bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice
Authors: Viriyakosol Suganya , Jimenez Maria del Pilar , Gurney Michael A. , Ashbaugh Mark E. , Fierer Joshua 
Published: February 2013

ABSTRACTWe assessed the role of Dectin-1 in the immune response to the pathogenic fungusCoccidioides, bothin vitroandin vivo, using mice with a targeted mutation inClec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflammatory cytokines in a Dectin-1- and β-glucan-dependent manner. The responses of bone marrow-derived dendritic cells (BMDC) to the same stimulants were more complex; interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) secretion was independent of Dectin-1, while IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were largely but not entirely dependent on Dectin-1. After intranasal infection, Dectin-1−/−mice had lower concentrations of IL-12p70, gamma interferon (IFN-γ), IL-1β, and the Th17 cytokines IL-22, IL-23, and 17A in the lung lavage fluid, which may explain why they were significantly more susceptible to pulmonary coccidioidomycosis two weeks after infection. The Dectin-1 mutation was even more deleterious in (B6 × DBA/2)F2mice, which are more resistant to coccidioidomycosis than B6 mice by virtue of protective genes from DBA/2, a genetically resistant strain. We also found that two susceptible strains of mice (B6 and BALB/c) expressed much less Dectin-1 in their lungs than did resistant DBA/2 mice. We conclude that Dectin-1 is necessary for resistance toCoccidioides immitis, that Dectin-1 promotes both Th1 and Th17 protective immune responses to this infection, and that there is a correlation between expression of Dectin-1 by the inflammatory infiltrate and resistance to coccidioidomycosis.IMPORTANCECoccidioidomycosis is a fungal infection endemic in the southwestern United States and neighboring Mexico, causing ~150,000 lung infections in people and resulting in ~17,000 hospitalizations annually in California alone. Very little is known about innate immunity to this fungus. This paper shows that Dectin-1, the primary β-glucan receptor on myeloid cells, is required for resistance to this pathogen. Dectin-1 is part of the innate immune system, and it is needed to direct the acquired immune response toward into a pathway that will lead to macrophage activation. Lungs from infected mice lacking Dectin-1 had lower concentrations of Th1 and Th17 cytokines, two cytokine pathways that are very important for acquired T cell immunity toCoccidioidesspp. This is the first demonstration that Dectin-1 is required for host resistance to a dimorphic, primary pathogenic fungus.
Perceptual Motor Features of Expert Acupuncture Lifting-Thrusting Skills
Authors: Li Jing , Grierson Lawrence E M , Wu Mary X , Breuer Ronny , Carnahan Heather 
Published: February 2013

Background Little is known with regard to how acupuncture skills are optimally taught, learnt and evaluated despite clear evidence that technical skill acquisition is important to trainee success in health professions. Objectives This study reports an investigation of the sensorimotor aspects of the acupuncture lifting-thrusting skill in order to highlight the important kinematic and kinetic features of the action. The study also explores the role of perceptual acuity in accurate acupuncture performance. Methods Twelve novice and 12 expert acupuncturists watched a standardised video demonstrating the mild reinforcing and reducing technique of lifting-thrusting on an acupuncture point and then performed 10 trials of the technique on an artificial skin pad mounted on a six-axis force transducer with an infrared light-emitting diode affixed to the index finger of their dominant hand. The force transducer measured the force applied by participants as they needled the acupuncture point while an optoelectric camera measured the position of the diode. Subsequently, the participants engaged in two tests of general perceptual acuity. Results Repeated measures analyses of variance indicated that experts are more consistent in their trial-by-trial amplitude (p=0.03) and lifting-thrusting velocity (p=0.029) than novices. Measures of perceptual acuity revealed no differences between novices and experts. Conclusions Movement amplitude and velocity consistency are the action features of the mild reinforcing and reducing lifting-thrusting skill that differentiate the performances of experts from novices. The acquisition of acupuncture expertise is a function of extended practice rather than any inherent perceptual ability.
MicroRNA-Related Genetic Variants Associated with Clinical Outcomes in Early-Stage Non–Small Cell Lung Cancer Patients
Authors: Pu Xia , Roth Jack A. , Hildebrandt Michelle A.T. , Ye Yuanqing , Wei Hua , Minna John D. , Lippman Scott M. , Wu Xifeng 
Published: February 2013

Abstract
Given the density of single-nucleotide polymorphisms (SNP) in the human genome and the sensitivity of single-nucleotide changes in microRNA (miRNA) functionality and processing, we asked whether polymorphisms within miRNA processing pathways and binding sites may influence non–small cell lung cancer (NSCLC) patients' prognosis. We genotyped 240 miRNA-related SNPs in 535 patients with stage I and II NSCLCs to determine associations with overall recurrence and survival as well as effect in specific treatment subgroups. After correcting for multiple comparisons, the G allele of FZD4:rs713065 displayed a significant association with decreased risk of death in surgery-only patients [HR, 0.46; 95% confidence interval (CI), 0.32–0.65]. DROSHA:rs6886834 variant A allele (HR, 6.38; 95% CI, 2.49–16.31) remained significant for increased risk of recurrence in the overall and surgery-only populations, respectively. FAS:rs2234978 G allele remained significantly associated with survival in all patients (HR, 0.59; 95% CI, 0.44–0.77), whereas borderline significant in subgroups (surgery-only: HR, 0.59; 95% CI, 0.42–0.84; surgery plus chemo: HR, 0.19; 95% CI, 0.07–0.46). Luciferase assays showed that the FAS SNP created a miR-651 functional binding site. Survival tree analysis was conducted to classify patients into distinct risk subgroups based on their risk genotype combinations. These results indicate that miRNA-related polymorphisms may be associated with NSCLC patients' clinical outcomes through altered miRNA regulation of target genes. Cancer Res; 73(6); 1867–75. ©2013 AACR.
Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signals
Authors: Miyabayashi Koji , Ijichi Hideaki , Mohri Dai , Tada Motohisa , Yamamoto Keisuke , Asaoka Yoshinari , Ikenoue Tsuneo , Tateishi Keisuke , Nakai Yousuke , Isayama Hiroyuki , Morishita Yasuyuki , Omata Masao , Moses Harold L. , Koike Kazuhiko 
Published: February 2013

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the EGF receptor (EGFR) inhibitor erlotinib with gemcitabine has been the only molecular-targeted drug tested so far that has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here, we show that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced mitogen-activated protein kinase signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment. Cancer Res; 73(7); 2221–34. ©2013 AACR.
Intrinsic Resistance to JAK2 Inhibition in Myelofibrosis
Authors: Kalota Anna , Jeschke Grace R. , Carroll Martin , Hexner Elizabeth O. 
Published: February 2013

Abstract
Purpose: Recent results have shown that myeloproliferative neoplasms (MPN) are strongly associated with constitutive activation of the Janus-activated kinase (JAK)2 tyrosine kinase. However, JAK2 inhibitors currently approved or under development for treating myeloproliferative neoplasms do not selectively deplete the malignant clone, and the inhibition of activity of the drug target (JAK2) has not been rigorously evaluated in the clinical studies. Therefore, in this study we developed an in vitro assay to gain insight into how effectively JAK2 activity is inhibited in the samples of patients.
Experimental Design: We treated primary cells from normal donors and patients with MPN with JAK2 inhibitors and measured phosphorylation of downstream targets STAT5 and STAT3 by flow cytometry. Obtained results were next correlated with JAK2 V617F allele burden and plasma cytokine level.
Results: We observed a dose-dependent decrease in pSTAT5 and pSTAT3 in ex vivo treated granulocytes. However, phosphorylation of STAT3 and STAT5 in cells from patients with myelofibrosis was significantly less inhibited when compared with cells from patients with polycythemia vera, essential thrombocythemia, and normal donors. Sensitivity to inhibition did not correlate with JAK2 V617F clonal burden. Mixing studies using plasma from patients with myelofibrosis did not transfer resistance to sensitive cells. Likewise, no single cytokine measured seemed to account for the observed pattern of resistance.
Conclusions:Taken together, these observations suggest that there are cell intrinsic mechanisms that define a priori resistance to JAK2 inhibition in myelofibrosis, and the lesion is localized upstream of STAT3 and STAT5. Clin Cancer Res; 19(7); 1729–39. ©2013 AACR.
EpCAM Modulates NF-κB Signaling and Interleukin-8 Expression in Breast Cancer
Authors: Sankpal Narendra V. , Fleming Timothy P. , Gillanders William E. 
Published: February 2013

Abstract
The epithelial cell adhesion molecule (EpCAM) is a 40-kD type I transmembrane protein that is overexpressed in human epithelial cancers and is currently the target of molecular therapy based on its overexpression at the cell surface. Recently, we and others have shown a role for EpCAM in cell signaling and carcinogenesis, and EpCAM expression seems to promote breast cancer invasion. Interleukin-8 (IL-8/CXCL-8) is an inflammatory cytokine that has recently been shown to modulate breast cancer invasion and angiogenesis. In preliminary experiments, we identified a correlation between EpCAM and IL-8 expression in primary human breast cancers. Specific ablation of EpCAM in breast cancer cell lines results in decreased IL-8 expression, and IL-8 contributes to EpCAM-dependent breast cancer invasion. Specific ablation of EpCAM is also associated with decreased NF-κB transcription factor activity, decreased phosphorylation of the NF-κB family member RELA, and increased IκBα protein expression. EpCAM modulates IL-8 expression at baseline, and following IL-1β stimulation, which is known to be a potent inducer of NF-κB in breast cancer. In functional rescue experiments, specific ablation of RELA or forced expression of the NF-κB inhibitor protein IκBα prevented EpCAM-dependent rescue of IL-8 promoter activity. These studies show for the first time that EpCAM can modulate NF-κB transcription factor activity and IL-8 expression in breast cancer and confirm the role of EpCAM signaling in modulating breast cancer invasion. Further study is required to define the molecular mechanism(s) of EpCAM signaling in breast cancer and to direct the rational development of molecular therapies targeting EpCAM. Mol Cancer Res; 11(4); 418–26. ©2013 AACR.
The HER2- and Heregulin β1 (HRG)–Inducible TNFR Superfamily Member Fn14 Promotes HRG-Driven Breast Cancer Cell Migration, Invasion, and MMP9 Expression
Authors: Asrani Kaushal , Keri Ruth A. , Galisteo Rebeca , Brown Sharron A.N. , Morgan Sarah J. , Ghosh Arundhati , Tran Nhan L. , Winkles Jeffrey A. 
Published: February 2013

Abstract
HER2 overexpression occurs in 15% to 20% of all breast cancers and is associated with increased metastatic potential and poor patient survival. Abnormal HER2 activation, either through HER2 overexpression or heregulin (HRG):HER3 binding, elicits the formation of potent HER2–HER3 heterodimers and drives breast cancer cell growth and metastasis. In a previous study, we found that fibroblast growth factor-inducible 14 (Fn14), a member of the TNF receptor superfamily, was frequently overexpressed in human HER2+ breast tumors. We report here that HER2 and Fn14 are also coexpressed in mammary tumors that develop in two different transgenic mouse models of breast cancer. In consideration of these findings, we investigated whether HER2 activation in breast cancer cells could directly induce Fn14 gene expression. We found that transient or stable transfection of MCF7 cells with a HER2 expression plasmid increased Fn14 protein levels. Also, HRG1-β1 treatment of MCF7 cells transiently induced Fn14 mRNA and protein expression. Both the HER2- and HRG1-β1–induced increase in Fn14 expression in MCF7 cells as well as basal Fn14 expression in HER2 gene-amplified AU565 cells could be reduced by HER2 kinase inhibition with lapatinib or combined HER2 and HER3 depletion using siRNA. We also report that Fn14-depleted, HER2-overexpressing MCF7 cells have reduced basal cell migration capacity and reduced HRG1-β1–stimulated cell migration, invasion, and matrix metalloproteinase (MMP)-9 expression. Together, these results indicate that Fn14 may be an important downstream regulator of HER2/HER3–driven breast cancer cell migration and invasion. Mol Cancer Res; 11(4); 393–404. ©2013 AACR.
Equivalent Benefit of Rapamycin and a Potent mTOR ATP-Competitive Inhibitor, MLN0128 (INK128), in a Mouse Model of Tuberous Sclerosis
Authors: Guo Yanan , Kwiatkowski David J. 
Published: February 2013

Abstract
Tuberous sclerosis complex (TSC) is a hamartoma syndrome in which brain, renal, and lung tumors develop and cause both morbidity and death. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1. Rapamycin and related drugs have been shown to have clinical benefit for these tumors in patients with TSC and those with sporadic forms of TSC-related neoplasms. However, lifelong therapy seems to be required, as tumors are not eliminated by this treatment. We examined the potential benefit of MLN0128, a novel potent mTOR ATP-competitive inhibitor, as a therapeutic strategy for renal cystadenomas that develop in A/J Tsc2+/− mice. Rapamycin given by intraperitoneal injection at 3 mg/kg 3 times per week, and MLN0128 given by gavage at 0.75 mg/kg 5 times per week had equivalent effects in suppressing tumor development during a 4-week treatment period, with an approximate 99% reduction in microscopic tumor cell volume. Marked reduction in activation of mTOR complex (mTORC)1 and blockade of cell growth was seen with both drugs, whereas only MLN0128 treatment had effects in blocking mTORC2 and 4EBP1 phosphorylation. However, when either drug was discontinued and mice were observed for two additional months, there was dramatic recovery of tumor growth, with extensive proliferation. Hence, longlasting tumor growth control is not achieved with transient treatment with either drug, and MLN0128 and rapamycin have equivalent therapeutic benefit in this mouse model. Differences in side-effect profiles might make MLN0128 more attractive for treatment of patients with TSC-related tumors, but will require additional study in humans. Mol Cancer Res; 11(5); 467–73. ©2013 AACR.
Resonance of Moral Shocks in Abolitionist Animal Rights Advocacy: Overcoming Contextual Constraints
Authors: Wrenn Corey Lee 
Published: February 2013

Abstract
Jasper and Poulsen (1995) have long argued that moral shocks are critical for recruitment in the nonhuman animal rights movement. Building on this, Decoux (2009) argues that the abolitionist faction of the nonhuman animal rights movement fails to recruit members because it does not effectively utilize descriptions of suffering. However, the effectiveness of moral shocks and subsequent emotional reactions has been questioned. This article reviews the literature surrounding the use of moral shocks in social movements. Based on this review, it is suggested that the exploitation of emotional reactions to depictions of suffering can sometimes prove beneficial to recruitment, but successful use is contextually rooted in preexisting frameworks, ideology, and identity. It is concluded that a reliance on images and narratives might be misconstrued in a society dominated by nonhuman animal welfare ideology.
Philo and the Physiognomic Tradition
Authors: Lincicum David 
Published: February 2013

Abstract
In the context of recent interest in physiognomy among students of ancient Judaism and Christianity, attention to Philo of Alexandria has been strangely lacking. But Philo does evince some knowledge of the practice of physiognomy. After brief orientating remarks, evidence of Philo’s acquaintance with physiognomic topoi is supplied, together with consideration of the weighty objections Philo has to the theoretical underpinnings of strict physiognomics. In the end, Philo may be said to operate with a certain “physiognomic consciousness” even if he does not have the psychological theory and trust in sense-perception necessary to sustain a more far-reaching commitment to the practice.
Role of Interactions between Aerosol Radiative Effect, Dynamics, and Cloud Microphysics on Transitions of Monsoon Intraseasonal Oscillations
Authors: Hazra Anupam , Goswami B. N. , Chen Jen-Ping 
Published: February 2013

Abstract
Extended-range prediction of monsoon intraseasonal oscillations (MISOs), crucial for agriculture and water management, is limited by their event-to-event variability. Here, the authors propose a hypothesis supported by a number of model simulations involving detailed cloud microphysical processes indicating that aerosols contribute significantly to the transitions from “break” to “active” phases of MISO. The role of aerosol indirect effect in the process of invigoration of precipitation is demonstrated with a high-resolution regional model for Indian summer monsoon breaks that are followed by an active condition (BFA) and contrasted with breaks that are not followed by an active condition (BNFA). The BFA are characterized by higher concentrations of absorbing aerosols that lead to a stronger north–south low-level temperature gradient and strong moisture convergence. Forced uplift beyond the freezing level initiates the cold-rain process involving mixed-phase microphysics and latent heat release at higher levels, thereby invigorating convection, enhancing precipitation, and resulting in an active condition. While more aerosols tend to reduce the cloud drop size and delay the warm rain, it is overcome by the higher moisture convergence during BFA and invigoration by cold-rain processes. The net production of rainfall is sensitive to cloud structure as it depends on the relative strength of the warm- and cold-rain initiation processes. The results indicate the importance of aerosols on transitions of MISO and a pathway by which they influence the transitions involving complex interactions between direct radiative forcing, large-scale dynamics, and cloud microphysics. Broader implications of these results in event-to-event variability of MISO and its predictability are also highlighted.
Limitations for Interpreting Failure on Individual Subtests of the Montreal Cognitive Assessment
Authors: Moafmashhadi Parastoo , Koski Lisa 
Published: February 2013

Background: The Montreal Cognitive Assessment (MoCA) is sensitive to mild forms of cognitive impairment in geriatric populations and asks questions under the subheadings visuospatial/executive, naming, attention, language, abstraction, delayed recall, and orientation. This study examined the extent to which these subsets of MoCA items evaluate their intended cognitive domains. Methods: Clinical data from 185 geriatric memory clinic outpatients who underwent cognitive screening and subsequent neuropsychological assessment were analyzed. Factor analysis of their neuropsychological test scores identified 5 cognitive domains memory, language, visuospatial ability, attention/processing speed, and cognitive control. Scores on MoCA subtests were examined for their correlations with individual factor scores and for their sensitivity and specificity in predicting impairment within each domain. Results: The MoCA subtest scores correlated significantly but modestly with neuropsychological test factor scores in their corresponding domains, for example, the correlation between 5-word recall and the memory factor was 0.46. However, subtest scores were poor predictors of impaired performance on the tests contributing to each cognitive domain. The best predictive accuracy was seen for the visuospatial/executive subtest that showed fair accuracy at predicting impairment on tests in the visuospatial domain. Other subtests showed unacceptably poor levels of accuracy when predicting impaired scores in their respective domains (60%-67%). Conclusions: In a sample of geriatric outpatients referred for cognitive assessment, performance on individual items and subtests of the MoCA yields insufficient information to draw conclusions about impairment in specific cognitive domains as determined by neuropsychological testing.
Hallux Valgus in Males—Part 1
Authors: Nery Caio , Coughlin Michael J. , Baumfeld Daniel , Ballerini Flávio José , Kobata Silvia 
Published: February 2013

Background: The high frequency of hallux valgus deformities in females is well known and has been widely reported in the literature. This finding tends to obscure the importance and the characteristic details of hallux valgus deformities in males. The severity of the deformity, its onset at an earlier age, and its inheritability seem to be more frequent in males, but there are no reports in the literature to substantiate these concepts. The purpose of this study was to analyze these questions in regard to males with hallux valgus. Methods: The records and plain radiographs of 31 males (53 feet) with a diagnosis of hallux valgus that were treated over a 20-year period (1985-2005) were analyzed. During that same period, the senior author (CN) performed 812 procedures for the correction of hallux valgus deformities in women. In order to compare gender-related differences associated with this deformity, 31 women’s charts—paired by age and affected side—were randomly selected and both clinical and radiological data were statistically compared. Results: The onset of the complaints of first ray pain in males was equally distributed by decades, indicating that the deformity begins earlier in this group. Among males, we found 68% of the subjects had a familial history of bunion deformities—58% were maternal and 10% were fraternal. In the control group of females, only 35% of the women reported inheritance of the deformity. No correlation with footwear was found among males. The radiographic measurements were significantly higher in the male group, which included the hallux valgus angle (HVA), the distal metatarsal articular angle (DMAA), and the tarsal metatarsal angle (TMA). The main gender difference was found to be the DMAA with first metatarsophalangeal (MTP) joint congruence being much more common in males (males = 57%, females = 30%). No correlations were found for metatarsus primus varus or pes planus. Conclusion: Based on our observations, we conclude that hallux valgus in males is commonly hereditary in nature and is mainly transmitted by the mother, with early onset and higher severity when compared to women. We report a female/male ratio of 15:1. The main intrinsic factor associated with a hallux valgus deformity in males is a high DMAA. Level of Evidence: Level III, retrospective comparative series.