Project description:Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.
Project description:In this study, Genome-wide transcriptomes of CD8+ T cells from HCV/HIV co-infected or mono-infected treatment-naive individuals were analyzed by using microarray assays. Pairwise comparisons were performed and differentially expressed genes were identified followed by quantitative real time PCR (qRT-PCR) validation. To identify the important functional categories, Directed Acyclic Graphs (DAG) from Web-based Gene SeT AnaLysis Toolkit (WebGestalt) was used to find out Gene Ontology (GO) categories with significantly enriched gene numbers. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also obtained by using the similar methods in the same website.
Project description:Abstract BACKGROUND Sacituzumab Govitecan (SG, TRODELVY™) is an antibody drug conjugate, with payload and linker characteristics preferable for CNS delivery. SG utilizes a pH hydrolysable linker, allowing SN-38 to be released at the tumor site. SN-38 is the active component of Irinotecan and 1000-fold more potent than the parent compound. We observed SG activity in intracranial xenografts and hypothesized that SG would achieve therapeutically relevant concentration of SN-38 within the CNS. METHODS We performed a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SG, SN-38, and SN-38G in patients undergoing craniotomy for breast cancer brain metastases (BCBM, n=10) or recurrent glioblastoma (rGBM, n=10). Patients received a single dose of SG at 10mg/kg IV the day prior to craniotomy and tumor collected. [SN-38] was analyzed via mass spectrometry (UHPLC-HRMS). Patients resumed SG 10mg/kg IV days 1 and 8 of 21 day cycle following recovery and were assessed every third cycle by MRI using RANO criteria. RESULTS To date 16 patients have been treated, including 8 BCBM and 8 rGBM. UHPLC-HRMS analysis was performed in the first 10 tumors (n=4 and 6 respectively). For the rGBM patients, total concentration of SN-38 varied from 93nM to 680nM, with a mean concentration of 420nM. For BCBM, total concentration of SN-38 varied from 173nM to 1160nM, with a mean concentration of 626nM. All GBM patients had residual measurable disease and 4 breast patients had measurable disease. With a median follow-up of 12 weeks from the first postoperative cycle in the first 14 patients, 2 partial responses from each group were observed (ORR of 28% and 50% at 12 weeks respectively). CONCLUSIONS SG achieves therapeutically relevant concentrations of SN-38 at 40-fold mean IC50s for GBM, and 150-fold mean IC50s for BCBM. Early intracranial responses are encouraging and merit further evaluation.
Project description:An integrated discovery to targeted proteomics approach was used to investigate the protein profiles of good and non–responders to anti-TNF-alpha and T-cell inhibitor treatments in PsA patients. Reverse phase liquid chromatography coupled to tandem mass spectrometry was used to generate protein profiles of synovial tissue obtained at baseline from 10 PsA patients who then commenced anti-TNF-alpha therapy (adalimumab). Targeted proteomics using multiple reaction monitoring was used to confirm and pre-validate a potential protein biomarker panel in 18 and 7 PsA patient samples respectively.
Project description:HLA-C expresion varies widely across the different HLA-C alleles. MicroRNA binding can partly explain the differences in HLA-C allele expression however other contributing factors still remain undetermined. Here we use two common HLA-C alleles, HLA-C*05:01 and HLA-C*07:02, to explore differences in expression levels. Using functional, structural and peptide repertoire comparisons we demonstrate that HLA-C expression levels are not only modulated at the RNA level but also at the protein level. This dataset contains RAW data and database search results for HLA-C*05:01 and HLA-C*07:02 from the 721.221 cell line.