bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum CD163 and TARC as Disease Response Biomarkers in Classical Hodgkin Lymphoma
Authors: Jones Kimberley , Vari Frank , Keane Colm , Crooks Pauline , Nourse Jamie P. , Seymour Louise A. , Gottlieb David , Ritchie David , Gill Devinder , Gandhi Maher K. 
Published: December 2012

Abstract
Purpose: Candidate circulating disease response biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin–Reed–Sternberg (HRS) cells or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, whereas benign CD163+ M2 tissue-associated macrophages (TAM) are prominent. CD163+ cells within the malignant node may be prognostic, but there is no data on serum CD163 (sCD163). The HRS-specific serum protein sTARC shows promise as a disease response biomarker. Tumor-specific and tumor-infiltrating circulating biomarkers have not been compared previously.
Experimental Design: We prospectively measured sCD163 and sTARC in 221 samples from 47 patients with Hodgkin lymphoma and 21 healthy participants. Blood was taken at five fixed time-points prior, during, and after first-line therapy. Results were compared with radiological assessment and plasma Epstein-Barr virus DNA (EBV-DNA). Potential sources of circulating CD163 were investigated, along with immunosuppressive properties of CD163.
Results: Pretherapy, both sCD163 and sTARC were markedly elevated compared with healthy and complete remission samples. sCD163 better reflected tumor burden during therapy, whereas sTARC had greater value upon completion of therapy. sCD163 correlated with plasma EBV-DNA, and associated with B symptoms, stage, and lymphopenia. Circulating CD163+ monocytes were elevated in patients, indicating that sCD163 are likely derived from circulating and intratumoral cells. Depletion of cHL CD163+ monocytes markedly enhanced T-cell proliferation, implicating monocytes and/or TAMs as potential novel targets for immunotherapeutic manipulation.
Conclusion: The combination of circulating tumor-infiltrate (sCD163) and tumor-specific (sTARC) proteins is more informative than either marker alone as disease response biomarkers in early and advanced disease during first-line therapy for cHL. Clin Cancer Res; 19(3); 731–42. ©2012 AACR.
PLK1 Inhibitors Synergistically Potentiate HDAC Inhibitor Lethality in Imatinib Mesylate–Sensitive or –Resistant BCR/ABL+ Leukemia Cells In Vitro and In Vivo
Authors: Dasmahapatra Girija , Patel Hiral , Nguyen Tri , Attkisson Elisa , Grant Steven 
Published: December 2012

Abstract
Purpose: To determine whether Polo-like kinase 1 (PLK1) inhibitors (e.g., BI2536) and histone deacetylase (HDAC) inhibitors (e.g., vorinostat) interact synergistically in the BCR/ABL+ leukemia cells sensitive or resistant to imatinib mesylate (IM) in vitro and in vivo.
Experimental Design: K562 and LAMA84 cells sensitive or resistant to imatinib mesylate and primary CML cells were exposed to BI2536 and vorinostat. Effects on cell viability and signaling pathways were determined using flow cytometry, Western blotting, and gene transfection. K562 and BV173/E255K animal models were used to test in vivo efficacy.
Results: Cotreatment with BI2536 and vorinostat synergistically induced cell death in parental or imatinib mesylate–resistant BCR/ABL+ cells and primary CD34+ bone marrow cells but was minimally toxic to normal cells. BI2536/vorinostat cotreatment triggered pronounced mitochondrial dysfunction, inhibition of p-BCR/ABL, caspase activation, PARP cleavage, reactive oxygen species (ROS) generation, and DNA damage (manifest by increased expression of γH2A.X, p-ATM, p-ATR), events attenuated by the antioxidant TBAP. PLK1 short hairpin RNA (shRNA) knockdown significantly increased HDACI lethality, whereas HDAC1–3 shRNA knockdown reciprocally increased BI2536-induced apoptosis. Genetic interruption of the DNA damage linker H1.2 partially but significantly reduced PLK1/HDAC inhibitor–mediated cell death, suggesting a functional role for DNA damage in lethality. Finally, BI2536/vorinostat cotreatment dramatically reduced tumor growth in both subcutaneous and systemic BCR/ABL+ leukemia xenograft models and significantly enhanced animal survival.
Conclusions: These findings suggest that concomitant PLK1 and HDAC inhibition is active against imatinib mesylate–sensitive or refractory CML and ALL cells both in vitro and in vivo and that this strategy warrants further evaluation in the setting of BCR/ABL+ leukemias. Clin Cancer Res; 19(2); 404–14. ©2012 AACR.
Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells
Authors: Sapra Puja , Damelin Marc , DiJoseph John , Marquette Kimberly , Geles Kenneth G. , Golas Jonathon , Dougher Maureen , Narayanan Bitha , Giannakou Andreas , Khandke Kiran , Dushin Russell , Ernstoff Elana , Lucas Judy , Leal Mauricio , Hu George , O'Donnell Christopher J. , Tchistiakova Lioudmila , Abraham Robert T. , Gerber Hans-Peter 
Published: December 2012

Abstract
Antibody–drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non–small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/cycle × 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38–47. ©2012 AACR.
Gamma-amino Butyric Acid (GABA) Prevents the Induction of Nicotinic Receptor–Regulated Signaling by Chronic Ethanol in Pancreatic Cancer Cells and Normal Duct Epithelia
Authors: Al-Wadei Mohammed H. , Al-Wadei Hussein A.N. , Schuller Hildegard M. 
Published: December 2012

Abstract
Pancreatic cancer has a high mortality rate and alcoholism is a risk factor independent of smoking. We have shown that nicotinic acetylcholine receptors (nAChR) regulate pancreatic ductal epithelia and pancreatic ductal adenocarcinoma (PDAC) cells in an autocrine fashion by stimulating their production of the stress neurotransmitters noradrenaline and adrenaline that signal through β-adrenergic receptors (β-AR). Our current study has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by γ-amino butyric acid (GABA).
Using MTT assays, cell migration assays, Western blotting, immunoassays, and gene knockdown of individual nAChRs in two PDAC cell lines and in immortalized human pancreatic duct epithelial cells, our data show that treatment for seven days with ethanol induced the protein expression and sensitivity of nAChRs α3, α5, and α7 resulting in increased production of noradrenaline and adrenaline, which drive proliferation and migration via cyclic AMP (cAMP)-dependent signaling downstream of β-ARs. Treatment with GABA prevented all of these responses to chronic ethanol, reducing cell proliferation and migration below base levels in untreated cells.
Our findings suggest that alcoholism induces multiple cAMP-dependent PDAC stimulating signaling pathways by upregulating the protein expression and sensitivity of nAChRs that regulate stress neurotransmitter production. Moreover, our data identify GABA as a promising agent for the prevention of PDAC in individuals at risk due to chronic alcohol consumption. Cancer Prev Res; 6(2); 139–48. ©2012 AACR.
Results From a Carotid Intima-Media Thickness Trial as a Decision Tool for Launching a Large-Scale Morbidity and Mortality Trial
Authors: Peters Sanne A. E. , den Ruijter Hester M. , Grobbee Diederick E. , Bots Michiel L. 
Published: December 2012

Background—
Trials with carotid intima-media thickness (CIMT) as primary end point may improve the efficiency of the evaluation of new therapies targeting atherosclerosis considerably, and the results of CIMT trials may be used as a decision tool to help in the choice to launch or not to launch a large-scale morbidity and mortality (M&M) trial. We evaluated the literature to provide evidence to support or refute this proposition.

Methods and Results—
PubMed Medline was systematically searched on May 1, 2012, for randomized double-blind controlled CIMT trials. The agreement between the results from CIMT and M&M trials was assessed, and positive and negative predictive values were calculated. Forty-eight CIMT trials were included. CIMT trials (n=20) on lipid-level modifying therapies are all, except one, in agreement with the M&M trial findings. For blood pressure-lowering trials (n=13), 3 were not congruent with the M&M trial. The positive and negative predictive value (95% confidence interval) of a CIMT trial to predict the outcome of a M&M trial are 96% (80–99%) and 83% (64–93%), respectively. The predictive values are higher for lipid-level modifying therapies than for other therapies.

Conclusions—
A CIMT trial positioned before an M&M trial may considerably improve the efficiency of the evaluation of new drug therapies on atherosclerosis and cardiovascular disease risk. Hence, the results of a CIMT trial should be seen as a decision tool to support or refute the start of a large-scale M&M trial on drugs targeting atherosclerosis.
Protein Kinase C-β Contributes to Impaired Endothelial Insulin Signaling in Humans With Diabetes Mellitus
Authors: Tabit Corey E. , Shenouda Sherene M. , Holbrook Monica , Fetterman Jessica L. , Kiani Soroosh , Frame Alissa A. , Kluge Matthew A. , Held Aaron , Dohadwala Mustali M. , Gokce Noyan , Farb Melissa G. , Rosenzweig James , Ruderman Neil , Vita Joseph A. , Hamburg Naomi M. 
Published: December 2012

Background—
Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling, through the activity of protein kinase C-β (PKCβ) and nuclear factor κB, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus.

Methods and Results—

We measured protein expression and insulin response in freshly isolated endothelial cells from patients with type 2 diabetes mellitus (n=40) and nondiabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes mellitus (
P
=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in nondiabetic subjects but not in diabetic patients (
P
=0.003), consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients, indicating endothelial oxidative stress. PKCβ expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=−0.541,
P
=0.02). Inhibition of PKCβ with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes mellitus. Endothelial nuclear factor κB activation was higher in diabetes mellitus and was reduced with PKCβ inhibition.

Conclusions—
We provide evidence for the presence of altered eNOS activation, reduced insulin action, and inflammatory activation in the endothelium of patients with diabetes mellitus. Our findings implicate PKCβ activity in endothelial insulin resistance.
fMRI Investigation of Monocular Pattern Rivalry
Authors: Mendola Janine D. , Buckthought Athena 
Published: December 2012

Abstract
In monocular pattern rivalry, a composite image is shown to both eyes. The patient experiences perceptual alternations in which the two stimulus components alternate in clarity or salience. We used fMRI at 3T to image brain activity while participants perceived monocular rivalry passively or indicated their percepts with a task. The stimulus patterns were left/right oblique gratings, face/house composites, or a nonrivalrous control stimulus that did not support the perception of transparency or image segmentation. All stimuli were matched for luminance, contrast, and color. Compared with the control stimulus, the cortical activation for passive viewing of grating rivalry included dorsal and ventral extrastriate cortex, superior and inferior parietal regions, and multiple sites in frontal cortex. When the BOLD signal for the object rivalry task was compared with the grating rivalry task, a similar whole-brain network was engaged, but with significantly greater activity in extrastriate regions, including V3, V3A, fusiform face area (FFA), and parahippocampal place area (PPA). In addition, for the object rivalry task, FFA activity was significantly greater during face-dominant periods whereas parahippocampal place area activity was greater during house-dominant periods. Our results demonstrate that slight stimulus changes that trigger monocular rivalry recruit a large whole-brain network, as previously identified for other forms of bistability. Moreover, the results indicate that rivalry for complex object stimuli preferentially engages extrastriate cortex. We also establish that even with natural viewing conditions, endogenous attentional fluctuations in monocular pattern rivalry will differentially drive object-category-specific cortex, similar to binocular rivalry, but without complete suppression of the nondominant image.
Neural Representation of Targets and Distractors during Object Individuation and Identification
Authors: Jeong Su Keun , Xu Yaoda 
Published: December 2012

Abstract
In many everyday activities, we need to attend and encode multiple target objects among distractor objects. For example, when driving a car on a busy street, we need to simultaneously attend objects such as traffic signs, pedestrians, and other cars, while ignoring colorful and flashing objects in display windows. To explain how multiple visual objects are selected and encoded in visual STM and in perception in general, the neural object file theory argues that, whereas object selection and individuation is supported by inferior intraparietal sulcus (IPS), the encoding of detailed object features that enables object identification is mediated by superior IPS and higher visual areas such as the lateral occipital complex (LOC). Nevertheless, because task-irrelevant distractor objects were never present in previous studies, it is unclear how distractor objects would impact neural responses related to target object individuation and identification. To address this question, in two fMRI experiments, we asked participants to encode target object shapes among distractor object shapes, with targets and distractors shown in different spatial locations and in different colors. We found that distractor-related neural processing only occurred at low, but not at high, target encoding load and impacted both target individuation in inferior IPS and target identification in superior IPS and LOC. However, such distractor-related neural processing was short-lived, as it was only present during the visual STM encoding but not the delay period. Moreover, with spatial cuing of target locations in advance, distractor processing was attenuated during target encoding in superior IPS. These results are consistent with the load theory of visual information processing. They also show that, whereas inferior IPS and LOC were automatically engaged in distractor processing under low task load, with the help of precuing, superior IPS was able to only encode the task-relevant visual information.
TMS Interference with Primacy and Recency Mechanisms Reveals Bimodal Episodic Encoding in the Human Brain
Authors: Innocenti Iglis , Cappa Stefano F. , Feurra Matteo , Giovannelli Fabio , Santarnecchi Emiliano , Bianco Giovanni , Cincotta Massimo , Rossi Simone 
Published: December 2012

Abstract
A classic finding of the psychology of memory is the “serial position effect.” Immediate free recall of a word list is more efficient for items presented early (primacy effect) or late (recency effect), with respect to those in the middle. In an event-related, randomized block design, we interfered with the encoding of unrelated words lists with brief trains of repetitive TMS (rTMS), applied coincidently with the acoustic presentation of each word to the left dorsolateral pFC, the left intraparietal lobe, and a control site (vertex). Interference of rTMS with encoding produced a clear-cut double dissociation on accuracy during immediate free recall. The primacy effect was selectively worsened by rTMS of the dorsolateral pFC, whereas recency was selectively worsened by rTMS of the intraparietal lobe. These results are in agreement with the double dissociation between short-term and long-term memory observed in neuropsychological patients and provide direct evidence of distinct cortical mechanisms of encoding in the human brain.
Decoding Attended Information in Short-term Memory: An EEG Study
Authors: LaRocque Joshua J. , Lewis-Peacock Jarrod A. , Drysdale Andrew T. , Oberauer Klaus , Postle Bradley R. 
Published: December 2012

Abstract
For decades it has been assumed that sustained, elevated neural activity—the so-called active trace—is the neural correlate of the short-term retention of information. However, a recent fMRI study has suggested that this activity may be more related to attention than to retention. Specifically, a multivariate pattern analysis failed to find evidence that information that was outside the focus of attention, but nonetheless in STM, was retained in an active state. Here, we replicate and extend this finding by querying the neural signatures of attended versus unattended information within STM with electroencephalograpy (EEG), a method sensitive to oscillatory neural activity to which the previous fMRI study was insensitive. We demonstrate that in the delay-period EEG activity, there is information only about memory items that are also in the focus of attention. Information about items outside the focus of attention is not detectable. This result converges with the fMRI findings to suggest that, contrary to conventional wisdom, an active memory trace may be unnecessary for the short-term retention of information.
Neurophysiological Correlates of Motor and Working Memory Performance following Subthalamic Nucleus Stimulation
Authors: Selzler Katherine , Burack Michelle , Bender Ryan , Mapstone Mark 
Published: December 2012

Abstract
Subthalamic nucleus (STN) deep brain stimulation (DBS) has become an accepted treatment for the motor manifestations of Parkinson disease (PD). The beneficial motor effects of STN DBS are likely due to modulation of BG output to frontal cortical regions associated with motor control, but the underlying neurophysiology of STN DBS effects, especially at the level of the cortex, is not well understood. In this study, we examined the effects of STN DBS on motor disability and visual working memory, a cognitive process supported by pFC. We tested 10 PD participants off medications, ON and OFF stimulation, along with 20 normal controls on a visual working memory task while simultaneously recording cortical EEG. In the OFF state, PD patients had poor motor function, were slower and less accurate in performing the working memory task, and had greater amplitudes and shorter latencies of the N200 ERP response. DBS improved clinical motor function, reduced N200 amplitudes, and increased N200 latencies but had little effect on working memory performance. We conclude that STN DBS normalizes neurophysiological activity in fronto striatal circuits and this may independently affect motor and cognitive function.
Some Revolutions in Neuroscience
Authors: Gross Charles 
Published: December 2012

AbstractIn the long history of the study of the nervous system, there have been a number of major developments that involved radical and permanent changes in fundamental beliefs and assumptions about the nervous system and in tactics and strategies for studying it. These may be termed Revolutions in Neuroscience. This essay considers eight of these, ranging from the 6th century BCE to the end of the 20th century.
Daytime Local Circulations and Their Interactions in the Seoul Metropolitan Area
Authors: Ryu Young-Hee , Baik Jong-Jin 
Published: December 2012

AbstractDaytime local circulations and their interactions in the Seoul, South Korea, metropolitan area are investigated using a high-resolution mesoscale model. It is found that the urban-breeze circulation interacts strongly with other local circulations, such as sea-breeze, cross-valley, and river-breeze circulations. Inland penetration of the sea breeze is retarded in the morning when moving over the coastal urban area because of the increased surface roughness but is accelerated in the afternoon after passing through the urban area as a result of the landward-convergent flow induced by urban heat islands in the inland urban areas. In the valley region, the cross-valley circulation prevails in the morning and the urban-breeze circulation prevails in the afternoon. The mountainside urban-breeze circulation weakens because of the cross-valley circulation in the opposite direction. On the other hand, the plainside urban-breeze circulation away from the mountain increases in strength as a result of the combined effect of heating from the urban surface and subsidence heating associated with the cross-valley circulation. This strengthened urban breeze acts to inhibit penetration of the sea breeze farther inland, causing the sea breeze to stagnate in Seoul. In the vicinity of the Han River, convergence zones with strong updrafts are formed as a result of the interaction between the urban breeze and the river breeze. When the sea-breeze front encounters the strong updrafts, the vertical velocity of the front at the intersection points increases.