bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-Man Phase I Study of GC33, a Novel Recombinant Humanized Antibody Against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma
Authors: Zhu Andrew X. , Gold Philip J. , El-Khoueiry Anthony B. , Abrams Thomas A. , Morikawa Hideo , Ohishi Norihisa , Ohtomo Toshihiko , Philip Philip A. 
Published: January 2013

AbstractPurpose: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC.Experimental Design: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5–20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria.Results: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P = 0.033).Conclusion: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation. Clin Cancer Res; 19(4); 920–8. ©2012 AACR.
Plasma MicroRNAs as Novel Biomarkers for Endometriosis and Endometriosis-Associated Ovarian Cancer
Authors: Suryawanshi Swati , Vlad Anda M. , Lin Hui-Min , Mantia-Smaldone Gina , Laskey Robin , Lee MinJae , Lin Yan , Donnellan Nicole , Klein-Patel Marcia , Lee Ted , Mansuria Suketu , Elishaev Esther , Budiu Raluca , Edwards Robert P. , Huang Xin 
Published: January 2013

AbstractPurpose: Endometriosis, a largely benign, chronic inflammatory disease, is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors. We aimed to identify plasma miRNAs that can be used to differentiate patients with endometriosis and ovarian cancer from healthy individuals.Experimental Design: We conducted a two-stage exploratory study to investigate the use of plasma miRNA profiling to differentiate between patients with endometriosis, patients with endometriosis-associated ovarian cancer (EAOC), and healthy individuals. In the first stage, using global profiling of more than 1,000 miRNAs via reverse transcriptase quantitative PCR (RT-qPCR) in a 20-patient initial screening cohort, we identified 23 candidate miRNAs, which are differentially expressed between healthy controls (n = 6), patients with endometriosis (n = 7), and patients with EAOC (n = 7) based on the fold changes. In the second stage, the 23 miRNAs were further tested in an expanded cohort (n = 88) of healthy individuals (n = 20), endometriosis (n = 33), EAOC (n = 14), and serous ovarian cancer cases (SOC; n = 21, included as controls).Results: We identified three distinct miRNA signatures with reliable differential expression between healthy individuals, patients with endometriosis, and patients with EAOC. When profiled against the control SOC category, our results revealed different miRNAs, suggesting that the identified signatures are reflective of disease-specific pathogenic mechanisms. This was further supported by the fact that the majority of miRNAs differentially expressed in human EAOCs were mirrored in a double transgenic mouse EAOC model.Conclusion: Our study reports for the first time that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and EAOC cases. Clin Cancer Res; 19(5); 1213–24. ©2013 AACR.
Functional Analysis of Genes in Regions Commonly Amplified in High-Grade Serous and Endometrioid Ovarian Cancer
Authors: Davis Sally J. , Sheppard Karen E. , Pearson Richard B. , Campbell Ian G. , Gorringe Kylie L. , Simpson Kaylene J. 
Published: January 2013

Abstract
Purpose: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors.
Experimental Design: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly amplified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene overexpression.
Results: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts.
Conclusion: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors. Clin Cancer Res; 19(6); 1411–21. ©2013 AACR.
NF-YA Underlies EZH2 Upregulation and Is Essential for Proliferation of Human Epithelial Ovarian Cancer Cells
Authors: Garipov Azat , Li Hua , Bitler Benjamin G. , Thapa Roshan J. , Balachandran Siddharth , Zhang Rugang 
Published: January 2013

Abstract
Epithelial ovarian cancer (EOC) accounts for the most gynecologic malignancy–associated deaths in the United States. Enhancer of zeste homolog 2 (EZH2), which silences gene expression through generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3), is often overexpressed in EOCs and has been suggested as a therapeutic target. However, the mechanism underlying EZH2 overexpression in EOCs is unknown. Here, we show that EZH2 is upregulated at the transcription level, and two CCAAT boxes in the proximal regions of the human EZH2 gene promoter are critical for its transcription in EOC cells. Indeed, NF-YA, the regulatory subunit of the CCAAT-binding transcription factor NF-Y, is expressed at higher levels in human EOCs than in primary human ovarian surface epithelial (HOSE) cells. In addition, there is a positive correlation between expression of NF-YA and EZH2 in EOCs. Notably, high NF-YA expression predicts shorter overall survival in patients with EOCs. The association of NF-YA with the promoter of the human EZH2 gene is enhanced in human EOC cells compared with primary HOSE cells. Significantly, knockdown of NF-YA downregulates EZH2, decreases H3K27Me3 levels, and suppresses the growth of human EOC cells both in vitro and in a xenograft mouse model. Notably, NF-YA knockdown induces apoptosis of EOC cells and ectopic EZH2 expression partially rescues apoptosis induced by NF-YA knockdown. Together, these data reveal that NF-Y is a key regulator of EZH2 expression and is required for EOC cell proliferation, thus representing a novel target for developing EOC therapeutics. Mol Cancer Res; 11(4); 360–9. ©2013 AACR.
Endovascular Treatment for Infrainguinal Vessels in Patients With Critical Limb Ischemia
Authors: Iida Osamu , Nakamura Masato , Yamauchi Yasutaka , Kawasaki Daizo , Yokoi Yoshiaki , Yokoi Hiroyoshi , Soga Yoshimistu , Zen Kan , Hirano Keisuke , Suematsu Nobuhiro , Inoue Naoto , Suzuki Kenji , Shintani Yoshiaki , Miyashita Yusuke , Urasawa Kazushi , Kitano Ikuro , Yamaoka Terutoshi , Murakami Takashi , Uesugi Michitaka , Tsuchiya Taketsugu , Shinke Toshiro , Oba Yasuhiro , Ohura Norihiko , Hamasaki Toshimitsu , Nanto Shinsuke 
Published: January 2013

Background—
Recent technical advances have made endovascular treatment (EVT) an alternative first-line treatment for critical limb ischemia.

Methods and Results—

A prospective multicenter study was conducted to evaluate the clinical outcomes of 314 Japanese critical limb ischemia patients (mean age, 73±10 years) with infrainguinal arterial lesions who underwent EVT. Patients were enrolled from December 2009 to July 2011 and were followed-up for 12 months. The primary end point was amputation-free survival (AFS) at 12 months. Secondary end points were anatomic, clinical, and hemodynamic measures, including 12-month freedom from major adverse limb events. The 12-month AFS rate was 74%, with body mass index <18.5 (hazard ratio [HR], 2.22;
P
=0.008), heart failure (HR, 1.73;
P
=0.04), and wound infection (HR, 1.89;
P
=0.03) associated with a poor prognosis for AFS. The 12-month major adverse limb event-free rate was 88%, with hemodialysis (HR, 1.98;
P
=0.005), heart failure (HR, 1.69;
P
=0.02), and Rutherford classification 6 (HR, 2.25;
P
=0.002) associated with a poor prognosis for major adverse limb events. The median time for wound healing was 97 days, with body mass index <18.5 (HR, 0.54;
P
=0.03) and wound infection (HR, 0.60;
P
=0.04) being significant risk factors for unhealed wounds after EVT. At 12 months, 34% had undergone reintervention (bypass surgery, 2.6%; repeat EVT, 31.7%), and 73% were major adverse event–free.

Conclusions—
The high reintervention rate notwithstanding, EVT was an effective treatment for Japanese critical limb ischemia patients with infrainguinal disease, with satisfactory AFS and major adverse limb event-free rates. The results of this study will be helpful for the future evaluation of critical limb ischemia therapy.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr
. Unique identifier: UMIN000002830.
G Protein–Coupled Estrogen Receptor Agonist Improves Cerebral Microvascular Function After Hypoxia/Reoxygenation Injury in Male and Female Rats
Authors: Murata Takahiro , Dietrich Hans H. , Xiang Chuanxi , Dacey Ralph G. 
Published: January 2013

Background and Purpose—
Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein–coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury.

Methods—
Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls.

Results—
G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls.

Conclusions—
GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury.
Chronic Apraxia of Speech and Broca’s Area
Authors: Trupe Lydia A. , Varma Daniel D. , Gomez Yessenia , Race David , Leigh Richard , Hillis Argye E. , Gottesman Rebecca F. 
Published: January 2013

Background and Purpose—
Apraxia of speech (AOS) is an impairment of motor planning and programming of speech articulation and is often considered an important stroke syndrome, localizable to Broca’s area. However, an influential study raised doubts on this localization and reported that AOS is attributable to lesions of the anterior insula, based on an association between chronic AOS and anterior insula lesions. We hypothesized that chronic AOS is associated with large lesions (which include the insula) or lesions to Broca’s area.

Method—
We tested 34 participants with chronic left supratentorial stroke on an AOS battery and obtained concurrent magnetic resonance imaging. We evaluated associations between AOS and locations and volume of infarct.

Results—
The presence of chronic AOS (n=17) was associated with volume of infarct, but was also associated with infarct in Broca’s area (and several other regions, but not anterior insula) in both volume- and age-adjusted linear regression and the dichotomous analysis. Carotid dissection was more common, and cardioembolism less common, as a cause of stroke in patients with AOS compared with those without. Severity of AOS was also strongly associated with lesion volume.

Conclusions—
Persistence of AOS after 12 months is associated with large left hemispheric stroke and strokes that involve Broca’s area or other relatively anterior areas to which it is structurally or functionally connected. Patients with such lesions may benefit from early training in the use of technologies to support speech production and communication.
Association of Parental Stroke With Brain Injury and Cognitive Measures in Offspring
Authors: Weinstein Galit , Beiser Alexa S. , Au Rhoda , DeCarli Charles , Wolf Philip A. , Seshadri Sudha 
Published: January 2013

Background and Purpose—
Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke.

Methods—
Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors.

Results—

Stroke- and dementia-free Framingham Offspring (n=1297, age, 61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (β=0.17±0.08;
P
=0.027) and with lower visual memory performance (β= −0.80±0.34;
P
=0.017). During a 6-year follow-up, parental stroke was also associated with increase in white matter hyperintensity volume (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.03–3.38) and decline in executive function (Trails B–A; OR, 1.81; 95% CI, 1.06–3.09). The associations with white matter hyperintensity volume and visual memory attenuated after additional adjustment for concomitant vascular risk factors.

Conclusions—
Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors.
The Functional Topography and Temporal Dynamics of Overlapping and Distinct Brain Activations for Adaptive Task Control and Stable Task-set Maintenance during Performance of an fMRI-adapted Clinical Continuous Performance Test
Authors: Olsen Alexander , Ferenc Brunner Jan , Evensen Kari Anne Indredavik , Garzon Benjamin , Landrø Nils Inge , Håberg Asta Kristine 
Published: January 2013

Abstract
Previous studies have demonstrated that stable and adaptive attention processes are mediated by partly overlapping, but distinct, brain areas. Dorsal medial PFC and anterior insula may form a “core network” for attention control, which is believed to operate on both temporal scales. However, both the existence of such a network as well as the unique functional topography for adaptive and stable attention processes is still highly debated. In this study, 87 healthy participants performed a clinical not-X continuous performance test optimized for use in a mixed block and event-related fMRI design. We observed overlapping activations related to stable and adaptive attention processes in dorsal medial PFC and anterior insula/adjacent cortex as well as in the right inferior parietal lobe and middle temporal gyrus. We also identified areas of activations uniquely related to stable and adaptive attention processes in widespread cortical, cerebellar, and subcortical areas. Interestingly, the functional topography within the PFC indicated a rostro-caudal distribution of adaptive, relative to stable, attention processes. There was also evidence for a time-on-task effect for activations related to stable, but not adaptive, attention processes. Our results provide further evidence for a “core network” for attention control that is accompanied by unique areas of activation involved in domain-specific processes operating on different temporal scales. In addition, our results give new insights into the functional topography of stable and adaptive attention processes and their temporal dynamics in the context of an extensively used clinical attention test.
Contextual Processing of Abstract Concepts Reveals Neural Representations of Nonlinguistic Semantic Content
Authors: Wilson-Mendenhall Christine D. , Simmons W. Kyle , Martin Alex , Barsalou Lawrence W. 
Published: January 2013

Abstract
Concepts develop for many aspects of experience, including abstract internal states and abstract social activities that do not refer to concrete entities in the world. The current study assessed the hypothesis that, like concrete concepts, distributed neural patterns of relevant nonlinguistic semantic content represent the meanings of abstract concepts. In a novel neuroimaging paradigm, participants processed two abstract concepts (convince, arithmetic) and two concrete concepts (rolling, red) deeply and repeatedly during a concept–scene matching task that grounded each concept in typical contexts. Using a catch trial design, neural activity associated with each concept word was separated from neural activity associated with subsequent visual scenes to assess activations underlying the detailed semantics of each concept. We predicted that brain regions underlying mentalizing and social cognition (e.g., medial prefrontal cortex, superior temporal sulcus) would become active to represent semantic content central to convince, whereas brain regions underlying numerical cognition (e.g., bilateral intraparietal sulcus) would become active to represent semantic content central to arithmetic. The results supported these predictions, suggesting that the meanings of abstract concepts arise from distributed neural systems that represent concept-specific content.
Neural Responses to Ambiguity Involve Domain-general and Domain-specific Emotion Processing Systems
Authors: Neta Maital , Kelley William M. , Whalen Paul J. 
Published: January 2013

Abstract
Extant research has examined the process of decision making under uncertainty, specifically in situations of ambiguity. However, much of this work has been conducted in the context of semantic and low-level visual processing. An open question is whether ambiguity in social signals (e.g., emotional facial expressions) is processed similarly or whether a unique set of processors come on-line to resolve ambiguity in a social context. Our work has examined ambiguity using surprised facial expressions, as they have predicted both positive and negative outcomes in the past. Specifically, whereas some people tended to interpret surprise as negatively valenced, others tended toward a more positive interpretation. Here, we examined neural responses to social ambiguity using faces (surprise) and nonface emotional scenes (International Affective Picture System). Moreover, we examined whether these effects are specific to ambiguity resolution (i.e., judgments about the ambiguity) or whether similar effects would be demonstrated for incidental judgments (e.g., nonvalence judgments about ambiguously valenced stimuli). We found that a distinct task control (i.e., cingulo-opercular) network was more active when resolving ambiguity. We also found that activity in the ventral amygdala was greater to faces and scenes that were rated explicitly along the dimension of valence, consistent with findings that the ventral amygdala tracks valence. Taken together, there is a complex neural architecture that supports decision making in the presence of ambiguity: (a) a core set of cortical structures engaged for explicit ambiguity processing across stimulus boundaries and (b) other dedicated circuits for biologically relevant learning situations involving faces.
The Involvement of the Thalamus in Semantic Retrieval: A Clinical Group Study
Authors: Pergola Giulio , Bellebaum Christian , Gehlhaar Britta , Koch Benno , Schwarz Michael , Daum Irene , Suchan Boris 
Published: January 2013

Abstract
There is increasing attention about the role of the thalamus in high cognitive functions, including memory. Although the bulk of the evidence refers to episodic memory, it was recently proposed that the mediodorsal (MD) and the centromedian–parafascicular (CM–Pf) nuclei of the thalamus may process general operations supporting memory performance, not only episodic memory. This perspective agrees with other recent fMRI findings on semantic retrieval in healthy participants. It can therefore be hypothesized that lesions to the MD and the CM–Pf impair semantic retrieval. In this study, 10 patients with focal ischemic lesions in the medial thalamus and 10 healthy controls matched for age, education, and verbal IQ performed a verbal semantic retrieval task. Patients were assigned to a target clinical group and a control clinical group based on lesion localization. Patients did not suffer from aphasia and performed in the range of controls in a categorization and a semantic association task. However, target patients performed poorer than healthy controls on semantic retrieval. The deficit was not because of higher distractibility but of an increased rate of false recall and, in some patients, of a considerably increased rate of misses. The latter deficit yielded a striking difference between the target and the control clinical groups and is consistent with anomia. Follow-up high-resolution structural scanning session in a subsample of patients revealed that lesions in the CM–Pf and MD were primarily associated with semantic retrieval deficits. We conclude that integrity of the MD and the CM–Pf is required for semantic retrieval, possibly because of their role in the activation of phonological representations.