Project description:Human antibody responses to AM/LAM are heterogenous and knowledge of reactivity to specific glycan epitopes at the monoclonal level is limited. Using novel glycan arrays, we characterized very high affinity monoclonal antibodies to AM/LAM, determined these mAbs are non-competing, and recognized distinct glycan epitopes. distinct from other anti-AM/LAM mAbs reported.
Project description:Phosphoinositide 3-kinase (PI3K) signaling activation is frequently observed in triple negative breast cancer, however, PI3K inhibitors have shown limited clinical activity. To investigate resistance mechanisms, we performed global transcriptome, proteome, phosphoproteome and kinome analysis of a panel of triple negative breast cancer patient derived xenograft models with varying responsiveness to buparlisib, a pan-PI3K inhibitor, for differentially expressed baseline and post-treatment biomarkers. Resistance was associated with incomplete inhibition of PI3K and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified additional candidates in association with buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAPK2K4 reduced both baseline and feedback MAPK/MEK signaling and enhanced buparlisib efficacy in vitro. Interestingly, we show that a complex ins/del in PIK3CA led to a change in buparlisib response in a NEK9/MAP2K4 dependent manner. In summary, our study indicates a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased global analyses in uncovering resistance mechanisms to targeted therapy.
Project description:Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer’s disease pathogenesis in the brain. While age-associated blood-borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here we investigate whether APOE allelic variation or presence of brain amyloid are associated with plasma proteomic changes and the molecular processes associated with these changes. Using the SOMAscan assay, we measured 1,305 plasma proteins from 53 homozygous, APOE3 and APOE4 subjects without dementia. We investigated the relationship of either the APOE-ε4 allele or amyloid positivity with plasma proteome changes by linear mixed effects modeling and ontology-based pathway and module trait correlation analyses. APOE4 is associated with plasma protein differences linked to atherosclerosis, tyrosine kinase activity, cholesterol transport, extracellular matrix, and synaptogenesis pathways. Independent of APOE4, we found that subjects likely harboring brain amyloid exhibit plasma proteome signatures associated with AD-linked pathways, including neurovascular dysfunction. Our results indicate that APOE4 status or presence of brain amyloid are associated with plasma proteomic shifts prior to the onset of symptoms, suggesting that systemic pathways in certain risk contexts may be plausible targets for disease modification.
Project description:The study objective was to find new biomarkers of treatment response and adverse events in patients receiving neoadjuvant therapy for locally advanced rectal cancer. Patients received neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) and underwent treatment evaluation four weeks after CRT completion. Radical pelvic surgery was planned 2-4 weeks later. Patients were scored for treatment adverse events, according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, throughout the neoadjuvant treatment course, including at NACT and CRT completion. Treatment response was assessed by histologic ypTN staging and tumor regression grade (TRG) scoring, as well as progression-free survival (time from Inclusion date to Date of local relapse or Date of metastatic disease, whichever came first) recorded for five years after surgery.
Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R or mTOR inhibition might suggest a number of therapeutic combinations that could improve their clinical activity.
Project description:To demonstrate the utility of the newly developed dendron-coated phosphokinase antibody array(DPA) in which the antibodies are immobilized on a dendron-coated glass slide, the phosphorylation profiles of brain tissue samples obtained from Alzheimer's disease (AD) model mice were generated.
Project description:57 serum samples from immunodeficiency patients were screened on custom designed protein microarrays for the presence of autoantibodies against cytokines, chemokines, growth factors, and other candidate autoantigens.
Project description:EGFR-inhibition is required for targeted therapies of ERBB2-positive/EGFR high breast cancer. Approximately 30% of human ERBB2-positive breast tumors also express EGFR.
Project description:A short sequence of 11 amino acids belonging to the cj0669 protein from Campylobacter jejuni NCTC 11168 which was previously identified as potentially immunogenig was analyzed via alanine scanning to narrow down the significant amino acid residues within the sequence.