and country-specific incidence rates as the reference. Results: The overall CR of HL in first-degree relatives of a patient with Hodgkin lymphoma was 0.6%, which represents 3-fold (SIR = 3.3, 95%CI = 2.8-3.9) increase over the general population risk (men 0.3%; women 0.2%). Significantly high CR (1%) was found among sisters with early-onset HL and unlike-sex siblings with HL diagnosed at age 30-59. The familial risk in sisters (9-fold) was higher than in brothers (4.5-fold) or unlike-sex siblings (6-fold). In general, the risk in siblings (6-fold) was higher than in parents/children (2-fold). Very high risk of HL was found for few men with two HL first-degree relatives (3-8%) and for twin brothers (18%). For the first time we found high familial risk of concordant histological subtypes of HL [lymphocyte-rich (81-fold, n = 6) and nodular sclerosis (4.6-fold, n = 22)] and also discordant subtypes. Conclusions: Lymphocytic-rich histology type of HL showed highest familial risk. The absolute risk of familial HL was generally less than 1.5%, except for men with multiple affected first-degree relatives (3-8%), twin brothers (18%), or brothers with early-onset HL (2%). Citation Format: Mahdi Fallah, Elham Kharazmi, Eero Pukkala, Jørgen H. Olsen, Laufey Tryggvadottir, Kristina Sundquist, Steinar Tretli, Kari Hemminki. Familial Hodgkin lymphoma by relationship, sex, age and histology: a joint study from five Nordic countries. [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 2740. doi:10.1158/1538-7445.AM2015-2740
E-cadherin germline gene (CDH1) mutation in hereditary gastric carcinoma families
Authors: H. Wang, J. Ren
Journal: Journal of Clinical Oncology (2004)

9634 Background: E-cadherin, the product of CDH1 gene, belongs to the functionally related trans-membrane glycoprotein family, is responsible for the Ca2+-dependent cell-cell adhesion mechanism and contributes to dissociation followed acquisition of cell motility, which usually occurs in the first step of cancer invasion and metastasis. Methods: This paper provides a bird's-eye view both in preclinical and clinical aspect of E-cadherin germline gene (CDH1) in gastric cancer patients and their families. Results: CDH1 gene germline mutation is common in many types of carcinoma, but very frequent in hereditary gastric carcinoma (HGC) patients and their families. Recently, more and more researches reinforce that E-cadherin plays an important role in the differentiation, growth and invasion of HGC. Conclusions: So it's of great value to clarify its mechanisms both for us to understand HGC process and for clinical therapy, especial in China, which has a high risk population of gastric cancer and a high HGC incidence rate. Recently researches on CDH1 gene mutation, especially what the mutation contributes to HGC, such as tumor genesis or progress will be reviewed, and the advances about the value of the mutation status for HGC diagnosis, therapy and prognosis, will also be discussed briefly. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Teaching and Research Award Program for Outstanding Young Teacher (TRAPOYT99– 016) by the National Education Ministry, P.R. China
Abstract 1938: Comprehesive RNA-sequencing pipeline of cancer xenograft models
Authors: Jinha Hwang, Jong-Il Kim, Jee-Soo Choi, Min Jung Kim, Charles Lee
Journal: Cancer Research (2015)

Abstract Since a solid pipeline for massively parallel sequencing in cancer xenograft model has not been built yet, it is necessary to establish a precise analysis pipeline. Massively parallel sequencing on xenograft samples result in mixed sequencing reads from the engrafted human tumor cells and murine tissue. It is necessary to accurately distinguish between these reads for subsequent data analysis. In the present study, we constructed an integrated RNA-Seq pipeline including genomic variation, expression profiling, and fusion gene analysis. To distinguish these reads into individual species, we used the merged reference that incorporates the two genome reference from human (hg19) and mouse (mm10). We tested our pipeline using 6 Primary and 4 metastatic gastric tumor of 6 patients and their derivative xenografts sequencing data. There were almost same amount of ambiguous reads when we aligned sequencing reads to merged reference or separate reference genome. Using merged reference, we efficiently distinguished compound sequencing reads between human and mouse without repetitive alignment processes. The proportion of sequencing reads from mouse in xenograft samples widely ranged from 2.64% to 49.25% per each sample. For expression profiling, we used HTSeq-count for measuring expression level of each sample. As expected, human-specific reads of ECM-receptor and focal adhesion related genes were specifically down-regulated in the xenograft tumors compared to primary tumor and normal tissues suggesting the depletion of human cells from the microenvironment of engrafted tumor tissues. Mouse-specific reads of those genes were highly expressed in the engrafted tissue. Differentially expressed genes between engraft tumor and paired normal tissue were shown to be enriched in the cell cycle and p53 signaling pathway and these showed that engrafted tumor tissues well represent characteristics of cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Jinha Hwang, Jong-Il Kim, Jee-Soo Choi, Min Jung Kim, Charles Lee. Comprehesive RNA-sequencing pipeline of cancer xenograft models. [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 1938. doi:10.1158/1538-7445.AM2015-1938
A Novel Sequential Treatment Utilizing CPX-351 As Salvage Chemotherapy Followed by a Reduced Intensity Conditioning Allogeneic Stem-Cell Transplantation for Patients with Refractory Leukemia
Authors: Usama Gergis, Gail J. Roboz, Ellen Ritchie, Joseph M. Scandura, Karen-Sue B. Carlson, Tsiporah B. Shore, Sebastian Mayer, Tomer M Mark, Roger N Pearse, June Greenberg, Tania J Curcio, Cindy Ippoliti, Marshall McKenna, Eric J Feldman
Journal: Blood (2011)
Risk Factors and Outcome after Second HLA-Matched Sibling Donor Transplantation for Graft Failure after a First HLA-Matched Sibling Transplant in Severe Aplastic Anemia.
Authors: John Horan, Jeanette Carreras, Sergey Tarima, Bruce Camitta, Robert Peter Gale, Wolfgang Hintergerger, Judith Marsh, Ricardo Pasquini, Marcelo Pasquini, Mark Walters, Mary Eapen
Journal: Blood (2007)
Abstract 550: Evaluation of NQO1 as a potential diagnostic marker for bladder cancer
Authors: Simone Cuff, Ruth Lewis, Mohammed Jaffar, Richard Knox, Ian Weeks
Journal: Cancer Research (2015)

Abstract The present method for detection of bladder cancer involves ultrasonography followed by cystoscopy. This process is time intensive, requires skilled personnel and is unpleasant for the patient as a result of its invasive nature. This results in patient drop-out and patients that have recovered from bladder cancer are lost to follow-up due to the necessity for hospital visits for monitoring. We have used a novel test in order to monitor NAD(P)H quinone oxidoreductase 1 (NQO1) activity in cells recovered from routine urine samples since expression of NQO1 has previously been reported to be increased in several tumour types including transitional cell carcinoma of the bladder. Informed consent and urine samples were obtained from 73 bladder cancer patients and 42 age-matched bladder cancer-negative outpatients at the University Hospital of Wales, Cardiff. Live exfoliated cells were collected from the urine and assessed for their ability to metabolise an NQO1-specific substrate into a highly fluorescent product. Fluorescence intensity was then measured in a simple, inexpensive instrument. Results were checked against clinical correlates, bladder cancer stage, age, medication, and smoking status. Initial tests in cell lines showed excellent correlation with NQO1 levels detected by other methods. We found that in patient samples, while cell numbers in urine and expression of NQO1 per cell were not in themselves significant, NQO1 per ml of urine was highly significantly increased in bladder cancer patients (p = 0.009). Further, NQO1 was higher in patients that had high grade tumours as described in the WHO 2004 guidelines (p = 0.003). The sensitive fluorescence-based method to detect NQO1 activity in exfoliated urothelial cells shows exceptional promise in the development of rapid, non-invasive bladder cancer diagnostics. The method will be used on larger numbers of samples in order to be able to verify these initial findings. Note: This abstract was not presented at the meeting. Citation Format: Simone Cuff, Ruth Lewis, Mohammed Jaffar, Richard Knox, Ian Weeks. Evaluation of NQO1 as a potential diagnostic marker for bladder cancer. [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 550. doi:10.1158/1538-7445.AM2015-550
Disease and Outcome Disparities in Multiple Myeloma (MM): Exploring the Role of Race/Ethnicity and Obesity in Cooperative Group Clinical Trials
Authors: Sikander Ailawadhi, Susanna Joan Jacobus, Rachael Sexton, A. Keith Stewart, Angela Dispenzieri, Mohamad A. Hussein, Jeffrey Zonder, John Crowley, Antje Hoering, Bart Barlogie, Robert Z. Orlowski, S. Vincent Rajkumar
Journal: Blood (2016)
428. VSV Produced in CD55 Expressing Cells Has Better Resistance To Neutralization With Non-Immune Human Serum
Authors: Mulu Z. Tesfay, Arun Ammayappan, Mark J. Federspiel, Glen N. Barber, Kah-Whye Peng, Stephen J. Russell
Journal: Molecular Therapy (2015)

VSV has shown promise as a systemic oncolytic therapy in many preclinical tumor models. However, its stability in blood circulation is largely compromised due to complement-dependent serum neutralization. In this work we have assessed the effect of producer cell type on serum neutralization of VSV. We show that VSV produced from HeLa cells is resistance to neutralization with non-immune human serum as compared to VSV produced from other cell lines tested (Vero, 3T3, 293, and BHK cell lines). We show that this resistance is associated with decay-accelerating factor (DAF or CD55) expression in HeLa cells as the other cell lines tested did not express detectable levels of CD55. Furthermore, using a recombinant VSV expressing full length human CD55, we show that CD55 expressing VSV is more resistant to neutralization with non-immune human serum as compared to the parental VSV that doesn't express CD55. Currently, we are characterizing Vero cell lines that stably express human CD55 and the VSV produced from these cell lines. We are also generating suspension 293 cell lines stably expressing human CD55 that we plan to use for large scale VSV production.