tbuckley/cabot-search huggingface dataset:
Abstract P6-14-06: Prospective Testing of Three Different Gene-Signatures for Patient Selection for Dasatinib Therapy in Metastatic Breast Cancer
Authors: L Pusztai, S Moulder, J Litton, V Valero, N Ueno, A Melhem-Bertrandt, PK Morrow, K Dotter, D Mattair, L Strauss, GN Hortobagyi, Y Qi, WF. Symmans
Journal: Cancer Research (2010)

Abstract Background: Several gene signature-based predictors of response to targeted drugs have been proposed in the literature but none has been prospectively tested as patient selection tools in the clinic. The goal of this trial is to assess the positive predictive value of 3 conceptually different multi-gene signatures as predictors of response to the multitargeted kinase inhibitor dasatinib. Methods: This clinical trial requires biopsy of a metastatic lesion for gene expression profiling and employs a parallel, multi-arm, two-step, phase II design. Three markers are assessed including a (i) cell-line derived dasatinib-sensitivity signature, (ii) a src-pathway activity signature and (iii) a dasatinib target index calculated as the weighted average expression of all known dasatinib targets. Only markerpositive patients are treated with dasatinib 100 mg po daily and each marker arm is considered as a separate study with early stopping rules for futility (minimum sample size 9, maximum sample size 40/marker arm). A predictor is considered worthy of further study if the clinical benefit rate (i.e. positive predictive value) is ≥25%. Results: Forty seven patients were accrued from July 2009 through June, 2010, 49 biopsies were performed (soft tissues n=31, liver n=8, bone n=3, lung n=1, adrenal gland n=1), 6 samples had poor cellularity and 3 failed array QC. There was no patient recall, hospitalization or emergency room visit due to biopsy procedure. The median time from biopsy to genomic prediction result was 5 days (range 3-7). Twenty three (57%) patients had positive result for at least 1 predictor (5 were positive for 2) and 20 are receiving therapy (3 withdraw or progressed before therapy began). Responses as of June 2010; Target index arm (n=9): 5 PD (progressive disease), 4 SD (3 stable disease at 8 weeks 1 SD at 16 weeks); SRC Pathway arm (n=5): 3 PD, 2 SD at 8 weeks; Cell line predictor arm (n=6): 2 PD, 1 SD at 8 weeks, 3 not yet reached response evaluation. None of the 3 predictive marker arms have met early stopping yet and accrual is ongoing. Conclusion: Gene-expression signature based patient selection for targeted therapy is feasible and FNA biopsies of metastatic lesions for genomic testing are safe. Updated efficacy results will be reported. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-06.
CANDIDACY FOR DEVICE CLOSURE OF COMPLEX MUSCULAR VENTRICULAR SEPTAL DEFECTS: NOVEL APPLICATION OF RAPID PROTOTYPING AND VIRTUAL 3D MODELS DERIVED FCARDIAC CT AND MRI
Authors: Puneet Bhatla, Sujata Chakravarti, Shi-Joon Yoo, Omar Thabit, Doff McElhinney, Achiau Ludomirsky
Journal: Journal of the American College of Cardiology (2015)
Hard-Water Syndrome
Authors: Richard M. Freeman, Richard L. Lawton, Mary A. Chamberlain
Journal: New England Journal of Medicine (1967)

HEMODIALYSIS has become an increasingly common therapeutic maneuver during the past decade. Concomitant with the more frequent use of the artificial kidney has been an increased awareness of potential hazards from this therapy. Many of the direct and indirect complications of chronic hemodialysis have recently been reviewed by Schreiner et al.1 Reports of dialysis-induced hypercalcemia and hypermagnesemia are rare. Whether this complication of hemodialysis is distinctly uncommon, or merely infrequently recognized, has not been established. Recently, failure of the water softener to function produced hypercalcemia and hypermagnesemia in our dialysis patients. It is our purpose to describe the symptoms resulting . . .
A4.04 A robust assay for fast quantification of multipotential stromal cells in bone marrow aspirates
Authors: JJ El-Jawhari, E Jones, PV Giannoudis
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Bone marrow (BM) aspirate has been used recently as a source of multipotential stromal cells (MSCs) for regenerative treatments of musculoskeletal diseases such as osteoarthritis.<sup>1</sup> However the doses of implanted MSCs remain poorly controlled. The numbersof BM MSCs&nbsp;are&nbsp;very low and widely variable depending on the aspiration technique<sup>2,3</sup> and donor-related factors.<sup>4</sup> Thus, there is a crucial need for a fast quantification method of BM MSCs that is suitable for use within the limited intraoperative/clinic timeframe. <h3>Materials and methods</h3> Flow-cytometer, Attune was used to enable automated counting of MSCs in BM aspirates (n = 40, 20 males and 20 females, age range 22–80, average 48 years old). For ‘gating out’ non-nucleated cells, Vybrant Ruby dye was employed. The staining concentration, temperature and time for antibodies against CD45 and CD271 to identify BM MSCs were optimised to reduce the staining time to only 5 min. The MSC numbers obtained by this method were compared to longer flow-cytometer-based method 3 and standard colony forming unit-fibroblast (CFU-F) assay. <h3>Results</h3> Within a total time of 15–20 min, we have successfully optimised an assay to quantify MSCs in only 100 µl of BM aspirate. This simple method was performed without a need to lyse red cells or to include volumetric counting beads. Importantly, the numbers of MSCs obtained using Attune (median 3871 MSCs/ml, range: 96–20,992) were significantly correlated with the counts obtained using LSRII-based method (median 3889 MSCs/ml, range: 87–20,471, r = 0.94, <i>p</i> &lt; 0.0001) or using CFU-F assay (median 128 colonies/ml, range: 3–900, r = 0.72,&nbsp;<i>p</i>&nbsp;= ﻿0.0004). <h3>Conclusions</h3> We developed a very fast assay for automated counting of MSCs in BM aspirates. This robust assay is ideal to be applied clinically prior to the use of BM aspirates helping to choose and evaluate the dose of MSCs and to improve the outcome of the regenerative therapies. <h3>References</h3> Veronesi F, Giavaresi G, Tschon M, ﻿﻿<i>et al</i>.&nbsp;Clinical Use of Bone Marrow, Bone Marrow Concentrate, and Expanded Bone Marrow Mesenchymal Stem Cells in Cartilage Disease. Stem cells Dev.&nbsp;2013;22:181–192 Hernigou P, Homma Y, Flouzat Lachaniette CH, <i>et al</i>. Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Int Orthop.&nbsp;2013;37:2279–2287 Cuthbert R, Boxall SA, Tan HB, <i>et al</i>. Single-platform quality control assay to quantify multipotential stromal cells in bone marrow aspirates prior to bulk manufacture or direct therapeutic use. Cytotherapy. 2012;14:431–440 Muschler GF, Nitto H, Boehm CA, <i>et al</i>. Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res. 2001;19:117–125
In Vivo Generation of Dendritic Cells by Intramuscular Codelivery of FLT3 Ligand and GM-CSF Plasmids
Authors: Yoav Peretz, Zheng Frank Zhou, Fawaz Halwani, Gérald J. Prud'homme
Journal: Molecular Therapy (2002)

Dendritic cells (DCs) are the major cells responsible for the uptake and the transport of antigens to regional lymphoid tissues and for the presentation of antigenic peptides to T cells. They are highly effective in immunotherapy. However, in lymphoid and other tissues, DCs constitute only a small population and are difficult to isolate in large numbers. Our objective was to devise a method with which to rapidly expand splenic DCs in vivo. We accomplished this by intramuscular injection of plasmids encoding mouse granulocyte-macrophage colony stimulating factor (GM-CSF) and fms-like tyrosine kinase 3-ligand (FLT3-L). Gene transfer was amplified by electroporation. Both cytokine vectors significantly increased DC numbers, but they were more effective in combination. When either control plasmid (Blank), or FLT3-L or GM-CSF expression plasmids were injected individually, the mean numbers of CD11c(+)/MHC II(+) DCs in spleen cell suspensions were, respectively, 6, 11, and 23 million. When FLT3-L and GM-CSF plasmids were codelivered, this increased to 36 million. Peak levels occurred 7 days postinjection of DNA. To further characterize these DCs, we stained them with myeloid (CD11b, F4/80)- and lymphoid (CD8alpha)-related markers. FLT3-L cDNA favored lymphoid DC expansion and GM-CSF cDNA favored myeloid DC expansion, whereas combined treatment expanded both types with a myeloid predominance. We confirm the ability of these DCs to present antigen to CD4(+) T cells and to stimulate in mixed lymphocyte cultures. We demonstrate that DCs can be rapidly expanded by this simple gene transfer method, which has numerous potential applications.
Abstract 685: PTX-008 antiproliferative effects in cancer cells are mediated though galectin-1 inhibition and MAPK-dependent G2/M cell cycle arrest
Authors: Lucile Astorgues-Xerri, Katiuscia Bonezzi, Maria Serova, Ivan Bieche, Maria E. Riveiro, Esteban Cvitkovic, Kay Noel, Raffaella Giavazzi, Giulia Taraboletti, Eric Raymond, Sandrine Faivre
Journal: Cancer Research (2011)

Abstract Background. Galectin-1 is a multifunctional protein involved in various aspects of tumorigenesis and has been described as a promising cancer target. PTX-008, a small molecule interacting with galectin-1, is currently investigated as an anticancer agent in various preclinical models. The aim of the present study was to study molecular mechanism associated with the cellular effects of PTX-008 in cancer cells. Materials and Methods. Antiproliferative effects were evaluated in a panel of 20 human cancer cell lines by MTT assay. Effects of PTX-008 on cell cycle and protein expression were assessed by flow cytometry and western blot analysis, respectively. mRNA expression was evaluated with qRT-PCR. Results. PTX-008 induces potent antiproliferative effects in our panel of cell lines at concentrations ranging 1-27µM. Interestingly, exposure to PTX-008 for &amp;gt;48 hours inhibits galectin-1 protein level. Furthermore, we have found a clear correlation between low expression of mRNA and proteins levels of galectin-1 and PTX-008 sensitivity in a panel of 20 cancer cell lines (R2=0.59, p&amp;lt;0.05). However, inhibition of galectin-1 by shRNA in SQ20B cells led to no significantly changed PTX-008 antiproliferative activity suggesting that PTX-008 may not exclusively act thought galectin-1 protein down expression. Previous studies showed that galectin-1 might interact with H-RAS and K-RAS, regulating the magnitude of MAPK signal output. In RAS/RAF wild-type SQ20B cells, exposure to 3µM PTX-008 for &amp;gt;5 hours inhibits pERK1/2, pAKT, and pS6, suggesting the important role of MAPK and AKT/mTOR in downstream signalling of galectin-1 in our model. Cell cycle analysis of SQ20B treated with PTX-008 showed a dose-dependent accumulation in G2/M phase without apoptosis induction. Consistent with the inhibition in G2 to mitosis transition, PTX008-induced cell cycle changes were associated with a decrease of Wee1 and an increase of Cdc2 phosphorylation but no inactivation of cdc25C. Inhibition of MAPK with UO126 abolished PTX-008 inhibition of cdc2 reinforcing the important role of MAPK-inhibition in cellular effects of PTX-008. Conclusion. Our findings show that PTX-008 inhibits cancer cells proliferation by interacting with galectin-1, blocking G2/M transition, and inhibiting MAPK signalling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 685. doi:10.1158/1538-7445.AM2011-685
Abstract 5397: Human mesenchymal stem cell-based cell carrier for tumor-homing delivery of replicating retrovirus vectors in glioblastoma models
Authors: Kei Hiraoka, Akihito Inagaki, Christopher R. Logg, Shuichi Kamijima, Kam Man Hui, Frank C. Marini, Noriyuki Kasahara
Journal: Cancer Research (2011)

Abstract In previous studies, we have demonstrated that replicating murine leukemia virus (RMLV)-based vectors can achieve highly efficient in vivo delivery of prodrug activating genes in glioblastoma models, with infection restricted to actively dividing tumor cells without spread to extratumoral sites, resulting in significantly prolonged survival upon prodrug administration; this approach is now being tested in a multi-center clinical trial. RMLV vectors can eventually spread to almost all actively dividing GBM cells over time. We are seeking to further improve the efficiency of this novel therapeutic strategy by engineering human mesenchymal stem cells (MSC) to function as RMLV vector producer cells (MSC-VPC). Primary MSC have been shown to actively migrate through tumor masses beyond the immediate injection site and track to diffusely infiltrating tumor foci. In the present study, we developed optimized methods for engineering MSC-VPC, and we then further examined tumor transduction efficiency of MSC-mediated RMLV delivery, and how this delivery method might affect vector replication kinetics in vivo. First, we evaluated the vector productivity of MSC-VPC in U87 human glioblastoma cells in vitro. Primary human MSCs were infected with RMLV vector AC3-GFP, expressing the GFP marker gene. These MSC were then re-plated at very low density onto a monolayer of naïve U87 glioma cells, and fluorescence was monitored over time. Under the fluorescent microscope, progressive spread of the RMLV vector released from the MSCs could be confirmed, as indicated by increasing GFP(+) U87 cells over time. Next, we tested MSC-VPC in intracranial U87 tumor models in vivo. Five days after intracranial tumor cell implantation, 1E3 transduction units (TU) of AC3-GFP vector or 5E3 MSC-VPC (∼20% pretransduced with AC3-GFP) were stereotactically injected at the tumor site. Tumors were harvested and digested on day 9 for FACS analysis to detect GFP expression. While the highest percentage of GFP(+) cells was 28.6% in the vector supernatant-treated group, up to 45% transduction efficiency was achieved in the MSC-VPC group. These results suggest the use of MSCs as tumor-homing carriers may be provide more efficient delivery of RMLV vectors in human glioma models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5397. doi:10.1158/1538-7445.AM2011-5397
Food Fallacies and Blood Sugar
Authors: Phyllis A. Crapo, Jerrold M. Olefsky
Journal: New England Journal of Medicine (1983)

For many years the dietary treatment of diabetes mellitus has been based on the belief that there are two major classifications of carbohydrates: simple and complex. It has been believed that simple sugars (glucose, sucrose, and fructose) are rapidly absorbed and cause a relatively large rise in blood sugar, whereas complex carbohydrates (or starches, such as those found in rice, potatoes, and legumes) are digested and absorbed slowly and result in smaller increases in blood sugar. Consequently, it has been recommended for years that diabetic patients avoid simple sugars; this recommendation usually referred only to refined sugars, since simple sugars . . .
Abstract 2967: The p53 target gene TRIM22 colocalizes with the centrosome independently of cell cycle phase
Authors: Jessica Petersson, Per Lönnbro, Anna-Maria Herr, Matthias Mörgelin, Urban Gullberg, Kristina Drott
Journal: Cancer Research (2010)

Abstract TRIM22 (Staf50) is an interferon (IFN)-inducible protein as well as a p53 target gene. The specific molecular function of TRIM22 is largely unknown, but TRIM22 is suggested to play a role in viral defense by restriction of viral replication. Furthermore, TRIM22 may function as an ubiquitin E3 ligase, targeting proteins for degradation. TRIM22 is highly expressed in lymphoid tissues as well as in peripheral blood leukocytes and in the ovary and lung. TRIM22 belongs to the TRIM family of proteins, named based on a characteristic tripartite-motif (TRIM), including a RING-finger, one or two B-boxes and a coiled-coil domain. The TRIM family consists of more than 70 proteins, implicated in diverse biological processes such as apoptosis, cell proliferation, viral defense and ubiquitylation. Several TRIM family members are involved in cancer. Interestingly, TRIM proteins have been suggested to identify specific cell compartments by means of multimerization. There have previously been conflicting reports regarding the subcellular localization of exogenous TRIM22. Utilizing immunoflourescence and subcellular fractionation, we show here that endogenous TRIM22 is localized to both nucleus and cytosol in the human osteosarcoma cell line U2OS. Furthermore, the same localization pattern is present in human peripheral blood mononuclear cells (PBMCs), an environment more relevant to its physiological function. Moreover, we demonstrate a colocalization of TRIM22 with the centrosomes in U2OS cells as well as in PBMCs, and show that this colocalization is independent of cell cycle phase, utilizing the centrosome markers gamma-tubulin, aurora A and pericentrin. The centrosomal localization was confirmed with electronic microscopy, suggesting TRIM22 to be localized in the pericentriolar material (PCM) and not at any specific site at the centrioles. Additionally, the colocalization with centrosomes appears to be independent on the microtubule network as shown by the microtubuli destabilizing agent nocodazole. Centrosomes are essential organelles, vital for mitosis and organization of the microtubule network as well as providing sites for viral replication, viral assembly and protein degradation. Our data suggest that centrosomal TRIM22 may have important functions in these processes. However, further studies are required to confirm this notion. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2967.
Abstract 5150: What is in control of DNA replication timing.
Authors: Yevgeniy Gindin, Paul S. Meltzer, Sven Bilke
Journal: Cancer Research (2013)

Abstract The initiation of DNA replication at specific sites in the genome is known to be far from perfect, where known initiation sites may or may not fire in a given single cell during specific cell cycle. At the same time, from larger scale perspective, one finds that the timing of DNA replication is highly orchestrated, where specific regions in the genome are copied at specific, reproducible time points throughout S-phase. In an attempt to reconcile these two somewhat discordant observations, many researchers have assumed that a yet unknown, active regulatory mechanism in the cell is responsible for coordinating replication timing. Here we present a mechanistic explanation for genome-wide replication timing patterns. Our model is purely stochastic, does not contain any active control components and reproduces existing replication timing data with extreme fidelity (correlation &amp;gt; 0.9, about the same as the correlation between technical replicates of the experiment). The main findings of our work are • Existence of reproducible genome-wide replication patterns do not logically necessitate existence of a complex, active control system in the cell • Integrative analysis of recently released ENCODE data identifies semi-local chromatin structure as the main determinant of replication timing • Plasticity of replication timing across different cell types are a direct consequence of changes in the chromatin structure between the different cell differentiation states • Replication timing is a “systems” phenomenon emerging from the collective action of many uncoordinated, stochastic replication initiation sites. Replication timing cannot be understood by investigating individual initiation sites: deleting up to 30% of high probability initiation sites does not significantly change replication timing Citation Format: Yevgeniy Gindin, Paul S. Meltzer, Sven Bilke. What is in control of DNA replication timing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5150. doi:10.1158/1538-7445.AM2013-5150
Inheritance and Drug Response
Authors: Richard Weinshilboum
Journal: New England Journal of Medicine (2003)

he promise of pharmacogenetics, the study of the role of in heritance in the individual variation in drug response, lies in its potential to identify the right drug and dose for each patient. Even though individual differences in drug response can result from the effects of age, sex, disease, or drug interactions, genetic factors also influence both the efficacy of a drug and the likelihood of an adverse reaction. 1-3 This article briefly reviews concepts that underlie the emerging fields of pharmacogenetics and pharmacogenomics, with an emphasis on the pharmacogenetics of drug metabolism. Although only a few examples will be provided to illustrate concepts and to demonstrate the potential contribution of pharmacogenetics to medical practice, it is now clear that virtually every pathway of drug metabolism will eventually be found to have genetic variation. The accompanying article by Evans and McLeod 4 expands on many of the themes introduced here. Once a drug is administered, it is absorbed and distributed to its site of action, where it interacts with targets (such as receptors and enzymes), undergoes metabolism, and is then excreted. 5,6 Each of these processes could potentially involve clinically significant genetic variation. However, pharmacogenetics originated as a result of the observation that there are clinically important inherited variations in drug metabolism. Therefore, this article — and the examples highlighted — focuses on the pharmacogenetics of drug metabolism. However, similar principles apply to clinically significant inherited variation in the transport and distribution of drugs and their interaction with their therapeutic targets. The underlying message is that inherited variations in drug effect are common and that some tests that incorporate pharmacogenetics into clinical practice are now available, with many more to follow. The concept of pharmacogenetics originated from the clinical observation that there were patients with very high or very low plasma or urinary drug concentrations, followed by the realization that the biochemical traits leading to this variation were inherited. Only later were the drug-metabolizing enzymes identified, and this discovery was followed by the identification of the genes that encoded the proteins and the DNA-sequence variation within the genes that was associated with the inherited trait. Most of the pharmacogenetic traits that were first identified were monogenic — that is, they involved only a single gene — and most were due to genetic polymorphisms; in other words, the allele or alleles responsible for the variation were relatively common. Although drug effect is a complex phenotype that depends on many factors, early and often dramatic examples involving succinylcholine and isoniazid facilitated acceptance of the fact that inheritance can have an important influence on the effect of a drug. Today there is a systematic search to identify functionally significant variations in DNA sequences in genes that influence the effects of various drugs. 4 t
DIRECT COMPARISON OF DABIGATRAN, RIVAROXABAN, AND APIXABAN FOR EFFECTIVENESS AND SAFETY IN NONVALVULAR ATRIAL FIBRILLATION
Authors: Peter Noseworthy, Xiaoxi Yao, Lindsey R. Sangaralingham, Neena Abraham, Robert McBane, Bernard Gersh, Nilay Shah
Journal: Journal of the American College of Cardiology (2016)