Adoptive T Cell Therapy for Metastatic Colorectal Cancer

Colorectal cancer is the second leading cause of cancer-related death in US (1). Most of the mortality reflects local, regional and distant metastatic tumors. Cancers that are confined within the wall of the colon are often curable with surgery while tumor cells that have spread into other organs like liver and lung has low curable possibility, even though the chemotherapies and monoclonal antibodies can extend the person\u27s life and improve quality of life(2, 3). Surgery is the main treatment for primary colorectal tumors but recurrence can happen and develop into metastasis. In addition, colorectal cancer has been proved resistant to chemotherapy although little success has been achieved using a combination of 5-fluorouracil and levamisole. Survival rate decreases from 90% for primary tumors to 10% for distal metastasis of colorectal cancer (1). More attention has been attracted to immunotherapy against metastatic colon cancer, because of its potential for higher specificity and less side effect(4). Our main aim is to increase the eradication of metastatic colorectal cancer cells by optimizing immunotherapeutic approaches that have been well-underway. Guanylyl cyclase C (GCC) is a mucosal antigen expressed on apical surface of intestinal epithelial cells. It is a potential target for colorectal cancer immunotherapeutic approaches, because of its expression on \u3e95% of colorectal cancer cells and their maintenance through all the stages of colorectal cancer (5-9).This is because GCC is mainly expressed in the intestine so that its expression can be utilized to detect metastasis of colon cancer. The aim of this project is to develop an immunotherapy based on GCC-specific TCR transduced CD8 T cells to attack metastatic cancer cells. The initial step of this project is cloning out CD8 TCR specific to GCC. This can be done by T-hybridoma technology by which we fused T cells from mice immunized by GCC vaccine with fusion partner cells (BWZ/CD8)(10)

Neuronally enriched microvesicle RNAs are differentially expressed in the serums of Parkinson’s patients

BackgroundCirculating small RNAs (smRNAs) originate from diverse tissues and organs. Previous studies investigating smRNAs as potential biomarkers for Parkinson’s disease (PD) have yielded inconsistent results. We investigated whether smRNA profiles from neuronally-enriched serum exosomes and microvesicles are altered in PD patients and discriminate PD subjects from controls.MethodsDemographic, clinical, and serum samples were obtained from 60 PD subjects and 40 age- and sex-matched controls. Exosomes and microvesicles were extracted and isolated using a validated neuronal membrane marker (CD171). Sequencing and bioinformatics analyses were used to identify differentially expressed smRNAs in PD and control samples. SmRNAs also were tested for association with clinical metrics. Logistic regression and random forest classification models evaluated the discriminative value of the smRNAs.ResultsIn serum CD171 enriched exosomes and microvesicles, a panel of 29 smRNAs was expressed differentially between PD and controls (false discovery rate (FDR) < 0.05). Among the smRNAs, 23 were upregulated and 6 were downregulated in PD patients. Pathway analysis revealed links to cellular proliferation regulation and signaling. Least absolute shrinkage and selection operator adjusted for the multicollinearity of these smRNAs and association tests to clinical parameters via linear regression did not yield significant results. Univariate logistic regression models showed that four smRNAs achieved an AUC ≥ 0.74 to discriminate PD subjects from controls. The random forest model had an AUC of 0.942 for the 29 smRNA panel.ConclusionCD171-enriched exosomes and microvesicles contain the differential expression of smRNAs between PD and controls. Future studies are warranted to follow up on the findings and understand the scientific and clinical relevance