bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulated discharge of Purkinje and stellate cells persists after unilateral loss of vestibular primary afferent mossy fibers in mice
Authors: Barmack N. H. , Yakhnitsa V.
Published: August 2013

Cerebellar Purkinje cells are excited by two afferent pathways: climbing and mossy fibers. Climbing fibers evoke large “complex spikes” (CSs) that discharge at low frequencies. Mossy fibers synapse on granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of “simple spikes” (SSs). Both afferent systems convey vestibular information to folia 9c–10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8–10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c–10, to which vestibular primary afferents project, and in folia 8–9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL-induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In summary, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. Whereas vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the nonspecific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers.
Regulation of dendritic calcium release in striatal spiny projection neurons
Authors: Plotkin Joshua L. , Shen Weixing , Rafalovich Igor , Sebel Luke E. , Day Michelle , Chan C. Savio , Surmeier D. James
Published: August 2013

The induction of corticostriatal long-term depression (LTD) in striatal spiny projection neurons (SPNs) requires coactivation of group I metabotropic glutamate receptors (mGluRs) and L-type Ca2+ channels. This combination leads to the postsynaptic production of endocannabinoids that act presynaptically to reduce glutamate release. Although the necessity of coactivation is agreed upon, why it is necessary in physiologically meaningful settings is not. The studies described here attempt to answer this question by using two-photon laser scanning microscopy and patch-clamp electrophysiology to interrogate the dendritic synapses of SPNs in ex vivo brain slices from transgenic mice. These experiments revealed that postsynaptic action potentials induce robust ryanodine receptor (RYR)-dependent Ca2+-induced-Ca2+ release (CICR) in SPN dendritic spines. Depolarization-induced opening of voltage-gated Ca2+ channels was necessary for CICR. CICR was more robust in indirect pathway SPNs than in direct pathway SPNs, particularly in distal dendrites. Although it did not increase intracellular Ca2+ concentration alone, group I mGluR activation enhanced CICR and slowed Ca2+ clearance, extending the activity-evoked intraspine transient. The mGluR modulation of CICR was sensitive to antagonism of inositol trisphosphate receptors, RYRs, src kinase, and Cav1.3 L-type Ca2+ channels. Uncaging glutamate at individual spines effectively activated mGluRs and facilitated CICR induced by back-propagating action potentials. Disrupting CICR by antagonizing RYRs prevented the induction of corticostriatal LTD with spike-timing protocols. In contrast, mGluRs had no effect on the induction of long-term potentiation. Taken together, these results make clearer how coactivation of mGluRs and L-type Ca2+ channels promotes the induction of activity-dependent LTD in SPNs.
Perceptual learning in sensorimotor adaptation
Authors: Darainy Mohammad , Vahdat Shahabeddin , Ostry David J.
Published: August 2013

Motor learning often involves situations in which the somatosensory targets of movement are, at least initially, poorly defined, as for example, in learning to speak or learning the feel of a proper tennis serve. Under these conditions, motor skill acquisition presumably requires perceptual as well as motor learning. That is, it engages both the progressive shaping of sensory targets and associated changes in motor performance. In the present study, we test the idea that perceptual learning alters somatosensory function and in so doing produces changes to human motor performance and sensorimotor adaptation. Subjects in these experiments undergo perceptual training in which a robotic device passively moves the subject's arm on one of a set of fan-shaped trajectories. Subjects are required to indicate whether the robot moved the limb to the right or the left and feedback is provided. Over the course of training both the perceptual boundary and acuity are altered. The perceptual learning is observed to improve both the rate and extent of learning in a subsequent sensorimotor adaptation task and the benefits persist for at least 24 h. The improvement in the present studies varies systematically with changes in perceptual acuity and is obtained regardless of whether the perceptual boundary shift serves to systematically increase or decrease error on subsequent movements. The beneficial effects of perceptual training are found to be substantially dependent on reinforced decision-making in the sensory domain. Passive-movement training on its own is less able to alter subsequent learning in the motor system. Overall, this study suggests perceptual learning plays an integral role in motor learning.
Spatiotemporal integration for tactile localization during arm movements: a probabilistic approach
Authors: Maij Femke , Wing Alan M. , Medendorp W. Pieter
Published: August 2013

It has been shown that people make systematic errors in the localization of a brief tactile stimulus that is delivered to the index finger while they are making an arm movement. Here we modeled these spatial errors with a probabilistic approach, assuming that they follow from temporal uncertainty about the occurrence of the stimulus. In the model, this temporal uncertainty converts into a spatial likelihood about the external stimulus location, depending on arm velocity. We tested the prediction of the model that the localization errors depend on arm velocity. Participants ( n = 8) were instructed to localize a tactile stimulus that was presented to their index finger while they were making either slow- or fast-targeted arm movements. Our results confirm the model's prediction that participants make larger localization errors when making faster arm movements. The model, which was used to fit the errors for both slow and fast arm movements simultaneously, accounted very well for all the characteristics of these data with temporal uncertainty in stimulus processing as the only free parameter. We conclude that spatial errors in dynamic tactile perception stem from the temporal precision with which tactile inputs are processed.
Electronegative LDL: A Circulating Modified LDL with a Role in Inflammation
Authors: Estruch Montserrat , Sánchez-Quesada José Luis , Ordóñez Llanos Jordi , Benítez Sònia
Published: August 2013

Electronegative low density lipoprotein (LDL(−)) is a minor modified fraction of LDL found in blood. It comprises a heterogeneous population of LDL particles modified by various mechanisms sharing as a common feature increased electronegativity. Modification by oxidation is one of these mechanisms. LDL(−) has inflammatory properties similar to those of oxidized LDL (oxLDL), such as inflammatory cytokine release in leukocytes and endothelial cells. However, in contrast with oxLDL, LDL(−) also has some anti-inflammatory effects on cultured cells. The inflammatory and anti-inflammatory properties ascribed to LDL(−) suggest that it could have a dual biological effect.
Molecular Data for the Sea Turtle Population in Brazil
Authors: Vilaça Sibelle Torres , Santos Fabricio Rodrigues dos
Published: August 2013

We report here a dataset comprising nine nuclear markers for the Brazilian population of Cheloniidae turtles: hawksbills (Eretmochelys imbricata), loggerheads (Caretta caretta), olive ridleys (Lepidochelys olivacea), and green turtles (Chelonia mydas). Because hybridization is a common phenomenon between the four Cheloniidae species nesting on the Brazilian coast, we also report molecular markers for the hybrids E. imbricata × C. caretta, C. caretta × L. olivacea, and E. imbricata × L. olivacea and for one hybrid E. imbricata × C. mydas and one between three species C. mydas × E. imbricata × C. caretta. The data was used in previous studies concerning (1) the description of frequent hybrids C. caretta × E. imbricata in Brazil, (2) the report of introgression in some of these hybrids, and (3) population genetics. As a next step for the study of these hybrids and their evolution, genome‐wide studies will be performed in the Brazilian population of E. imbricata, C. caretta, and their hybrids.
Unsteady Hydromagnetic Heat and Mass Transfer Flow of a Heat Radiating and Chemically Reactive Fluid Past a Flat Porous Plate with Ramped Wall Temperature
Authors: Nandkeolyar R. , Das M. , Sibanda P.
Published: August 2013

Unsteady hydromagnetic free convective flow of a viscous, incompressible, electrically conducting, and heat radiating fluid past a flat plate with ramped wall temperature and suction/blowing is studied. The governing equations are first subjected to Laplace transformation and then inverted numerically usingINVLAProutine of Matlab. The numerical solutions of the fluid properties are presented graphically while the skin friction and heat and mass transfer coefficients are presented in tabular form. The results are verified by a careful comparison with results in the literature for certain parameter values.
Effect of Catalyst Morphology on the Quality of CVD Grown Graphene
Authors: Hsieh Ya-Ping , Wang Yi-Wen , Ting Chu-Chi , Wang Hsiang-Chen , Chen Kuang-Yao , Yang Chang-Chung
Published: August 2013

The strong interest in graphene has motivated large effort in the scalable production of high‐quality material. The potential of chemical vapor deposition on Cu foil to produce such graphene is impeded by lacking understanding of the relation between catalyst properties and graphene performance. We here present a systematic analysis of the catalyst morphology and its effect on electrical properties of graphene. We find that nanometer sized particles increase the density of bilayer regions but have no significant effect on carrier transport. Long wavelength roughness (waviness), on the other hand, generates defective graphitic regions that deteriorate carrier mobility. These findings shed light on the graphene formation process on Cu substrates and open a route to improve graphene quality for electronics applications.
Cognitive Vulnerabilities and Depression in Young Adults: An ROC Curves Analysis
Authors: Balsamo Michela , Imperatori Claudio , Sergi Maria Rita , Belvederi Murri Martino , Continisio Massimo , Tamburello Antonino , Innamorati Marco , Saggino Aristide
Published: August 2013

Objectives and Methods.The aim of the present study was to evaluate, by means of receiver operating characteristic (ROC) curves, whether cognitive vulnerabilities (CV), as measured by three well-known instruments (the Beck Hopelessness Scale, BHS; the Life Orientation Test-Revised, LOT-R; and the Attitudes Toward Self-Revised, ATS-R), independently discriminate between subjects with different severities of depression. Participants were 467 young adults (336 females and 131 males), recruited from the general population. The subjects were also administered the Beck Depression Inventory-II (BDI-II).Results.Four first-order (BHS Optimism/Low Standard; BHS Pessimism; Generalized Self-Criticism; and LOT Optimism) and two higher-order factors (Pessimism/Negative Attitudes Toward Self, Optimism) were extracted using Principal Axis Factoring analysis. Although all first-order and second-order factors were able to discriminate individuals with different depression severities, the Pessimism factor had the best performance in discriminating individuals with moderate to severe depression from those with lower depression severity.Conclusion.In the screening of young adults at risk of depression, clinicians have to pay particular attention to the expression of pessimism about the future.
A Qualitative Study of Barriers to Enrollment into Free HIV Care: Perspectives of Never-in-Care HIV-Positive Patients and Providers in Rakai, Uganda
Authors: Nakigozi Gertrude , Atuyambe Lynn , Kamya Moses , Makumbi Fredrick E. , Chang Larry W. , Nakyanjo Neema , Kigozi Godfrey , Nalugoda Fred , Kiggundu Valerian , Serwadda David , Wawer Maria , Gray Ronald
Published: August 2013

Background. Early entry into HIV care is low in Sub-Saharan Africa. In Rakai, about a third (31.5%) of HIV-positive clients who knew their serostatus did not enroll into free care services. This qualitative study explored barriers to entry into care from HIV-positive clients who had never enrolled in care and HIV care providers.Methods. We conducted 48 in-depth interviews among HIV-infected individuals aged 15–49 years, who had not entered care within six months of result receipt and referral for free care. Key-informant interviews were conducted with 12 providers. Interviews were audio-recorded and transcripts subjected to thematic content analysis based on the health belief model.Results. Barriers to using HIV care included fear of stigma and HIV disclosure, women’s lack of support from male partners, demanding work schedules, and high transport costs. Programmatic barriers included fear of antiretroviral drug side effects, long waiting and travel times, and inadequate staff respect for patients. Denial of HIV status, belief in spiritual healing, and absence of AIDS symptoms were also barriers.Conclusion. Targeted interventions to combat stigma, strengthen couple counseling and health education programs, address gender inequalities, and implement patient-friendly and flexible clinic service hours are needed to address barriers to HIV care.
Endometrial Polyps in Women Affected by Levothyroxine-Treated Hypothyroidism—Histological Features, Immunohistochemical Findings, and Possible Explanation of Etiopathogenic Mechanism: A Pilot Study
Authors: Saccardi Carlo , Gizzo Salvatore , Ludwig Kathrin , Guido Maria , Scarton Mara , Gangemi Michele , Tinelli Raffaele , Litta Pietro Salvatore
Published: August 2013

The aim of the study was to investigate the possible overexpression of estrogen (ERs) and progesterone (PRs) receptors both in EPs glandular and stromal cells in postmenopausal women with levothyroxine-treated hypothyroidism in comparison to EPs detected in women with physiological thyroid hormone levels. During the study period (January-February 2013) 22 patients were eligible (12 treated, 10 controls). The two groups were homogenous for general, EPs sonographic and hysteroscopic features. None of the cases of atypia was found. Immunohistochemistry showed that the two groups were similar for ERs and PRs intensity rates in EPs glandular cells despite a trend of ERs percentage expression more than 60% in 2/3 of treated patients versus 1/3 of controls. In stromal EPs components, ERs intensity was high positive in 10 (83,3%) treated cases while it was high positive in 1 control (10%). Percentage of ERs stromal expression showed a different trend between the two groups despite a borderline statistical significance. Our hypothesis is based on a possible double action of hypothyroidism and thyroxine intake: the subclinical TSH increased levels and its possible circadian oscillation could stimulate the endometrial TSHRs (increasing type 2 DIO activity); the circulating levels of exogenous thyroxine could be locally metabolized in active form by type 2 DIO stimulating ERs.
Clinical Characteristics of Endogenous Cushing’s Syndrome at a Medical Center in Southern Taiwan
Authors: Tung Shih-Chen , Wang Pei-Wen , Liu Rue-Tsuan , Chen Jung-Fu , Hsieh Ching-Jung , Kuo Ming-Chun , Yang Joseph W. , Lee Wei-Ching , Cheng Min-Hsiung , Lee Tao-Chen
Published: August 2013

From January 1987 to December 2011, over a total of 25 years, 84 patients with Cushing’s syndrome (CS) were identified at a medical center in southern Taiwan. We observed a higher incidence of ACTH-independent CS (75%) than ACTH-dependent CS (25%). A higher incidence of adrenocortical adenoma (58.3%) than Cushing’s disease (CD, 21.4%) was also found. The sensitivity of the definitive diagnostic tests for CS, including loss of plasma cortisol circadian rhythm, a baseline 24 h urinary free cortisol (UFC) value >80 μg, and overnight and 2-day low-dose dexamethasone suppression test, was between 94.4% and 100%. For the 2-day high-dose dexamethasone suppression test for the differential diagnosis of CD, the sensitivity of 0800 h plasma cortisol and 24 h UFC was 44.4% and 85.7%, respectively. For the differential diagnosis of adrenal CS, the sensitivities of the 0800 h plasma cortisol and 24 h UFC were 95.5% and 88.9%, respectively. In patients with ACTH-independent CS and ACTH-dependent CS, the baseline plasma ACTH levels were all below 29 pg/mL and above 37 pg/mL, respectively. The postsurgical hospitalization stay following retroperitoneoscopic adrenalectomy was shorter than that observed for transabdominal adrenalectomy (4.3 ± 1.6 versus 8.8 ± 3.7 days,P<0.001). It was easy to develop retroperitoneal and peritoneal seeding of adrenocortical carcinoma via laparoscopic adrenalectomy.
Health Professionals’ Role in Helping Patients Quit Tobacco Use: Attitudes among Iranian Dental Students
Authors: Keshavarz Hooman , Jafari Ahmad , Khami Mohammad Reza , Virtanen Jorma I.
Published: August 2013

Background. Health professionals play an essential role in tobacco control. Our objective was to assess Iranian dental students' attitudes towards tobacco control. Methods. Eight dental schools were randomly selected, and a survey using Global Health Professions Student Survey (GHPSS) instrument was conducted among dental students in 2010 in Iran. The chi-square test served for statistical analyses. Results. Of the participants (325 students, 66% female), about one-fifth (21%) were current tobacco (including cigarettes and waterpipe) users. A clear majority (over 80%) of the students agreed as to the responsibility of health professionals on serving as role models for patients and the public, routinely advising patients using tobacco to quit, and giving patients advice about smoking cessation. Over 75% believed that cigarette-smoking health professionals are less likely to advise their patients to stop smoking. Current tobacco users were significantly less likely to agree with these beliefs (P<0.05). Conclusion. Future oral health professionals have generally positive attitudes towards tobacco control. However, their own current tobacco use has a significant negative impact on these attitudes, an impact which ought to be taken into account in tobacco control.
Clitocybe nudaActivates Dendritic Cells and Acts as a DNA Vaccine Adjuvant
Authors: Chen Mei-Hsing , Li Wei-Sung , Lue Yun-Sheng , Chu Ching-Liang , Pan I-Hong , Ko Ching-Huai , Chen Der-Yuan , Lin Ching-Hsiung , Lin Sheng-Hao , Chang Chih-Peng , Lin Chi-Chen
Published: August 2013

This work represents the first evaluation of the effects of water extract ofC. nuda(WE-CN), an edible mushroom, on murine bone marrow-derived dendritic cells (BMDCs) and the potential pathway through which the effects are mediated. Our experimental results show that WE-CN could induce phenotypic maturation of DCs, as shown by the increased expression of MHC and costimulatory molecules. In addition, it also induced the proinflammatory cytokines expression on DCs and enhanced both the proliferation and IFN-γsecretion of allogenic T cells. Therefore, since WE-CN did not induce maturation of DCs generated from mice with mutated TLR-4 or TLR-2, suggesting that TLR4 and TLR2 might function as membrane receptors for WE-CN. Moreover, the mechanism of action of WE-CN may be mediated by increased phosphorylation of ERK, p38, and JNK mitogen-activated protein kinase (MAPK) and increased NF-κB p65 activity, which are important signaling molecules downstream of TLR-4 and TLR-2. Finally, coimmunization of mice with WE-CN and a HER-2/neu DNA vaccine induced a HER-2/neu-specific Th1 response that resulted in significant inhibition of HER-2/neu overexpressing mouse bladder tumor (MBT-2) growth. These data suggest that WE-CN induces DC maturation through TLR-4 and/or TLR-2 and that WE-CN can be used as an adjuvant in cancer vaccine immunotherapy.
Review on the HVAC System Modeling Types and the Shortcomings of Their Application
Authors: Homod Raad Z.
Published: August 2013

The modeling of the heating, ventilation, and air conditioning (HVAC) system is a prominent topic because of its relationship with energy savings and environmental, economical, and technological issues. The modeling of the HVAC system is concerned with the indoor thermal sensation, which is related to the modeling of building, air handling unit (AHU) equipments, and indoor thermal processes. Until now, many HVAC system modeling approaches are made available, and the techniques have become quite mature. But there are some shortcomings in application and integration methods for the different types of the HVAC model. The application and integration processes will act to accumulate the defective characteristics for both AHU equipments and building models such as nonlinear, pure lag time, high thermal inertia, uncertain disturbance factors, large-scale systems, and constraints. This paper shows types of the HVAC model and the advantages and disadvantages for each application of them, and it finds out that the gray-box type is the best one to represent the indoor thermal comfort. But its application fails at the integration method where its response deviated to unreal behavior.
Epigenetic Alterations and an Increased Frequency of Micronuclei in Women with Fibromyalgia
Authors: Menzies Victoria , Lyon Debra E. , Archer Kellie J. , Zhou Qing , Brumelle Jenni , Jones Kimberly H. , Gao G. , York Timothy P. , Jackson-Cook Colleen
Published: August 2013

Fibromyalgia (FM), characterized by chronic widespread pain, fatigue, and cognitive/mood disturbances, leads to reduced workplace productivity and increased healthcare expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM (n=10) to those seen in comparably aged healthy controls (n=42(MN);n=8(methylation)). The mean (sd) MN frequency of women with FM (51.4 (21.9)) was significantly higher than that of controls (15.8 (8.5)) (χ2=45.552; df = 1;P=1.49×10-11). Significant differences (n=69sites) in methylation patterns were observed between cases and controls considering a 5% false discovery rate. The majority of differentially methylated (DM) sites (91%) were attributable to increased values in the women with FM. The DM sites included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1. Results support the need for future research to further examine the potential role of epigenetic and acquired chromosomal alterations as a possible biological mechanism underlying FM.
Almost Periodic Solution of a Modified Leslie-Gower Predator-Prey Model with Beddington-DeAngelis Functional Response
Authors: Zhang Zhimin
Published: August 2013

We consider a predator-prey model with modified Leslie-Gower and Beddington-DeAngelis functional response. By applying the comparison theorem of the differential equation and constructing a suitable Lyapunov function, sufficient conditions which guarantee the permanence and existence of a unique globally attractive positive almost periodic solution of the system are obtained. Our results not only supplement but also improve some existing ones. One example is presented to verify our main results.
Quality of Life after Stapled Hemorrhoidopexy: A Prospective Observational Study
Authors: Garg Pankaj Kumar , Kumar Gopal , Jain Bhupendra Kumar , Mohanty Debajyoti
Published: August 2013

Objective. The objective of the study was to assess the change in quality of life (QOL) of patients undergoing stapled hemorrhoidopexy (SH) using WHO Quality of Life-BREF (WHOQOL-BREF) questionnaire.Methods. The study sample comprised patients with symptomatic II, III, and IV degree hemorrhoids, undergoing SH. The patients were asked to complete WHOQOL-BREF questionnaire before and one month following the surgery.Result. There were 20 patients in the study group. The postoperative pain score measured by visual analogue scale at six hours postoperatively was at 24 hours. The items in the WHOQOL-BREF had high-internal consistency or reliability as shown by high Cronbach's alpha coefficient which was 0.82 and 0.90 for pre- and postoperative questionnaires. There was significant improvement in the overall perception of QOL and health, and in physical and psychological domains. There was modest improvement in environmental domain, while no change was noted in social domain.Conclusion. SH improved the quality of life of patients treated for hemorrhoids.
Comparative Analysis of Context-Dependent Mutagenesis Using Human and Mouse Models
Authors: Medvedeva Sofya A. , Panchin Alexander Y. , Alexeevski Andrey V. , Spirin Sergey A. , Panchin Yuri V.
Published: August 2013

Substitution rates strongly depend on their nucleotide context. One of the most studied examples is the excess of C > T mutations in the CG context in various groups of organisms, including vertebrates. Studies on the molecular mechanisms underlying this mutation regularity have provided insights into evolution, mutagenesis, and cancer development. Recently several other hypermutable motifs were identified in the human genome. There is an increased frequency of T > C mutations in the second position of the words ATTG and ATAG and an increased frequency of A > C mutations in the first position of the word ACAA. For a better understanding of evolution, it is of interest whether these mutation regularities are human specific or present in other vertebrates, as their presence might affect the validity of currently used substitution models and molecular clocks. A comprehensive analysis of mutagenesis in 4 bp mutation contexts requires a vast amount of mutation data. Such data may be derived from the comparisons of individual genomes or from single nucleotide polymorphism (SNP) databases. Using this approach, we performed a systematical comparison of mutation regularities within 2–4 bp contexts inMus musculusandHomo sapiensand uncovered that even closely related organisms may have notable differences in context-dependent mutation regularities.
EGFR-Activating Mutations Correlate with a Fanconi Anemia–like Cellular Phenotype That Includes PARP Inhibitor Sensitivity
Authors: Pfäffle Heike N. , Wang Meng , Gheorghiu Liliana , Ferraiolo Natalie , Greninger Patricia , Borgmann Kerstin , Settleman Jeffrey , Benes Cyril H. , Sequist Lecia V. , Zou Lee , Willers Henning
Published: August 2013

In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2–M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer. Cancer Res; 73(20); 6254–63. ©2013 AACR.
mRNA Splicing Variants: Exploiting Modularity to Outwit Cancer Therapy
Authors: Dehm Scott M.
Published: August 2013

Systemic cancer therapy has traditionally exploited vulnerabilities in cancer cells, a strategy which has become more precise with the identification and targeting of driver oncogenes. However, persistent tumor growth due to primary (de novo) or secondary (acquired) resistance limits therapeutic efficacy for many patients. Alternative splicing is important for increasing the diversity of the cellular proteome, and is a process frequently deregulated during cancer development and progression. In cancer cells, diverse splicing alterations have been identified that eliminate protein domains or enzymatic activities required for efficacy of cancer therapies, promote gain of novel signaling functions that circumvent cancer therapies, and uncouple signaling pathways from upstream regulatory points that are blocked by cancer therapies. The mechanisms underlying these splicing changes range from stable alterations in gene sequence/structure to deregulation of splicing regulatory factors. In this review, the role of splice variants in cancer therapy resistance will be discussed, with examples of how mechanistic understanding of these processes has led to the development of novel strategies for therapy resensitization. Cancer Res; 73(17); 5309–14. ©2013 AACR.
FOXO Transcription Factors Control E2F1 Transcriptional Specificity and Apoptotic Function
Authors: Shats Igor , Gatza Michael L. , Liu Beiyu , Angus Steven P. , You Lingchong , Nevins Joseph R.
Published: August 2013

The transcription factor E2F1 is a key regulator of proliferation and apoptosis but the molecular mechanisms that mediate these cell fate decisions remain unclear. Here, we identify FOXO transcription factors as E2F1 target genes that act in a feed-forward regulatory loop to reinforce gene induction of multiple apoptotic genes. We found that E2F1 forms a complex with FOXO1 and FOXO3. RNAi-mediated silencing of FOXO impaired E2F1 binding to the promoters of cooperative target genes. A FOXO3 mutant insensitive to inactivation by survival kinases rescued the inhibitory effect of growth factor signaling on E2F1-mediated transcription and apoptosis. The E2F1/FOXO axis is frequently blocked in cancer, as evidenced by the specific downregulation of the FOXO-dependent E2F1 transcriptional program in multiple cancer types and by the association of a reduced E2F1/FOXO transcriptional program with poor prognosis. HDAC and phosphoinositide 3-kinase (PI3K) inhibitors were identified as specific activators of E2F1/FOXO transcription, acting to enhance E2F1-induced apoptosis in a FOXO3-dependent manner. Notably, combining the histone deacetylase inhibitor vorinostat with a PI3K inhibitor led to enhanced FOXO-dependent apoptosis. Collectively, our results identify E2F1/FOXO cooperation as a regulatory mechanism that places E2F1 apoptotic activity under the control of survival signaling. Therapeutic reactivation of this tumor suppressive mechanism may offer a novel broad-acting therapy for cancer. Cancer Res; 73(19); 6056–67. ©2013 AACR.
Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas
Authors: Paugh Barbara S. , Zhu Xiaoyan , Qu Chunxu , Endersby Raelene , Diaz Alexander K. , Zhang Junyuan , Bax Dorine A. , Carvalho Diana , Reis Rui M. , Onar-Thomas Arzu , Broniscer Alberto , Wetmore Cynthia , Zhang Jinghui , Jones Chris , Ellison David W. , Baker Suzanne J.
Published: August 2013

The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. Cancer Res; 73(20); 6219–29. ©2013 AACR.
Pralatrexate Pharmacology and Clinical Development
Authors: Marchi Enrica , Mangone Michael , Zullo Kelly , O'Connor Owen A.
Published: August 2013

Folates are well known to be essential for many cellular processes, including cellular proliferation. As a consequence, antifolates, the fraudulent mimics of folic acid, have been shown to be potent therapeutic agents in many cancers. Over the past several decades, efforts to improve on this class of drugs have met with little success. Recently, one analog specifically designed to have high affinity for the reduced folate carrier, which efficiently internalizes natural folates and antifolates, has been shown to be very active in T-cell lymphoma. Pralatrexate, approved by the U.S. Food and Drug Administration in 2009, is highly active across many lymphoid malignancies, including chemotherapy-resistant T-cell lymphoma. Emerging combination studies have now shown that pralatrexate is highly synergistic with gemcitabine, histone deacetylase inhibitors like romidepsin and bortezomib. These insights are leading to a number of novel phase I and II combination studies which could challenge existing regimens like CHOP, and improve the outcome of patients with T-cell lymphoma Clin Cancer Res; 19(24); 6657–61. ©2013 AACR.
MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways
Authors: Gong Meng , Ma Junrong , Guillemette Ryan , Zhou Mingliang , Yang Yan , Yang Yujing , Hock Janet M. , Yu Xijie
Published: August 2013

Small cell lung cancer (SCLC) is a rapidly progressing, incurable cancer that frequently spreads to bone. New insights are needed to identify therapeutic targets to prevent or retard SCLC metastatic progression. Human SCLC SBC-5 cells in mouse xenograft models home to skeletal and nonskeletal sites, whereas human SCLC SBC-3 cells only pervade nonskeletal sites. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of SCLC. miRNA expression profiling revealed selective and reduced expression of miRNA (miR)-335 and miR-29a in SBC-5 cells, compared with SBC-3 cells. In SBC-5 cells, miR-335 expression correlated with bone osteolytic lesions, whereas miR-29a expression did not. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro. Importantly, in miR-335 overexpressing SBC-5 cell xenografts (n = 10), there were minimal osteolytic lesions in the majority of mice and none in three mice. Expression of RANK ligand (RANKL) and insulin-like growth factor-I receptor (IGF-IR), key mediators of bone metastases, were elevated in SBC-5 as compared with SBC-3 cells. Mechanistically, overexpression of miR-335 in SBC-5 cells reduced RANKL and IGF-IR expression. In conclusion, loss of miR-335 promoted SCLC metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions.

Implications: These preclinical findings establish a need to pursue the role of miR-335 in human SCLC with metastatic skeletal disease. Mol Cancer Res; 12(1); 101–10. ©2013 AACR.
Cold versus Hot Tonsillectomy: State of the Art and Recommendations
Authors: Blanchford Hannah , Lowe David
Published: August 2013

An investigation of the risk factors for haemorrhage after tonsillectomy with particular reference to the use of bipolar diathermy for tonsillar dissection and haemostasis, diathermy power settings and coblation tonsillectomy. The findings of the National Prospective Tonsillectomy Audit and subsequent related research are summarised and discussed with reference to the issue of use of hot versus cold tonsillectomy techniques. Additional unpublished data on coblation tonsillectomy is presented. Overall, increased haemorrhage rates were noted for diathermy dissection tonsillectomy (adjusted odds ratio 2.47, p < 0.0001) and coblation tonsillectomy (adjusted odds ratio 3.07, p < 0.0001) compared to the reference category of cold steel tonsillectomy. Use of bipolar diathermy for haemostasis only carried an intermediate risk of haemorrhage (adjusted odds ratio 1.57, p = 0.004). Further investigation of diathermy power settings demonstrated a quantitative relationship between increasing power usage and subsequent haemorrhage. Use of diathermy for haemostasis at the lowest effective setting may carry a comparable risk of haemorrhage to that of cold steel tonsillectomy. Recommendations are given on the optimum tonsillectomy technique for both the older child or adolescent and the particularly young or low weight child.
Phosphatase of Regenerating Liver-3 Induces Angiogenesis by Increasing Extracellular Signal-Regulated Kinase Phosphorylation in Endometrial Adenocarcinoma
Authors: Ming Jian , Jiang Yanduo , Jiang Guocheng , Zheng Huachuan
Published: August 2013

Objective: The aim of this study was to investigate the mechanism by which phosphatase of regenerating liver-3 (PRL-3) induces angiogenesis in endometrial adenocarcinoma tissues and cells. Methods: We investigated the expression of PRL-3 and vascular endothelial growth factor (VEGF) in samples from 124 patients with endometrial adenocarcinoma using immunohistochemical staining. The relationship between PRL-3 expression and microvessel density (MVD), clinicopathological factors and surgical treatment outcome was also studied. Following this, we studied the effect on cell lines of blocking or upregulating PRL-3. Results: PRL-3 expression in endometrial adenocarcinoma was high, and this overexpression is correlated with advanced clinical stage (p = 0.008), lymph node metastasis (p = 0.016) and poor postoperative survival. PRL-3 overexpression was associated with VEGF (p = 0.001) expression and MVD (p = 0.005). Upregulating PRL-3 expression promoted VEGF and phosphorylated extracellular signal-regulated kinase (pERK) expression. Blocking PRL-3 expression inhibited VEGF and pERK expression. Following inhibition of pERK, VEGF expression was downregulated. Conclusions: PRL-3 induces microvascular vessel formation by facilitating VEGF expression in endometrial adenocarcinoma tissues. PRL-3 upregulates pERK expression and activity, facilitating VEGF expression and accelerating angiogenesis.
Effects of Indocyanine Green Staining on the Recovery of Visual Acuity and Macular Morphology after Macular Hole Surgery
Authors: Shiono Akira , Kogo Jiro , Klose Gerd , Ueno Satoki , Takagi Hitoshi
Published: August 2013

Purpose: To evaluate whether indocyanine green (ICG)-assisted internal limiting membrane peeling affects visual outcome and macular morphologic changes in spectral-domain optical coherence tomography images after macular hole (MH) surgery. Methods: A retrospective analysis was performed of 34 eyes in 34 patients who had undergone surgical treatment for MH. Best-corrected visual acuity (BCVA) and optical coherence tomography parameters including central foveal thickness, length of the external limiting membrane (ELM) defect, and length of the inner segment and outer segment (IS/OS) defect were analyzed pre- and postoperatively. Results: The eyes were divided into 2 groups based on ICG use (ICG+/-). The changes in BCVA did not differ significantly between the 2 groups at 6 months. However, the ICG+ group had poorer changes compared with the ICG- group at 1 and 3 months (p = 0.038, p = 0.012, respectively). Central foveal thickness and ELM defect did not differ between the 2 groups at each period. The IS/OS defect in the ICG+ group was significantly greater at 1 and 3 months than that in the ICG- group (p = 0.026, p = 0.048, respectively). Conclusions: ICG staining may affect the recovery process of macular morphology and visual acuity in the first several months after MH surgery.
Drug-Induced Hypothermia as Beneficial Treatment before and after Cerebral Ischemia
Authors: Johansen Flemming F. , Hasseldam Henrik , Rasmussen Rune S. , Bisgaard Anne Sofie , Bonfils Peter K. , Poulsen Steen S. , Hansen-Schwartz Jacob
Published: August 2013

Objectives: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. Methods: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. Results: Talipexole induced mild hypothermia (35.1 ± 1.1 to 36.0 ± 0.5°C) for <20 h. Hypothermic pre- and postconditioning reduced infarct sizes by more than 60% as monitored during the first 90 days after experimental stroke (p < 0.05). Conclusion: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug-induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke.
Gene Expression Analysis Detected a Low Expression Level of C1s Gene in ICR-Derived Glomerulonephritis (ICGN) Mice
Authors: Tamura Kotaro , Uchio-Yamada Kozue , Manabe Noboru , Noto Takahisa , Hirota Rika , Unami Akira , Matsumoto Masahiro , Miyamae Yoichi
Published: August 2013

Background: ICR-derived glomerulonephritis (ICGN) strain is a novel inbred strain of mice with a hereditary nephrotic syndrome. Deletion mutation of tensin 2 (Tns2), a focal adhesion molecule, has been suggested to be responsible for nephrotic syndrome in ICGN mice; however, the existence of other associative factors has been suggested. Methods and Results: To identify additional associative factors and to better understand the onset mechanism of nephrotic syndrome in ICGN mice, we conducted a comprehensive gene expression analysis using DNA microarray. Immune-related pathways were markedly altered in ICGN mice kidney as compared with ICR mice. Furthermore, the gene expression level of complement component 1, s subcomponent (C1s), whose human homologue has been reported to associate with lupus nephritis, was markedly low in ICGN mouse kidney. Real-time quantitative reverse transcription-polymerase chain reaction confirmed a low expression level of C1s in ICGN mouse liver where the C1s protein is mainly synthesized. A high serum level of anti-dsDNA antibody and deposits of immune complexes were also detected in ICGN mice by enzyme-linked immunosorbent assay and immunohistochemical analyses, respectively. Conclusion: Our results suggest that the immune system, especially the complement system, is associated with nephrotic syndrome in ICGN mice. We identified a low expression level of C1s gene as an additional associative factor for nephrotic syndrome in ICGN mice. Further studies are needed to elucidate the role of the complement system in the onset of nephrotic syndrome in ICGN mice.
Cauda Equina Syndrome Caused by Spontaneous Bleeding in the Filum Terminale Myxopapillary Ependymoma: A Rare Pediatric Case
Authors: Becco de Souza Rodrigo , Brasileiro de Aguiar Guilherme , Saade Nelson , Esteves Veiga José Carlos
Published: August 2013

The majority of the filum terminale ependymomas are of the myxopapillary type, which most commonly present as lumbago or sciatic pain, an insidious clinical condition, at times accompanied by paraparesis, bladder paresis and vesical alterations. We report the case of a 13-year-old patient who presented with acute cauda equina. He underwent total resection of the lesion, which resulted in progressive improvement. The clinical conditions, diagnoses and treatments of the medullary cone and cauda equina myxopapillary ependymomas are also discussed.