CD1a and skin T cells: a pathway for therapeutic intervention.

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.

The Long Noncoding RNA RP11-728F11.4 Promotes Atherosclerosis.

OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in psoriasis: a systematic review and meta-analysis.

Psoriasis is a chronic, inflammatory skin disorder characterized by well-demarcated erythematous lesions with surface scaling. The disease is underpinned by a dysregulated immune response with a shift in the balance of neutrophils, lymphocytes and platelets. We sought to evaluate the novel systemic inflammatory markers, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as psoriatic indicators. Pubmed, Web of Science and Scopus were systematically searched for relevant studies. Twenty-four studies consisting of a total of 2,275 psoriatic patients (1,301 males and 974 females) and 2,334 healthy controls (1,401 males and 933 females) were identified for inclusion in the quantitative analysis. The NLR and PLR were found to be significantly increased in psoriatic patients [standardized mean difference (SMD) = 0.68, 95% CI 0.56-0.80, p < 0.01, and SMD = 0.37, 95% CI 0.14-0.60, p < 0.01, respectively]. However, no association between the NLR and PLR with psoriasis severity was detected (p = 0.93, and p = 0.83, respectively). In conclusion, the NLR and PLR are simple and cost-effective markers of psoriatic presence, but their value as severity markers requires further study.

Antibody therapies for the treatment of acute myeloid leukemia: exploring current and emerging therapeutic targets.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions.

Capitalist theory and socialist practice: The organization of Chinese mathematics in the early 1950s.

This article explores how the Chinese state organized scientific research in the 1950s, through a case study of mathematics. By examining the organizing process of the Chinese Mathematical Society and the establishment of the Institute of Mathematics of the Chinese Academy of Sciences, the article explains how a number of state agents were selected to lead national level research institutes as a means for guiding scientists in serving the needs of the state. In addition, under state corporatism, all scientists were attached to discipline-specific academic societies, forming a large hierarchy consisting of societies at different levels. When the political leaders needed to transform the agendas of the scientists, these organizations served as channels for communicating to constituent members what to do. Given this kind of organizational structure in the early days of the People's Republic of China, it was hard to differentiate between scientists and the organizational apparatus, especially for the scientists holding top-level leadership positions. Nevertheless, this study shows that individual researchers often resisted official mandates and found ways to pursue independent research interests by employing the state's rhetoric.

Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN.

Noncoding RNAs are emerging as important players in gene regulation and disease pathogeneses. Here, we show that a previously uncharacterized long noncoding RNA, nexilin F-actin binding protein antisense RNA 1 (NEXN-AS1), modulates the expression of the actin-binding protein NEXN and that NEXN exerts a protective role against atherosclerosis. An expression microarray analysis showed that the expression of both NEXN-AS1 and NEXN was reduced in human atherosclerotic plaques. In vitro experiments revealed that NEXN-AS1 interacted with the chromatin remodeler BAZ1A and the 5' flanking region of the NEXN gene and that it also upregulated NEXN expression. Augmentation of NEXN-AS1 expression inhibited TLR4 oligomerization and NF-κB activity, downregulated the expression of adhesion molecules and inflammatory cytokines by endothelial cells, and suppressed monocyte adhesion to endothelial cells. These inhibitory effects of NEXN-AS1 were abolished by knockdown of NEXN. In vivo experiments using ApoE-knockout mice fed a Western high-fat diet demonstrated that NEXN deficiency promoted atherosclerosis and increased macrophage abundance in atherosclerotic lesions, with heightened expression of adhesion molecules and inflammatory cytokines, whereas augmented NEXN expression deterred atherosclerosis. Patients with coronary artery disease were found to have lower blood NEXN levels than healthy individuals. These results indicate that NEXN-AS1 and NEXN represent potential therapeutic targets in atherosclerosis-related diseases.

Spatial and Temporal Confined Photothermolysis of Cancer Cells Mediated by Hollow Gold Nanospheres Targeted to Epidermal Growth Factor Receptors.

To date, a few studies have investigated the potential use of a short-pulsed laser in selective tumor cell destruction or its mechanism of cell killing. Computer simulation of the spatial and temporal profiles of temperature elevation after pulsed laser irradiation on an infinitesimal point source estimated that the temperature reached its highest point at ∼35 ns after a single 15 ns laser pulse. Moreover, temperature elevation was confined to a radius of sub-micrometer and returned to baseline within 100 ns. To investigate the effect of 15 ns laser pulses on A431 tumor cells, we conjugated hollow gold nanospheres (HAuNSs) to an antibody (C225) directed at the epithelial growth factor receptor. The resulting nanoparticles, C225-HAuNSs, bound to the cell membrane, internalized, and distributed throughout the cytoplasm, with some nanoparticles transported to the vicinity of the nuclear membrane. On using an optical microscope mounted to a tunable pulsed Ti:sapphire laser, rapid and extensive damage of live cancer cells was observed, whereas irradiation of A431 cells pretreated with nontargeted HAuNSs with a pulsed laser or pretreated with C225-HAuNSs with a continuous-wave laser-induced minimal cellular damage. Furthermore, after a single 15 ns laser pulse, C225-HAuNS-treated A431 cells cocultured with 3T3 fibroblasts showed signs of selective destruction. Thus, compared with a continuous-wave laser, shots of a short-pulsed laser were the most damaging to tumor cells that bound HAuNSs and generated the least heat to the surrounding environment. This mode of action by a short-pulsed laser on cancer cells (i.e., confined photothermolysis) may have potential applications in selective tumor cell destruction.

Conformation and self-assembly changes of isomeric peptide amphiphiles influenced by switching tyrosine in the sequences.

Self-assemblies of peptide amphiphiles feature unique structures, high biocompatibility, and potential for various applications, and have attracted increasing interest in supramolecular chemistry, protein science and polymer science. In this paper, isomeric peptide amphiphiles derived from lauric acid and silk fibroin-based peptides with different amino acid sequences (GAGAGAGY, GAGAGYGA, GAGYGAGA and GYGAGAGA) are investigated systematically to figure out the predominant endogenous and exogenous factors for their assembly in aqueous solution. With the position of tyrosine (Y) in the peptide segment gradually moving towards the alkane tails, the assembled peptide amphiphiles substantially change their secondary structures from the ß-sheet to the disorder dominant one under neutral pH conditions, because the increase of steric hindrance induced by the position change of Y disturbs the hydrogen bonds relevant to the formation of ß-sheets of (GA)n. Strong alkaline conditions are able to accelerate such a conformational change, due to the synergy of destruction of hydrogen bonds, the steric hindrance effect and electrostatic repulsion. As a consequence, the assembled peptide amphiphiles alter their nanostructures in aqueous solution from well-defined nanofibers to nanospheres with varying sizes. Therefore, it is summarized that the location of Y rather than the other effects such as pH value, etc. plays an essential role in the assembly of our isomeric peptide amphiphiles, which sheds light on the design of various isomeric peptides/peptide amphiphiles for their aggregation as well as potential functionality.

Determination of oral bioavailability of fusaric acid in male Sprague-Dawley rats.

Head and neck squamous cell cancer accounts for 3 % of new cancer cases and 2 % of cancer mortality annually in the United States. Current treatment options for most head and neck cancers continue to be surgical excision with or without radiation, radiation alone, or chemotherapy with radiation depending on location, stage of disease, and patient preference. Fusaric acid (FA) is a novel compound from a novel class of nicotinic acid derivatives that have activity against head and neck squamous cell carcinoma (HNSCC). Although its exact mechanism is still unknown, FA is thought to be active by increasing damage to DNA and preventing its synthesis and repair. The novel mechanism of FA provides an alternative to present therapies, as a single agent whether given parenterally or orally. It has synergy with conventional agents taxol, carboplatin, and erlotinib. In order to determine if FA has reasonable oral bioavailability, we have determined the pharmacokinetics of FA in male Sprague Dawley rats following administration by gavage and by intravenous injection. The bioavailability of FA was sufficient (58 %) to suggest that FA may be viable as an orally administered medication. Despite the encouraging bioavailability of FA, the intravenous (IV) pharmacokinetics suggested non-linear behavior within the IV dose range of 10, 25, and 75 mg/kg. These results demonstrate that further pharmacokinetic and toxicity studies in larger animals such as dogs and non-human primates are warranted.

Orthotopic VX rabbit tongue cancer model with FDG-PET and histologic characterization.

BACKGROUND: We present our experience with the use of an immunocompetent medium-sized animal model of tongue cancer that may be suitable for imaging and surgical studies. METHODS: A New Zealand white rabbit model of tongue cancer was created by injecting a VX tumor cell suspension grown in culture into the tongue of our model. The tumor was examined 7 days following implantation by physical examination, photography, and (18) fluoro 2-deoxyglucose-positron emission tomography (FDG-PET). At 12 days postimplantation, the model was again studied as described above prior to euthanization, and then tongue excision and bilateral neck dissections were performed. All tissue was examined by histology. RESULTS: We confirmed a successful orthotopic tongue cancer model that resulted in cervical nodal metastases. CONCLUSION: This model may be a useful model of orthotopic head and neck cancer for future surgical or imaging research.

Synthetic IgE peptide vaccine for immunotherapy of allergy.

An immunotherapeutic vaccine for allergy was produced by designing IgE-based synthetic peptide immunogens and selecting them for functional immunogenicity. The vaccine targets the binding site on IgE for the high affinity receptor Fc epsilon RI, by active immunization. The peptide target site on IgE heavy chain was selected from among the amino acid sequences for the C epsilon 2, C epsilon 3, and C epsilon 4 domains. These were characterised by epitope mapping studies for cross-reactivity to IgE and functional antigenicity. A peptide, modified from positions 413-435 of a loop region of C epsilon 3 and subjected to conformational constraint, elicited anti-IgE antibodies that blocked IgE-mediated histamine release. It was immunopotentiated by linkage to a promiscuous T helper site to produce a wholly synthetic chimaeric immunogen. This immunogen was shown to induce polyclonal site-specific anti-IgE antibodies that obstruct binding to Fc epsilon RI, inhibit histamine release by IgE-sensitised basophils, inhibit passive cutaneous anaphylaxis, and do not signal degranulation. Immunized dogs experienced significant reductions in total serum IgE.

How potent is potent? Evaluation of sexual function and bother in men who report potency after treatment for prostate cancer: data from CaPSURE.

OBJECTIVES: To characterize the association between potency and comprehensive sexual function. The accurate assessment of sexual function is critical for the evaluation of outcomes after treatment of prostate cancer. The assessments of potency typically used in this context, however, may be oversimplified. METHODS: CaPSURE is a large, observational database of men with prostate cancer. Participants complete health-related quality-of-life questionnaires, including the University of California, Los Angeles Prostate Cancer Index, every 6 months after treatment. A total of 5135 men completed at least one questionnaire and did not use medications for erectile function. The men were categorized as potent or impotent based on their ability to have erections and/or intercourse in the prior 4 weeks. Using the remaining questions on the Prostate Cancer Index, sexual function and bother scores were calculated for each group. RESULTS: Of the 5135 men, 27.4% were potent. The mean sexual function scores were 56 and 13 for potent and impotent men, respectively (P <0.0001). The corresponding mean bother scores were 62 and 36 (P <0.0001). The function scores ranged from 0 to 100 and 0 to 92 among potent and impotent men, respectively, and bother scores from 0 to 100 in both groups. Function was inversely associated with age in both groups, but bother did not change among potent men and ameliorated among impotent men. Individual Prostate Cancer Index questions correlated with potency to a variable extent. CONCLUSIONS: Although potent and impotent men have divergent sexual function and bother scores after treatment, the wide range of these scores in both groups denotes a complex picture of sexual function. The simple documentation of potency after treatment provides an insufficient measure of sexual health-related quality of life and should be supplemented with more comprehensive measures.

Effective synthetic peptide vaccine for foot-and-mouth disease in swine.

We have designed a peptide-based vaccine for foot-and-mouth disease (FMD) effective in swine. The peptide immunogen has a G-H loop domain from the VP1 capsid protein of foot-and-mouth disease virus (FMDV) and a novel promiscuous T helper (Th) site for broad immunogenicity in multiple species. The G-H loop VP1 site was optimised for cross-reactivity to FMDV by the inclusion into the peptide of cyclic constraint and adjoining sequences. The incorporation of consensus residues into the hypervariable positions of the VP1 site provided for broad immunogenicity. The vaccine protected 20 out of 21 immunised pigs from infectious challenge by FMDV O1 Taiwan using peptide doses as low as 12.5 microg, and a mild adjuvant that caused no lesions. A safe chemically-defined product would have considerable advantages for vaccination against FMD.

Synthetic AIDS vaccine by targeting HIV receptor.

A class of synthetic peptide immunogens for the cell surface HIV receptor complex has been developed to elicit antibodies that block viral entry by inhibiting gp120-CD4 interaction. These peptides extend our HIV receptor-directed approach from passive immunotherapy with mAb B4 (Proc. Natl. Acad. Sci. U.S.A. 96 (1999) 10367) to active immunization by a synthetic peptide-based vaccine. A peptide site from CD4 was identified as a B cell epitope capable of mimicking a susceptible site on the HIV receptor complex, and then rendered immunogenic. An effective target antigenic site (B cell epitope) for the cell surface HIV receptor complex was selected by epitope mapping from among diverse CD4 and chemokine receptor peptides. It is a cyclized sequence modified from the CDR2-like domain of CD4 (AA 39-66), that was predicted to produce steric hindrance of the discontinuous recognition site of mAb B4. The immunogenicity of the targeted epitope was augmented by tandem combination with promiscuous T helper cell epitopes (Th). The antibody response to this class of immunogens attained sufficient concentrations and affinities of the correct specificity to block the interactions of HIV env glycoprotein with the cellular receptor, and prevent infection. The polyclonal antibodies generated against these fusion constructs in multiple animal species neutralized a broad array of HIV-1 primary isolates from clades A to E. Despite eliciting antibodies to the key CD4 immunomodulatory molecule, the site-specific and chemically defined immunogens displayed no overt immunotoxicity in baboons and have potential for the immunotherapy and immunoprophylaxis of HIV infection.