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Summary Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo . These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.

Cytotoxic chemotherapy is the standard of care for patients with triple negative breast cancer (TNBC). Most patients with advanced TNBC progress after chemotherapy and die from metastatic disease. MCL1 is an anti-apoptotic Bcl-2 family member known to sequester and inactivate pro-apoptotic Bcl-2 family proteins and, thus, contribute to chemotherapy resistance. We previously reported that ~45% of residual TNBCs that remain in the breast after neoadjuvant chemotherapy harbor MCL1 amplification, suggesting a causal role for MCL1 in drug resistance. A recent report (Goodwin et al. 2015) suggested that siRNA-mediated ablation of MCL1 does not induce apoptosis in claudin-low TNBC cells with a cancer stem cell (CSC) gene expression signature. CSCs comprise a rare population of cells with tumor-initiating properties and refractoriness to chemotherapy. In this study, we showed that MCL1 expression is elevated in claudin-low TNBC SUM159PT and MDA436 CSCs as measured by ALDH+ by flow cytometry and ability to form mammospheres. RNA interference of MCL1 in SUM159PT cells reduced CSCs and attenuated tumor formation in vivo. Mitochondrial oxidative phosphorylation (mtOXPHOS) plays a crucial role in maintenance of CSCs. MCL1 has been shown to localize in the mitochondrial matrix and contribute to mitochondrial respiration. Thus, we hypothesized that MCL1 contributes to enrichment of TNBC CSCs and chemotherapy resistance via mitochondrial regulation. Stable transfection and overexpression of MCL1 in MDA468 cells increased oxygen consumption ratio, mitochondrial membrane potential, and production of reactive oxygen species (ROS), all features of activated mtOXPHOS. Conversely, RNAi-mediated ablation of MCL1 in SUM159PT and MDA436 cells repressed these markers of activated mtOXPHOS. A mutant of MCL1 lacking its mitochondrial target sequences (MTS) was unable to localize in mitochondria and, when transfected into MDA468 cells, reduced the CD44high/CD24low fraction and mammosphere formation. We next tested VU0659158, a BH3 mimetic in development at Vanderbilt that disrupts MCL1 interactions with BH3 domain-containing proteins, such as BID, BIM, NOXA and PUMA. Treatment of SUM159PT cells with VU0659158 increased caspase activity but did not attenuate mammosphere formation. Analysis of mRNA expression in TCGA revealed that genes induced by mtOXPHOS involved in the hypoxia pathway are significantly up-regulated in MCL1 amplified breast cancers. Finally, pharmacological inhibition of HIF-1α, a key regulator of hypoxia, with digoxin decreased CSCs and attenuated tumor formation in vivo. These data suggest that 1) MCL1 confers resistance to chemotherapy by expanding CSCs via mtOXPHOS independent of its BH3 domain-mediated, anti-apoptotic function, and 2) targeting mitochondrial respiration and the hypoxia pathway may delay or reverse chemotherapy resistance in MCL1 amplified TNBC. Citation Format: Kyung-min Lee, Jennifer Giltnane, Justin Balko, Luis Schwarz, Angel Guerrero, Katie Hutchinson, Mellissa Hicks, Violeta Sanchez, Melinda Sanders, Taekyu Lee, Edward Olejniczak, Stephen Fesik, Carlos Arteaga. Mitochondrial MCL1 maintains triple negative breast cancer stem cells and contributes to chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3890. doi:10.1158/1538-7445.AM2017-3890

This study examines the effect of the booth Recommender system (BRS) embedded in a mobile device on the goals of exhibition attendees, based on two main theories that are unplanned behaviour and goal frame theories. Previous studies have overlooked the importance of the unplanned behavioural effectiveness of IT devices for understanding motivation and delivering unexpected outcomes at exhibitions. The BRS offers customized, personalized, and advanced information to attendees; experiences with the BRS lead to unplanned behaviour. In this paper, we distinguish several goal frames, including hedonic, gain, and normative goals, which contribute to the relationship between continued BRS use and unplanned booth visits. Continued BRS use directly influences revisit intentions to an exhibition and contributes to unplanned booth visits. We analysed data from 508 attendees at a franchise exhibition using structural equation modelling (SEM) method. Our research empirically determined that goal framing theory and unplanned behaviour via continued BRS use embedded in a mobile device are connected. Continued BRS use in an exhibition can contribute to attendees’ impulsive behaviour and can induce them to return to an exhibition. The results and implications are discussed.

The anterior cingulate cortex (ACC) is known for its role in perception of nociceptive signals and the associated emotional responses. Recent optogenetic studies, involving modulation of neuronal activity in the ACC, show that the ACC can modulate mechanical hyperalgesia. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC in a model of chronic inflammatory pain to assess their motivational effect in the conditioned place preference (CPP) test. Selective inhibition of pyramidal neurons induced preference during the CPP test, while activation of parvalbumin (PV)-specific neurons did not. Moreover, chemogenetic inhibition of the excitatory pyramidal neurons alleviated mechanical hyperalgesia, consistent with our previous result. Our results provide evidence for the analgesic effect of inhibition of ACC excitatory pyramidal neurons and a prospective treatment for chronic pain.

Cytokeratin19 (KRT19) is widely used as a biomarker for the detection of disseminated tumors. Using an LC-MS/MS proteomics approach, we found that KRT19 was upregulated in HER2-overexpressing cells and tissues. KRT19 expression was induced by HER2-downstream ERK at the transcriptional level. Another HER2-downstream kinase, Akt, was found to phosphorylate KRT19 on Ser35 and induce membrane translocation of KRT19 and remodeling of KRT19 from filamentous to granulous form. KRT19 phosphorylated by Akt could bind HER2 on the plasma membrane and stabilized HER2 via inhibition of proteasome-mediated degradation of HER2. Silencing of KRT19 by shRNA resulted in increased ubiquitination and destabilization of HER2. Moreover, treatment of KRT19 antibody resulted in downregulation of HER2 and reduced cell viability. These data provide a new rationale for targeting HER2-positive breast cancers.

Purpose To develop a novel, simplified method for correcting the ischemic index of nonperfused areas in diabetic retinopathy (DR). Methods We performed a retrospective review of 103 eyes with naive DR that underwent ultra-widefield angiography (UWFA) over a year. UWFAs were graded according to the quantity of retinal non-perfusion, and uncorrected ischemic index (UII) and corrected ischemic index (CII) were calculated using a simplified, novel method. Results The average differences between UII and CII in the non-proliferative DR group and the proliferative DR group were 0.7 ± 0.9% in the 50% CII group, respectively. A CII >25% was critical for determining DR progression (p < 0.001). Conclusions Distortion created by UWFA needs to be corrected because the difference between UII and CII in DR increases with the ischemic index.

The Warburg effect is an oncogenic metabolic switch that allows cancer cells to take up more glucose than normal cells and favors anaerobic glycolysis. Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein that is overexpressed in various types of carcinoma. Using two-dimensional digest-liquid chromatography-mass spectrometry (LC-MS)/MS, we showed that the expression of proteins associated with the Warburg effect was upregulated in trastuzumab-resistant BT-474 cells that overexpressed ECM1 compared to control cells. We further demonstrated that ECM1 induced the expression of genes that promote the Warburg effect, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and hypoxia-inducible factor 1 α (HIF-1α). The phosphorylation status of pyruvate kinase M2 (PKM-2) at Ser37, which is responsible for the expression of genes that promote the Warburg effect, was affected by the modulation of ECM1 expression. Moreover, EGF-dependent ERK activation that was regulated by ECM1 induced not only PKM2 phosphorylation but also gene expression of GLUT1 and LDHA. These findings provide evidence that ECM1 plays an important role in promoting the Warburg effect mediated by PKM2.

Treatment of adult, noninfectious uveitis remains a major challenge for ophthalmologists around the world, especially in regard to recalcitrant cases. It is reported to comprise approximately 10% of preventable blindness in the USA. The cause of uveitis can be idiopathic or associated with infectious and systemic disorders. The era of biologic medical therapies provides new options for patients with otherwise treatment-resistant inflammatory eye disease.This two-part review gives a comprehensive overview of the existing medical treatment options for patients with adult, noninfectious uveitis, as well as important advances for the treatment ocular inflammation. Part I covers classic immunomodulation and latest information on corticosteroid therapy. In part II, emerging therapies are discussed, including biologic response modifiers, experimental treatments and ongoing clinical studies for uveitis.The hazard of chronic corticosteroid use in the treatment of adult, noninfectious uveitis is well documented. Corticosteroid-sparing therapies, which offer a very favorable risk-benefit profile when administered properly, should be substituted. Although nothing is currently approved for on-label use in this indication, many therapies, through either translation or novel basic science research, have the potential to fill the currently exposed gaps.

Extracellular Matrix Protein 1 (ECM1) is a marker for tumorigenesis and is correlated with invasiveness and poor prognosis in various types of cancer. However, the functional role of ECM1 in cancer metastasis is unclear. Here, we detected high ECM1 level in breast cancer patient sera that was associated with recurrence of tumor. The modulation of ECM1 expression affected not only cell migration and invasion, but also sphere-forming ability and drug resistance in breast cancer cell lines. In addition, ECM1 regulated the gene expression associated with the epithelial to mesenchymal transition (EMT) progression and cancer stem cell (CSC) maintenance. Interestingly, ECM1 increased β-catenin expression at the post-translational level through induction of MUC1, which was physically associated with β-catenin. Indeed, the association between β-catenin and the MUC1 cytoplasmic tail was increased by ECM1. Furthermore, forced expression of β-catenin altered the gene expression that potentiated EMT progression and CSC phenotype maintenance in the cells. These data provide evidence that ECM1 has an important role in cancer metastasis through β-catenin stabilization.

S100A4, also known as the mts1 gene, has been reported as an invasive and metastatic marker for many types of cancers. S100A4 interacts with various target genes that affect tumor cell metastasis; however, little is known about cellular signaling pathways elicited by S100A4. In the current study, we demonstrate an inhibitory effect of S100A4 on β-catenin signaling in breast cancer cells. By overexpressing S100A4 in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells, we observed the down-regulation of β-catenin expression and β-catenin-dependent TCF/LEF transcriptional activities. The activity of GSK3β, which phosphorylates β-catenin and induces proteasomal degradation of β-catenin, was increased in S100A4-overexpressing cell lines. Blocking Glycogen Synthase Kinase (GSK3β) activity by lithium chloride or Dvl gene overexpression restored β-catenin expression. We also found that increased GSK3β activity was due to decrease in Akt activity resulting from Egr-1-induced phosphatase and tensin homolog (PTEN) expression. S100A4 induced Egr-1 nuclear localization by increasing the association between Egr-1 and importin-7 and this effect was reduced in S100A4 mutants that harbored a defect in nuclear localization signals. Collectively, we verify herein that S100A4 may act as a tumor suppressor in breast cancers by down-regulating the central signaling axis for tumor cell survival.

Playing games on mobile devices is very popular. Recently, cloud gaming – where datacenter servers execute the games on behalf of thin clients that merely transmit UI input events and display output rendered by the servers – has emerged as an interesting alternative to traditional clientside game execution. Cloud Gaming-as-a-Service (GaaS) offers several advantages salient to mobile clients. First, users with low end devices can get the same high quality experience as users with high end devices. Second, mobile game developers avoid two challenges that arise with the huge diversity of mobile devices: platform compatibility headaches and per-platform performance tuning. Third, upgrading servers (e.g., for bug fixes, game updates, etc.) becomes far easier than redeploying new software to clients. Finally, players can select from a vast library of games and instantly play any of them. However, GaaS on mobile devices faces a key technical dilemma: how can players attain real-time interactivity in the face of wide-area latency? Real-time interactivity means client input events should be quickly reflected on the client display. User studies have shown that players are sensitive to as little as 60 ms latency, and are aggravated at latencies in excess of 100 ms [1]. A further delay degradation from 150 ms to 250 ms lowers user engagement by 75% [2]. Instead, we propose to mitigate wide-area latency via speculative execution. We present DeLorean a system that delivers real-time gaming interactivity as fast as traditional local client-side execution, despite with network latencies. DeLorean’s basic approach combines input prediction with speculative execution to render mulitple possible frame outputs which could occur RTT milliseconds in the future. DeLorean employs the following techniques to accomplish this.

Much interest in the superconducting proximity effect in three-dimensional (3D) topological insulators (TIs) has been driven by the potential to induce Majorana bound states at the interface. Most candidate materials for 3D TI, however, are bulk metals, with bulk states at the Fermi level coexisting with well-defined surface states exhibiting spin-momentum locking. In such topological metals, the proximity effect can differ qualitatively from that in TIs. By studying a model topological metal-superconductor (TM-SC) heterostructure within the Bogoliubov-de Gennes formalism, we show that the pair amplitude reaches the naked surface, unlike in a topological insulator-superconductor (TI-SC) heterostructure where it is confined to the interface. Furthermore, we predict vortex-bound-state spectra to contain a Majorana zero-mode localized at the naked surface, separated from the bulk vortex-bound-state spectra by a finite energy gap in such a TM-SC heterostructure. These naked-surface-bound modes are amenable to experimental observation and manipulation, presenting advantages of TM-SC over TI-SC., 7 pages, 3 figures

Objectives: To investigate patients with Proliferative Diabetic Retinopathy (PDR) using ultra-wide field fluorescein angiography (UWFA) images and to compare the detection rate of PDR progression using conventional seven standard field angiography (7SF) images. Methods: One hundred and one eyes of 67 patients with PDR who underwent fluorescein angiography using the Optos Optomap Panoramic 200A imaging system were included. Three hundred three images of 101 eyes at different time points (initial, Post-Panretinal Photocoagulation [PRP], and follow-up) were evaluated. In comparing 101 follow-up with 101 post-PRP images, we found newly developed Neovascularization (NNV) and newly developed non-perfusion (NNP) areas, which were then analyzed using two different methodologies: UWFA and 7SF. NNVs were counted while NNP area was measured in pixels using ImageJ software. Results: UWFA detected 21 eyes with NNV, which was approximately twice the number of eyes detected using 7SF (11 eyes). Ten eyes presented with NNV outside the 7SF area with apparently clean 7SF without NNV. UWFA detected 25 eyes with NNP areas, which was more than the six eyes detected using 7SF (19 eyes). Six eyes presented with NNP areas outside the 7SF, which were apparently fully perfused by 7SF. In addition, UWFA detected 2.59 times more NNP area than that by 7SF. Conclusion: Compared with conventional 7SF imaging, UWFA shows significantly improved retinal visualization and improves progression detection rates in patients with PDR.

When some products move to other storage in cold chain, the related continuous queries should be also redefined for different storages. To avoid redefining the existing continuous queries, we introduce a new concept of floating continuous query (FCQ) for solving the problem of redefinition of the transformed continuous queries. Dynamic processing of FCQ not only simplifies query management but also improves query processing performance.

Mobile applications often predict the future to make decisions in the present. Although such predictions are inherently uncertain, applications typically assume that they are completely accurate. This assumption can lead to incorrect decisions resulting in unnecessary delays, wasted resources, or worse.

Many electrophysiological properties of neuron including firing rates and rhythmical oscillation change in response to a temperature variation, but the mechanism underlying these correlations remains unverified. In this study, we analyzed various action potential (AP) parameters of bursting pacemaker neurons in the abdominal ganglion of Aplysia juliana to examine whether or not bursting patterns are altered in response to temperature change. Here we found that the inter-burst interval, burst duration, and number of spike during burst decreased as temperature increased. On the other hand, the numbers of bursts per minute and numbers of spikes per minute increased and then decreased, but interspike interval during burst firstly decreased and then increased. We also tested the reproducibility of temperature-dependent changes in bursting patterns and AP parameters. Finally we performed computational simulations of these phenomena by using a modified Plant model composed of equations with temperature-dependent scaling factors to mathematically clarify the temperature-dependent changes of bursting patterns in burst-firing neurons. Taken together, we found that the modified Plant model could trace the ionic mechanism underlying the temperature-dependent change in bursting pattern from experiments with bursting pacemaker neurons in the abdominal ganglia of Aplysia juliana.

Purpose: To determine if short term effects of intravitreal anti-vascular endothelial growth factor or steroid injection are correlated with fluid turbidity, as detected by spectral domain optical coherence tomography (SD-OCT) in diabetic macular edema (DME) patients. Methods: A total of 583 medical records were reviewed and 104 cases were enrolled. Sixty eyes received a single intravitreal bevacizumab injection (IVB) on the first attack of DME and 44 eyes received triamcinolone acetonide treatment (IVTA). Intraretinal fluid turbidity in DME patients was estimated with initialintravitreal SDOCT and analyzed with color histograms from a Photoshop program. Central macular thickness and visual acuity using a logarithm from the minimum angle of resolution chart, were assessed at the initial period and 2 months after injections. Results: Visual acuity and central macular thickness improved after injections in both groups. In the IVB group, visual acuity and central macular thickness changed less as the intraretinal fluid became more turbid. In the IVTA group, visual acuity underwent less change while central macular thickness had a greater reduction (r = -0.675, p = 0.001) as the intraretinal fluid was more turbid. Conclusions: IVB and IVTA injections were effective in reducing central macular thickness and improving visual acuity in DME patients. Further, fluid turbidity, which was detected by SD-OCT may be one of the indexes that highlight the influence of the steroid-dependent pathogenetic mechanism.

This paper proposes voltage equalizer for lithium-ion battery string. Proposed equalizer uses LC resonant tank for energy transfer between battery cells. LC resonant tank is connected to the cells by switch network and can store and release energy from any cell in the battery string. Therefore energy can be transferred from strong cell to weak cell directly, which is effective for both of top and bottom balancing. In order to improve balancing performance, adjustable speed structure is employed. Prototype was implemented for 5 cell lithium-ion battery string. Experimental results showed that proposed circuit is suitable for battery cell balancing.

Vehicular environments require continuous awareness of the road ahead. It is critical that mobile applications used in such environments (e.g., GPS route planners and location-based search) do not distract drivers from the primary task of operating the vehicle. Fortunately, a large body of research on vehicular interfaces provides best practices that mobile application developers can follow. However, when we studied the most popular vehicular applications in the Android marketplace, no application followed these guidelines. In fact, vehicular applications were not substantially better at meeting best practice guidelines than non-vehicular applications.To remedy this problem, we have developed a tool called AMC that uses model checking to automatically explore the graphical user interface (GUI) of Android applications and detect violations of vehicular design guidelines. AMC is designed to give developers early feedback on their application GUI and reduce the amount of time required by a human expert to assess an application's suitability for vehicular usage. We have evaluated AMC by comparing the violations that it reports with those reported by an industry expert for 12 applications. AMC generated a definitive assessment for 85% of the guidelines checked; for these cases, it had no false positives and a false negative rate of under 2%. For the remaining 15% of cases, AMC reduced the number of application screens that required manual verification by 95%.

BACKGROUND Although previous studies have provided reference values for the lower limb alignment in children with physiological genu varum, those often have methodologic flaws, including problems with assumptions of statistical independence. In this study we intend to use appropriate statistical methods to determine reference values of the recovery of physiological genu varum by using a linear mixed model (LMM). METHODS The database of our institution was searched and teleroentgenograms of patients up to 5 years of age with clinical diagnosis of physiological genu varum were selected. The mechanical tibiofemoral angle (mTFA), mechanical lateral distal femoral angle (mLDFA), and mechanical medial proximal tibial angle (mMPTA) were measured from each radiograph. These measures were then incorporated in LMM. The reference values for mTFA, mLDFA, and mMPTA were calculated by LMMs with age, sex, and side of the limbs, as the fixed effects with each subject as random effects. RESULTS A total of 425 teleroentgenograms were evaluated from 161 patients with physiological genu varum. Age, sex, and limb side terms were found to be significant contributing factors to the measures. In the LMM, with the age as quadratic, mTFA was equal to -0.3-degree varus [95% confidence interval (CI), -5.9 to 5.3 degrees] at the age of 3 years. The mLDFA was equal to 87.8 degrees (95% CI, 82.8-92.8 degrees) at the age of 4.5 years. The mMPTA was equal to 88.8 degrees (95% CI, 80.4-97.2 degrees) at the age of 2.5 years. CONCLUSIONS An LMM fitted well to estimate the natural recovery of physiological genu varum. Age, sex, and side of the limbs were found to be significant factors in the estimation of mTFA, and age and side of limbs were significant in estimation of mLDFA and mMPTA. LEVEL OF EVIDENCE Level III-diagnostic study.

Phosphoinositide 3-kinases (PI3Ks) play key roles in synaptic plasticity and cognitive functions in the brain. We recently found that genetic deletion of PI3K gamma, the only known member of class IB PI3Ks, results in impaired N-methyl-D-aspartate receptor-dependent long-term depression (NMDAR-LTD) in the hippocampus. The activity of RalA, a small GTP-binding protein, increases following NMDAR-LTD inducing stimuli, and this increase in RalA activity is essential for inducing NMDAR-LTD. We found that RalA activity increased significantly in PI3K gamma knockout mice. Furthermore, NMDAR-LTD-inducing stimuli did not increase RalA activity in PI3K gamma knockout mice. These results suggest that constitutively increased RalA activity occludes further increases in RalA activity during induction of LTD, causing impaired NMDAR-LTD. We propose that PI3K gamma regulates the activity of RalA, which is one of the molecular mechanisms inducing NMDAR-dependent LTD. [BMB Reports 2013; 46(2): 103-106]

This paper proposes a new burst-mode driving method to increase the power-conversion efficiency (PCE) of a power supply at light load. The burst mode minimizes the power consumption by stopping the converter operation when load is light. The proposed method changes the off-period of the converter according to the load to achieve optimized efficiency across the entire load range. The PCE at 6% load was measured as 83.6% and 85.1 % for 75-W flyback and LLC Half-bridge converters, repectively, when applying the proposed burst mode; these values were 8% and 16.5% higher respectively than those for the converters without it.

High-dose chemotherapy supported by autologous stem cell transplantation is an effective treatment for patients with relapsed or refractory non-Hodgkin's lymphomas (NHLs) and fit patients with multiple myeloma (MM). However, failure rates of hematopoietic stem cell mobilization are estimated to be between 5 and 30%, respectively. Thus, we investigated the efficacy of the combination chemotherapy of high-dose methotrexate (MTX) and cytarabine with granulocyte-colony-stimulating factor (G-CSF) as a remobilization method in those who failed a prior mobilization and collection with chemotherapy and G-CSF.Mobilization failure was defined as a collection of fewer than 5 × 10(6) CD34+ cells after three to five apheresis procedures. MTX (3500 mg/m(2) in a 120-min infusion) on Day 1 and cytarabine (3000 mg/m(2) infusion for 120 min) on Day 4 and Day 5 were followed by G-CSF (10 μg/kg daily).A total of eight patients (six NHL and two MM; median age, 55 years) who had failed in prior mobilization with conventional chemotherapy and G-CSF underwent the second mobilization as described in the method. Successful collection of CD34+ cells (5 × 10(6) /kg) was achieved in six patients (75%) with three to five apheresis procedures. The total yield of CD34+ cells/kg body weight was 6.28 × 10(6) /kg (median; range, 1.53 × 10(6) -10.09 × 10(6) /kg).This preliminary result warrants further investigation of high-dose MTX and cytarabine plus G-CSF as a means to remobilize stem cells in those with prior failure to mobilize stem cells with chemotherapy and G-CSF.

In breast cancer, the HER2 (human epidermal growth factor receptor 2) receptor tyrosine kinase is associated with extremely poor prognosis and survival. Notch signalling has a key role in cell-fate decisions, especially in cancer-initiating cells. The Notch intracellular domain produced by Notch cleavage is translocated to the nucleus where it activates transcription of target genes. To determine the combinatory effect of HER2 and Notch signalling in breast cancer, we investigated the effect of HER2 on Notch-induced cellular phenomena. We found the down-regulation of Notch-dependent transcriptional activity by HER2 overexpression. Also, the HER2/ERK (extracellular-signal-regulated kinase) signal pathway down-regulated the activity of γ-secretase. When we examined the protein level of Notch target genes in HER2-overexpressing cells, we observed that the level of survivin, downstream of Notch, increased in HER2 cells. We found that activation of ERK resulted in a decrease in XAF1 [XIAP (X-linked inhibitor of apoptosis)-associated factor 1] which reduced the formation of the XIAP–XAF1 E3 ligase complex to ubiquitinate survivin. In addition, Thr34 of survivin was shown to be the most important residue in determining survivin stability upon phosphorylation after HER2/Akt/CDK1 (cyclin-dependent kinase 1)–cyclin B1 signalling. The results of the present study show the combinatorial effects of HER2 and Notch during breast oncogenesis.

Triple negative breast cancer is the most virulent subtype of this malignancy. Although initially responsive to cytotoxic chemotherapy, most patients with TNBC eventually develop drug-resistant disease. We previously reported co-amplification of MYC and MCL1 in a cohort of TNBCs after neoadjuvant chemotherapy (Balko et al. Cancer Discov. 2014). In addition, MYC and MCL1 are overexpressed in paclitaxel-resistant compared to paclitaxel-sensitive TNBC cells. We hypothesized that MYC and MCL1 play a role in chemotherapy resistance. TNBC cell lines with claudin-low gene expression exhibited the highest levels of MYC and MCL1 mRNAs. This molecular subtype of breast cancer is enriched for cancer stem cells (CSCs) and exhibits resistance to neoadjuvant chemotherapy. Knockdown of both MYC and MCL1 by siRNA in SUM159PT and MDA-MB-436 TNBC cells significantly reduced mammosphere formation and CSC markers such as ALDH and CD44high/CD24low. Conversely, overexpression of ectopic MYC and MCL1 in MDA-MB-468 cells increased mammosphere formation and CSC markers. It has been reported that mitochondrial oxidative phosphorylation (OXPHOS) is enhanced in CSCs. Thus, we investigated a role for MYC and MCL1 in mitochondrial OXPHOS using Seahorse XFe extracellular flux analyzer. CSCs with high expression of MYC and MCL1 sorted by flow cytometry exhibited increased mitochondrial OXPHOS compared to non-CSCs. Transfection of MYC and MCL1 expression vectors into MDA-MB-468 cells enhanced mitochondrial OXPHOS activity. Conversely, knockdown of MYC and MCL1 in SUM159PT and MDA-MB-436 cells reduced mitochondrial OXPHOS activity. MYC mediated these effects by promoting mitochondrial biogenesis whereas MCL1 potentiated mitochondrial OXPHOS via localization into the mitochondrial matrix, independent of its ability to associate with BH3-domain containing anti-apoptotic proteins (BAD, BCL2, BCL-XL). Deletion of the mitochondrial target sequence (MTS) of MCL1 impaired its ability to increase mitochondrial OXPHOS and mammosphere formation. Reactive oxygen species (ROS), which are produced in CSCs as a by-product of activated mitochondrial OXPHOS, were abrogated by MYC and MCL1 siRNA. To determine the effect of ROS on CSCs, we treated SUM159PT and MDA-MB-436 cells with hydrogen peroxide (H2O2). Treatment with H2O2 enriched CSCs, which showed up-regulation of several cancer stem cell genes such as Nanog and IL-8. Enrichment of CSCs by H2O2 was diminished by n-acetylcysteine (NAC), an antioxidant. These data suggest that MYC and MCL1 co-amplification confers drug resistance to TNBC via mitochondrial OXPHOS-mediated enrichment of CSCs. Moreover, MYC and MCL1 stimulate H2O2 production, which potentiates CSCs. Thus, targeting mitochondrial OXPHOS and H2O2 may be an effect strategy to delay or reverse resistance to chemotherapy in MYC and MCL1 amplified TNBC. Citation Format: Kyung-min Lee, Jennifer Giltnane, Justin Balko, Carlos Arteaga. MYC and MCL1 cooperatively promote chemotherapy-resistant cancer stem cells through regulation of mitochondrial biogenesis and oxidative phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3328.

Summary: Breast cancer is a heterogeneous type of cancer accompanying extensive immune cell infiltration. Although its mortality rate has been decreasing with early diagnosis and introduction of molecular targeted therapies, it is still one of the world leading cause of cancer death in women. In breast cancer, molecular subtyping is used for the patient stratification and treatment decisions, emphasizing the importance of inter-patient tumoral heterogeneity in the tumor cell behavior. Tumor cells within a patient may also manifest intra-tumoral heterogeneity, which may cause treatment resistance. Single cell gene expression profiling would reveal both inter- and intra-tumoral heterogeneity in breast cancer encompassing tumor cells and associated stromal and immune cells. Experimental Process: From 4 different subtype primary breast cancer and 2 lymph node metastases, single cells were captured and amplified through C1™Single-cell Auto Prep System (Fluidigm) with the SMARTer Ultra Low RNA Kit. Sequencing libraries were constructed with the Nextera XT DNA sample Prep Kit and sequenced through a Hiseq2500 (Illumina) as 100-bp paired end mode of the TruSeq Rapid PE Cluster kit and Truseq Rapid SBS kit. Computational Process: RNA sequencing reads were aligned to the modified human genome reference using 2-pass mode of STAR_2.4.0b, and transcript per million (TPM) values were obtained as the relative gene expression levels of single cells through RSEM v1.2.17. Results: As most breast cancers originate from the mammary epithelium, we distinguished carcinoma cells from associated non-tumor cells by epithelial cell adhesion molecule (EPCAM) signature genes. We validated the distinction with chromosomal gene expression patterns and gene set enrichment analyses using tumor, stromal, or immune genesets. With or without removal of non-tumor cells, TNBC tumor cells showed the highest gene expression heterogeneity, recapitulating the known inter-patient heterogeneity. TNBC tumor cells from a single patient were categorized into 6 different TNBC-subtypes, further demonstrating intra-tumoral heterogeneity. In addition, immune cells identified in the TNBC tumor were naïve B cells and regulatory T cells, suggesting non-activated status of the immune system. Conclusions: The high resolution gene expression profiling revealed features of breast cancer transcriptome which may provide clues for molecular directed therapies targeting the tumor or the immune compartment. Citation Format: Woosung Chung, Hye Hyeon Eum, Kyu-Tae Kim, Kyung-Min Lee, Arum Jo, WonShik Han, Hae-Ock Lee, Woong-Yang Park. Identification of the carcinoma and immune cells in the breast cancer by single-cell RNA sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 160.

Retinoblastoma is the most common intraocular malignant tumor in children, affecting approximately 1 in 20,000 live births. In this study, we investigated the role of L1, a transmembrane protein, in proliferation and chemoresistance of retinoblastoma to figure out the potential for the novel therapeutic target. Retinoblastoma tissues demonstrated varying degrees of L1 positivity in 86.6% (26/30) of samples. In particular, the degree of L1 positivity was inversely related with that of Flexner-Wintersteiner rosette formation. Further in vitro studies using stable cell lines which showed up- or down-regulation of L1 demonstrated that L1 was associated with cell-cell adhesion and proliferation of retinoblastoma cells. Retinoblastoma cells with low expression of L1 showed decreased tumor formation in vivo. In addition, L1 expression was related with resistance to carboplatin, one of the most-widely utilized chemotherapeutic agents against retinoblastoma. In line with these results, retinoblastoma cells with higher expression of L1 demonstrated increased resistance to carboplatin in vivo. We also observed diffuse and dense expression of L1 in retinoblastoma tissues from 4 patients who underwent enucleation despite intensive chemotherapy based on carboplatin. Taken together, L1 was related with proliferation and chemoresistance of retinoblastoma and might be a potential therapeutic target of retinoblastoma. Citation Format: Dong Hyun Jo, Kyungmin Lee, Jin Hyoung Kim, Hyoung Oh Jun, Young Hoon Kim, Young-Lai Cho, Young Suk Yu, Jeong-Ki Min, Jeong Hun Kim. The role of L1 in proliferation and chemoresistance of retinoblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2469.

Background Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function. Results Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses. Conclusions These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus.

The consolidation of long-term memory for sensitization and synaptic facilitation in Aplysia requires synthesis of new mRNA including the immediate early gene Aplysia CCAAT enhancer-binding protein ( ApC/EBP ). After the rapid induction of ApC/EBP expression in response to repeated treatments of 5-hydroxytryptamine (5-HT), ApC/EBP mRNA is temporarily expressed in sensory neurons of sensory-to-motor synapses. However, the molecular mechanism underlying the rapid degradation of ApC/EBP transcript is not known. Here, we cloned an AU-rich element (ARE)-binding protein, ApAUF1, which functions as a destabilizing factor for ApC/EBP mRNA. ApAUF1 was found to bind to the 3′ UTR of ApC/EBP mRNA that contains AREs and subsequently reduces the expression of ApC/EBP 3′ UTR-containing reporter genes. Moreover, overexpression of ApAUF1 inhibited the induction of ApC/EBP mRNA in sensory neurons and also impaired long-term facilitation of sensory-to-motor synapses by repetitive 5-HT treatments. These results provide evidence for a critical role of the posttranscriptional modification of ApC/EBP mRNA during the consolidation of synaptic plasticity.

Branch retinal vein occlusion (BRVO) is the second most common major retinal vascular disease after diabetic retinopathy [1]. Epidemiologic studies found that the prevalence of BRVO ranged from 0.3% [2] to 1.6% [3], and major risk factors for the condition were increasing age, hypertension, and co-existing cardiovascular disease [2-6]. Macular edema is a major cause of visual acuity loss attributable to BRVO [7-9]. The Branch Vein Occlusion Study [7] found that grid photocoagulation was effective for treatment of macular edema. The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) project showed that grid photocoagulation was the best option for standard care when used to treat macular edema secondary to BRVO [10]. In recent decades, several novel treatments for BRVO have been introduced in major studies such as the BRAVO [11] and GENOVA studies [12]. However, the effects of such treatments remain unclear [1,9,13]. Furthermore, the cited works did not mimic the true clinical situation in that intravitreal bevacizumab injections (IVBs) were consecutively administered over a 3-month period to form a loading dose, the treatment strategy to be adopted after initial treatment failure was not considered, and lastly, no study has compared intravitreal triamcinolone acetate, bevacizumab, and drug combination injections for the treatment of macular edema secondary to BRVO. In the present study, we reviewed the medical records of patients treated for visual loss caused by macular edema secondary to BRVO 1) to evaluate whether intravitreal triamcinolone acetate, bevacizumab, and a combination of triamcinolone and bevacizumab injections, with or without rescue laser therapy, improved visual acuity compared with standard care of the type administered in the SCORE study, and 2) to determine whether such treatment modalities reduced unfavorable outcomes in patients with macular edema caused by BRVO, compared with those of the SCORE study.

To determine the role of CD24 in breast cancer cells, we knocked down CD24 in MCF-7 human breast cancer cells by retroviral delivery of shRNA. MCF-7 cells with knocked down CD24 (MCF-7 hCD24 shRNA) exhibited decreased cell proliferation and cell adhesion as compared to control MCF-7 mCD24 shRNA cells. Decreased proliferation of MCF-7 hCD24 shRNA cells resulted from the inhibition of cell cycle progression from G1 to S phase. The specific inhibition of MEK/ERK signaling by CD24 ablation might be responsible for the inhibition of cell proliferation. Phosphorylation of Src/FAK and TGF-β1-mediated epithelial to mesenchymal transition was also down-regulated in MCF-7 hCD24 shRNA cells. Reduced Src/FAK activity was caused by a decrease in integrin β1 bound with CD24 and subsequent destabilization of integrin β1. Our results suggest that down-regulation of Raf/MEK/ERK signaling via Src/FAK may be dependent on integrin β1 function and that this mechanism is largely responsible for the CD24 ablation-induced decreases in cell proliferation and epithelial to mesenchymal transition.

Virtualization technology has recently been widely used due to its various benefits, such as reducing system management efforts and increasing system utilization. Each execution environment can be isolated from other environments as each user can have access to virtual resources provided by the virtualization layer. This achieves benefits such as increasing reliability and security, and increases system mobility because applications and operating systems running on a virtual machine can migrate to other systems using the same virtualization layer. Virtualization technology is being extended to embedded systems, such as mobile phones, as well as to traditional IT systems, such as servers and PCs. Such extended virtualization technology to this domain requires migrating virtual machines between heterogeneous platforms, such as PCs, TVs, and mobile phones, beyond the existing virtual machine migration between homogeneous platforms. Virtual machine migration between heterogeneous platforms has additional benefits, such as increasing computing power of the execution environment, increasing device expandability, and achieving real migration of the user environment.In this paper, we present the real user- environment migration between heterogeneous platforms and design the architecture. We execute and evaluate virtual machine migration between the x86 platforms and the SPARC platform using our modified QEMU to verify the concept. Users can experience real user-environment migration between heterogeneous platforms using this method.

Today, multi-core processors are being used widely in mobile environments in addition to the existing PC-based environment. In order to use a multi-core processor efficiently, parallel programming skills are required. However, incorrect parallelization can degrade the performance of the overall system in a mobile multitasking environment. Therefore, a profiling technique that measures the performance of the whole system is needed. Also, it should to be possible to compare the performance of parallelization operations. In this paper, we propose a profiling method that analyzes the utilization of each application's processor when multiple applications are loaded at the same time. We also verified the profiling method by using some benchmark programs running on the Android operating system.

Recently, pluripotency induction or cellular reprogramming by introducing critical transcription factors has been extensively studied, but has been demonstrated only in vitro. Based on re- ports that Oct4 is critically involved in transforming neural stem cells into pluripotent cells, we used the lentiviral vector to in- troduce the Oct4 gene into the hippocampal dentate gyrus (DG) of adult mice. We examined whether this manipulation led to cellular or behavioral changes, possibly through processes in- volving the transformation of NS cells into pluripotent cells. The Oct4 lentivirus-infused group and the green fluorescent protein lentivirus-infused group showed a similar thickness of the DG and a comparable level of synaptophysin expression in the DG. Furthermore, our behavioral analyses did not show any differ- ences between the groups concerning exploratory activity, anxi- ety, or memory abilities. This first trial for pluripotency in- duction in vivo, despite negative results, provides implications and information for future studies on in vivo cellular reprogra- mming. (BMB reports 2011; 44(12): 793-798)

As more services have come to rely on sensor data such as audio and photos collected by mobile phone users, verifying the authenticity of this data has become critical for service correctness. At the same time, clients require the flexibility to tradeoff the fidelity of the data they contribute for resource efficiency or privacy. This paper describes YouProve, a partnership between a mobile device's trusted hardware and software that allows untrusted client applications to directly control the fidelity of data they upload and services to verify that the meaning of source data is preserved. The key to our approach is trusted analysis of derived data, which generates statements comparing the content of a derived data item to its source. Experiments with a prototype implementation for Android demonstrate that YouProve is feasible. Our photo analyzer is over 99% accurate at identifying regions changed only through meaning-preserving modifications such as cropping, compression, and scaling. Our audio analyzer is similarly accurate at detecting which sub-clips of a source audio clip are present in a derived version, even in the face of compression, normalization, splicing, and other modifications. Finally, performance and power costs are reasonable, with analyzers having little noticeable effect on interactive applications and CPU-intensive analysis completing asynchronously in under 70 seconds for 5-minute audio clips and under 30 seconds for 5-megapixel photos.

Although the effects of temperature changes on the activity of neurons have been studied in Aplysia, the reproducibility of the temperature dependence of the action potential (AP) parameters has not been verified. To this end, we performed experiments using Aplysia neurons. Fourteen AP parameters were analyzed using the long-term data series recorded during the experiments. Our analysis showed that nine of the AP parameters decreased as the temperature increased: the AP amplitude (A(AP)), membrane potential at the positive peak (V(pp)), interspike interval, first half (Δt(r1)) and last half (Δt(r2)) of the temperature rising phase, first half (Δt(f1)) and last half (Δt(f2)) of the temperature falling phase, AP (Δt(AP, 1/2)), and differentiated signal (Δt(DS, 1/2)) half-width durations. Five of the AP parameters increased with temperature: the differentiated signal amplitude (A(DS)), absolute value of the membrane potential at negative peak (|V(np)|), absolute value of the maximum slope of the AP during the temperature rising (|-MSR|) and falling (|MSF|) phases, and spiking frequency (Frequency). This work could provide the basis for a better understanding of the elementary processes underlying the temperature-dependent neuronal activity in Aplysia.

A versatile wearable computer for drivers (VWCD) was proposed that can extend in-vehicle multi-modal display spaces. In the first development phase, LEDs, mini video displays, earphones, and vibrators were included as visual, auditory and tactile displays, and were all attached to an eyeglass frame. One electrocardiographic electrode was attached to the VWCD to obtain the driver’s heart rate signal at the posterior auricular artery, and a gyro sensor was used to track the driver’s head position. Finally, a Bluetooth device was included to enable communication between VWCD and its mobile phone platform.

Aim of the study We performed this study to investigate the anti-cancer activity of Pharbitis nil (PN) ethanol extract which has been used for herbal medicinal treatment against diseases in East Asia. Materials and methods We analyzed the effects of PN extract on proliferation of breast cancer cell lines, MCF-7 control vector (vec) and MCF-7 human epidermal growth factor receptor 2 (HER2) cells engineered to overexpress oncogenic HER2 via retroviral infection. We performed the proliferation assay to measure the growth rate of the cells. FACS analysis was used to analyze the cell cycle. Western blot analysis was used to investigate the effect of PN on the level and activation of intracellular molecules. Results We found that PN extract inhibited the proliferation of both MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with the increase of sub G0/G1 apoptotic fractions. When we check the efficiency of PN on the level of intracellular signaling molecules, we found that PN extract induced the inhibition of phosphorylation of HER2 and its downstream effectors, Akt and extracellular signal-regulated kinases (ERK). Active forms of both Akt and ERK were gradually decreased in PN-treated MCF-7 vec and MCF-7 HER2 cells suggesting that the growth suppressive activity of PN is related to signaling pathway. The level of cyclin D also diminished in PN-treated both cells suggesting that PN may inhibit the growth of MCF-7 vec and MCF-7 HER2 cells by perturbing cell cycle progression. It should be noted that PN decreased the growth rate of both MCF-7 vec and MCF-7 HER2 cells without changing the level and activation of p53. Conclusion PN extract suppressed the proliferation rate of HER-2 overexpressing MCF-7 breast cancer cells inducing apoptotic cell death in vitro . Our data demonstrates that PN extracts contain useful anti-tumor activity especially against HER2 overexpressing breast cancer.

To assess the effects of endocrine-disrupting chemicals on the expression and activity of aromatase in the gonads of Bombina orientalis, a common amphibian, we intraperitoneally injected nonylphenol or bisphenol-A and then examined aromatase mRNA levels by RT-PCR as well as aromatase enzymatic activity by tritiated water release assays. To design primers for the RT-PCR, we cloned the B. orientalis aromatase gene using RT-PCR and degenerate primers. The full-length cDNA was obtained by 5'- and 3'-RACE PCR. The complete sequence of the B. orientalis aromatase gene revealed an open reading frame of 1500 bp encoding a deduced protein of 500 amino acids. Semi-quantitative RT-PCR indicated that nonylphenol or bisphenol-A injection did not significantly affect the expression of B. orientalis aromatase mRNA. However, a 48-hr treatment with nonyphenol or bisphenol A reduced aromatase activity to 47% and 32% of the control, respectively. These results suggest that endocrine disrupters can effectively modulate the activity of B. orientalis aromatase without affecting its mRNA levels.

Purpose The effects of small interfering (si)RNA of nuclear factor kappa B (NF-kappaB) on the development of posterior capsule opacification (PCO) were investigated both in vitro and in vivo in rabbits. Methods After application of p105 NF-kappaB siRNA to lens epithelial cells (LECs), Western blot analyses were performed to detect p105 and p50 NF-kappaB and a scratch assay was used to determine cell migration. In the capsular bag model, immunocytochemistry was performed to determine expression of p50 NF-kappaB and Western blot analyses for the presence of epithelial-to-mesenchymal transition (EMT) markers. Two sequences of p105 NF-kappaB siRNA were used in cataract surgery in 15 New Zealand White rabbits. PCO grading was conducted by slit lamp biomicroscopy and a computer-based PCO grading program. One month after surgery, the eyes of the rabbits were enucleated, and sections were prepared for examination of the posterior capsule and other ocular tissues by light microscopy. Results Application of p105 NF-kappaB siRNA to LECs decreased p105 NF-kappaB and p50 NF-kappaB expression, and migration of LECs was shown to be inhibited on the scratch assay. In the capsular bag model, the LEC count was significantly decreased, and immunocytochemistry showed reduced p50 NF-kappaB expression on the posterior capsule. EMT markers were significantly decreased after application of p105 NF-kappaB siRNA in the capsular bag model. In the in vivo study in rabbits, p105 NF-kappaB siRNA effectively decreased PCO, as determined by both slit lamp examination and the PCO grading program. Conclusions NF-kappaB seems to be related to migration and proliferation of LECs. NF-kappaB siRNA was effective in inhibiting the migration and proliferation of LECs in vitro and decreased PCO formation after cataract surgery in an in vivo rabbit model.

The problem of data association for target tracking in a multi-sensor cluttered environment is discussed. The probabilistic data association filter (PDAF) is useful to obtain proper estimate of state in this environment. We propose two distributed algorithms for PDAF to acquire high accuracy system and reduce computation burden caused by clutter. The distributed process and its modified fusion algorithm for the PDAF is introduced, such as the optimal fusion formula (OFF) and covariance intersection (CI). The OFF is optimal in view of each local sensor and it has the great accuracy among the distributed fusion algorithms. On the other hands, the CI has weighted convex combination without cross-covariance, so it has the advantage of fastness. Finally, the simulation results show that the proposed algorithms have advantages over robustness and lower computation burden.

Peripheral nerve injury leading to neuropathic pain induces the upregulation of interleukin (IL)-6 and microglial CX3CR1 expression, and activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord. Here, we investigated whether IL-6 regulates CX3CR1 expression through p38 MAPK activation in the spinal cord in rats with chronic constriction injury (CCI) of the sciatic nerve. Similar temporal changes in the expression of IL-6, phosphorylated p38 MAPK and CX3CR1 were observed following CCI. The increases in CX3CR1 expression, p38 MAPK activation and pain behavior after CCI were suppressed by blocking IL-6 action with a neutralizing antibody, while they were enhanced by supplying exogenous recombinant rat IL-6 (rrIL-6). rrIL-6 also induced increases in spinal CX3CR1 expression, p38 MAPK activation and pain behavior in naive rats without nerve injury. Furthermore, treatment with the p38 MAPK-specific inhibitor, SB203580, suppressed the increase in CX3CR1 expression induced by CCI or rrIL-6 treatment. Finally, blocking CX3CR1 or p38 MAPK activation prevented the development of mechanical allodynia and thermal hyperalgesia induced by CCI or rrIL-6 treatment. These results suggest a new mechanism of neuropathic pain, in which IL-6 induces microglial CX3CR1 expression in the spinal cord through p38 MAPK activation, enhancing the responsiveness of microglia to fractalkine in the spinal cord, thus playing an important role in neuropathic pain after peripheral nerve injury.

On finite samples redescending M-estimators outperform linear bounded Huber's M-estimators. To provide stable detection of a weak signal of arbitrary shape, robust Neyman–Pearson detection rules based on redescending M-estimators of location are introduced and studied. It is shown that, on the whole, robust detectors based on redescending M-estimators outperform conventional Huber's linear bounded detectors rules under light- and heavy-tailed noise distributions both on large and small samples. Copyright © 2009 John Wiley & Sons, Ltd.

In IEEE 802.16j standard, relays are added to increase coverage and improve throughput. However, some overhead results from the inclusion of the relays. One typical example is an addition of R-MAP (Relay MAP) to be included in the header of the frames transmitted from BS (Base Station) to RS (Relay Stations) in non-transparent mode [1]. The R-MAP conveys transmission schedules for the burst data from BS to an RS. Since R-MAP is mostly modulated by the lower MCS (Modulation and Coding Scheme) level (QPSK 1/2 for example), the bandwidth consumption is considerable. Compared with higher MCS level (64QAM 3/4 for example) used by data bursts, it uses 5 times the bandwidth. In this paper, we propose a scheme to compress the R-MAP and show its efficiency through simulation. We also show how to reduce the CID (Connection identifiers) information in MAC headers to further reduce the overhead from relaying. Compression of R-MAP will greatly reduce the overhead from relaying. In other words, we reduce the overhead from relaying in control plane (R-MAP) as well as in data plane (MAC header). As confirmed by the performance evaluation, MAC Efficiency of the proposed schemes is higher than that of the Standard schemes by approximately 11%.