TNF-alpha differentially modulates subunit levels of respiratory electron transport complexes of ER/PR plus ve/-ve breast cancer cells to regulate mitochondrial complex activity and tumorigenic potential

Background: Tumor necrosis factor-α (TNF-α) is an immunostimulatory cytokine that is consistently high in the breast tumor microenvironment (TME); however, its differential role in mitochondrial functions and cell survival in ER/PR +ve and ER/PR −ve breast cancer cells is not well understood. Methods: In the current study, we investigated TNF-α modulated mitochondrial proteome using high-resolution mass spectrometry and identified the differentially expressed proteins in two different breast cancer cell lines, ER/PR positive cell line; luminal, MCF-7 and ER/PR negative cell line; basal-like, MDA-MB-231 and explored its implication in regulating the tumorigenic potential of breast cancer cells. We also compared the activity of mitochondrial complexes, ATP, and ROS levels between MCF-7 and MDA-MB-231 in the presence of TNF-α. We used Tumor Immune Estimation Resource (TIMER) webserver to analyze the correlation between TNF-α and mitochondrial proteins in basal and luminal breast cancer patients. Kaplan-Meier method was used to analyze the correlation between mitochondrial protein expression and survival of breast cancer patients. Results: The proteome analysis revealed that TNF-α differentially altered the level of critical proteins of mitochondrial respiratory chain complexes both in MCF-7 and MDA-MB-231, which correlated with differential assembly and activity of mitochondrial ETC complexes. The inhibition of the glycolytic pathway in the presence of TNF-α showed that glycolysis is indispensable for the proliferation and clonogenic ability of MDA-MB-231 cells (ER/ PR −ve) as compared to MCF-7 cells (ER/PR +ve). The TIMER database showed a negative correlation between the expressions of TNF-α and key regulators of mitochondrial OXPHOS complexes in basal breast vs lobular carcinoma. Conversely, patient survival analysis showed an improved relapse-free survival with increased expression of identified proteins of ETC complexes and survival of the breast cancer patients. Conclusion: The evidence presented in our study convincingly demonstrates that TNF-α regulates the survival and proliferation of aggressive tumor cells by modulating the levels of critical assembly factors and subunits involved in mitochondrial respiratory chain supercomplexes organization and function. This favors the rewiring of mitochondrial metabolism towards anaplerosis to support the survival and proliferation of breast cancer cells. Collectively, the results strongly suggest that TNF-α differentially regulates metabolic adaptation in ER/PR +ve (MCF- 7) and ER/PR −ve (MDA-MB-231) cells by modulating the mitochondrial supercomplex assembly and activity

Proximal Analysis and the Minimal Time Function of a Class of Semilinear Control Systems

The minimal time function of a class of semilinear control systems is considered in Banach spaces, with the target set being a closed ball. It is shown that the minimal time functions of the Yosida approximation equations converge to the minimal time function of the semilinear control system. Complete characterization is established for the subdifferential of the minimal time function satisfying the Hamilton–Jacobi–Bellman equation. These results extend the theory of finite dimensional linear control systems to infinite dimensional semilinear control systems

Quantum-Dot Light-Emitting Diodes with Nitrogen-Doped Carbon Nanodot Hole Transport and Electronic Energy Transfer Layer

Electroluminescence efficiency is crucial for the application of quantum-dot light-emitting diodes (QD-LEDs) in practical devices. We demonstrate that nitrogen-doped carbon nanodot (N-CD) interlayer improves electrical and luminescent properties of QD-LEDs. The N-CDs were prepared by solution-based bottom up synthesis and were inserted as a hole transport layer (HTL) between other multilayer HTL heterojunction and the red-QD layer. The QD-LEDs with N-CD interlayer represented superior electrical rectification and electroluminescent efficiency than those without the N-CD interlayer. The insertion of N-CD layer was found to provoke the Forster resonance energy transfer (FRET) from N-CD to QD layer, as confirmed by time-integrated and - resolved photoluminescence spectroscopy. Moreover, hole-only devices (HODs) with N-CD interlayer presented high hole transport capability, and ultraviolet photoelectron spectroscopy also revealed that the N-CD interlayer reduced the highest hole barrier height. Thus, more balanced carrier injection with sufficient hole carrier transport feasibly lead to the superior electrical and electroluminescent properties of the QD-LEDs with N-CD interlayer. We further studied effect of N-CD interlayer thickness on electrical and luminescent performances for high-brightness QD-LEDs. The ability of the N-CD interlayer to improve both the electrical and luminescent characteristics of the QD-LEDs would be readily exploited as an emerging photoactive material for high-efficiency optoelectronic devices.ope

Suprasellar cysts: clinical presentation, surgical indications, and optimal surgical treatment

<p>Abstract</p> <p>Background</p> <p>To describe the clinical presentation of suprasellar cysts (SSCs) and surgical indications, and compare the treatment methods of endoscopic ventriculocystostomy (VC) and ventriculocystocisternotomy (VCC).</p> <p>Methods</p> <p>We retrospectively reviewed the records of 73 consecutive patients with SSC who were treated between June 2002 and September 2009. Twenty-two patients were treated with VC and 51 with VCC. Outcome was assessed by clinical examination and magnetic resonance imaging.</p> <p>Results</p> <p>The patients were divided into five groups based on age at presentation: age less than 1 year (n = 6), 1-5 years (n = 36), 6-10 years (n = 15), 11-20 years (n = 11), and 21-53 years (n = 5). The main clinical presentations were macrocrania (100%), motor deficits (50%), and gaze disturbance (33.3%) in the age less than 1 year group; macrocrania (75%), motor deficits (63.9%), and gaze disturbance (27.8%) in the 1-5 years group; macrocrania (46.7%), symptoms of raised intracranial pressure (ICP) (40.0%), endocrine dysfunction (40%), and seizures (33.3%) in the 6-10 years group; symptoms of raised ICP (54.5%), endocrine dysfunction (54.5%), and reduced visual field or acuity (36.4%) in the 11-20 years group; and symptoms of raised ICP (80.0%) and reduced visual field or acuity (40.0%) in the 21-53 years group. The overall success rate of endoscopic fenestration was 90.4%. A Kaplan-Meier curve for long-term efficacy of the two treatment modalities showed better results for VCC than for VC (p = 0.008).</p> <p>Conclusions</p> <p>Different age groups with SSCs have different main clinical presentations. VCC appears to be more efficacious than VC.</p

Dimethyl Sulfoxide Promotes the Multiple Functions of the Tumor Suppressor HLJ1 through Activator Protein-1 Activation in NSCLC Cells

Background: Dimethyl sulfoxide (DMSO) is an amphipathic molecule that displays a diversity of antitumor activities. Previous studies have demonstrated that DMSO can modulate AP-1 activity and lead to cell cycle arrest at the G1 phase. HLJ1 is a newly identified tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. Its transcriptional activity is regulated by the transcription factor AP-1. However, the effects of DMSO on HLJ1 are still unknown. In the present study, we investigate the antitumor effects of DMSO through HLJ1 induction and demonstrate the mechanisms involved. Methods and Findings: Low-HLJ1-expressing highly invasive CL1–5 lung adenocarcinoma cells were treated with various concentrations of DMSO. We found that DMSO can significantly inhibit cancer cell invasion, migration, proliferation, and colony formation capabilities through upregulation of HLJ1 in a concentration-dependent manner, whereas ethanol has no effect. In addition, the HLJ1 promoter and enhancer reporter assay revealed that DMSO transcriptionally upregulates HLJ1 expression through an AP-1 site within the HLJ1 enhancer. The AP-1 subfamily members JunD and JunB were significantly upregulated by DMSO in a concentration-dependent manner. Furthermore, pretreatment with DMSO led to a significant increase in the percentage of UV-induced apoptotic cells. Conclusions: Our results suggest that DMSO may be an important stimulator of the tumor suppressor protein HLJ1 throug

A Mutation in MRH2 Kinesin Enhances the Root Hair Tip Growth Defect Caused by Constitutively Activated ROP2 Small GTPase in Arabidopsis

Root hair tip growth provides a unique model system for the study of plant cell polarity. Transgenic plants expressing constitutively active (CA) forms of ROP (Rho-of-plants) GTPases have been shown to cause the disruption of root hair polarity likely as a result of the alteration of actin filaments (AF) and microtubules (MT) organization. Towards understanding the mechanism by which ROP controls the cytoskeletal organization during root hair tip growth, we have screened for CA-rop2 suppressors or enhancers using CA1-1, a transgenic line that expresses CA-rop2 and shows only mild disruption of tip growth. Here, we report the characterization of a CA-rop2 enhancer (cae1-1 CA1-1) that exhibits bulbous root hairs. The cae1-1 mutation on its own caused a waving and branching root hair phenotype. CAE1 encodes the root hair growth-related, ARM domain-containing kinesin-like protein MRH2 (and thus cae1-1 was renamed to mrh2-3). Cortical MT displayed fragmentation and random orientation in mrh2 root hairs. Consistently, the MT-stabilizing drug taxol could partially rescue the wavy root hair phenotype of mrh2-3, and the MT-depolymerizing drug Oryzalin slightly enhanced the root hair tip growth defect in CA1-1. Interestingly, the addition of the actin-depolymerizing drug Latrunculin B further enhanced the Oryzalin effect. This indicates that the cross-talk of MT and AF organization is important for the mrh2-3 CA1-1 phenotype. Although we did not observe an apparent effect of the MRH2 mutation in AF organization, we found that mrh2-3 root hair growth was more sensitive to Latrunculin B. Moreover, an ARM domain-containing MRH2 fragment could bind to the polymerized actin in vitro. Therefore, our genetic analyses, together with cell biological and pharmacological evidence, suggest that the plant-specific kinesin-related protein MRH2 is an important component that controls MT organization and is likely involved in the ROP2 GTPase-controlled coordination of AF and MT during polarized growth of root hairs

Computed Tomography Imaging of Primary Lung Cancer in Mice Using a Liposomal-Iodinated Contrast Agent

To investigate the utility of a liposomal-iodinated nanoparticle contrast agent and computed tomography (CT) imaging for characterization of primary nodules in genetically engineered mouse models of non-small cell lung cancer.Primary lung cancers with mutations in K-ras alone (Kras(LA1)) or in combination with p53 (LSL-Kras(G12D);p53(FL/FL)) were generated. A liposomal-iodine contrast agent containing 120 mg Iodine/mL was administered systemically at a dose of 16 µl/gm body weight. Longitudinal micro-CT imaging with cardio-respiratory gating was performed pre-contrast and at 0 hr, day 3, and day 7 post-contrast administration. CT-derived nodule sizes were used to assess tumor growth. Signal attenuation was measured in individual nodules to study dynamic enhancement of lung nodules.A good correlation was seen between volume and diameter-based assessment of nodules (R(2)>0.8) for both lung cancer models. The LSL-Kras(G12D);p53(FL/FL) model showed rapid growth as demonstrated by systemically higher volume changes compared to the lung nodules in Kras(LA1) mice (p<0.05). Early phase imaging using the nanoparticle contrast agent enabled visualization of nodule blood supply. Delayed-phase imaging demonstrated significant differential signal enhancement in the lung nodules of LSL-Kras(G12D);p53(FL/FL) mice compared to nodules in Kras(LA1) mice (p<0.05) indicating higher uptake and accumulation of the nanoparticle contrast agent in rapidly growing nodules.The nanoparticle iodinated contrast agent enabled visualization of blood supply to the nodules during the early-phase imaging. Delayed-phase imaging enabled characterization of slow growing and rapidly growing nodules based on signal enhancement. The use of this agent could facilitate early detection and diagnosis of pulmonary lesions as well as have implications on treatment response and monitoring

Anti-Arthritic Effects of Magnolol in Human Interleukin 1β-Stimulated Fibroblast-Like Synoviocytes and in a Rat Arthritis Model

Fibroblast-like synoviocytes (FLS) play an important role in the pathologic processes of destructive arthritis by producing a number of catabolic cytokines and metalloproteinases (MMPs). The expression of these mediators is controlled at the transcriptional level. The purposes of this study were to evaluate the anti-arthritic effects of magnolol (5,5′-Diallyl-biphenyl-2,2′-diol), the major bioactive component of the bark of Magnolia officinalis, by examining its inhibitory effects on inflammatory mediator secretion and the NF-κB and AP-1 activation pathways and to investigate its therapeutic effects on the development of arthritis in a rat model. The in vitro anti-arthritic activity of magnolol was tested on interleukin (IL)-1β-stimulated FLS by measuring levels of IL-6, cyclooxygenase-2, prostaglandin E2, and matrix metalloproteinases (MMPs) by ELISA and RT-PCR. Further studies on how magnolol inhibits IL-1β-stimulated cytokine expression were performed using Western blots, reporter gene assay, electrophoretic mobility shift assay, and confocal microscope analysis. The in vivo anti-arthritic effects of magnolol were evaluated in a Mycobacterium butyricum-induced arthritis model in rats. Magnolol markedly inhibited IL-1β (10 ng/mL)-induced cytokine expression in a concentration-dependent manner (2.5–25 µg/mL). In clarifying the mechanisms involved, magnolol was found to inhibit the IL-1β-induced activation of the IKK/IκB/NF-κB and MAPKs pathways by suppressing the nuclear translocation and DNA binding activity of both transcription factors. In the animal model, magnolol (100 mg/kg) significantly inhibited paw swelling and reduced serum cytokine levels. Our results demonstrate that magnolol inhibits the development of arthritis, suggesting that it might provide a new therapeutic approach to inflammatory arthritis diseases

Association between Low Density Lipoprotein Receptor-Related Protein 2 Gene Polymorphisms and Bone Mineral Density Variation in Chinese Population

Low density lipoprotein receptor-related protein 2 gene (LRP2) is located next to the genomic region showing suggestive linkage with both hip and wrist bone mineral density (BMD) phenotypes. LRP2 knockout mice showed severe vitamin D deficiency and bone disease, indicating the involvement of LRP2 in the preservation of vitamin D metabolites and delivery of the precursor to the kidney for the generation of 1α,25(OH)2D3. In order to investigate the contribution of LRP2 gene polymorphisms to the variation of BMD in Chinese population, a total of 330 Chinese female-offspring nuclear families with 1088 individuals and 400 Chinese male-offspring nuclear families with 1215 individuals were genotyped at six tagSNPs of the LRP2 gene (rs2389557, rs2544381, rs7600336, rs10210408, rs2075252 and rs4667591). BMD values at the lumbar spine 1–4 (L1-4) and hip sites were measured by DXA. The association between LRP2 polymorphisms and BMD phenotypes was assessed by quantitative transmission disequilibrium tests (QTDTs) in female- and male-offspring nuclear families separately. In the female-offspring nuclear families, rs2075252 and haplotype GA of rs4667591 and rs2075252 were identified in the nominally significant total association with peak BMD at L1-4; however, no significant within-family association was found between peak BMD at the L1-4 and hip sites and six tagSNPs or haplotypes. In male-offspring nuclear families, neither the six tagSNPs nor the haplotypes was in total association or within-family association with the peak BMD variation at the L1-4 and hip sites by QTDT analysis. Our findings suggested that the polymorphisms of LRP2 gene is not a major factor that contributes to the peak BMD variation in Chinese population

Granulocyte-macrophage colony stimulatory factor enhances the pro-inflammatory response of interferon-γ-treated macrophages to pseudomonas aeruginosa infection

Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-γ production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-γ and IL-17A playing protective and detrimental roles, respectively, in CF. In order to explore the protective effect of IFN-γ in CF, the effect of IFN-γ alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), on the ability of human macrophages to control P. aeruginosa growth, resist the cytotoxicity induced by this bacterium or promote inflammation was investigated. Treatment of macrophages with IFN-γ, in the presence and absence of GM-CSF, failed to alter bacterial growth or macrophage survival upon P. aeruginosa infection, but changed the inflammatory potential of macrophages. IFN-γ caused up-regulation of monocyte chemoattractant protein-1 (MCP-1) and TNF-α and down-regulation of IL-10 expression by infected macrophages. GM-CSF in combination with IFN-γ promoted IL-6 production and further reduction of IL-10 synthesis. Comparison of TNF-α vs. IL-10 and IL-6 vs. IL-10 ratios revealed the following hierarchy in regard to the pro-inflammatory potential of human macrophages infected with P. aeruginosa: untreated < treated with GM-CSF < treated with IFN-γ < treated with GM-CSF and IFN-γ