The effects of erythrocyte alloantigen L on the avian immune response

Experiment 1 examined the alloantigen system L effects on Rous sarcomas in three B complex genotypes. The parental stock were 50% Modified Wisconsin Line 3 and 50% inbred Line 6.15- 5. B2B5 L1L2 x B2B5 L 1L2 matings produced experimental chicks. Chicks were inoculated with 20 pock-forming units (pfu) Rous sarcoma virus (RSV) at 6 weeks-of-age. Tumors were scored six times over 10 weeks postinoculation. Tumor scores were used to assign a tumor profile index (TPI) to each chicken. Results were evaluated by ANOVA. The B complex affected the responses. Separate analyses revealed L system effects ( P \u3c 0.05) only in B5B 5 chickens. Experiment 2 examined the influence of Ea-L on antibody response to SRBC and Brucella abortus (BA). The mating protocol was the same as in Experiment 1. At 4 and 11 weeks of age the experimental birds were injected intravenously with standard concentrations of SRBC and BA. Total and ME-resistant antibody titers were determined as described. Results were analyzed by ANOVA. Ea-L had an effect on total primary antibody titer to SRBC in a B5B 5 background (p \u3c 0.004) and on total (p \u3c 0.011) and ME-resistant (p \u3c 0.017) secondary titer to SRBC in a B5 B5 genotypic background. Ea-L also affected total (p \u3c 0.004) and ME-resistant (p \u3c 0.005) secondary titer to Brucella abortus in a B5 B5 background. Experiment 3 examined the effect of Ea-L on resistance and acquired immunity to E. tenella infection. The mating protocol was the same as in Experiments 1 and 2. In the resistance and susceptibility study, chicks were weighed and inoculated with 30,000 E. tenella oocysts at 6 weeks of age. 6 days post-inoculation, the birds were weighed again and assigned a cecal lesion score. In the immunity study, the challenge procedure was preceded by inoculations of 500 oocysts per day beginning at 5 weeks. Weight gain and cecal lesion scores were evaluated by ANOVA. The B complex affected lesion score in the immunity but not the resistance and susceptibility study and did not affect weight gain in either study. The L system had no effect in either study

In Vivo Detection of miRNA Expression in Tumors Using an Activatable Nanosensor

Purpose The development of tools for the analysis of microRNA (miRNA) function in tumors can advance our diagnostic and prognostic capabilities. Here, we describe the development of technology for the profiling of miRNA expression in the tumors of live animals. Procedures The approach is based on miRNA nanosensors consisting of sensor oligonucleotides conjugated to magnetic nanoparticles for systemic delivery. Feasibility was demonstrated for the detection of miR-10b, implicated in epithelial to mesenchymal transition and the development of metastasis. The miR-10b nanosensor was tested in vivo in two mouse models of cancer. In the first model, mice were implanted subcutaneously with MDA-MB-231-luc-D3H2LN tumors, in which miR-10b was inhibited. In the second model, mice were implanted bilaterally with metastatic MDA-MB-231 and nonmetastatic MCF-7 cells. The nanosensors were injected intravenously, and fluorescence intensity in the tumors was monitored over time. Results We showed that the described nanosensors are capable of discriminating between tumors based on their expression of miR-10b. Radiant efficiency was higher in the miR-10b-active tumors than in the miR-10b-inhibited tumors and in the MDA-MB-231 tumors relative to the MCF-7 tumors. Conclusions The described technology provides an important tool that could be used to answer questions about microRNA function in cancer.National Institutes of Health (U.S.) (National Cancer Institute R01CA16346101A1)Breast Cancer Alliance (Young Investigator Award

A Novel Imaging Approach for Early Detection of Prostate Cancer Based on Endogenous Zinc Sensing

The early detection of prostate cancer is a life-saving event in patients harboring potentially aggressive disease. With the development of malignancy, there is a dramatic reduction in the zinc content of prostate tissue associated with the inability of cancer cells to accumulate the ion. In the current study, we used endogenous zinc as an imaging biomarker for prostate cancer detection and progression monitoring. We employed a novel fluorescent sensor for mobile zinc (ZPP1) to detect and monitor the development of prostate cancer in a transgenic mouse model of prostate adenocarcinoma, using in vivo optical imaging correlated with biological fluid-based methods. We showed that the progression of prostate cancer could be monitored in vivo judging by the decreasing zinc content in the prostates of tumor-bearing mice in an age-dependent manner. In a novel quantitative assay, we determined the concentration of mobile zinc in both prostate cell lysates and mouse prostate extracts through simple titration of the ZPP1 sensor. Our findings fulfill the promise of zinc-based prostate cancer diagnostics with the prospect for immediate clinical translation.National Institute of General Medical Sciences (U.S.) (grant GM065519)National Cancer Institute (U.S.) (grant R00CA129070)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (grant RC1DK086242)Massachusetts Biomedical Research CorporationMassachusetts Biomedical Research Corporation (Tosteson Postdoctoral Fellowship

Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer: Imaging of Chemotherapeutic Response

The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response

Molecular Imaging: A Promising Tool to Monitor Islet Transplantation

Replacement of insulin production by pancreatic islet transplantation has great potential as a therapy for type 1 diabetes mellitus. At present, the lack of an effective approach to islet grafts assessment limits the success of this treatment. The development of molecular imaging techniques has the potential to fulfill the goal of real-time noninvasive monitoring of the functional status and viability of the islet grafts. We review the application of a variety of imaging modalities for detecting endogenous and transplanted beta-cell mass. The review also explores the various molecular imaging strategies for assessing islet delivery, the metabolic effects on the islet grafts as well as detection of immunorejection. Here, we highlight the use of combined imaging and therapeutic interventions in islet transplantation and the in vivo monitoring of stem cells differentiation into insulin-producing cells

Guidelines for Rational Cancer Therapeutics

Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors