Adjuvants are critical for the success of vaccines, and agonists for microbial pattern recognition receptors are promising new candidates. A mechanism for the immune enhancing role of adjuvants is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double stranded RNA (poly ICLC), a ligand for TLR3 and MDA-5 cytosolic RNA helicase. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC showed upregulation of genes involved in multiple innate immune pathways in all subjects, including interferon and inflammasome signaling. Blocking of type I interferon receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate pathways were similarly induced in volunteers immunized with the highly efficacious Yellow Fever Vaccine. Therefore a chemically defined microbial agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immunity, here for a live attenuated viral vaccine in humans.
Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans.
Time
View SamplesZinc-finger genes Fezf1 and Fezf2 encode transcriptional repressors. Fezf1 and Fezf2 are expressed in the early neural stem/progenitor cells and control neuronal differentiation in mouse dorsal telencephalon.
Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain.
Specimen part
View SamplesThere is a continuing need for driver strains to enable cell type-specific manipulation in the nervous system. Each cell type expresses a unique set of genes, and recapitulating expression of marker genes by BAC transgenesis or knock-in has generated useful transgenic mouse lines. However since genes are often expressed in many cell types, many of these lines have relatively broad expression patterns. We report an alternative transgenic approach capturing distal enhancers for more focused expression. We identified an enhancer trap probe often producing restricted reporter expression and developed efficient enhancer trap screening with the PiggyBac transposon. We established more than 200 lines and found many lines that label small subsets of neurons in brain substructures, including known and novel cell types. Images and other information about each line are available online (http://enhnacertrap.bio.brandeis.edu). Overall design: Examination of 6 cortical mouse neuronal cell types. 5 of which are in layer 6 in 3 different cortical regions.
A Mammalian enhancer trap resource for discovering and manipulating neuronal cell types.
Sex, Cell line, Subject
View SamplesGIST is considered to invariably arise through gain-of-function KIT or PDGFRA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GIST is poorly understood.
Distinct gene expression-defined classes of gastrointestinal stromal tumor.
Sex, Age
View SamplesA functional interaction between peroxisome proliferator-activated receptor alpha (PPARalpha) and components of the circadian clock has been suggested; however, it remains to be clarified whether those transcriptional factors interact with each other to regulate the expression of their target genes.
Bezafibrate induces plasminogen activator inhibitor-1 gene expression in a CLOCK-dependent circadian manner.
Sex
View SamplesThe purpose of the present study was to investigate the association of glutathione S-transferase P1 (GSTP1) expression with resistance to neoadjuvant paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (P-FEC) in human breast cancers. The relationship of GSTP1 expression and GSTP1 promoter hypermethylation with intrinsic subtypes was also investigated. In this study, primary breast cancer patients (n = 123, stage II-III) treated with neoadjuvant P-FEC were analyzed. Tumor samples were obtained by vacuum-assisted core biopsy before P-FEC. GSTP1 expression was determined using immunohistochemistry, GSTP1 promoter methylation index (MI) using bisulfite methylation assay and intrinsic subtypes using DNA microarray. The pathological complete response (pCR) rate was significantly higher in GSTP1-negative tumors (80.0%) than GSTP1-positive tumors (30.6%) (P = 0.009) among estrogen receptor (ER)-negative tumors but not among ER-positive tumors (P = 0.267). Multivariate analysis showed that GSTP1 was the only predictive factor for pCR (P = 0.013) among ER-negative tumors. Luminal A, luminal B and HER2-enriched tumors showed a significantly lower GSTP1 positivity than basal-like tumors (P = 0.002, P < 0.001 and P = 0.009, respectively), while luminal A, luminal B and HER2-enriched tumors showed a higher GSTP1 MI than basal-like tumors (P = 0.076, P < 0.001 and P < 0.001, respectively). In conclusion, these results suggest the possibility that GSTP1 expression can predict pathological response to P-FEC in ER-negative tumors but not in ER-positive tumors. Additionally, GSTP1 promoter hypermethylation might be implicated more importantly in the pathogenesis of luminal A, luminal B and HER2-enriched tumors than basal-like tumors.
GSTP1 expression predicts poor pathological complete response to neoadjuvant chemotherapy in ER-negative breast cancer.
Age, Specimen part, Disease stage
View SamplesCollismycin A is a microbial product. We used microarrays to examine the effect of collismycin A on gene expression of HeLa cells.
Proteomic profiling reveals that collismycin A is an iron chelator.
Specimen part, Cell line
View SamplesThe agonistic anti-human CD3 antibody , OKT-3, has been used to control acute transplant rejection. The in vivo administration of OKT-3 was previously shown to induce the partial depletion of T cells and anergy in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3 Ab, 20-2b2 (#1 abs), which recognized a close, but different determinant on the CD3 molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT-3. Our results indicated that the CD3 molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT-3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT-3 in terms of the induction of cytokine production.
Modulation of the human T cell response by a novel non-mitogenic anti-CD3 antibody.
Specimen part, Disease, Disease stage
View SamplesDendritic cells (DCs) are critical regulators of Foxp3+ regulatory T (Treg) cell-homeostasis. Recent reports have suggested that Langerin+ DCs, especially epidermal Langerhans cells (LCs), play an important role in inducing Treg cells. We investigated the roles of Langerin+ DCs in expanding Treg cells after ultraviolet B (UVB) exposure. We found that Treg cells were expanded in UVB-exposed skin in vivo even without Langerin+ DCs including LCs. In the UVB-exposed skin, Langerin- DCs showed a mature phenotype, and the Treg-expansion induced by UVB was significantly abrogated by CD86/CD80 blockade. Thus, maturing Langerin- DCs, rather than LCs and Langerin+ dermal DCs, are the main contributors to UVB-induced Treg expansion in the skin. These results indicate that a new mechanism for UVB-mediated tolerance, which can provide a new concept of treatment using DC-mediated tolerance.
Ultraviolet B-Induced Maturation of CD11b-Type Langerin<sup>-</sup> Dendritic Cells Controls the Expansion of Foxp3<sup>+</sup> Regulatory T Cells in the Skin.
Specimen part, Cell line
View SamplesBackground. The in vivo distribution status and molecular signature of bone marrow mesenchymal stem cells (MSC) remain unknown, although ex vivo expanded MSC have been used in numerous studies.
Identification of mesenchymal stem cell (MSC)-transcription factors by microarray and knockdown analyses, and signature molecule-marked MSC in bone marrow by immunohistochemistry.
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