bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFRvIII mCAR-Modified T-Cell Therapy Cures Mice with Established Intracerebral Glioma and Generates Host Immunity against Tumor-Antigen Loss
Authors: Sampson John H. , Choi Bryan D. , Sanchez-Perez Luis , Suryadevara Carter M. , Snyder David J. , Flores Catherine T. , Schmittling Robert J. , Nair Smita K. , Reap Elizabeth A. , Norberg Pamela K. , Herndon James E. , Kuan Chien-Tsun , Morgan Richard A. , Rosenberg Steven A. , Johnson Laura A. 
Published: December 2013

Abstract
Purpose: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues.
Experimental Design: We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma.
Results: At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIIINEG tumors, suggesting generation of host immunity against additional tumor antigens.
Conclusion: All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. Clin Cancer Res; 20(4); 972–84. ©2013 AACR.
Cellular Uptake of Imatinib into Leukemic Cells Is Independent of Human Organic Cation Transporter 1 (OCT1)
Authors: Nies Anne T. , Schaeffeler Elke , van der Kuip Heiko , Cascorbi Ingolf , Bruhn Oliver , Kneba Michael , Pott Christiane , Hofmann Ute , Volk Christopher , Hu Shuiying , Baker Sharyn D. , Sparreboom Alex , Ruth Peter , Koepsell Hermann , Schwab Matthias 
Published: December 2013

Abstract
Purpose: In addition to mutated BCR-ABL1 kinase, the organic cation transporter 1 (OCT1, encoded by SLC22A1) has been considered to contribute to imatinib resistance in patients with chronic myeloid leukemia (CML). As data are conflicting as to whether OCT1 transports imatinib and may serve as a clinical biomarker, we used a combination of different approaches including animal experiments to elucidate comprehensively the impact of OCT1 on cellular imatinib uptake.
Experimental Design: Transport of imatinib was studied using OCT1-expressing Xenopus oocytes, mammalian cell lines (HEK293, MDCK, V79) stably expressing OCT1, human leukemic cells, and Oct1-knockout mice. OCT1 mRNA and protein expression were analyzed in leukemic cells from patients with imatinib-naïve CML as well as in cell lines.
Results: Transport and inhibition studies showed that overexpression of functional OCT1 protein in Xenopus oocytes or mammalian cell lines did not lead to an increased cellular accumulation of imatinib. The CML cell lines (K562, Meg-01, LAMA84) and leukemic cells from patients expressed neither OCT1 mRNA nor protein as demonstrated by immunoblotting and immunofluorescence microscopy, yet they showed a considerable imatinib uptake. Oct1 deficiency in mice had no influence on plasma and hepatic imatinib concentrations.
Conclusions: These data clearly demonstrate that cellular uptake of imatinib is independent of OCT1, and therefore OCT1 is apparently not a valid biomarker for imatinib resistance. Clin Cancer Res; 20(4); 985–94. ©2013 AACR.
Identification of CalDAG-GEFI as an intracellular target for the vicinal dithiol binding agent phenylarsine oxide in human platelets
Authors: Kuo Chih-Yun , Wang Hui-Chun , Kung Po-Hsiung , Lu Chi-Yu , Liao Chieh-Yu , Wu Ming-Tsang , Wu Chin-Chung 
Published: December 2013

SummaryCalDAG-GEFI, a guanine nucleotide exchange factor activating Rap1, is known to play a key role in Ca2+-dependent glycoprotein (GP)IIb/IIIa activation and platelet aggregation. Although inhibition of CalDAG-GEFI could be a potential strategy for antiplatelet therapy, no inhibitor of this protein has been identified. In the present study, phenylarsine oxide (PAO), a vicinal dithiol blocker, potently prevented Rap1 activation in thrombin-stimulated human platelets without significantly inhibiting intracellular Ca2+ mobilisation and protein kinase C activation. PAO also prevented the Ca2+ ionophore-induced Rap1 activation and platelet aggregation, which are dependent on CalDAG-GEFI. In the biotin-streptavidin pull-down assay, CalDAG-GEFI was efficiently pull-downed by streptavidin beads from the lysates of biotin-conjugated PAO-treated platelets, suggesting that PAO binds to intracellular CalDAG-GEFI with high affinity. The above effects of PAO were reversed by a vicinal dithiol compound 2,3-dimercaptopropanol. In addition, CalDAG-GEFI formed disulfide-linked oligomers in platelets treated with the thiol-oxidant diamide, indicating that CalDAG-GEFI contains redox-sensitive thiols. In a purified recombinant protein system, PAO directly inhibited CalDAG-GEFI-stimulated GTP binding to Rap1. Using CalDAG-GEFI and Rap1-overexpressed human embryonic kidney 293T cells, we further confirmed that PAO abolished Ca2+-mediated Rap1 activation. Taken together, these results have demonstrated that CalDAG-GEFI is one of the targets of action of PAO, and propose an important role of vicinal cysteines for the functions of CalDAG-GEFI.
Benign FGB (148Lys→Asn, and 448Arg→Lys), and novel causative γ211Tyr→His mutation distinguished by time of flight mass spectrometry in a family with hypofibrinogenaemia
Authors: Mangos Hilda , Faed James M. , Brennan Stephen O. 
Published: December 2013

SummaryWe describe a novel procedure for the direct analysis of plasma fibrinogen by HPLC time of flight (TOF) mass spectrometry and apply it to the investigation of a family with hypofibrinogenaemia. Electrospray TOF analysis provided much higher resolution than was possible with our previous quadrupole analyser and revealed three different mass changes within the fibrinogen Bβ and γ chains of the family. It also demonstrated the actual hypofibrinogenaemia phenotype was caused by an aberrant _ chain (-23 Da) which was expressed at a diminished ratio of 0.2:1 relative to γA and co-inherited with a second coequally expressed Bβ variant (BβM /BβA, 1:1). Co-segregation was confirmed by gene analysis that showed the affected father and son had a very rare Bβ148Lys→Arg mutation (-14 Da) inherited together with a unique new γ211Tyr→His mutation (-26 Da). This latter causative substitution occurs at a site that is absolutely conserved across all fibrinogen chains and preserved across all species. TOF analysis also identified a variant B_ chain (54,186 Da) that was coequally expressed with normal Bβ chains (54,213 Da) in the unaffected mother.
Acanthoplesiops cappuccino, a new species of acanthoclinine fish from the Red Sea (Teleostei: Plesiopidae)
Authors: GILL ANTHONY C. , BOGORODSKY SERGEY V. , MAL AHMAD O. 
Published: December 2013

Acanthoplesiops cappuccino is described from the 16.4 mm SL holotype collected from Jeddah, Saudi Arabia, Red Sea. The following combination of characters distinguishes it from congeners: dorsal-fin rays XVIII,4; anal-fin rays VII,4; pectoral-fin rays 18; caudal fin not connected to last rays of dorsal and anal fins by membrane; and caudal peduncle with a pale yellowish brown bar, which extends broadly on to caudal fin. An underwater photo of the anaesthetised holotype is provided, as well as one of the freshly dead holotype and only known specimen of the similar species A. naka. Tables summarizing diagnostic characters of the six known species of Acanthoplesiops are included. n�Uhd�_u�_k congeners by possessing both rostral and maxillary barbels; having the last simple dorsal-fin ray weak and smooth; the lateral line complete, with 40–42+1 pored scales; ½7–½8/1/3½ scales in transverse line from dorsal-fin origin to pelvic-fin origin; 4½ scales between lateral line and anal-fin origin. Hypselobarbus kolus is considered a synonym of H. curmuca, which is redescribed: it is distinguished from all congeners by possessing maxillary barbels only; the last simple dorsal-fin ray weak and smooth; 41–43+1 lateral-line scales; 9–10/1/4½–5 scales in transverse line between origins of dorsal and pelvic fins; and 5½–6 scales between lateral line and anal-fin origin.
Change in the Odds of Warm Years and Seasons Due to Anthropogenic Influence on the Climate
Authors: Christidis Nikolaos , Stott Peter A. 
Published: December 2013

AbstractThe new Hadley Centre system for attribution of weather and climate extremes provides assessments of how human influence on the climate may lead to a change in the frequency of such events. Two different types of ensembles of simulations are generated with an atmospheric model to represent the actual climate and what the climate would have been in the absence of human influence. Estimates of the event frequency with and without the anthropogenic effect are then obtained. Three experiments conducted so far with the new system are analyzed in this study to examine how anthropogenic forcings change the odds of warm years, summers, or winters in a number of regions where the model reliably reproduces the frequency of warm events. In all cases warm events become more likely because of human influence, but estimates of the likelihood may vary considerably from year to year depending on the ocean temperature. While simulations of the actual climate use prescribed observational data of sea surface temperature and sea ice, simulations of the nonanthropogenic world also rely on coupled atmosphere–ocean models to provide boundary conditions, and this is found to introduce a major uncertainty in attribution assessments. Improved boundary conditions constructed with observational data are introduced in order to minimize this uncertainty. In more than half of the 10 cases considered here anthropogenic influence results in warm events being 3 times more likely and extreme events 5 times more likely during September 2011–August 2012, as an experiment with the new boundary conditions indicates.
Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells
Authors: Katz Samuel G. , LaBelle James L. , Meng Hailong , Valeriano Regina P. , Fisher Jill K. , Sun Heather , Rodig Scott J. , Kleinstein Steven H. , Walensky Loren D. 
Published: December 2013

Key PointsImmune stimulation of cyclin D1 transgenic mice bearing Bim-deficient B cells induces an MCL phenotype. The induced lymphoma of EμCycD1CD19CREBimfl/fl mice highlights the collaborative roles of Bim deletion and cyclin D1 expression in MCL.
A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential
Authors: Rocanin-Arjo Ares , Cohen William , Carcaillon Laure , Frère Corinne , Saut Noémie , Letenneur Luc , Alhenc-Gelas Martine , Dupuy Anne-Marie , Bertrand Marion , Alessi Marie-Christine , Germain Marine , Wild Philipp S. , Zeller Tanja , Cambien Francois , Goodall Alison H. , Amouyel Philippe , Scarabin Pierre-Yves , Trégouët David-Alexandre , Morange Pierre-Emmanuel ,   and the CardioGenics Consortium
Published: December 2013

Key PointsGenetic variations at the ORM1 locus and concentrations of the encoded protein associate with thrombin generation. These findings may guide the development of novel antithrombotic treatments.
Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas
Authors: Voorham Quirinus JM , Janssen Jerry , Tijssen Marianne , Snellenberg Suzanne , Mongera Sandra , van Grieken Nicole CT , Grabsch Heike , Kliment Martin , Rembacken Bjorn J , Mulder Chris JJ , van Engeland Manon , Meijer Gerrit A , Steenbergen Renske DM , Carvalho Beatriz 
Published: December 2013

Abstract

Background
Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas.

Methods
Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples.

Results
Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05).

Conclusions
Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.
Monocyte depletion increases local proliferation of macrophage subsets after skeletal muscle injury
Authors: Côté Claude H , Bouchard Patrice , van Rooijen Nico , Marsolais David , Duchesne Elise 
Published: December 2013

Abstract

Background
Sequential accumulation of M1 and M2 macrophages is critical for skeletal muscle recovery after an acute injury. While M1 accumulation is believed to rely on monocyte infiltration, the mechanisms of M2 accumulation remain controversial, but could involve an infiltrating precursor. Yet, strong depletion of monocytes only partially impairs skeletal muscle healing, supporting the existence of alternative mechanisms to palliate the loss of infiltrating macrophage progenitors. The aims of this study are thus to investigate if proliferation occurs in macrophage subsets within injured skeletal muscles; and to determine if monocyte depletion leads to increased proliferation of macrophages after injury.

Methods
Injury was induced by bupivacaine injection in the tibialis anterior muscle of rats. Blood monocytes were depleted by daily intravenous injections of liposome-encapsulated clodronate, starting 24 h prior to injury. In separate experiments, irradiation of hind limb was also performed to prevent resident cell proliferation. Upon euthanasia, blood and muscles were collected for flow cytometric analyses of macrophage/monocyte subsets.

Results
Clodronate induced a 80%-90% depletion of monocyte but only led to 57% and 41% decrease of M1 and M2 macrophage accumulation, respectively, 2 d following injury. Conversely, the number of M1 macrophages in monocyte-depleted rats was 2.4-fold higher than in non-depleted rats 4 d after injury. This was associated with a 16-fold increase in the number of proliferative M1 macrophages, which was reduced by 46% in irradiated animals. Proliferation of M2 macrophages was increased tenfold by clodronate treatment 4 d post injury. The accumulation of M2 macrophages was partially impaired by irradiation, regardless of monocyte depletion.

Conclusions
M1 and M2 subsets proliferate after skeletal muscle injury and their proliferation is enhanced under condition of monocyte depletion. Our study supports the conclusion that both infiltrating and resident precursors could contribute to M1 or M2 macrophage accumulation in muscle injury.
The effect of prosthetic feedback on the strategies and synergies used by vestibular loss subjects to control stance
Authors: Honegger Flurin , Hillebrandt Imke MA , van den Elzen Nadja GA , Tang Kok-Sing , Allum John HJ 
Published: December 2013

AbstractBackgroundThis study investigated changes in stance movement strategies and muscle synergies when bilateral peripheral vestibular loss (BVL) subjects are provided feedback of pelvis sway angle.MethodsSix BVL (all male) and 7 age-matched male healthy control (HC) subjects performed 3 stance tasks: standing feet hip width apart, eyes closed, on a firm and foam surface, and eyes open on foam. Pelvis and upper trunk movements were recorded in the roll and pitch planes. Surface EMG was recorded from pairs of antagonistic muscles at the lower leg, trunk and upper arm. Subjects were first assessed without feedback. Then, they received training with vibrotactile, auditory, and fall-warning visual feedback during stance tasks before being reassessed with feedback.ResultsFeedback reduced pelvis sway angle displacements to values of HCs for all tasks. Movement strategies were reduced in amplitude but not otherwise changed by feedback. These strategies were not different from those of HCs before or after use of feedback. Low frequency motion was in-phase and high frequency motion anti-phasic. Feedback reduced amplitudes of EMG, activity ratios (synergies) of antagonistic muscle pairs and slightly reduced baseline muscle activity.ConclusionsThis is the first study demonstrating how vestibular loss subjects achieve a reduction of sway during stance with prosthetic feedback. Unchanged movement strategies with reduced amplitudes are achieved with improved antagonistic muscle synergies. This study suggests that both body movement and muscle measures could be explored when choosing feedback variables, feedback location, and patient groups for prosthetic devices which reduce sway of those with a tendency to fall.
Kinetic and isotherm studies of adsorption and biosorption processes in the removal of phenolic compounds from aqueous solutions: comparative study
Authors: Gholizadeh Abdolmajid , Kermani Majid , Gholami Mitra , Farzadkia Mehdi 
Published: December 2013

Abstract
The phenolic compounds are known by their carcinogenicity and high toxicity as well as creating unpleasant taste and odor in water resources. The present study develops a cost-effective technology for the treatment of water contaminated with phenolic compounds, including Phenol (Ph), 2-chlorophenol (2-CP), and 4-chlorophenol (4-CP). So, two sorbents, rice bran ash (RBA) and biomass of brown algae, Cystoseiraindica, were used and results were compared with the commercially granular activated carbon (GAC). The phenolic compounds were determined using a high performance liquid chromatography (HPLC) under batch equilibrium conditions. The effects of contact time, pH, initial adsorbate concentration, and adsorbent dosages on the removal efficiency were studied. The adsorption data were simulated by isotherm and kinetic models. Results indicated that RBA and GAC had the lowest efficiency for the removal of 2-CP, while the order of removal efficiency for C. indica biomass was as follows: 2-CP > 4-CP > phenol. The efficiency of GAC was higher than those of other adsorbents for all of the phenolic compounds. Furthermore, the adsorption capacity of RBA was found to be higher than that of C. indica biomass. The optimal initial pH for the removal of phenol, 2-CP and 4-CP was determined to be 5, 7, and 7 for RBA, GAC, and algal biomass, respectively. Kinetic studies suggested that the pseudo-second order best fitted the kinetic data.
Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties
Authors: Lin Xue , Li Jian , Yin Guangliang , Zhao Qian , Elias Daniel , Lykkesfeldt Anne E , Stenvang Jan , Brünner Nils , Wang Jun , Yang Huanming , Bolund Lars , Ditzel Henrik J 
Published: December 2013

Abstract
Introduction
Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Tamoxifen resistance may be the result of acquisition of epigenetic regulation within breast cancer cells, such as DNA methylation, resulting in changed mRNA expression of genes pivotal for estrogen-dependent growth. Alternatively, tamoxifen resistance may be due to selection of pre-existing resistant cells, or a combination of the two mechanisms.

Methods
To evaluate the contribution of these possible tamoxifen resistance mechanisms, we applied modified DNA methylation-specific digital karyotyping (MMSDK) and digital gene expression (DGE) in combination with massive parallel sequencing to analyze a well-established tamoxifen-resistant cell line model (TAMR), consisting of 4 resistant and one parental cell line. Another tamoxifen-resistant cell line model system (LCC1/LCC2) was used to validate the DNA methylation and gene expression results.

Results
Significant differences were observed in global gene expression and DNA methylation profiles between the parental tamoxifen-sensitive cell line and the 4 tamoxifen-resistant TAMR sublines. The 4 TAMR cell lines exhibited higher methylation levels as well as an inverse relationship between gene expression and DNA methylation in the promoter regions. A panel of genes, including NRIP1, HECA and FIS1, exhibited lower gene expression in resistant vs. parental cells and concurrent increased promoter CGI methylation in resistant vs. parental cell lines. A major part of the methylation, gene expression, and pathway alterations observed in the TAMR model were also present in the LCC1/LCC2 cell line model. More importantly, high expression of SOX2 and alterations of other SOX and E2F gene family members, as well as RB-related pocket protein genes in TAMR highlighted stem cell-associated pathways as being central in the resistant cells and imply that cancer-initiating cells/cancer stem-like cells may be involved in tamoxifen resistance in this model.

Conclusion
Our data highlight the likelihood that resistant cells emerge from cancer-initiating cells/cancer stem-like cells and imply that these cells may gain further advantage in growth via epigenetic mechanisms. Illuminating the expression and DNA methylation features of putative cancer-initiating cells/cancer stem cells may suggest novel strategies to overcome tamoxifen resistance.