bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Imaging of Ewing Sarcoma in Preclinical Models Using a 64Cu-Labeled Anti-CD99 Antibody
Authors: O'Neill Allison F. , Dearling Jason L.J. , Wang Yuchuan , Tupper Tanya , Sun Yanping , Aster Jon C. , Calicchio Monica L. , Perez-Atayde Antonio R. , Packard Alan B. , Kung Andrew L. 
Published: November 2013

AbstractPurpose: Ewing sarcoma is a tumor of the bone and soft tissue characterized by diffuse cell membrane expression of CD99 (MIC2). Single-site, surgically resectable disease is associated with an excellent 5-year event-free survival; conversely, patients with distant metastases have a poor prognosis. Noninvasive imaging is the standard approach to identifying sites of metastatic disease. We sought to develop a CD99-targeted imaging agent for staging Ewing sarcoma and other CD99-expressing tumors.Experimental Design: We identified a CD99 antibody with highly specific binding in vitro and labeled this antibody with 64Cu. Mice with either subcutaneous Ewing sarcoma xenograft tumors or micrometastases were imaged with the 64Cu-labeled anti-CD99 antibody and these results were compared with conventional MRI and 2[18F]fluoro-2-deoxy-d-glucose–positron emission tomography (FDG–PET) imaging.Results: 64Cu-labeled anti-CD99 antibody demonstrated high avidity for the CD99-positive subcutaneous tumors, with a high tumor-to-background ratio, greater than that demonstrated with FDG–PET. Micrometastases, measuring 1 to 2 mm on MRI, were not detected with FDG–PET but were readily visualized with the 64Cu-labeled anti-CD99 antibody. Probe biodistribution studies demonstrated high specificity of the probe for CD99-positive tumors.Conclusions: 64Cu-labeled anti-CD99 antibody can detect subcutaneous Ewing sarcoma tumors and metastatic sites with high sensitivity, outperforming FDG–PET in preclinical studies. This targeted radiotracer may have important implications for the diagnosis, surveillance, and treatment of Ewing sarcoma. Similarly, it may impact the management of other CD99 positive tumors. Clin Cancer Res; 20(3); 678–87. ©2013 AACR.
Tumor-Reactive CD8+ T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy
Authors: Turcotte Simon , Gros Alena , Tran Eric , Lee Chyi-Chia R. , Wunderlich John R. , Robbins Paul F. , Rosenberg Steven A. 
Published: November 2013

AbstractPurpose: To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.Experimental Design: Expansion of CD8+ tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity.Results: TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8+ TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8+ TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8+ TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8+ TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8+ TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype.Conclusions: This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8+ TIL at the molecular level. Clin Cancer Res; 20(2); 331–43. ©2013 AACR.
Busulfan in Infant to Adult Hematopoietic Cell Transplant Recipients: A Population Pharmacokinetic Model for Initial and Bayesian Dose Personalization
Authors: McCune Jeannine S. , Bemer Meagan J. , Barrett Jeffrey S. , Scott Baker K. , Gamis Alan S. , Holford Nicholas H.G. 
Published: November 2013

Abstract
Purpose: Personalizing intravenous busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1–66 years) that accounts for differences in age and body size.
Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models.
Results: A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size—specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%).
Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults. Clin Cancer Res; 20(3); 754–63. ©2013 AACR.
Erb-041, an Estrogen Receptor-β Agonist, Inhibits Skin Photocarcinogenesis in SKH-1 Hairless Mice by Downregulating the WNT Signaling Pathway
Authors: Chaudhary Sandeep C. , Singh Tripti , Talwelkar Sarang S. , Srivastava Ritesh K. , Arumugam Aadithya , Weng Zhiping , Elmets Craig A. , Afaq Farrukh , Kopelovich Levy , Athar Mohammad 
Published: November 2013

Abstract
Estrogen receptors (ER), including ER-α and ER-β, are known to regulate multiple biologic responses in various cell types. The expression of ER-β is lost in various cancers. ER-β agonists were shown to modulate inflammation, cancer cell proliferation, and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ER-β agonist, using a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively, in the Erb-041–treated group as compared with UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in proliferating cell nuclear antigen (PCNA), cyclin D1, VEGF, and CD31, and an increase in apoptosis. The lost ER-β expression in squamous cell carcinomas (SCC) was significantly recovered by Erb-041 treatment. In addition, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity, levels of cytokines (interleukin (IL)-1β, IL-6, and IL-10), and expression of p-ERK (extracellular signal–regulated kinase) 1/2, p-p38, p-IκB, iNOS, COX-2, and nuclear NF-κBp65 were diminished. The number of tumor-associated inflammatory cells (GR-1+/CD11b+ and F4/80+) was also decreased. Tumors excised from Erb-041–treated animal were less invasive and showed reduced epithelial–mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-cadherin, Snail, Slug, and Twist characterized these lesions. The WNT/β-catenin signaling pathway, which underlies pathogenesis of skin cancer, was found to be downregulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent that acts by dampening the WNT/β-catenin signaling pathway. Cancer Prev Res; 7(2); 186–98. ©2013 AACR.
Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity
Authors: Redmond William L. , Linch Stefanie N. , Kasiewicz Melissa J. 
Published: November 2013

AbstractLigation of the TNF receptor family costimulatory molecule OX40 (CD134) with an agonist anti-OX40 monoclonal antibody (mAb) enhances antitumor immunity by augmenting T-cell differentiation as well as turning off the suppressive activity of the FoxP3+CD4+ regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the “brakes” on T cells to augment tumor immunotherapy. However, monotherapy with these agents has limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell–dependent manner. Mechanistic studies revealed that the combination immunotherapy directed the expansion of effector T-bethigh/Eomeshigh granzyme B+ CD8 T cells. Dual immunotherapy also induced distinct populations of Th1 [interleukin (IL)-2, IFN-γ], and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining the Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T-cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents. Cancer Immunol Res; 2(2); 142–53. ©2013 AACR.
Cancer–Testis Antigen Expression in Digestive Tract Carcinomas: Frequent Expression in Esophageal Squamous Cell Carcinoma and Its Precursor Lesions
Authors: Chen Yao-Tseng , Panarelli Nicole C. , Piotti Kathryn C. , Yantiss Rhonda K. 
Published: November 2013

Abstract
Cancer–testis (CT) antigens are attractive tumor antigens for cancer immunotherapy. They comprise a group of proteins normally expressed in germ cells and aberrantly activated in a variety of human cancers. The protein expression of eight cancer–testis antigens [MAGEA, NY-ESO-1, GAGE, MAGEC1 (CT7), MAGEC2 (CT10), CT45, SAGE1, and NXF2] was evaluated by immunohistochemistry in 61 esophageal carcinomas (40 adenocarcinoma and 21 squamous cell carcinoma), 50 gastric carcinomas (34 diffuse and 16 intestinal type), and 141 colorectal carcinomas. The highest frequency of expression was found in esophageal squamous cell carcinomas: Positive staining for MAGEA, CT45, CT7, SAGE1, GAGE, NXF2, NY-ESO-1, and CT10 was observed in 57%, 38%, 33%, 33%, 29%, 29%, 19%, and 14% of squamous cell carcinomas, respectively. Similar staining patterns were observed in squamous dysplasias. Expression frequencies of cancer–testis antigens were seen in 2% to 24% of gastroesophageal adenocarcinomas and were not significantly different between adenocarcinomas of the stomach versus the esophagus, or between diffuse and intestinal types of gastric adenocarcinomas. Colorectal cancers did not express NY-ESO-1, CT7, CT10, or GAGE, and only infrequently expressed SAGE1 (0.7%) MAGEA (1.4%), CT45 (3.5%), and NXF2 (8.5%). We conclude that cancer–testis antigens are frequently expressed in esophageal squamous neoplasms. Although cancer–testis antigens are generally considered to be expressed later in tumor progression, they are found in squamous dysplasias, suggesting a potential diagnostic role for cancer–testis antigens in the evaluation of premalignant squamous lesions. Cancer Immunol Res; 2(5); 480–6. ©2013 AACR.
Sick Sinus Syndrome in HCN1-Deficient Mice
Authors: Fenske Stefanie , Krause Stefanie C. , Hassan Sami I.H. , Becirovic Elvir , Auer Franziska , Bernard Rebekka , Kupatt Christian , Lange Philipp , Ziegler Tilman , Wotjak Carsten T. , Zhang Henggui , Hammelmann Verena , Paparizos Christos , Biel Martin , Wahl-Schott Christian A. 
Published: November 2013

Background—
Sinus node dysfunction (SND) is a major clinically relevant disease that is associated with sudden cardiac death and requires surgical implantation of electric pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electric instability of the heart. Although the pathologies of acquired SND have been studied extensively, little is known about the molecular and cellular mechanisms that cause congenital SND.

Methods and Results—
Here, we show that the HCN1 protein is highly expressed in the sinoatrial node and is colocalized with HCN4, the main sinoatrial pacemaker channel isoform. To characterize the cardiac phenotype of HCN1-deficient mice, a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparation, telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology was performed. On the basis of these experiments we demonstrate that mice lacking the pacemaker channel HCN1 display congenital SND characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses. As a consequence of SND, HCN1-deficient mice display a severely reduced cardiac output.

Conclusions—
We propose that HCN1 stabilizes the leading pacemaker region within the sinoatrial node and hence is crucial for stable heart rate and regular beat-to-beat variation. Furthermore, we suggest that HCN1-deficient mice may be a valuable genetic disease model for human SND.
Wind Shear and Buoyancy Reversal at the Top of Stratocumulus
Authors: Mellado Juan Pedro , Stevens Bjorn , Schmidt Heiko 
Published: November 2013

Abstract
A numerical experiment is designed to study the interaction at the stratocumulus top between a mean vertical shear and the buoyancy reversal due to evaporative cooling, without radiative cooling. Direct numerical simulation is used to eliminate the uncertainty introduced by turbulence models. It is found that the enhancement by shear-induced mixing of the turbulence caused by buoyancy reversal can render buoyancy reversal comparable to other forcing mechanisms. However, it is also found that (i) the velocity jump across the capping inversion Δu needs to be relatively large and values of about 1 m s−1 that are typically associated with the convective motions inside the boundary layer are generally too small and (ii) there is no indication of cloud-top entrainment instability. To obtain these results, parameterizations of the mean entrainment velocity and the relevant time scales are derived from the study of the cloud-top vertical structure. Two overlapping layers can be identified: a background shear layer with a thickness (⅓)(Δu)2/Δb, where Δb is the buoyancy increment across the capping inversion and a turbulence layer dominated by free convection inside the cloud and by shear production inside the relatively thin overlap region. As turbulence intensifies, the turbulence layer encroaches into the background shear layer and defines thereby the entrainment velocity. Particularized to the first research flight of the Second Dynamics and Chemistry of the Marine Stratocumulus (DYCOMS II) field campaign, the analysis predicts an entrainment velocity of about 3 mm s−1 after 5–10 min—a velocity comparable to the measurements and thus indicative of the relevance of mean shear in that case.
Low-dose computed tomography of the lumbar spine: a phantom study on imaging parameters and image quality
Authors: Alshamari Muhammed , Geijer Mats , Norrman Eva , Geijer Håkan 
Published: November 2013

Background Lumbar spine radiography has limited diagnostic value but low radiation dose compared with computed tomography (CT). The average effective radiation dose from lumbar spine radiography is about 1.1 mSv. Low-dose lumbar spine CT may be an alternative to increase the diagnostic value at low radiation dose, around 1 mSv. Purpose To determine the optimal settings for low-dose lumbar spine CT simultaneously aiming for the highest diagnostic image quality possible. Material and Methods An ovine lower thoracic and lumbar spine phantom, with all soft tissues around the vertebrae preserved except the skin, was placed in a 20 L plastic container filled with water. The phantom was scanned repeatedly with various technical settings; different tube potential, reference mAs, and with different convolution filters. Five radiologists evaluated the image quality according to a modification of the European guidelines for multislice computed tomography (MSCT) quality criteria for lumbar spine CT 2004. In a visual comparison the different scans were also ranked subjectively according to perceived image quality. Image noise and contrast were measured. Results A tube potential of 120 kV with reference mAs 30 and medium or medium smooth convolution filter gave the best image quality at a sub-millisievert dose level, i.e. with an effective dose comparable to that from lumbar spine radiography. Conclusion Low-dose lumbar spine CT thus opens a possibility to substitute lumbar spine radiography with CT without obvious increase in radiation dose.
Usefulness of monochromatic imaging with metal artifact reduction software for computed tomography angiography after intracranial aneurysm coil embolization
Authors: Shinohara Yuki , Sakamoto Makoto , Iwata Naoki , Kishimoto Junichi , Kuya Keita , Fujii Shinya , Kaminou Toshio , Watanabe Takashi , Ogawa Toshihide 
Published: November 2013

Background Recently, a newly developed fast-kV switching dual energy CT scanner with a gemstone detector generates virtual high keV images as monochromatic imaging (MI). Each MI can be reconstructed by metal artifact reduction software (MARS) to reduce metal artifact. Purpose To evaluate the degree of metal artifacts reduction and vessel visualization around the platinum coils using dual energy CT with MARS. Material and Methods Dual energy CT was performed using a Discovery CT750 HD scanner (GE Healthcare, Milwaukee, WI, USA). In a phantom study, we measured the mean standard deviation within regions of interest around a 10-mm-diameter platinum coil mass on MI with and without MARS. Thirteen patients who underwent CTA after endovascular embolization for cerebral aneurysm with platinum coils were included in a clinical study. We visually assessed the arteries around the platinum coil mass on MI with and without MARS. Results Each standard deviation near the coil mass on MI with MARS was significantly lower than that without MARS in a phantom study. On CTA of a clinical study, better visibility of neighboring arteries was obtained in 11 of 13 patients on MI with MARS compared to without MARS due to metal artifact reduction. Conclusion: Dual energy CT with MARS reduces metal artifact of platinum coils, resulting in favorable vessel visualization around the coil mass on CTA after embolization.
Amygdala opioid receptors mediate the electroacupuncture-induced deterioration of sleep disruptions in epilepsy rats
Authors: Yi Pei-Lu , Lu Chin-Yu , Cheng Chiung-Hsiang , Tsai Yi-Fong , Lin Chung-Tien , Chang Fang-Chia 
Published: November 2013

Abstract

Background
Clinical and experimental evidence demonstrates that sleep and epilepsy reciprocally affect each other. Previous studies indicated that epilepsy alters sleep homeostasis; in contrast, sleep disturbance deteriorates epilepsy. If a therapy possesses both epilepsy suppression and sleep improvement, it would be the priority choice for seizure control. Effects of acupuncture of Feng-Chi (GB20) acupoints on epilepsy suppression and insomnia treatment have been documented in the ancient Chinese literature, Lingshu Jing (Classic of the Miraculous Pivot). Therefore, this study was designed to investigate the effect of electroacupuncture (EA) stimulation of bilateral Feng-Chi acupoints on sleep disruptions in rats with focal epilepsy.

Results
Our result indicates that administration of pilocarpine into the left central nucleus of amygdala (CeA) induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep. High-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints, in which a 30-min EA stimulation was performed before the dark period of the light:dark cycle in three consecutive days, further deteriorated pilocarpine-induced sleep disruptions. The EA-induced exacerbation of sleep disruption was blocked by microinjection of naloxone, μ- (naloxonazine), κ- (nor-binaltorphimine) or δ-receptor antagonists (natrindole) into the CeA, suggesting the involvement of amygdaloid opioid receptors.

Conclusion
The present study suggests that high-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints exhibits no benefit in improving pilocarpine-induced sleep disruptions; in contrast, EA further deteriorated sleep disturbances. Opioid receptors in the CeA mediated EA-induced exacerbation of sleep disruptions in epileptic rats.
Comparative genomics reveals candidate carotenoid pathway regulators of ripening watermelon fruit
Authors: Grassi Stefania , Piro Gabriella , Lee Je Min , Zheng Yi , Fei Zhangjun , Dalessandro Giuseppe , Giovannoni James J , Lenucci Marcello S 
Published: November 2013

AbstractBackgroundMany fruits, including watermelon, are proficient in carotenoid accumulation during ripening. While most genes encoding steps in the carotenoid biosynthetic pathway have been cloned, few transcriptional regulators of these genes have been defined to date. Here we describe the identification of a set of putative carotenoid-related transcription factors resulting from fresh watermelon carotenoid and transcriptome analysis during fruit development and ripening. Our goal is to both clarify the expression profiles of carotenoid pathway genes and to identify candidate regulators and molecular targets for crop improvement.ResultsTotal carotenoids progressively increased during fruit ripening up to ~55 μg g-1fw in red-ripe fruits.Trans-lycopene was the carotenoid that contributed most to this increase. Many of the genes related to carotenoid metabolism displayed changing expression levels during fruit ripening generating a metabolic flux toward carotenoid synthesis. Constitutive low expression of lycopene cyclase genes resulted in lycopene accumulation. RNA-seq expression profiling of watermelon fruit development yielded a set of transcription factors whose expression was correlated with ripening and carotenoid accumulation. Nineteen putative transcription factor genes from watermelon and homologous to tomato carotenoid-associated genes were identified. Among these, six were differentially expressed in the flesh of both species during fruit development and ripening.ConclusionsTaken together the data suggest that, while the regulation of a common set of metabolic genes likely influences carotenoid synthesis and accumulation in watermelon and tomato fruits during development and ripening, specific and limiting regulators may differ between climacteric and non-climacteric fruits, possibly related to their differential susceptibility to and use of ethylene during ripening.