tbuckley/cabot-search huggingface dataset:
Abstract 1659: The non-cardiotoxic anticancer drug pixantrone targets topoisomerase II
Authors: Brian B. Hasinoff, Xing Wu, Daywin Patel, Jack C. Yalowich
Journal: Cancer Research (2015)

Abstract Pixantrone is a new non-cardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones such as doxorubicin and mitoxantrone. Pixantrone is approved in the EU for the treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanisms of its anticancer activity and its lack of cardiotoxicity. The reduced cardiotoxicity of pixantrone compared to doxorubicin may be due to the fact that it did not bind iron(II) or iron(III). Thus, unlike doxorubicin it would not be able to induce iron-based oxidative stress in the heart. Pixantrone did, however, form a weak complex with Cu(II). Pixantrone was 10-fold less damaging to neonatal rat myocytes than doxorubicin as measured by LDH release. As measured by EPR spectrometry pixantrone generated about two-fold higher levels of its semiquinone free radical than doxorubicin in the hypoxanthine-xanthine oxidase reducing system. Conversely, in intact K562 cells under nitrogen, doxorubicin produced much more semiquinone radical than pixantrone. The reduced myocyte toxicity and semiquinone-forming ability in K562 cells compared to doxorubicin may be due low cell accumulation of dicationic pixantrone. Multidrug resistant Pgp- (ABCB1) overexpressing MDCK/MDR cells were 40-fold cross resistant to pixantrone, compared to parental cells. Pixantrone bound to DNA much more strongly than doxorubicin as determined in a DNA melting point assay. Pixantrone targeted topoisomerase II as evidenced by its ability to inhibit kDNA decatenation, to produce linear double-stranded DNA in a pBR322 DNA cleavage assay, and to form covalent topoisomerase II-DNA complexes in a cellular ICE assay. Pixantrone was 3-fold cross-resistant to K562-derived etoposide-resistant cells. DNA double strand breaks produced by pixantrone assessed in a cellular γH2AX assay were also characteristic of a topoisomerase II-targeted drug. These results support the conclusion that pixantrone displays characteristics that are consistent with targeting topoisomerase II. Support: CIHR; a Canada Research Chair in Drug Development; R01 CA090787. Citation Format: Brian B. Hasinoff, Xing Wu, Daywin Patel, Jack C. Yalowich. The non-cardiotoxic anticancer drug pixantrone targets topoisomerase II. [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 1659. doi:10.1158/1538-7445.AM2015-1659
Successful Treatment of Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PCNS-PTLD) with Zidovudine (AZT), Ganciclovir (GCV), Rituximab and Dexamethasone: A Single-Institution Case Series
Authors: Ludmila Katherine Martin, Mark E Lustberg, Fengting Yan, John T. Patton, Pierluigi Porcu, Gerard Nuovo, Robert Cavaliere, Robert A. Baiocchi
Journal: Blood (2011)
SOCS1 Mutation Subtypes Predict Divergent Outcomes in DLBCL Patients
Authors: Jochen K Lennerz, Birgit Schif, Christian W Kohler, Stefan Bentink, Markus Kreuz, Ingo Melzner, Lorenz Trümper, Markus Löffler, Rainer Spang, Peter Moeller
Journal: Blood (2012)
Marrow Fibrosis in Myelodysplastic Syndromes - Its Significance in the Context of the WHO Classification of Disease and the International Prognostic Scoring System.
Authors: Guntram Buesche, Arnold Ganser, Ludwig Wilkens, Brigitte Schlegelberger, Hartmut Hecker, Axel Georgii, Hans H. Kreipe
Journal: Blood (2004)
Providing Unrestricted Access to Prenatal Testing Does Not Translate to Enhanced Autonomy
Authors: Vardit Ravitsky, Francois Rousseau, Anne-Marie Laberge
Journal: The American Journal of Bioethics (2016)

In “A Framework for Unrestricted Prenatal Whole-Genome Sequencing: Respecting and Enhancing the Autonomy of Prospective Parents,” Chen and Wasserman (2017) argue in favor of an unrestricted albeit ...
89. Expanding the Toolkit of Protease-Activatable Viruses to Optimize Their Versatility and Efficiency
Authors: Caitlin Guenther, Michelle Ho, Annicka Evans, Paul Chariou, Momona Yamagami, Michael Lam, Junghae Suh
Journal: Molecular Therapy (2016)

Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viral vectors. However, its wide adoption as a safe and effective gene therapy treatment for disease may rely on targeting the vector to deliver transgenes to desired cell populations. To this end, our group has developed a protease-activatable virus (PAV) based on AAV that responds to elevated protease activity commonly found in many diseased tissue microenvironments. Small peptide "locks" were inserted into the viral capsid near its primary receptor binding domain, interfering with the virus-cell receptor interaction and preventing binding and transduction. The peptide locks are flanked by two proteolytically cleavable peptides, which are cleaved off in the presence of matrix metalloproteinases (MMPs), restoring virus-receptor interaction and allowing transduction to resume. Cleavage sequences were chosen from literature based on well-characterized linear peptide substrates. Initial testing demonstrated the desired MMP-activated cellular binding and transduction behavior, but it was discovered that cleavage efficiency and transduction activity of the PAV variants were uncorrelated with the reported specificity constants of the cleavage sequences. We therefore devised several ways to tune the sensitivity and specificity of our PAV. For example, by controlling the ratio of wild type to MMP-activatable protein subunits in the self-assembling 60-mer capsid, we can modulate the level of transduction achieved by the PAVs to attain targeted gene delivery to a range of human pathologies. A new lock format was also designed to allow for more predictable kinetics. This new "linearizable" lock format is modified by replacing one of the two flanking MMP cleavage motifs with the enterokinase cleavage motif, DDDDK, on the C-terminal side of the lock. When the enterokinase-linearized PAVs (ePAVs) are pretreated with enterokinase, the peptide locks are cleaved on one side, allowing the peptides to assume a more flexible conformation protruding from the capsid. The newly linearized peptide locks are cleaved with greater efficiency and kinetics that more closely correlate with expected activity. The PAV platform was also expanded into several AAV serotypes to allow for more diverse clinical applications. Our PAVs have demonstrated targeted delivery to several cancer models, including ovarian and pancreatic cancers, as well as ischemic tissue resulting from myocardial infarction.
Abstract 2950: Epigenetic silencing BCL6B inactivates p53 signaling and causes human hepatocellular carcinoma cell resist to 5-FU
Authors: Xin Li, Jie Yu, Malcolm Brock, Qian Tao, James Herman, Ping Liang, Mingzhou Guo
Journal: Cancer Research (2015)

Abstract BCL6B is a potential tumor suppressor in human gastric cancer, but the regulation and mechanism of BCL6B in human hepatocellular carcinogenesis remain unclear. This study is to explore the epigenetic change and mechanism of BCL6B in human hepatocellular carcinoma (HCC). 14 hepatic cancer cell lines, 8 cases of normal hepatic tissue and 149 cases of HCC were employed. Semi-quantitative RT-PCR, methylation specific PCR (MSP), gene expression array, flow cytometry assay, colony formation, western blot and immunohistochemistry were used. BCL6B is methylated in 100% (14/14) of human HCC cell lines and 86.6% (129/149) of primary cancer samples. Methylation of BCL6B is associated with HBV positive (p&amp;lt;0.05). But no association was found with age, sex, tumor size, differentiation, TNM stage, recurrence and survival. Loss of BCL6B expression was found in 14 of completely methylated HCC cell lines. BCL6B was re-expressed after 5-aza-2′-deoxycytidine (5-AZA) treatment. Restoration of BCL6B expression suppressed cell proliferation, induced apoptosis and G1/S arrest in HCC cells. The expression of EGR1, a key component of p53 signaling, was increased after re-expression BCL6B in HCC cells. Re-expression of BCL6B activated P53 signaling and sensitized HepG2 and SNU449cells to 5-fluorouracil (5-FU). BCL6B is frequently methylated in human HCC and the expression of BCL6B is regulated by promoter region hypermethylation. BCL6B suppresses cell proliferation and induces apoptosis in HCC cells. BCL6B activates P53 signaling by increasing EGR1 expression in HCC. BCL6B sensitizes HCC cells to 5-FU by activating P53 signaling. Note: This abstract was not presented at the meeting. Citation Format: Xin Li, Jie Yu, Malcolm Brock, Qian Tao, James Herman, Ping Liang, Mingzhou Guo. Epigenetic silencing BCL6B inactivates p53 signaling and causes human hepatocellular carcinoma cell resist to 5-FU. [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 2950. doi:10.1158/1538-7445.AM2015-2950
A phase I, dose-escalation, multicenter study of ACT-PFK-158, 2HCl in patients with advanced solid malignancies explores a first-in-human inhibitor of glycolysis.
Authors: Rebecca Ann Redman, Paula Raffin Pohlmann, Michael R. Kurman, Gilles Tapolsky, Jason Chesney
Journal: Journal of Clinical Oncology (2015)

TPS494 Background: In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate (F2,6BP), which is an activator of 6-phosphofructo-1-kinase, a crucial step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms and dictates the rate of glycolytic flow. The vast majority of pancreatic ductal adenocarcinomas and approximately 50% of colon adenocarcinomas harbor activating mutations in Ras and these tumors have been reported to be highly glycolytic. PFK158 is a potent small molecule inhibitor of PFKFB3 that is selectively cytotoxic to Ras-transformed epithelial cells and displays broad anti-tumor activity causing ~80% growth inhibition in several mouse models of human-derived tumors and syngeneic murine models of colon cancer. Importantly, IND-enabling safety and toxicity studies have demonstrated that PFK158 is well tolerated in rats and dogs with an expected good therapeutic index, lending support for a phase 1 trial that is now underway. Methods: The primary objective of the study is to describe the dose limiting toxicity and to determine either the maximum tolerated dose or biological effective dose of PFK-158 in a “3+3” cohort-based dose escalation design that follows a modified Fibonacci scheme. Multiple secondary endpoints have been incorporated to assess the effects of PFK-158 on peripheral blood mononuclear cell F2,6BP activity and on glucose uptake using FDG-PET imaging. This trial is currently enrolling at two US sites; Cohort 1 has been completed without dose-limiting toxicity and Cohort 2 is enrolling with two subjects under treatment as of September 2014. In conclusion, PFK158 is the first-in-man and first-in-class PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: NCT02044861.
Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c
Authors: Kacey E. Rajkovich, Kristofer W. Loerwald, Carly F. Hale, Carolyn T. Hess, Jay R. Gibson, Kimberly M. Huber
Journal: Neuron (2016)
Abstract 4738: Maximize recovery of quality nucleic acid from formalin-fixed paraffin-embedded tissue samples using a novel, flexible purification technology
Authors: Doug Wieczorek, Brad Hook, Eric Vincent, Trista Schagat
Journal: Cancer Research (2015)

Abstract Formalin-fixed paraffin-embedded (FFPE) tissue samples are a valuable source of genetic information for gene expression and clinical research. Extraction of nucleic acid (NA) from FFPE tissues is a challenge because the fixation process results in cross-linking between proteins and nucleic acid, as well as between different strands of DNA or RNA molecules. Recent advances in sample preparation enables access to the valuable information contained within these difficult samples. We use a novel purification technology that does not rely on use of any harsh organic solvents and concentrates the NA for low volume elution on a specially designed spin column, thus maximizing concentration. Using this technology, we examined several aspects of the purification protocol for flexibility and adaptability: effect of de-crosslinking time on the quality and length of nucleic acids released from diverse FFPE tissues, effect of overnight storage between lysis and extraction steps, and whether the technology could be adapted to extract both DNA and RNA from the same FFPE tissue sample. Yield and quality of isolated nucleic acids were examined by absorbance, fluorescent binding dye, and real-time qPCR and RT-qPCR. We demonstrate that amplification-based quantitation gave the best indication of the quality of NA recovered. We found that a short decrosslinking time gave significant yields, but only with longer decrosslinking, times were amplifiable yields maximized for many of the tissue types tested. Preprocessing conditions were determined that allow release of both DNA and RNA for subsequent capture and elution in separate spin columns, enabling recovery of high quality DNA and RNA from the same sample in separate tubes. In this study, we demonstrate that de-crosslinking conditions can affect the recovery of amplifiable nucleic acid from FFPE samples and that RNA and DNA can be recovered from the same FFPE sample using an optimized protocol. Citation Format: Doug Wieczorek, Brad Hook, Eric Vincent, Trista Schagat. Maximize recovery of quality nucleic acid from formalin-fixed paraffin-embedded tissue samples using a novel, flexible purification technology. [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 4738. doi:10.1158/1538-7445.AM2015-4738
Military-civilian cooperative emergency response to infectious disease prevention and control in China
Authors: Hui Ma, Ji-Ping Dong, Na Zhou, Wei Pu
Journal: Military Medical Research (2016)

In recent years, the incidence of severe infectious diseases has increased, and the number of emerging infectious diseases continues to increase. The Chinese government and military forces have paid a great deal of attention to infectious disease prevention and control, and using military-civilian cooperation, they have successfully prevented numerous severe epidemic situations, such as severe acute respiratory syndrome (SARS), influenza A (H1N1), avian influenza H5N1 and H7N9, and Ebola hemorrhagic fever, while actively maintained public health, economic development, and national construction. This paper focuses on the mechanisms of the military-cooperative emergency response to infectious diseases--the joint working mechanism, the information-sharing mechanism, the research collaboration mechanism, and the joint disposal mechanism--and presents a sorted summary of the practices and experiences of cooperative emergency responses to infectious diseases. In the future, the Chinese military and the civilian sector will further strengthen the cooperative joint command system and emergency rescue force and will reinforce their collaborative information-sharing platform and technical equipment system to further improve military-civilian collaborative emergency infectious diseases disposal, advance the level of infectious disease prevention and control, and maintain public health.
Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials
Authors: Charles Peterfy, Vibeke Strand, Lu Tian, Mikkel Østergaard, Ying Lu, Julie DiCarlo, Peter Countryman, Atul Deodhar, Robert Landewé, Veena K Ranganath, Orrin Troum, Philip G Conaghan
Journal: Annals of the Rheumatic Diseases (2016)

In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray.Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses.Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively).Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.
Abstract 1939: Discovery and proteogenomic investigation of genetic variants in human cancers
Authors: Kuan-lin Huang, Jaiyin Wang, Song Cao, Mingchao Xie, Reyka Jayasinghe, Jie Ning, Michael McLellan, Michael Wendl, Adam Scott, Kimberly Johnson, Sherri Davies, David Fenyö, Reid Townsend, Feng Chen, Jeffrey Parvin, Matthew Ellis, Li Ding
Journal: Cancer Research (2015)

Abstract A significant fraction of cancers have a heritable component, and require an interplay between somatic and germline variants. Common and rare germline variants have been investigated by previous GWAS and family based studies. However, a comprehensive analysis of both somatic and germline variants in cancer using high throughput sequencing data to discover genetic variants of functional relevance is lacking. Herein, we investigated the potential role of somatic and germline variants from over 20 major cancer types from large-scale studies such as TCGA and ICGC and discovered thousands of somatic and germline variants in cancer genomes. To link these genetic variants to cancer phenotypes, we analyzed the proteomics data in breast, ovarian and colorectal cancers generated by the Clinical Proteomic Tumour Analysis Consortium (CPTAC) using a PepScan pipeline that can detect whether a genomic variant is observed at the peptide level. The pipeline incorporated QUILTS to construct patient-specific protein database and MS-GF+ to identify peptide sequences in the database from MS spectra. Our analysis validated roughly 2% of non-synonymous genetic variants in peptides with matched spectra. We correlated the effect of genetic mutations on proteomic subtypes based on global protein expression levels. Additionally, we assessed the role of genetic variations in kinase genes using phosphoproteome profiles, and identified downstream markers that may be candidate targets for diagnosis or treatment. This analysis also helped us prioritize kinase variants that are likely functional candidates for experimental validation. In conclusion, the comprehensive study of genetic variants utilizing an integrated proteogenomic approach revealed genetic variants with potential functional impacts in cancer. Citation Format: Kuan-lin Huang, Jaiyin Wang, Song Cao, Mingchao Xie, Reyka Jayasinghe, Jie Ning, Michael McLellan, Michael Wendl, Adam Scott, Kimberly Johnson, Sherri Davies, David Fenyö, Reid Townsend, Feng Chen, Jeffrey Parvin, Matthew Ellis, Li Ding. Discovery and proteogenomic investigation of genetic variants in human cancers. [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 1939. doi:10.1158/1538-7445.AM2015-1939
Abstract 2012: Accurate measurement of free and complexed PSA concentrations in serum of women using a novel technology with fg/mL sensitivity
Authors: Galina N. Nikolenko, Martin K. Stengelin, Laukik Sardesai, Eli N. Glezer, Jacob N. Wohlstadter
Journal: Cancer Research (2015)

Abstract Measurement of free and complexed PSA (prostate specific antigen; complexed with ACT) in certain patient groups such as prostatectomy patients and women at risk of breast and ovarian cancer has been limited by the sensitivity of current immunoassay technology (5-30 pg/mL for common clinical analyzers). Fifth generation assays for total PSA with detection limits of 0.05 to 0.1 pg/mL have been described (McDermet 2009; Thaxton 2009; Wilson 2011). We developed a next-generation assay format based on MSD's MULTI-ARRAY® electrochemiluminescence technology with detection limits of 2 fg/mL (0.002 pg/mL) for complexed PSA (cPSA) and 20 fg/mL for free PSA (fPSA), requiring only 25 μL of serum or plasma per measurement. Assays were calibrated against the WHO standards 96/668 (free PSA) and 98/670 (90% complexed, 10% free PSA). The dynamic range of both assays was three to four orders of magnitude. Typical intra-plate coefficients of variation ranged from 5% to 15%. LLOQ's of cPSA and fPSA assays were 5 fg/mL and 55 fg/mL, respectively. Spike recovery and dilution linearity were between 80% and 120%. Approximately 100 serum samples from women were evaluated. Free PSA was detectable in 95% of samples and cPSA was detectable in all samples. Multiple literature reports indicate that free PSA might be a marker for early detection of breast cancer; however, the concentrations of many samples were close to or below the detection limits of the assays used for the studies. We tested 48 serum samples from patients with breast cancer and 37 serum samples from apparently healthy women. As the table below shows, there was no clear difference between PSA concentrations in cases and controls. Free PSA [fg/mL] (Median, IQR)cPSA [fg/mL] (Median, IQR)Free/cPSA (Median, IQR)Apparently Healthy (n = 37)150 (80-260)560 (210-1,500)0.29 (0.18-0.73)Breast Cancer (n = 48)90 (50-260)180 (90-480)0.36 (0.17-0.77)Breast Cancer, ER positive (n = 10)160 (80-660)170 (120-13,000)0.62 (0.22-1.8)Breast Cancer, HER2 positive (n = 10)160 (50-290)460 (110-8,300)0.10 (0.03-0.44)Breast Cancer, triple negative (n = 10)90 (40-370)140 (50-300)0.68 (0.34-1.9) In conclusion, we developed a next-generation assay format that is 100 to 1000 times more sensitive than the currently available clinical PSA assays. This enables accurate determination of free PSA and cPSA concentrations in the serum of females. Citation Format: Galina N. Nikolenko, Martin K. Stengelin, Laukik Sardesai, Eli N. Glezer, Jacob N. Wohlstadter. Accurate measurement of free and complexed PSA concentrations in serum of women using a novel technology with fg/mL sensitivity. [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 2012. doi:10.1158/1538-7445.AM2015-2012