tbuckley/cabot-search huggingface dataset:
Abstract KP01: Identification of genes and pathways that prevent genome instability
Authors: Richard Kolodner
Journal: Clinical Cancer Research (2015)

Abstract The genome of many cancers is characterized by ongoing genome instability; however, the causes of genome instability in cancer are not well understood. To understand the control genome instability, we developed three types of genetic assays for measuring the rate of accumulating gross chromosomal rearrangements (GCRs) in the yeast Saccharomyces cerevisiae - one that detects GCRs containing breakpoints in single copy sequences, a second that detects GCRs mediated by segmental duplications, and a third that detects GCRs mediated by Ty elements which are similar to mammalian LINE elements. Initial studies characterizing these three types of assays found that there are specific pathways that suppress duplication-mediated GCRs and identified sequences that are hotspots for the formation of GCRs. We have subsequently used these three assays to perform a genetic screen of the non-essential genes in S. cerevisiae to identify the genetic network that acts to prevent genome instability. This screen involved three steps: a novel bioinformatics screen to identify and prioritize candidate genome instability suppressing genes; a biological genetic screen to identify which of the predicted genes actually suppress genome instability; and a biological genetic screen to identify interacting genes. As a result of these screens, we have identified 184 genes in which defects cause increased GCRs and an additional 459 genes in which mutations only cause increased GCRs when combined with a second mutation thus defining multiple pathways that prevent GCRs. Control experiments indicated that this approach led to the identification of greater than 95% of the non-essential genes that act to suppress genome instability. In a second screen, we identified 44 essential genes in which defects caused increased GCRs. We are now beginning to use the S. cerevisiae genome instability suppressing genes to predict the mammalian genome instability genetic suppressing network. Citation Format: Richard Kolodner, PhD. Identification of genes and pathways that prevent genome instability [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 KP01.
270. Optogenetic Activation of Remnant Cone Cells Can Restore Ganglion Cell Light Responses in a Canine Model of Retinitis Pigmentosa
Authors: Pavitra S. Ramachandran, Sergei Nikonov, Keirnan Willett, Rachel Huckfeldt, Arkady Lyubarsky, Jessica Morgan, Tomas Aleman, Albert Maguire, Jean Bennett
Journal: Molecular Therapy (2016)

In retinitis pigmentosa, the rod photoreceptor cells are generally lost first followed by a slow loss of cone cells. Remnant cone cell bodies have been observed even after many years of vision loss in retinitis pigmentosa patients. Proof-of-principle studies in retinal degeneration mice have demonstrated vision restoration upon expression of the optogene halorhodopsin in remnant cone cells. However, whether this will work in a large animal model of retinal degeneration is unclear. Here we look at light responses and histology post-treatment with halorhodopsin in a dog model of autosomal recessive retinitis pigmentosa. Halorhodopsin was expressed in the cone cells unilaterally in rcd1 dogs (PDE6β mutation) with mid- to late stage retinal degeneration using recombinant adeno-associated viral vectors. The retinas were imaged using OCT and function was evaluated using ERG and pupillometry. The spiking activity of retinal ganglion cells (RGCs) in retinal patches adjacent to and distant from the point of injection was tested using multi electrode array recordings. Retinal patches were stimulated with 589 nm light of different durations/intensities. OCT revealed significant thinning of the photoreceptor layer in the retinas of the dogs. While the ERG and pupillometry data did not show a significant difference between the treated and untreated eyes, multi-electrode array recordings revealed a restoration of ganglion cell light responses (ON, OFF and ON/OFF-responses to discrete flashes and responses to 4Hz flicker, 589nm light) in the treated retinal patch compared to an untreated control patch of retina. The lowest intensities where responses become clearly detectable for two animals were 0.1 mW/cm2 and 2.8 mW/cm2 probably reflecting different levels of NpHR expression. We observed halorhodopsin expression by histology in the remnant cone cell bodies of the treated retinas. Restoration of ganglion cell responses in the treated retinal patches suggests that the retina can be sensitized to light even after major photoreceptor cell loss. Ongoing work will determine if this restoration of ganglion cell light responses in the dogs translate to being able to navigate in the light.
Abstract 4155: Interstitial fluid flow-induced hepatocellular carcinoma cell invasion requires MEK/ERK signaling
Authors: Arpit D. Shah, Michael Bouchard, Adrian C. Shieh
Journal: Cancer Research (2015)

Abstract Background: Worldwide hepatocellular carcinoma (HCC) is the third leading cancer-related cause of death. Within the United States, HCC maintains a rising incidence rate of 3% each year since 1992 with a 5 year survival rate of less than 15%. The American Cancer Society has estimated 33,190 new cases off HCC and 23,000 HCC related deaths in the year 2014 within the United States. Our work aims to determine the role of biomechanical forces such as interstitial fluid flow (IFF) in HCC cell invasion. We hypothesized that HCC cells utilize the hypothesized ‘autologous chemotaxis’ mechanism to invade via secretion of the chemokine CXCL12 and expression of its receptor CXCR4. Autologous chemotaxis occurs when a biologically significant chemokine gradient is established by IFF, driving downstream invasion. In an effort to elucidate signaling pathways involved in IFF-induced HCC invasion, we have identified a potential role for MEK/ERK signaling. Materials and Methods: HCC cells or primary rat hepatocytes (PRH) were seeded into in a 3-D matrix composed of Matrigel and type I rat tail collagen, then exposed to static or interstitial flow conditions for 24 hours. The functional role of CXCR4 was tested using the CXCR4-antagonist AMD3100. MEK and ERK were inhibited using U0126 (25 μM) and FR180294 (10 μM), respectively. Phospho-MEK/ERK was assessed using western blot. Results and Discussion: The 3D invasion assay demonstrated that the HCC cells, Huh7 and Hep3B, invaded significantly more in response to IFF (5.5 fold increase in invasion compared to their respective static condition), while PRHs showed no response. AMD3100 was used to block the CXCR4 receptor which resulted in reduced invasion in Huh7 and Hep3B cells. Furthermore when U0126 and FR180204 were incorporated into the 3D invasion assay a significant reduction in flow-induced invasion was observed in Huh7 cells. However, interstitial flow or CXCR4 inhibition did not affect pMEK/ERK, suggesting that MEK/ERK are not modulated directly by IFF and are not downstream of CXCR4. Conclusion: Our results demonstrate that interstitial fluid flow stimulates HCC cell invasion. CXCR4/CXCL12 signaling and MEK/ERK signaling both are required for invasion, but appear to operate via separate mechanisms. Further investigation into these two separate mechanisms would provide better insight into flow-induced HCC invasion. This information could potentially enhance current cancer therapies and provide patients with better treatment options. Citation Format: Arpit D. Shah, Michael Bouchard, Adrian C. Shieh. Interstitial fluid flow-induced hepatocellular carcinoma cell invasion requires MEK/ERK 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 4155. doi:10.1158/1538-7445.AM2015-4155
Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations
Authors: Anthony H. V. Schapira, Susan H. Fox, Robert A. Hauser, Joseph Jankovic, Wolfgang H. Jost, Christopher Kenney, Jaime Kulisevsky, Rajesh Pahwa, Werner Poewe, Ravi Anand
Journal: JAMA Neurology (2016)

Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge.To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations.From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with "off" time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient's regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group.Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg.The prespecified primary outcome was each treatment group's mean change from baseline to week 24 (or last "on" treatment value) in daily "on" time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data.At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]).The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off.clinicaltrials.gov Identifier NCT00627640.
Efficacy and Safety of a Single-Course of Yttrium-90 (90Y) Ibritumomab Tiuxetan (Zevalin®) in Patients with Relapsed or Refractory Mantle Cell Lymphoma (MCL) After/Not Appropriate for Autologous Stem Cell Transplantation (ASCT) - A Phase II Trial of the European MCL Network.
Authors: Oliver Weigert, Christoph von Schilling, Mathias J. Rummel, Antonio Pezzutto, Michael Unterhalt, Wolfgang Hiddemann, Martin Dreyling
Journal: Blood (2005)
Abstract 1132: Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway
Authors: Wei-Hsiang Hsu, Hong-Jhih Jhuang, Chi-Ying Huang
Journal: Cancer Research (2015)

Abstract Peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1α), a major metabolic regulator of gluconeogenesis and lipogenesis, is known to be strongly induced to coactivate HBV gene expression in the liver of fasting mice. In this study, we found that the combination of 8-Br-cAMP and glucocorticoids showed the synergistic induction of PGC-1α and its downstream gene expression, including the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, HBV corepromoter activity was synergistically enhanced by the combination of 8-Br-cAMP and glucocorticoid treatment. Graptopetalum paraguayense (GP), a herbal medicine, is commonly used in Taiwan to treat liver disorders. Here, we found that a partially purified fraction of GP (named HH-F3) dose dependently suppressed 8-Br-cAMP/glucocorticoid-induced G6Pase, PEPCKand PGC-1α expression as well as suppressed HBV core promoter activity. Additionally, HH-F3 blocked HBV core promoter activity via the inhibition of PGC-1α expression. The ectopic expression of PGC-1α effectively reversed the HH-F3-mediated inhibition of HBV core promoter activity.HH-F3-reduced HBV surface antigen expression, HBV mRNA production, core protein level, and HBV replication were drastically rescued by ectopically expressed PGC-1α. In addition, HH-F3 could also inhibit fatty acid synthase (FASN) expression as well as decrease lipid accumulation by the down-regulation of PGC-1α in human hepatocarcinoma cell lines. In conclusion, HH-F3 could inhibit HBV replication, gluconeogenesis, and lipogenesis through the down-regulation of PGC-1α. Our study indicates that targeting PGC-1α may be a novel therapeutic strategy for HBV infection. Together, HH-F3mighthave potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome. Citation Format: Wei-Hsiang Hsu, Hong-Jhih Jhuang, Chi-Ying Huang. Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway. [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 1132. doi:10.1158/1538-7445.AM2015-1132
Abstract LB-131: In vivo chromosomal engineering with the CRISPR/Cas9 model: a new frontier for mouse modeling
Authors: Danilo Maddalo
Journal: Cancer Research (2015)

Abstract Introduction: Chromosomal rearrangements are often detected in several types of cancer and result in expression of aberrant genes with oncogenic functions. In spite of their importance in tumor formation, modeling such rearrangements has been proven challenging and requires heavy and long germline manipulation. Purpose of the study: in this study we propose to induce chromosomal rearrangements in vivo by delivering the CRISPR/Cas9 system making use of viral vectors. Experimental procedures: for in vitro studies we transfected NIH/3T3 cells with plasmids expressing the Cas9 protein and the specific sgRNA. For in vivo delivery of the CRISPR/Cas9 system to the lung of adult mice we made use of Adenoviral vectors containing the Cas9 and two sgRNAs expressed under the control of two independent U6 promoters. Imaging of the lungs was performed with μCT scan. Results: two sgRNAs to direct the endonuclease Cas9 to the intron 19 of Alk and the intron 14 of Eml4 to induce the Eml4-Alk inversion were designed to induce Eml4-Alk inversion, detected in a subset of patients with non-small cell lung cancer (NSCLC). Co-delivery of the sgRNAs and the Cas9 resulted in the expected rearrangements, indicating that two sgRNAs and the endonuclease are sufficient to induce chromosomal rearrangements in vitro. For in vivo delivery to the lung of adult mice, we generated an adenoviral system for the concomitant delivery of the Cas9 and the two sgRNAs (Ad-EA) or the Cas9 alone (Ad-Cas9). Within 8 weeks post-infection with Ad-EA, mice developed lung adenomas while mice infected with Ad-Cas9 were tumor free. All the tumors carried the genomic inversion Eml4-Alk and were negative for p63 and positive for TTF-1 resembling the histological feature of NSCLC. Finally we tested the sensitivity of the tumors to the ALK/MET inhibitor crizotinib, used in therapy for the treatment of ALK+ NSCLC. Radiological and histological analysis showed in all cases tumor regression, indicating that our CRISPR-induced mouse model closely resembles human NSCLC. Conclusion: In conclusion the strategy here presented expands significantly our possibility of modeling cancers driven by chromosomal rearrangements and represents an opportunity to test novel targeted therapies and thee mechanisms leading to drug resistance. Citation Format: Danilo Maddalo. In vivo chromosomal engineering with the CRISPR/Cas9 model: a new frontier for mouse modeling. [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-131. doi:10.1158/1538-7445.AM2015-LB-131
Abstract IA13: Deconvoluting the molecular circuitry of cancerous cells with high-throughput experimentation
Authors: Lawrence Lum
Journal: Cancer Research (2015)

Abstract Developmentally important signal transduction pathways such as those controlled by the secreted Wnt and Hedgehog (Hh) ligands are frequently exploited in cancerous cells to promote unfettered growth. We describe functional and chemical genomics-based efforts to recover actionable mechanisms sustaining cancer-associated Wnt and Hh signaling. Our findings extend the portfolio of druggable enzymes with anti-cancer relevance and reveal novel prosurvival mechanisms in cancerous cells. Citation Format: Lawrence Lum. Deconvoluting the molecular circuitry of cancerous cells with high-throughput experimentation. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA13.
Molecular prognostic markers in advanced gastric cancer: Correlative study in the Japan Clinical Oncology Group trial JCOG9912.
Authors: Y. Yamada, J. Mizusawa, A. Takashima, K. Nakamura, Y. Tsuji, Y. Suzuki, K. Amagai, K. Yamaguchi, K. Konishi, T. Yoshino, T. Denda, W. Koizumi, S. Ohkawa, H. Kawai, H. Kojima, H. Nishizaki, T. Nishina, A. Tsuji, H. Fukuda, N. Boku
Journal: Journal of Clinical Oncology (2011)

4021 Background: JCOG9912, a randomized phase III trial of advanced gastric cancer (AGC), revealed significant non-inferiority of S-1 to 5-FU (P<0.001); however, neither S-1 nor irinotecan plus cisplatin (IP) was superior to 5-FU (P=0.034 and 0.055, respectively) for overall survival (Lancet Oncol 2009). We correlated expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and 5 other genes related to anticancer drug metabolism or targets with disease stage and outcome in patients treated with first-line IP, S-1, or 5-FU monotherapy under controlled conditions. Methods: Blocks from endoscopic biopsy specimens of primary lesions before chemotherapy were available from 445 of 704 pts in JCOG9912. Using laser-capture microdissection and real-time RT-PCR, we categorized mRNA expression of 8 genes into low and high values relative to the median. Covariates in multivariate Cox analysis were 9 baseline characteristics and the genes with P<0.05 in univariate analysis. Results: Baseline factors of the subjects were similar over the entire JCOG9912 trial; 322 samples were assessable for ERCC1, 317 for TS, and 304 for DPD. The median values of DPD were 0.50 in diffuse type and 0.29 in intestinal type (P<0.0001) whereas for ERCC1 the median values were 1.49 and 1.18, respectively (P=0.003). Multivariate analyses showed that high ERCC1 expression correlated with poor prognosis (HR, 1.37; 95% CI, 1.08 to 1.75; P=0.010), unresectable status (HR, 1.66; 95% CI, 1.28 to 2.16, P=0.049), ≥2 metastatic sites (HR, 1.66; 95% CI, 1.28 to 2.16, P<.0001), and PS 2 (HR, 1.45; 95% CI, 1.13-1.86, P=0.003) associated with poor prognosis. High TS was not significantly associated with worse survival (HR, 1.21; 95% CI, 0.95 to 1.54; P=0.117). While OS of IP tended to be worse than S-1 in high TS (HR, 1.31), it was similar in low TS (HR, 0.97) (P for interaction=0.24). Conclusions: These correlative analyses suggest ERCC1 as an independent prognostic factor for OS after first-line treatment of AGC. Prospective studies to validate prognostic or predictive molecular markers are warranted in future personalized phase III studies.
12-Year Experience with High-Dose Rituximab-Containing Autologous Stem Cell Transplantation for SOX11-Positive Mantle Cell Lymphoma Patients in First Remission: Emerging Lymphoma-Free Survival Plateau After 3 Years,
Authors: Zaher I Chakhachiro, Rima M Saliba, Grace-Julia Okoroji, Martin Korbling, Amin M Alousi, Chitra M Hosing, Marcos De Lima, Paolo Anderlini, Uday Popat, Barry I Samuels, L. Jeffrey Medeiros, Carlos E. Bueso-Ramos, Richard Champlin, Issa F Khouri
Journal: Blood (2011)
Activity of anti-CD20-interferon-α fusion protein against human B-cell lymphomas.
Authors: G. Ngarmchamnanrith, R. E. Yamada, K. K. Steward, S. Khare, R. Sachdev, S. L. Morrison, J. Timmerman
Journal: Journal of Clinical Oncology (2011)

8047 Background: Interferon-α (IFNα) has anti-proliferative and pro-apoptotic effects against many cancers, including non-Hodgkin lymphomas (NHL), and immunostimulatory effects including activation of natural killer cells, dendritic cells, and T cell anti-tumor immunity. We recently reported the ability of an anti-CD20 antibody-IFNα fusion protein to induce apoptosis and promote in vivo eradication of CD20-expressing murine and human B cell lymphomas (C. Xuan et al, Blood 115:2864, 2010). We now report on the preclinical anti-lymphoma activity of an anti-CD20-human IFNα (anti-CD20-hIFNα) fusion protein. Methods: Anti-CD20-hIFNα was evaluated against a large panel of human B cell NHL lines representing aggressive histologies including Burkitt (Daudi, Raji, Ramos), diffuse large B cell (SUDHL-4, OCI-Ly2, OCI-Ly3, OCI-Ly19, HBL-1, RC-K8), and mantle cell (Granta-519) lymphomas. Cell proliferation was measured by [3H]-thymidine incorporation, and ADCC by LDH release using peripheral blood mononuclear cell effectors. NHL xenografts Daudi, Raji, and Namalwa were grown in SCID mice. Rituximab was compared to equimolar doses of fusion protein in each assay. Results: Against IFN-sensitive CD20-negative tumor cells, anti-CD20-hIFNα had attenuated bioactivity (10-15% that of recombinant IFNα). Anti-CD20-hIFNα fusion protein induced stronger direct growth inhibition than rituximab (23.3-93.1% vs. 0.0-39.8%), particularly against Burkitt (44.7-93.1% vs. 0.0-10.4%) and germinal center-type diffuse large B cell (59.0-88.8% vs. 10.5-39.8%) NHLs. ADCC activity of fusion protein against Daudi, Ramos, and Raji cells was identical to that of rituximab. Against established human NHL xenografts (Daudi, Raji, and Namalwa), fusion protein achieved improved survival compared to rituximab. Conclusions: Anti-CD20-hIFNα fusion protein has substantially stronger direct anti-proliferative effects than rituximab against human lymphomas, and retains potent ADCC activity. Fusion protein was also superior to rituximab in vivo against multiple human NHL xenografts. These results support the further development of anti-CD20-hIFNα fusion protein for treatment of B cell malignancies.