tbuckley/cabot-search huggingface dataset:
Abstract 817: Lipid, glucose and global oxidation in relation to prostate cancer development
Authors: Tianying Wu
Journal: Cancer Research (2015)

Abstract Oxidative stress has been implicated in the development of prostate cancer (PCa); however, no study has comprehensively examined the associations between lipid, glucose and global oxidation with the development of prostate cancer. Using a prospective study design, we collected blood and urine samples among participants who are free of cancer in Ohio area. These participants were followed up 14 years. We selected 24 men who developed PCa during this period and matched them with 24 healthy controls by age and race among these participants (who did not develop prostate cancer) during this period. We measured the following biomarkers in these 48 samples (24 PCa cases and 24 health controls). Biomarkers included urine F2-isoprostanes (a marker of lipid oxidation), plasma advanced glycation end products (AGEs; a marker of advanced glycation and glucose oxidation), and plasma fluorescent oxidation products (FlOPs; markers of global oxidation). We have found that only AGEs were significantly higher in PCa cases than in health controls (182 vs. 152 μg/ml, P &amp;lt; 0.05). In the conditional logistic regression model, one standard deviation higher levels of AGEs were associated with increased risk of incident PCa (Relative risk = 1.79, 95% confidence interval = 1.00-3.21). In the model, one standard deviation higher levels of AGEs accounted for ∼8% variance of prostate cancer liability. Our results suggest that glycation and glucose oxidation but not lipid and global oxidation is an important etiology pathway for prostate cancer development. Lipid and global oxidation do not occur in parallel for the development of prostate cancer. If our results are confirmed by other studies, it may suggest a new pathway for prostate cancer prediction and treatment. Note: This abstract was not presented at the meeting. Citation Format: Tianying Wu. Lipid, glucose and global oxidation in relation to prostate cancer development. [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 817. doi:10.1158/1538-7445.AM2015-817
Primary adenosquamous carcinoma of the liver: a case report
Authors: Kyung Han Nam, Ji Yeon Kim
Journal: Clinical and Molecular Hepatology (2016)

Primary adenosquamous cell carcinoma of the liver, a variant of cholangiocarcinoma is very rare disease and its prognosis is known to be very poor. We describe here a case of primary adenosquamous carcinoma of the liver. The patient was a 60-year-old woman who complained of an eight-month history of intermittent upper abdominal pain. Abdominal computed tomography scan revealed a low density mass and intrahepatic duct stones within the dilated left intrahepatic duct in the left lateral segment. Needle biopsy of the mass was done and the histologic diagnosis was cholangiocarcinoma. Left lobectomy was then performed. Upon gross examination, there was a well defined solid mass and intrahepatic duct stone in the dilated bile duct. Microscopically, the tumor was composed of both adenocarcinoma and squamous cell carcinoma.
NPM1 Haploinsufficiency Results in Increased Numbers of Hematopoietic Stem Cells and Progenitor Cells.
Authors: Aparna Raval, Christopher Y. Park, Wendy W Pang, Brenda Kusler, Kunju Joshi Sridhar, Jason R Gotlib, Peter L Greenberg, Irving L. Weissman, Beverly S. Mitchell
Journal: Blood (2009)
An evaluation of CD133 as a biomarker for malignant transformation of colon polyps.
Authors: J. S. Hamdan, F. Saghir, R. Benya, A. Chan, A. Blunier, L. Dunham, G. Guzman, N. Mahmud
Journal: Journal of Clinical Oncology (2011)

e14045 Background: CD133 is a pentaspan membrane glycoprotein expressed by blood and neuronal stem cells but its biological role in colon cancer remains controversial. The expression of CD133 in normal colonic tissue and benign and malignant polyps has not been studied in a progressive manner. We hypothesize that expression of CD133 increases as the polyp progresses from non-cancerous to adenocarcinoma of the colon. Methods: Archived normal colonic epithelium and non-cancerous polyps as well as adenocarcinomas were evaluated immunohistochemically using CD133 antibody. A grading scale was used to classify staining patterns as negative (no staining) or positive (any staining). Positive staining was further classified as low (<50%) and high (>50%) glandular staining as described previously. Results: A gradation of CD133 expression was noted with almost no expression in normal colon (100% negative, n = 5) to higher expression, gradually increasing from hyperplastic polyps to adenocarcinoma. In the hyperplastic polyps (n=12), 9 were classified as negative and 3 classified as positive (25%) with 1 having high and 2 having low expression. In the tubular polyps (n=18), all 18 samples were positive (100%), with 10 high expression and 8 low. In the villous polyps (n=7), all 7 samples were positive (100%) with high expression. Finally, with colonic adenocarcinoma tissue (n=12), all 12 samples had positive expression (100%) for CD133 with 8 having high expression and 4 low expression. Most interestingly the expression of CD133 in the samples examined increased from 25% positive in benign hyperplastic polyps to 100% positive in tubular polyps indicating the potential importance of CD133 as an early biomarker for malignant transformation. Conclusions: Our results indicate a gradual increase in CD133 expression in the progression from normal colonic epithelium, to hyperplastic, to tubular/villous polyps and adenocarcinoma, which displayed the highest expression (Cochran-Armitage test for trend, p <.0001). Taken together, our studies indicate that expression of CD133 may serve as an early bio-marker for malignant transformation and provide a platform to examine the potential benefit of antibody based therapy in patients with colon cancer.
248. Results of a Phase 1 and 2a Trial on rAAV. sFlt-1 in Treatment of Wet Age-Related Macular Degeneration
Authors: Chooi-May Lai, Aaron L. Magno, Martyn A. French, Samuel B. Barone, Steven D. Schwartz, Mark S. Blumenkranz, Mariapia A. Degli-Esposti, Ian J. Constable, Elizabeth P. Rakoczy
Journal: Molecular Therapy (2016)

Purpose: To assess safety following subretinal rAAV.sFlt-1 injection at one year. Secondary endpoints were assessed for evidence of biologic activity. Methods: Under the protocol, Phase 1 followed a dose escalation design where eligible subjects received subretinal injection of low dose (LD, N=3, 10E10 vg) and high dose (HD, N=3, 10E11 vg) rAAV.sFlt-1, or control regimen (N=2). In Phase 2a eligible subjects were randomized to receive HD (N=21) rAAV. sFlt-1 or control regimen (N=11). All 40 subjects were assessed using ophthalmic exam and laboratory testing, and received intravitreal ranibizumab retreatment according to protocol-driven criteria for worsening wet Age-related Macular Degeneration (AMD). Results: During the 1-year follow-up to the primary endpoint, no serious adverse events related to rAAV. sFlt-1 were observed. However, transient adverse events such as subretinal hemorrhage, inflammation, and increased intraocular pressure were reported. One LD subject and 11 HD subjects were phakic at baseline; following subretinal injection with vitrectomy all of these subjects experienced cataract progression which was operated by month 10. In the control group, 13 subjects received a mean 3.5 (median 4, range 0-5) ranibizumab retreatments, and had a change in mean Best Corrected Visual Acuity (BCVA) of -8.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and a decrease in mean retinal Center Point Thickness (CPT) from 450 µm at baseline (BL) to 355 µm. Subjects in the LD group received a mean 0.33 (median 0, range 0-1) ranibizumab retreatments, and had a mean vision gain of 8.7 ETDRS letters and decreased mean CPT from 449 µm to 315 µm. Retreatment outcomes in the HD group suggested a bimodal distribution: 14 subjects received ≤ 2 ranibizumab retreatments (HD. 1 subgroup) with a mean vision gain of 6.6 ETDRS letters and a mean CPT decrease from 406 µm to 360 µm, and 10 HD subjects received ≥ 3 ranibizumab retreatments (HD. 2 subgroup) with a mean vision change of -2.7 ETDRS letters and increase mean CPT from 407 µm to 456 µm. At BL, serum neutralizing antibodies to AAV were detected in 5/13 (38%) controls, 1/3 LD group (33%), 11/14 HD. 1 subgroup (77%) and 2/10 (20%) HD. 2 subgroup. Five HD group subjects who were seronegative at BL seroconverted after rAAV.sFlt-1 therapy. Conclusions: Subretinal rAAVsFlt-1 was well-tolerated with a favorable safety profile in subjects with wet AMD. Encouraging signs of a response with vision gain and fewer ranibizumab retreatment were observed in the majority of the subjects. Serum neutralizing antibodies to AAV prior to treatment did not adversely affect clinical outcomes.
OC-031 Outreach community testing for hepatitis C in an ethnic population
Authors: H Jafferbhoy, M Miller, P McIntyre, S Mcleod, J F Dillon
Journal: Gut (2010)

<h3>Introduction</h3> Hepatitis C (HCV) is a leading cause of liver disease worldwide The World Health Organisation (WHO) estimates a worldwide prevalence of 170 million or 2.2%, although there is considerable geographical variation, Scotland, due to intravenous drug misuse, has higher prevalence of HCV infection compared with other European countries, estimated at 1% of the population. There is considerable ethnic diversity in Scotland, with a large Pakistani subpopulation. In Pakistan the prevalence of HCV is between 6 and 10%.1 <h3>Methods</h3> We arranged a series of HCV awareness meetings in Mosques and Pakistani Women9s Associations in Dundee. Thereafter we set up a series of sessions in the same venues offering HCV testing. Venous blood samples were taken for testing of HCV IgG and HBsAg, using the Abbott Architect system. Relevant past medical, family and travel history was also recorded as well as history of risk factors for HCV. <h3>Results</h3> 170 people were tested, representing 10% of the Dundee Pakistani population of which 145 were male. The mean age±SD was 45.11 (16.7) years. Seven patients (4.1%) of the cohort were Anti HCV positive and five (2.9%) were PCR positive. Only two people had previous testing for HCV, although 86.5% of the cohort had attended their GP within the past 2 years. 76.5% of the cohort had resided in the UK for at least 5 years. Less than 7% of the cohort was born in the UK. Risk factors for HCV transmission were only noted in a minority of patients who were HCV positive. One of seven had a family history and two of seven had a previous injection (IM or IV) in Pakistan. None had a history of drug misuse or transfusion. Of the entire group 33.5% reported previous therapeutic injections and 10% had a previous surgical procedure carried out in Pakistan. 3.5% of the cohort had a blood transfusion. 15.2% reported a family history of HCV infection. <h3>Conclusion</h3> This pilot project confirms that the Hepatitis C incidence in the healthy Pakistani migrant is higher than the native population. At-risk groups for HCV can be targeted for testing and treatment with outreach clinics. Using Scottish Intercollegiate Guidelines Network (SIGN) recommendations for assessing risk factors we would not have tested majority of those infected.2 Awareness needs to be raised among physicians regarding screening of ethnic populations for HCV.
101. Rational Design and Cloning of a Stable RPGR ORF15 cDNA Encoding the Full-Length Native RPGR Protein
Authors: Jilin Liu, Andrew Espejo, Weihong Pan, Guojie Ye
Journal: Molecular Therapy (2016)

Introduction: The retinitis pigmentosa GTPase regulator (RPGR) cDNA contains a long purine-rich repetitive sequence in ORF15 exon that is unstable during recombinant DNA manipulation. This complicates efforts to develop AAV-based vectors for gene therapy of X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene. We reasoned that the stability of RPGR-ORF15 cDNA could be significantly improved by rational design of the cDNA sequence through codon modification without changing the amino acid sequence. Methods: A human RPGR cDNA was designed based on Genbank reference mRNA sequence NM_001034853 that encodes hRPGR isoform C. The 3459 bp coding sequence was codon-optimized based on human codon usage and further modified to reduce tandem repeats, and adjust G/C content, where possible. The codon-modified cDNA (hRPGRco), which encodes a full-length hRPGR protein of 1152 amino acids that is 100% identical to the published sequence, was synthesized and cloned into conventional cloning vector pUC57 and sub-cloned into various vectors, including an AAV plasmid (used for AAV production by transfection) and an HSV shuttle plasmid (used to make an HSV helper for AAV production using AGTC's proprietary HSV-based AAV manufacturing system). Stability of the hRPGRco cDNA sequence was verified by DNA sequencing at multiple steps: after sub-cloning, large scale plasmid production, production of recombinant HSV helper virus clones that carry the hRPGRco expression cassette and production of AAV vector. Stability of plasmids carrying the hRPGRco expression cassette was also analyzed after serial passage of bacterial clones cultured at various temperatures and during multiple passages. Results: Plasmids carrying the redesigned hRPGRco cDNA were grown stably in bacteria at 37°C. The hRPGRco cDNA was 100% correct in AAVplasmids, in shuttle vectors used to produce HSV helpers, and in the rHSV helper virus passed multiple rounds in mammalian cells. The sequence was also confirmed 100% correct in AAV vectors produced by plasmid transfection for animal efficacy studies. Conclusions: A stable RPGR cDNA that encodes full-length, native RPGR protein was obtained and will allow large scale production of an AAV vector for treatment of patients with XLRP.
Changes in FDG PET SUV and correlation with Ki-67 following 2 weeks of aromatase inhibitor therapy or trastuzumab in a pilot imaging study.
Authors: H. M. Linden, B. F. Kurland, R. B. Livingston, G. K. Ellis, V. K. Gadi, J. M. Specht, J. Gralow, L. Peterson, E. K. Schubert, S. Xiaoyu, D. A. Mankoff
Journal: Journal of Clinical Oncology (2011)

e21077
Abstract B27: Identification of novel anti-metastatic drugs targeting oncogenic E2F1:coregulator complexes by applying a systems pharmacology approach
Authors: Deborah Goody, David Engelmann, Stefan Mikkat, Shailendra K. Gupta, Brigitte M. Pützer
Journal: Cancer Research (2016)

Abstract Tumour metastasis is considered to be one of the most important problems in cancer research and the identification of mechanisms that drive this multistep process provides urgently needed opportunities for therapeutic interventions. Many cancer types are driven by the dysfunction of transcriptional coregulators which interact with transcription factors such as E2F1 that has been associated with cancer aggressiveness and poor patient survival prognosis. Although the role of E2F1 in malignant progression is not fully understood, its physical interaction with oncogenic coregulators is clearly linked to the activation of prometastatic gene expression programs. In order to identify metastatic E2F1:coregulator complexes that determine occurrence of metastases and clinical outcome, we employed co-immunoprecipitation assays in advanced-stage metastatic cancer cells combined with high throughput mass spectrometry. We identified a hitherto unknown regulatory network of E2F1 interaction partners, which were validated by Western blotting, confocal laser scanning microscopy, ChIP and promoter reporter assays. Knockdown and overexpression studies in a large panel of metastatic cell lines originating from various tumor entities showed a clear impact of these proteins on cancer motility and invasiveness. Genome-wide transcriptome analyses were applied to uncover the metastasis gene signature regulated by the E2F1-coregulator complexes that predicts aggressive behavior. Finally, we developed a pharmacophore model of E2F1 interacting proteins and predicted potential drug molecules which can be used as inhibitors of E2F1:coregulator complexes based on a computer-assisted virtual screening of FDA-approved compounds. Taken together, our straight forward approach on finding new prometastatic E2F1 coregulators and potential inhibitors to disrupt these complexes may shed new light into future cancer therapy. This research was funded by grants from the German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.). Note: This abstract was not presented at the conference. Citation Format: Deborah Goody, David Engelmann, Stefan Mikkat, Shailendra K. Gupta, Brigitte M. Pützer. Identification of novel anti-metastatic drugs targeting oncogenic E2F1:coregulator complexes by applying a systems pharmacology approach. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B27.
Abstract 1027: Apoptotic resistance in arsenic transformed cells attributed to decreased SIRT3-FOXO3A signaling
Authors: Ram V. Roy, Xinglin Shi
Journal: Cancer Research (2015)

Abstract SIRT3 is the primary mitochondrial protein deacetylase that regulates mitochondrial proliferation and DNA integrity. SIRT3 is the only sirtuin whose increased expression was shown to be associated with extended lifespan in humans. Interestingly, very few studies have examined the role of SIRT3 in cancers. Here, we report cellular function of SIRT3 in Beas-2B cells under arsenic stress, and in AT cells. Upon treatment with arsenic, in Beas-2B cells, SIRT3 levels increased and induced apoptosis - nuclear translocation and binding of SIRT3 to FOXO3A - while AT cells exhibited lower levels of SIRT3 which can be attributed to apoptotic resistance, as over-expression of SIRT3 restores sensitivity to apoptosis. In AT cells, lower expression of SIRT3 caused hyperacetylation and aberrant localization of its target protein - FOXO3A. One of the consequences of low SIRT3 levels is absence of SIRT3-FOXO3A interaction in AT cells, which increases the proportion of transcriptionally hyperactive, highly depolarized mitochondria (high ΔΨm) with higher mitochondrial DNA content compared to passage matched parent Beas-2B cells. Conversely, Resveratrol-induced high expression of SIRT3 improves nuclear-mitochondrial crosstalk (increased FOXO3A binding in the D-loop region) and raises sensitivity towards apoptosis. By disconnecting crosstalk between nucleus and mitochondria (SIRT3-FOXO3A interactions), AT cells increase depolarized mitochondrial number, so that the transformed cells maintain low basal ROS and proliferate rapidly. This is the first time that a study has shown functional role of SIRT3-FOXO3A in promoting apoptosis in Beas-2B cells under arsenic stress, and in AT cells. Citation Format: Ram V. Roy, Xinglin Shi. Apoptotic resistance in arsenic transformed cells attributed to decreased SIRT3-FOXO3A signaling. [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 1027. doi:10.1158/1538-7445.AM2015-1027
352. Functional Benefits of Systemic rAAV9-hIDS Gene Delivery in MPS II Mouse Model
Authors: Douglas M. McCarty, Kimberly Zaraspe, Aaron S. Meadows, Naoka Murakami, Ricardo Pineda, Marybeth Camboni, Joseph Muenzer, Haiyan Fu
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis (MPS) II is an X-linked recessive lysosomal storage disease caused by defect in iduronate-2-sulfatase (IDS), leading to in the accumulation of glycosaminoglycans (GAGs) in cells in the CNS and peripheral organs, and profound multisystem disorders in the majority of patients. No treatment is available for the neurological disorders of MPS II. In this study, we developed 2 self-complementary (sc) AAV9 vectors expressing human IDS and tested them in MPS II mice via systemic delivery. At a dose 5e12vg/kg, an IV injection of either scAAV9-U1a-hIDS or scAAV9-mCMV-IDS, led to rapid and persistent IDS expression and the correction of lysosomal GAG storage throughout the CNS, peripheral nervous system (PNS) and periphery tissues, as well as diminishing of astrocytosis in the CNS and PNS, in MPS II mice treated at 1mo, 3mo or 6mo of age. Importantly, we demonstrate significant improvement in cognitive and motor function, and extension of survival (ongoing) in the rAAV9-treated MPS II mice. These data demonstrate substantial functional benefits of a systemic scAAV9-hIDS gene delivery for treating MPS II at early and advanced disease stages, supporting the clinical potential of the approach.
Integrin Alpha E (CD103) Beta 7 Expression Marks A Subset of Human Bone Marrow-Derived CD207+ Dendritic Cells Which Induce T Regulatory Cells Via Indoleamine 2,3-Dioxygenase,
Authors: Antonio Curti, Darina Ocadlikova, Sara Trabanelli, Cecilia Evangelisti, Marilena Ciciarello, Michele Baccarani, Roberto M. Lemoli
Journal: Blood (2011)
233. The Efficacy of Megakaryocytic Progenitor Products Generated from Cord Blood in Acute Myeloid Leukemia Patients: A Before-After Phase 2 Trial
Authors: Xuetao Pei
Journal: Molecular Therapy (2016)

Infusion of cord blood-derived megakaryocytic progenitors (MPs) products shows safe and feasible for treatment of thrombocytopenia in hematological malignancies in our phase 1 study. This phase 2, before-after study assigned 54 patients with acute myeloid leukemia (AML) to receiving MPs products or not after consolidation chemotherapy with high-dose ara-C (HDAC). One patient from MPs group and one from control group withdraw the study. Compared to control group, the MPs group achieved a decreased platelet infusion rate (7.5% [4/53] vs. 22.6% [12/53], p=0.03), platelet infusion units (1.0 vs. 2.0 Units, p=0.001), time of platelet count recovery normal (>100×109/L, p=0.01). Only two patients had reversible fever (below 38°C) and one patient had reversible local skin rash. No patients withdraw due to adverse event. MPs products were active and well tolerated, with decreased platelet infusion rate and platelet count recovery after chemotherapy. This study was registered at http://www.chictr.org as # ChiCTR-TRC-11001691.
HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing the NF-κB pathway and ROS production
Authors: Xin Yu, Peixiang Lan, Xuben Hou, Qiuju Han, Nan Lu, Tao Li, Chenwei Jiao, Jian Zhang, Cai Zhang, Zhigang Tian
Journal: Journal of Hepatology (2016)