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Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer that has limited therapeutic options. Thus, developing novel treatments for metastatic TNBC is an urgent need. Here, we show that nanoparticle-mediated delivery of transforming growth factor-β1-activated kinase-1 (TAK1) inhibitor 5Z-7-Oxozeaenol can inhibit TNBC lung metastasis in most animals tested. P38 is a central signal downstream of TAK1 in TNBC cells in TAK1-mediated response to multiple cytokines. Following co-culturing with macrophages or fibroblasts, TNBC cells express interleukin-1 (IL1) or tumor necrosis factor-α (TNFα), respectively. Compared to TAK1 inhibition, suppressing IL1 signaling with recombinant IL1 receptor antagonist (IL1RA) is less efficient in reducing lung metastasis, possibly due to the additional TAK1 signals coming from distinct stromal cells. Together, these observations suggest that TAK1 may play a central role in promoting TNBC cell adaptation to the lung microenvironment by facilitating positive feedback signaling mediated by P38. Approaches targeting the key TAK1-P38 signal could offer a novel means for suppressing TNBC lung metastasis. [ABSTRACT FROM AUTHOR]

Peptides constructed with the 20 natural amino acids are generally considered to have little therapeutic potential because they are unstable in the presence of proteases and peptidases. However, proteolysis cleavage can be idiosyncratic, and it is possible that natural analogues of functional sequences exist that are highly resistant to cleavage. Here, we explored this idea in the context of peptides that bind to the signaling protein Gai1. To do this, we used a two-step in vitro selection process to simultaneously select for protease resistance while retaining function-first by degrading the starting library with protease (chymotrypsin), followed by positive selection for binding via mRNA display. Starting from a pool of functional sequences, these experiments revealed peptides with 100-400 fold increases in protease resistance compared to the parental library. Surprisingly, selection for chymotrypsin resistance also resulted in similarly improved stability in human serum (~100 fold). Mechanistically, the decreases in cleavage results from both a lower rate of cleavage (kcat) and a weaker interaction with the protease (Km). Overall, our results demonstrate that the hydrolytic stability of functional, natural peptide sequences can be improved by two orders of magnitude simply by optimizing the primary sequence. [ABSTRACT FROM AUTHOR]

Background: In response to dramatic increases in obesity prevalence, clinical guidelines urge health care providers to prevent and treat obesity more aggressively.Objective: To describe the proportion of obese primary care patients receiving obesity care over a 5-year period and identify factors predicting receipt of care.Design: Retrospective cohort study utilizing VHA administrative data from 6 of 21 VA administrative regions.Patients: Veterans seen in primary care in FY2002 with a body mass index (BMI) > or =30 kg/m(2) based on heights and weights recorded in the electronic medical record (EMR), survival through FY2006, and active care (1 or more visits in at least 3 follow-up years FY2003-2006).Main Measures: Receipt of outpatient visits for individual or group education or instruction in nutrition, exercise, or weight management; receipt of prescriptions for any FDA-approved medications for weight reduction; and receipt of bariatric surgery.Key Results: Of 933,084 (88.6%) of 1,053,228 primary care patients who had recorded heights and weights allowing calculation of BMI, 330,802 (35.5%) met criteria for obesity. Among obese patients who survived and received active care (N = 264,667), 53.5% had a recorded obesity diagnosis, 34.1% received at least one outpatient visit for obesity-related education or counseling, 0.4% received weight-loss medications, and 0.2% had bariatric surgery between FY2002-FY2006. In multivariable analysis, patients older than 65 years (OR = 0.62; 95% CI: 0.60-0.64) were less likely to receive obesity-related education, whereas those prescribed 5-7 or 8 or more medication classes (OR = 1.41; 1.38-1.45; OR = 1.94; 1.88-2.00, respectively) or diagnosed with obesity (OR = 4.0; 3.92-4.08) or diabetes (OR = 2.23; 2.18-2.27) were more likely to receive obesity-related education.Conclusions: Substantial numbers of VHA primary care patients did not have sufficient height or weight data recorded to calculate BMI or have recorded obesity diagnoses when warranted. Receipt of obesity education varied by sociodemographic and clinical factors; providers may need to be cognizant of these when engaging patients in treatment. [ABSTRACT FROM AUTHOR]

The reaction of indium (In) and silver (Ag) during the electroplating process of indium over a thick silver layer was investigated. It was found that the plated In atoms react with Ag to form AgIn2 intermetallic compounds at room temperature. Indium is commonly used in the electronics industry to bond delicate devices due to its low yield strength and low melting temperature. In this study, copper (Cu) substrates were electroplated with a 60- μm-thick Ag layer, followed by electroplating an In layer with a thickness of 5 μm or 10 μm, at room temperature. To investigate the chemical reaction between In and Ag, the microstructure and composition on the surface and the cross section of samples were observed by scanning electron microscopy (SEM) with energy-dispersive x-ray spectroscopy (EDX). The x-ray diffraction method (XRD) was also employed for phase identification. It was clear that indium atoms reacted with underlying Ag to form AgIn2 during the plating process. After the sample was stored at room temperature in air for 1 day, AgIn2 grew to 5 μm in thickness. With longer storage time, AgIn2 continued to grow until all indium atoms were consumed. The indium layer, thus, disappeared and could barely be detected by XRD. [ABSTRACT FROM AUTHOR]

Abstract Purpose  The purpose of this study was to investigate the potential of a T-cell-related targeting method using a lentiviral vector-based gene delivery system. Materials and Methods  A lentiviral vector system was constructed by co-incorporating an anti-CD3 antibody (OKT3) and a fusogen into individual viral particles. The incorporation of OKT3 and fusogen was analyzed using confocal microscopy and the in vitro transduction efficiency was evaluated using flow cytometry. Blocking reagents (ammonium chloride (NH4Cl) and soluble OKT3 antibody) were added into vector supernatants during transduction to study the mechanism of this two-molecule targeting strategy. To demonstrate the ability of targeted transduction in vivo, Jurkat.CD3 cells were xenografted subcutaneously into the right flank of each mouse and the lentiviral vector was injected subcutaneously on both sides of each mouse 8 h post-injection. Subsequently, the reporter gene (firefly luciferase) expression was monitored using a noninvasive bioluminescence imaging system. Results  By co-displaying OKT3 and fusogen on the single lentiviral surface, we could achieve targeted delivery of genes to CD3-positive T-cells both in vitro and in vivo. Conclusions  These results suggest the potential utility of this engineered lentiviral system as a new tool for cell type-directed gene delivery. [ABSTRACT FROM AUTHOR]

Hemolytic uremic syndrome (HUS) is not a commonly reported complication in post-transplantation patients treated with cyclosporine-A (CSA), and is extremely rare in systemic sclerosis (SSc) patients treated with this drug. CSA may contribute to the development of chronic ischemic glomerulonephropathy and vasculopathy, features not easily distinguished from SSc-related nephropathy. Here, we describe a 41-year-old Chinese man with diffuse-type SSc treated with CSA who developed thrombocytopenia, acute renal failure and hemolytic anemia and was diagnosed with HUS. Renal function and thrombocytopenia improved gradually after intensive treatment of plasma exchange (PE) and high-dose steroid therapy. After PE, renal biopsy showed ischemic glomerulonephropathy and obliterative vasculopathy. This case illustrates that PE can improve the hematological disorders and characteristic renal changes of HUS in SSc patients treated with CSA. However, this therapy may not be effective in normalizing serum creatinine level in SSc patients once CSA has triggered the normal kidney to develop glomerulonephropathy and vasculopathy with ischemic and sclerotic changes. [ABSTRACT FROM AUTHOR]

We report a method of inducing antigen production in dendritic cells by in vivo targeting with lentiviral vectors that specifically bind to the dendritic cell–surface protein DC-SIGN. To target dendritic cells, we enveloped the lentivector with a viral glycoprotein from Sindbis virus engineered to be DC-SIGN–specific. In vitro, this lentivector specifically transduced dendritic cells and induced dendritic cell maturation. A high frequency (up to 12%) of ovalbumin (OVA)-specific CD8+ T cells and a significant antibody response were observed 2 weeks after injection of a targeted lentiviral vector encoding an OVA transgene into naive mice. This approach also protected against the growth of OVA-expressing E.G7 tumors and induced regression of established tumors. Thus, lentiviral vectors targeting dendritic cells provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens. [ABSTRACT FROM AUTHOR]

Because of the reason that the individuals' thoughts have the complicated and uncertain characteristics in the field of social science, this study makes the most of the fuzzy sets, which solve uncertain and imprecise conditions, to transform the opinions belonging to human beings into the quantitative numbers. Advertising involvement is regarded as the object for this empirical study which comprehensively collects plenty of antecedents and consequences for advertising involvement. We take advantage of the fuzzy automata to develop an integrated model of advertising involvement. The results indicate that in addition to the selection of implications, a fitting model relies on the selection of compositions in the fuzzy automata. On the average, the standard composition, which is one of compositions in this study, is the most appropriate method for developing a model of advertising involvement. [ABSTRACT FROM AUTHOR]

Abstract  In All-IP networks, each computer or communication equipment needs an IP address. To supply enough IP addresses, the new Internet protocol IPv6 will be used in next generation mobile communication. Although IPv6 improves the existing Internet protocol (IPv4), Duplicate Address Detection (DAD) mechanism may consume resources and suffer from long delay. DAD is used to make sure whether the IP address is unique or not. When a mobile node performs an inter-domain handoff, it will first generate a new IP and perform a DAD procedure. The DAD procedure not only wastes time but also increases the signaling load on Internet. In this paper, we propose a new DAD mechanism to speed up the DAD procedure. We create a DAD table in access or mobility routers in All-IP networks and record all IP addresses of the area. When a new IP address needs to perform DAD, it can just search in the DAD table to confirm the uniqueness of the address. Furthermore, we propose a new method, Fast Duplicate Address Detection (Fast DAD), to reduce data search time. Simulation results show that our method outperforms the existing DAD methods. [ABSTRACT FROM AUTHOR]

Acute anterior uveitis (AAU) is the most frequently extra-articular manifestation of ankylosing spondylitis (AS). To investigate whether AAU has an association with disease activity, functional ability and physical mobility in AS patients, 146 Chinese AS patients in Taiwan were enrolled in a cross-sectional study. These patients fulfilled the 1984 modified New York criteria and visited the Outpatient Department of the Veterans General Hospital-Taipei from April 2004 to July 2005. Patients completed questionnaires assessing disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)], functional ability [Bath Ankylosing Spondylitis Functional Index (BASFI)] and patient’s global assessment [Bath Ankylosing Spondylitis Patient Global Score (BAS-G)]. Meanwhile, physical examinations were performed, including Schober test, finger-to-floor, lateral spinal flexion, occiput-to-wall and chest expansion. The history of AAU was accepted only if diagnosed by an ophthalmologist. The prevalence of AAU in this Chinese AS cohort was 15.8% (23/146). Patients with AAU had a significantly higher BASDAI than those without [absolute differences=0.96, 95% confidence intervals (CI): 0.35∼1.88]. Additionally, patients with AAU had significantly increased BASFI than those without (absolute differences=1.46, 95% CI: 0.33∼2.59). Moreover, there was advanced limitation of physical motility in patients with AAU, including finger-to-floor, occiput-to-wall distances and Schober test, (95% CI: 3.89∼16.95 and p=0.046, respectively). Disease duration mildly correlated with BASFI ( r=0.24, p=0.003) but not with BASDAI ( p=0.838). There was no difference of disease duration between patients with and without AAU ( p=0.343). These results suggested that the presence of AAU in AS patients may be associated with higher disease activity, poor functional ability and advanced physical impairment. [ABSTRACT FROM AUTHOR]

This report describes the identification of a new toxigenic strain ofBacillus thuringiensisspecific for long-horned beetles.B. thuringiensisBt866 encodes acry3Aa-like gene (Bt886cry3Aa) that is 1,956 bp in length and is predicted to encode an 85.78-kDa protein. The gene is highly similar tocry3Aa1, differing in only six nucleotides and four amino acids. The four disparate amino acids occur within the conserved domains of the Cry3Aa toxin. The expression ofBt866cry3AinEscherichia colicells resulted in a high level of toxicity towardApriona germariHope larvae. More than 75% of the larvae were killed; and the remaining survivors exhibited slower growth. These results indicate that the toxigenic strainBt886cry3Aaencodes a protein that is specific against long-horned beetles. Genetic engineering of theBt866cry3Aagene into poplar plantations may provide resistance to long-horned beetles. [ABSTRACT FROM AUTHOR]

The Fet3 protein in Saccharomyces cerevisiae is a multicopper oxidase tethered to the outer surface of the yeast plasma membrane. Fet3p catalyzes the oxidation of Fe 2+ to Fe 3+; this ferroxidation reaction is an obligatory first step in high-affinity iron uptake through the permease Ftr1p. Here, kinetic analyses of several Fet3p mutants identify residues that contribute to the specificity that Fet3p has for Fe 2+, one of which is essential also to the coupling of the ferroxidase and uptake processes. The spectral and kinetic properties of the D278A, E185D and A, Y354F and A, and E185A/Y354A mutants of a soluble form of Fet3p showed that all of the mutants exhibited the normal absorbance at 330 nm and 608 nm due to the type 3 and type 1 copper sites in Fet3p, respectively. The EPR spectra of the mutants were also equivalent to wild-type, showing that the type 1 and type 2 Cu(II) sites in the proteins were not perturbed. The only marked kinetic defects measured in vitro were increases in K M for Fe 2+ exhibited by the D278A, E185A, Y354A, and E185A/Y354A mutants. These results suggest that these three residues contribute to the ferroxidase specificity site in Fet3p. In vivo analysis of these mutant proteins in their membrane-bound form showed that only E185 mutants exhibited kinetic defects in 59Fe uptake. For the Fet3p(E185D) mutant, K M for iron was 300-fold greater than the wild-type K M, while Fet3p(E185A) was completely inactive in support of iron uptake. In situ fluorescence demonstrated that all of the mutant Fet3 proteins, in complex with an Ftr1p:YFP fusion protein, were trafficked normally to the plasma membrane. These results suggest that E185 contributes to Fe 2+binding to Fet3p and to the subsequent trafficking of the Fe 3+ produced to Ftr1p. [ABSTRACT FROM AUTHOR]

In this paper, we propose a hierarchical Mobile RSVP (HMRSVP) that can achieve mobility independent QoS-guaranteed services in mobile computing environments. The HMRSVP integrates RSVP with Mobile IP regional registration and makes advance resource reservations only when an inter-region movement may possibly occur. We first show that, by NS simulator, our HMRSVP can achieve the same QoS guarantees as MRSVP does with fewer resource reservations. Then, we show that HMRSVP outperforms MRSVP in terms of reservation blocking, forced termination and session completion probabilities. [ABSTRACT FROM AUTHOR]

A 79-year-old male with acute myelogenous leukemia developed acute right knee arthritis during admission, after the use of broad-spectrum antibiotics before chemotherapy. The initial synovial fluid sample appeared to be mildly inflammatory with a low white cell count. The fungal septic arthritis was not diagnosed until Candida tropicalis, a rare species of Candida, was isolated in the synovial fluid. Although fluconazole is effective in treating the microorganism, the untreated leukemia rendered the infection incurable and led to the growth of fluconazole-resistant Candida krusei. We reported the unusual case of fungal arthritis and reviewed the literature. [ABSTRACT FROM AUTHOR]

Autoimmune inner ear disease (AIED) is a very rare disorder with distinct clinical features and can occur in patients with malignancy or autoimmune diseases. We report a 72-year-old male patient with polyarteritis nodosa treated continuously for 5 years with aggressive immunosuppressive drugs, including cyclophosphamide, who experienced three episodes of acute hearing loss during treatment. Organic lesions of the external and middle ear were excluded by repeated examinations, and if one subscribes to McCabe’s (Ann Otol Rhinol Laryngol 88:585–589, ) definition of AIED, this condition must be considered as the likely cause of the hearing loss. During the period of treatment, three episodes of AIED occurred, and eventually, lung cancer developed. From the time relationship and clinical manifestations of neuropathy and livedo reticularis, the first episode of hearing loss was more likely to be related to vasculitis itself, while the third episode may well have been associated with the development of lung cancer given the dramatic improvement in the clinical condition following treatment of the tumor by excision and cancer chemotherapy. Coexistence of AIED, vasculitis, and malignancy in the same patient has only been reported infrequently, and our case suggests that this coexistence may not be coincidental. For those patients with autoimmune disease who are on long-term immunosuppressive drug therapy, active surveillance for a nascent malignant tumor should be exercised if AIED recurs or persists. [ABSTRACT FROM AUTHOR]