Gong Y.,Molecular Imaging Program |
Robbins R.C.,Molecular Imaging Program |
Robbins R.C.,Stanford University |
Wu J.C.,Stanford University
Circulation | Year: 2011
Background-Although stem cell therapy has provided a promising treatment for myocardial infarction, the low survival of the transplanted cells in the infarcted myocardium is possibly a primary reason for failure of long-term improvement. Therefore, the development of novel prosurvival strategies to boost stem cell survival will be of significant benefit to this field. Methods and Results-Cardiac progenitor cells (CPCs) were isolated from transgenic mice, which constitutively express firefly luciferase and green fluorescent protein. The CPCs were transduced with individual lentivirus carrying the precursor of miR-21, miR-24, and miR-221, a cocktail of these 3 microRNA precursors, or green fluorescent protein as a control. After challenge in serum free medium, CPCs treated with the 3 microRNA cocktail showed significantly higher viability compared with untreated CPCs. After intramuscular and intramyocardial injections, in vivo bioluminescence imaging showed that microRNA cocktail-treated CPCs survived significantly longer after transplantation. After left anterior descending artery ligation, microRNA cocktail-treated CPCs boost the therapeutic efficacy in terms of functional recovery. Histological analysis confirmed increased myocardial wall thickness and CPC engraftment in the myocardium with the microRNA cocktail. Finally, we used bioinformatics analysis and experimental validation assays to show that Bim, a critical apoptotic activator, is an important target gene of the microRNA cocktail, which collectively can bind to the 3′UTR region of Bim and suppress its expression. Conclusions-We have demonstrated that a microRNA prosurvival cocktail (miR-21, miR-24, and miR-221) can improve the engraftment of transplanted cardiac progenitor cells and therapeutic efficacy for treatment of ischemic heart disease. © 2011 American Heart Association, Inc.
Mittra E.S.,Molecular Imaging Program |
Fan-Minogue H.,Molecular Imaging Program |
Lin F.I.,Molecular Imaging Program |
Sriram V.,Merck And Co. |
And 3 more authors.
Clinical Cancer Research | Year: 2013
Purpose: Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma. Experimental Design: Sequential experiments were done using eight- to nine-week-old nude mice injected with 3 × 105 U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted to evaluate for significant differences in the response. Results: There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[18F]fluoro-2-deoxy-D-glucose (FDG) PET. In addition, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later. Conclusions: Targeting the HGF/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate. © 2013 AACR.
Double knockdown of prolyl hydroxylase and factor-inhibiting hypoxia-inducible factor with nonviral minicircle gene therapy enhances stem cell mobilization and angiogenesis after myocardial infarction
Jia F.,Molecular Imaging Program |
Hu S.,Molecular Imaging Program |
Gong Y.,Stanford University |
Kay M.A.,Stanford University |
And 3 more authors.
Circulation | Year: 2011
Background-Under normoxic conditions, hypoxia-inducible factor (HIF)-1α is rapidly degraded by 2 hydroxylases: prolyl hydroxylase (PHD) and factor-inhibiting HIF-1 (FIH). Because HIF-1α mediates the cardioprotective response to ischemic injury, its upregulation may be an effective therapeutic option for ischemic heart failure. Methods and Results-PHD and FIH were cloned from mouse embryonic stem cells. The best candidate short hairpin (sh) sequences for inhibiting PHD isoenzyme 2 and FIH were inserted into novel, nonviral, minicircle vectors. In vitro studies after cell transfection of mouse C2C12 myoblasts, HL-1 atrial myocytes, and c-kit cardiac progenitor cells demonstrated higher expression of angiogenesis factors in the double-knockdown group compared with the single-knockdown and short hairpin scramble control groups. To confirm in vitro data, shRNA minicircle vectors were injected intramyocardially after left anterior descending coronary artery ligation in adult FVB mice (n=60). Functional studies using MRI, echocardiography, and pressure-volume loops showed greater improvement in cardiac function in the double-knockdown group. To assess mechanisms of this functional recovery, we performed a cell trafficking experiment, which demonstrated significantly greater recruitment of bone marrow cells to the ischemic myocardium in the double-knockdown group. Fluorescence-activated cell sorting showed significantly higher activation of endogenous c-kit cardiac progenitor cells. Immunostaining showed increased neovascularization and decreased apoptosis in areas of injured myocardium. Finally, western blots and laser-capture microdissection analysis confirmed upregulation of HIF-1α protein and angiogenesis genes, respectively. Conclusions-We demonstrated that HIF-1α upregulation by double knockdown of PHD and FIH synergistically increases stem cell mobilization and myocardial angiogenesis, leading to improved cardiac function. © 2011 American Heart Association, Inc.
News Article | October 31, 2016
Molecular imaging pioneer Christopher Contag of Stanford University has been named as recipient of the 2017 Britton Chance Biomedical Optics Award, the Awards Committee for SPIE, the international society for optics and photonics, has announced. The prestigious award is presented annually in recognition of outstanding lifetime contributions to the field of biomedical optics through the development of innovative, high-impact technologies. Contag will accept the award at SPIE Photonics West in San Francisco in January, and give a talk on his work during the BiOS Hot Topics session. A frequent contributor to the event, he has authored more than three dozen proceedings papers in the SPIE Digital Library, and nearly 20 articles in the Journal of Biomedical Optics published by SPIE. Contag is associate chief of Neonatal and Developmental Medicine at Stanford University, director of Stanford’s Center for Innovation in In Vivo Imaging (SCI3), and co-director of the Molecular Imaging Program at Stanford (MIPS). He is also a professor in the Departments of Pediatrics, Radiology, and Microbiology and Immunology, and a member of Bio-X faculty for interdisciplinary sciences, and the Immunology faculty. Contag’s lab was the first to use biological sources of light to image key biological processes in living mammals. This work included the first in vivo bioluminescent images (BLI) of bacterial infection, gene expression patterns, stem cell biology, cancer growth and transplantation biology of solid organs and responses to therapy. His laboratory now develops macroscopic and microscopic optical imaging tools that have enabled in vivo studies of drug targets and agents such that every large drug company now uses BLI to accelerate drug development. In its citation, the SPIE Awards Committee commended Contag for his significant changes to the way we study biology in living tissue through his invention of in vivo optical imaging using bioluminescent and fluorescent reporters. This invention is one of the most significant advances in biomedical research in recent history, the citation noted. “Dr. Contag’s passion for unraveling cancer biology and his ability to recognize unmet needs and create new tools to solve them makes him an extraordinary candidate for the Britton Chance Biomedical Optics Award,” said Anna Moore, professor of Radiology and director of the Molecular Imaging Laboratory at Massachusetts General Hospital, in support of Contag’s nomination. SPIE is the international society for optics and photonics, an educational not-for-profit organization founded in 1955 to advance light-based science, engineering, and technology. The Society serves nearly 264,000 constituents from approximately 166 countries, offering conferences and their published proceedings, continuing education, books, journals, and the SPIE Digital Library. In 2015, SPIE provided more than $5.2 million in support of education and outreach programs. http://www.spie.org
Muller B.G.,Molecular Imaging Program |
Muller B.G.,U.S. National Institutes of Health |
Shih J.H.,Biometric Research Branch |
Sankineni S.,Molecular Imaging Program |
And 10 more authors.
Radiology | Year: 2015
Purpose: To evaluate accuracy and interobserver variability with the use of the Prostate Imaging Reporting and Data System (PI-RADS) version 2.0 for detection of prostate cancer at multiparametric magnetic resonance (MR) imaging in a biopsy-naïve patient population. Materials and Methods: This retrospective HIPAA-compliant study was approved by the local ethics committee, and written informed consent was obtained from all patients for use of their imaging and histopathologic data in future research studies. In 101 biopsy-naïve patients with elevated prostate-specific antigen levels who underwent multiparametric MR imaging of the prostate and subsequent transrectal ultrasonography (US)-MR imaging fusion-guided biopsy, suspicious lesions detected at multiparametric MR imaging were scored by five readers who were blinded to pathologic results by using to the newly revised PI-RADS and the scoring system developed in-house. Interobserver agreement was evaluated by using k statistics, and the correlation of pathologic results with each of the two scoring systems was evaluated by using the Kendall t correlation coefficient. Results: Specimens of 162 lesions in 94 patients were sampled by means of transrectal US-MR imaging fusion biopsy. Results for 87 (54%) lesions were positive for prostate cancer. Kendall t values with the PI-RADS and the in-house-developed scoring system, respectively, at T2-weighted MR imaging in the peripheral zone were 0.51 and 0.17 and in the transitional zone, 0.45 and 20.11; at diffusion-weighted MR imaging, 0.42 and 0.28; at dynamic contrast material-enhanced MR imaging, 0.23 and 0.24, and overall suspicion scores were 0.42 and 0.49. Median k scores among all possible pairs of readers for PI-RADS and the in-house-developed scoring system, respectively, for T2-weighted MR images in the peripheral zone were 0.47 and 0.15; transitional zone, 0.37 and 0.07; diffusion-weighted MR imaging, 0.41 and 0.57; dynamic contrast-enhanced MR imaging, 0.48 and 0.41; and overall suspicion scores, 0.46 and 0.55. Conclusion: Use of the revised PI-RADS provides moderately reproducible MR imaging scores for detection of clinically relevant disease. © RSNA, 2015.
Turkbey B.,Molecular Imaging Program |
Xu S.,Laboratory of Pathology |
Kruecker J.,Laboratory of Pathology |
Locklin J.,Urologic |
And 7 more authors.
BJU International | Year: 2011
OBJECTIVE: To develop a system that documents the location of transrectal ultrasonography (TRUS)-guided prostate biopsies by fusing them to MRI scans obtained prior to biopsy, as the actual location of prostate biopsies is rarely known. PATIENTS AND METHODS Fifty patients (median age 61) with a median prostate-specific antigen (PSA) of 5.8 ng/ml underwent 3T endorectal coil MRI prior to biopsy. 3D TRUS images were obtained just prior to standard TRUS-guided 12-core sextant biopsies wherein an electromagnetic positioning device was attached to the needle guide and TRUS probe in order to track the position of each needle pass. The 3D-TRUS image documenting the location of each biopsy was fused electronically to the T2-weighted MRI. Each biopsy needle track was marked on the TRUS images and these were then transposed onto the MRI. Each biopsy site was classified pathologically as positive or negative for cancer and the Gleason score was determined. RESULTS The location of all (n= 605) needle biopsy tracks was successfully documented on the T2-weighted (T2W) MRI. Among 50 patients, 20 had 56 positive cores. At the sites of biopsy, T2W signal was considered 'positive' for cancer (i.e. low in signal intensity) in 34 of 56 sites. CONCLUSION It is feasible to document the location of TRUS-guided prostate biopsies on pre-procedure MRI by fusing the pre-procedure TRUS to an endorectal coil MRI using electromagnetic needle tracking. This procedure may be useful in documenting the location of prior biopsies, improving quality control and thereby avoiding under-sampling of the prostate as well as directing subsequent biopsies to regions of the prostate not previously sampled. © 2010 BJU International.
Agarwal H.K.,Philips |
Mertan F.V.,Molecular Imaging Program |
Sankineni S.,Molecular Imaging Program |
Bernardo M.,Frederick National Laboratory for Cancer Research |
And 8 more authors.
Journal of Magnetic Resonance Imaging | Year: 2016
Purpose: To retrospectively determine the optimal b-value(s) of diffusion-weighted imaging (DWI) associated with intermediate-high risk cancer in the peripheral zone (PZ) of the prostate. Materials and Methods: Forty-two consecutive patients underwent multi b-value (16 evenly spaced b-values between 0 and 2000 s/mm2) DWI along with multi-parametric MRI (MP-MRI) of the prostate at 3 Tesla followed by trans-rectal ultrasound/MRI fusion guided targeted biopsy of suspicious lesions detected at MP-MRI. Computed DWI images up to a simulated b-value of 4000 s/mm2 were also obtained using a pair of b-values (b = 133 and 400 or 667 or 933 s/mm2) from the multi b-value DWI. The contrast ratio of average intensity of the targeted lesions and the background PZ was determined. Receiver operator characteristic curves and the area under the curve (AUCs) were obtained for separating patients eligible for active surveillance with low risk prostate cancers from intermediate-high risk prostate cancers as per the cancer of the prostate risk assessment (CAPRA) scoring system. Results: The AUC first increased then decreased with the increase in b-values reaching maximum at b = 1600 s/mm2 (0.74) with no statistically significant different AUC of DWI with b-values 1067-2000 s/mm2. The AUC of computed DWI increased then decreased with the increase in b-values reaching a maximum of 0.75 around b = 2000 s/mm2. There was no statistically significant difference between the AUC of optimal acquired DWI and either of optimal computed DWI. Conclusion: The optimal b-value for acquired DWI in differentiating intermediate-high from low risk prostate cancers in the PZ is b = 1600 s/mm2. The computed DWI has similar performance as that of acquired DWI with the optimal performance around b = 2000 s/mm2. © 2016 Wiley Periodicals, Inc.
Kobayashi H.,Molecular Imaging Program
Japanese Journal of Clinical Radiology | Year: 2011
The goal of this review is to introduce the definition, and the past and current status of the molecular imaging in the United States, including grants, infrastructures, and directions of scientific researches. In the research and development of the molecular imaging, in vivo imaging methods to visualize the molecular events and functions in organs or animals/humans are stressed and discussed especially focusing on the multimodality imaging agents based on the nanotechnology.