bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I, Open-Label Study of Siltuximab, an Anti–IL-6 Monoclonal Antibody, in Patients with B-cell Non-Hodgkin Lymphoma, Multiple Myeloma, or Castleman Disease
Authors: Kurzrock Razelle , Voorhees Peter M. , Casper Corey , Furman Richard R. , Fayad Luis , Lonial Sagar , Borghaei Hossein , Jagannath Sundar , Sokol Lubomir , Usmani Saad Z. , van de Velde Helgi , Qin Xiang , Puchalski Thomas A. , Hall Brett , Reddy Manjula , Qi Ming , van Rhee Frits 
Published: May 2013

Abstract
Purpose: To evaluate the safety and pharmacokinetics of siltuximab, an anti–interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease.
Experimental Design: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease.
Results: Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose–toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR.
Conclusion: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. Clin Cancer Res; 19(13); 3659–70. ©2013 AACR.
Dysregulating IRES-Dependent Translation Contributes to Overexpression of Oncogenic Aurora A Kinase
Authors: Dobson Tara , Chen Juan , Krushel Les A. 
Published: May 2013

Abstract
Overexpression of the oncoprotein Aurora A kinase occurs in multiple types of cancer, often early during cell transformation. To identify the mechanism(s) contributing to enhanced Aurora A protein expression, a comparison between normal human lung fibroblast and breast epithelial cells to nontumorigenic breast (MCF10A and MCF12A) and tumorigenic breast (MCF-7) and cervical cell lines (HeLa S3) was performed. A subset of these immortalized lines (MCF10A, MCF12A, and HeLa S3) exhibited increased levels of Aurora A protein, independent of tumorigenicity. The increase in Aurora A protein in these immortalized cells was not due to increased transcription/RNA stability, protein half-life, or cap-dependent translation. Assays utilizing monocistronic and dicistronic RNA constructs revealed that the 5′-leader sequence of Aurora A contains an internal ribosomal entry site (IRES), which is regulated in a cell cycle–dependent manner, peaking in G2/M phase. Moreover, IRES activity was increased in the immortalized cell lines in which Aurora A protein expression was also enhanced. Additional studies indicated that the increased internal initiation is specific to the IRES of Aurora A and may be an early event during cancer progression. These results identify a novel mechanism contributing to Aurora A kinase overexpression.
Implications: The current study indicates that Aurora A kinase contributes to immortalization and tumorigenesis. Mol Cancer Res; 11(8); 887–900. ©2013 AACR.
TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis
Authors: Pang Yanli , Gara Sudheer Kumar , Achyut Bhagelu R. , Li Zhaoyang , Yan Hannah H. , Day Chi-Ping , Weiss Jonathan M. , Trinchieri Giorgio , Morris John C. , Yang Li 
Published: May 2013

Abstract
TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2MyeKO) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2MyeKO bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2MyeKO mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.
Significance: Our study identifies myeloid-specific TGF-β signaling as a critical mediator in tumor metastasis, distinct from the tumor-suppressive effect of TGF-β signaling in epithelial cells, fibroblasts, and T cells. We further provide mechanistic insight into host antitumor immunity and suggest a cell type–specific cancer-targeting strategy. Cancer Discov; 3(8); 936–51. ©2013 AACR.
See related commentary by Souza-Fonseca-Guimaraes and Smyth, p. 846
This article is highlighted in the In This Issue feature, p. 826
Angptl3 Deficiency Is Associated With Increased Insulin Sensitivity, Lipoprotein Lipase Activity, and Decreased Serum Free Fatty Acids
Authors: Robciuc Marius R. , Maranghi Marianna , Lahikainen Anna , Rader Daniel , Bensadoun Andre , Öörni Katariina , Metso Jari , Minicocci Ilenia , Ciociola Ester , Ceci Fabrizio , Montali Anna , Arca Marcello , Ehnholm Christian , Jauhiainen Matti 
Published: May 2013

Objective—

Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in
ANGPTL3
cause familial combined hypolipidemia through an unknown mechanism.

Approach and Results—

We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in
ANGPTL3
and in age- and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects.

Conclusions—
These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism.
Top–Down Inhibitory Control Exerted by the Medial Frontal Cortex during Action Selection under Conflict
Authors: Duque Julie , Olivier Etienne , Rushworth Matthew 
Published: May 2013

Abstract
Top–down control is critical to select goal-directed actions in changeable environments, particularly when several conflicting options compete for selection. In humans, this control system is thought to involve an inhibitory mechanism that suppresses the motor representation of unwanted responses to favor selection of the most appropriate action. Here, we aimed to evaluate the role of a region of the medial frontal cortex, the pre-SMA, in this form of inhibition by using a double coil TMS protocol combining repetitive TMS (rTMS) over the pre-SMA and a single-pulse TMS over the primary motor cortex (M1) during a visuomotor task that required participants to choose between a left or right button press according to an imperative cue. M1 stimulation allowed us to assess changes in motor excitability related to selected and nonselected (unwanted) actions, and rTMS was used to produce transient disruption of pre-SMA functioning. We found that when rTMS was applied over pre-SMA, inhibition of the nonselected movement representation was reduced. Importantly, this effect was only observed when the imperative cue produced a substantial amount of competition between the response alternatives. These results are consistent with previous studies pointing to a role of pre-SMA in competition resolution. In addition, our findings indicate that this function of pre-SMA involves the control of inhibitory influences directed at unwanted action representations.
The Role of Transverse Occipital Sulcus in Scene Perception and Its Relationship to Object Individuation in Inferior Intraparietal Sulcus
Authors: Bettencourt Katherine C. , Xu Yaoda 
Published: May 2013

Abstract
The parietal cortex has been functionally divided into various subregions; however, very little is known about how these areas relate to each other. Two such regions are the transverse occipital sulcus (TOS) scene area and inferior intraparietal sulcus (IPS). TOS exhibits similar activation patterns to the scene selective parahippocampal place area, suggesting its role in scene perception. Inferior IPS, in contrast, has been shown to participate in object individuation and selection via location. Interestingly, both regions have been localized to the same general area of the brain. If these two were actually the same brain region, it would have important implications regarding these regions' role in cognition. To explore this, we first localized TOS and inferior IPS in individual participants and examined the degree of overlap between these regions in each participant. We found that TOS showed only a minor degree of overlap with inferior IPS (∼10%). We then directly explored the role of TOS and inferior IPS in object individuation and scene perception by examining their responses to furnished rooms, empty rooms, isolated furniture, and multiple isolated objects. If TOS and inferior IPS were the same region, we would expect to see similar response patterns in both. Instead, the response of TOS was predominantly scene selective, whereas activity in inferior IPS was primarily driven by the number of objects present in the display, regardless of scene context. These results show that TOS and inferior IPS are nearby but distinct regions, with different functional roles in visual cognition.
Unconscious Priming Requires Early Visual Cortex at Specific Temporal Phases of Processing
Authors: Persuh Marjan , Ro Tony 
Published: May 2013

Abstract
Although examples of unconscious shape priming have been well documented, whether such priming requires early visual cortex (V1/V2) has not been established. In the current study, we used TMS of V1/V2 at varying temporal intervals to suppress the visibility of preceding shape primes while the interval between primes and targets was kept constant. Our results show that, although conscious perception requires V1/V2, unconscious priming can occur without V1/V2 at an intermediate temporal interval but not at early (5–25 msec) or later (65–125 msec) stages of processing. Because the later time window of unconscious priming suppression has been proposed to interfere with feedback processing, our results further suggest that feedback processing is also essential for unconscious priming and may not be a sufficient condition for conscious vision.
The relationship between psychosocial functioning and resilience and negative symptoms in individuals at ultra-high risk for psychosis
Authors: Kim Kyung Ran , Song Yun Young , Park Jin Young , Lee Eun Hye , Lee Mikyung , Lee Su Young , Kang Jee In , Lee Eun , Yoo Sang Woo , An Suk Kyoon , Kwon Jun Soo 
Published: May 2013

Objective: Decline in psychosocial functioning seems to be a core feature in schizophrenia across various phases of the disorder. Little is known about the relationship between psychosocial functioning and protective factors or psychopathologies in individuals in the prodrome phase of psychosis. We aimed to investigate whether psychosocial functioning is impaired in individuals in the putative prodromal phase of schizophrenia, and, if so, to identify factors associated with compromised psychosocial functioning. Method: Sixty participants at ultra-high risk (UHR) for psychosis and 47 healthy controls were recruited. All subjects were assessed in terms of psychosocial functioning using the Quality of Life Scale. A clinical assessment of psychopathology and protective factors, including resilience and coping style, was also conducted. Results: Psychosocial functioning in UHR participants was found to be compromised; this dysfunction was associated with negative symptoms, adaptive coping, and resilience. In addition, baseline resilience was lower among those in the UHR group who converted to frank psychosis than among those who did not. Conclusions: These findings imply that treatment strategies for individuals at UHR for psychosis should be comprehensive, promoting resilience as well as targeting the reduction of positive and negative symptoms to foster social reintegration and recovery.
Computed tomography quantitative analysis of components: a new method monitoring the growth of pulmonary nodule
Authors: Linning E , Wu Shan , Wang Kai , Meng Huiqiang , Sun Dong , Wu Zhifeng 
Published: May 2013

Background The estimation of the growth of solitary pulmonary nodules by using non-invasive methods is increasingly gaining clinical importance for performing the timely adequate treatment of these nodules. Purpose To evaluate the application value of computed tomography (CT) quantitative analysis of components for dynamic assessment of the growth of solitary pulmonary nodules, and compare this approach with three-dimensional (3D) volumetric measurement of pulmonary nodules. Material and Methods The imaging data of 21 patients who had undergone multiple follow-up CT scans for solitary pulmonary nodules were retrospectively analyzed, and the total volume of pulmonary nodules and the percentage change in the total volume of pulmonary nodules after multiple follow-up CT scans were measured using 3D volume measurement software. The volume of solid components in pulmonary nodules was measured using CT quantitative analysis; the percentage change in the volume of solid components across examinations was calculated; and the percentage change in the total volume of pulmonary nodules was compared and contrasted with the percentage change in the volume of solid components in the pulmonary nodules. Results All 21 cases were malignant adenocarcinomas. In the 21 cases of malignant nodules, the 3D volumes of the nodules and solid components were both increased, with the percentage change in the volume of the solid components (115.78–418.91%, 130.45 ± 119.48) significantly different from the percentage change in the total volume of the nodules (78.56–105.73% , 42.34 ± 32.17) ( P = 0.02). Conclusion By measuring volume changes in solid components in the nodules, CT quantitative analysis offers more sensitive and earlier evaluation of the dynamic growth of the nodules than measurement of volume changes in the nodules alone.
Bone mineral density and geometry parameters determined in vitro from dual-energy digital radiography images in the assessment of bone maximal load of reindeer femora
Authors: Toljamo Päivi S , Pulkkinen Pasi , Lammentausta Eveliina , Tervonen Osmo , Jämsä Timo , Nieminen Miika T 
Published: May 2013

Background Dual-energy digital radiography (DEDR) has been shown to be a potential method to determine bone mineral density (BMD) and predict maximal load with similar accuracy as standard bone densitometry using DXA (dual-energy X-ray absorptiometry). In addition to bone density, bone geometry has also been shown to have effect on bone fragility and fracture risk. Purpose To examine the combination of BMD and geometry parameters, as determined from a DEDR experiment, to predict bone maximal load. Material and Methods Reindeer femora ( n = 47) were imaged at two energies (79 kVp and 100 kVp) using a clinical digital radiography system. BMD was determined in four regions from these images using the DXA calculation principle. Various geometrical parameters were determined from the 79 kVp image. Femora were mechanically tested using axial loading configuration. Pearson correlation coefficients were determined between geometrical parameters and BMDs or maximal load. Multiple stepwise linear regression analysis was used to find the best combination to predict bone maximal load. Results From the geometrical parameters, femoral shaft diameter (FSD) and femoral neck axis length (FNAL) correlated best with the maximal load ( r = 0.629 and r = 0.446, P < 0.01, respectively). The best combination of parameters to predict bone fragility was BMD at Ward's triangle, FSD and FNAL ( r = 0.787, P < 0.05), whereas the correlation coefficient between BMD at Ward's triangle and maximal load was 0.653 ( P < 0.05). Conclusion The combination of DEDR-based BMD and geometrical parameters predicts reindeer bone maximal load with reasonable accuracy and the combined analysis improves the prediction of maximal load compared to BMD prediction only.
Evaluation of the relationship between extremity soft tissue sarcomas and adjacent major vessels using contrast-enhanced multidetector CT and three-dimensional volume-rendered CT angiography: a preliminary study
Authors: Li YangKang , Zheng Yu , Lin JianBang , Cai AiQun , Zhou XiuGuo , Wei XiaoLong , Cheng Ying , Liu GuoRui 
Published: May 2013

Background Accurate description of the relationship between extremity soft tissue sarcoma and the adjacent major vessels is crucial for successful surgery. In addition to magnetic resonance imaging (MRI) or in patients who cannot undergo MRI, two-dimensional (2D) postcontrast computed tomography (CT) images and three-dimensional (3D) volume-rendered CT angiography may be valuable alternative imaging techniques for preoperative evaluation of extremity sarcomas. Purpose To preoperatively assess extremity sarcomas using multidetector CT (MDCT), with emphasis on postcontrast MDCT images and 3D volume-rendered MDCT angiography in evaluating the relationship between tumors and adjacent major vessels. Material and Methods MDCT examinations were performed on 13 patients with non-metastatic extremity sarcomas. Conventional CT images and 3D volume-rendered CT angiography were evaluated, with focus on the relationship between tumors and adjacent major vessels. Kappa consistency statistics were performed with surgery serving as the reference standard. Results The relationship between sarcomas and adjacent vessels was described as one of three patterns: proximity, adhesion, and encasement. Proximity was seen in five cases on postcontrast CT images or in eight cases on volume-rendered images. Adhesion was seen in three cases on both postcontrast CT images and volume-rendered images. Encasement was seen in five cases on postcontrast CT images or in two cases on volume-rendered images. Compared to surgical results, postcontrast CT images had 100% sensitivity, 83.3% specificity, 87.5% positive predictive value, 100% negative predictive value, and 92.3% accuracy in the detection of vascular invasion (κ = 0.843, P = 0.002). 3D volume-rendered CT angiography had 71.4% sensitivity, 100% specificity, 100% positive predictive value, 75% negative predictive value, and 84.6% accuracy in the detection of vascular invasion (κ = 0.698, P = 0.008). On volume-rendered images, all cases with adhesion or encasement had arterial stenosis and all tumors' feeding arteries were clearly depicted. Conclusion 2D postcontrast CT images are superior to 3D volume-rendered CT angiography in evaluating the relationship between extremity sarcomas and adjacent major vessels. 3D volume-rendered CT angiography is good at assessing the tumor's blood supply, the longitudinal extent of vascular involvement, and the vascular narrowing due to the tumor.
Electromyographic response of facial nerve stimulation under different levels of neuromuscular blockade during middle-ear surgery
Authors: Choe Won Joo , Kim Jun Hyun , Park Si Young , Kim Jin 
Published: May 2013

Objective To investigate facial nerve monitoring in patients receiving the partial nondepolarizing neuromuscular blocking agents (NMBAs), remifentanil and propofol. Methods Patients with normal facial function and advanced middle-ear disease were enrolled. For total intravenous anaesthesia (TIVA), propofol and remifentanil were infused as induction/maintenance anaesthesia. Stimulation thresholds and amplitudes were recorded at each train-of-four (TOF) nerve stimulation level. Time differences between start of TOF and electromyographic (EMG) amplitude decreases (Ti), and between complete recovery of TOF and EMG amplitudes (Tr), were calculated. Results Fifteen patients were enrolled. Mean ± SD Ti was 3.4 ± 1.28 min; Tr was 18.7 ± 4.41 min. Amplitude of stimulation was apparent mostly at TOF level 1. In most cases, no or a weak response (<100 µV) was observed at TOF 0. Mean ± SD threshold of electrical stimulation was 0.31 ± 0.10 mA at TOF 1. At TOF > 2, all cases showed EMG response on electrical stimulation. Conclusions Induction of TIVA using propofol and remifentanil provided reliable conditions for delicate microsurgery. Minimal NMBA use, considered as producing TOF levels >1, was sufficient for facial nerve monitoring in neuro-otological surgery.