Person: Heidari, Pedram
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Heidari
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Pedram
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Heidari, Pedram
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Publication Optical Imaging with a Cathepsin B Activated Probe for the Enhanced Detection of Esophageal Adenocarcinoma by Dual Channel Fluorescent Upper GI Endoscopy(Ivyspring International Publisher, 2012) Habibollahi, Peiman; Figueiredo, Jose-Luiz; Heidari, Pedram; Dulak, Austin M; Imamura, Yu; Bass, Adam; Ogino, Shuji; Chan, Andrew; Mahmood, UmarDespite significant advances in diagnosis and treatment, the prognosis of esophageal adenocarcinoma remains poor highlighting the importance of early detection. Although white light (WL) upper endoscopy can be used for screening of the esophagus, it has limited sensitivity for early stage disease. Thus, development of new imaging technology to improve the diagnostic capabilities of upper GI endoscopy for early detection of esophageal adenocarcinoma is an important unmet need. The goal of this study was to develop a method for the detection of malignant lesions in the esophagus using WL upper endoscopy combined with near infrared (NIR) imaging with a protease activatable probe (Prosense750) selective for cathepsin B (CTSB). An orthotopic murine model for distal esophageal adenocarcinoma was generated through the implantation of OE-33 and OE-19 human esophageal adenocarcinoma lines in immunocompromised mice. The mice were imaged simultaneously for WL and NIR signal using a custom-built dual channel upper GI endoscope. The presence of tumor was confirmed by histology and target to background ratios (TBR) were compared for both WL and NIR imaging. NIR imaging with ProSense750 significantly improved upon the TBRs of esophageal tumor foci, with a TBR of 3.64\(\pm\)0.14 and 4.50\(\pm\)0.11 for the OE-33 and OE-19 tumors respectively, compared to 0.88\(\pm\)0.04 and 0.81\(\pm\)0.02 TBR for WL imaging. The combination of protease probes with novel imaging devices has the potential to improve esophageal tumor detection by fluorescently highlighting neoplastic regions.Publication A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis(Backwell Publishing Ltd, 2014) Zadra, Giorgia; Photopoulos, Cornelia; Tyekucheva, Svitlana; Heidari, Pedram; Weng, Qing Ping; Fedele, Giuseppe; Liu, Hong; Scaglia, Natalia; Priolo, Carmen; Sicinska, Ewa; Mahmood, Umar; Signoretti, Sabina; Birnberg, Neal; Loda, Massimo5′AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63–78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63–78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.Publication An EGFR Targeted PET Imaging Probe for the Detection of Colonic Adenocarcinomas in the Setting of Colitis(Ivyspring International Publisher, 2014) Turker, N. Selcan; Heidari, Pedram; Kucherlapati, Raju; Kucherlapati, Melanie; Mahmood, UmarColorectal cancer is a serious complication associated with inflammatory bowel disease, often indistinguishable by screening with conventional FDG PET probes. We have developed an alternative EGFR-targeted PET imaging probe that may be used to overcome this difficulty, and successfully assessed its utility for neoplastic lesion detection in preclinical models. Cetuximab F(ab′)2 fragments were enzymatically generated, purified, and DOTA-conjugated. Radiolabeling was performed with 67Ga for cell based studies and 64Cu for in vivo imaging. Competitive binding studies were performed on CT26 cells to assess affinity (KD) and receptors per cell (Bmax). In vivo imaging using the EGFR targeted PET probe and 18F FDG was performed on CT26 tumor bearing mice in both control and dextran sodium sulfate (DSS) induced colitis settings. Spontaneous adenomas in genetically engineered mouse (GEM) models of colon cancer were additionally imaged. The EGFR imaging agent was generated with high purity (> 98%), with a labeling efficiency of 60 ± 5% and ≥99% radiochemical purity. The KD was 6.6 ± 0.7 nM and the Bmax for CT26 cells was 3.3 ± 0.1 × 106 receptors/cell. Target to background ratios (TBR) for CT26 tumors compared to colonic uptake demonstrated high values for both 18F-FDG (3.95 ± 0.13) and the developed 64Cu-DOTA-cetuximab-F(ab′)2 probe (4.42 ± 0.11) in control mice. The TBR for the EGFR targeted probe remained high (3.78 ± 0.06) in the setting of colitis, while for 18F FDG, this was markedly reduced (1.54 ± 0.08). Assessment of the EGFR targeted probe in the GEM models demonstrated a correlation between radiotracer uptake in spontaneous colonic lesions and the EGFR staining level ex vivo. A clinically translatable PET imaging probe was successfully developed to assess EGFR. The imaging agent can detect colonic tumors with a high TBR for detection of in situ lesions in the setting of colitis, and opens the possibility for a new approach for screening high-risk patients.Publication Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors(Ivyspring International Publisher, 2016) Esfahani, Shadi; Heidari, Pedram; Kim, Sun A.; Ogino, Shuji; Mahmood, UmarPurpose: To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. Materials and Methods: MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (Kd). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Results: Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R2 = 0.99, p < 0.001). Probe binding affinity to MET (Kd) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that in vivo probe uptake in xenografts is specific and can be blocked when co-injected with unlabeled peptide; for instance the epifluorescence TBR is reduced from 13.5 ± 1.2 to 1.7 ± 0.3 (p < 0.05) in HT-29 and from 5.3 ± 0.8 to 1.4 ± 0.2 (p < 0.05) in Huh-7 xenografts after co-injection with unlabeled peptides. Biodistribution studies showed predominantly renal clearance of the probe. Conclusion: Optical imaging of MET resulted in high TBR in animal models of primary and metastatic hepatic tumors suggesting its utility for procedural guidance.Publication The Role of Ultrasound in Diagnosis of the Causes of Low Back Pain: a Review of the Literature(Kowsar, 2015) Heidari, Pedram; Farahbakhsh, Farzin; Rostami, Mohsen; Noormohammadpour, Pardis; Kordi, RaminContext: Low back pain (LBP) is among the most prevalent musculoskeletal conditions in the developed countries. It is a common problem causing disability and imposing a huge economic burden to individuals and state organizations. Imaging plays an important role in diagnosis of the etiology of LBP. Evidence Acquisition: The electronic databases included: PubMed (1950 to present), Ovid SP Medline (1950 to present) and ISI (1982 to present) and Google Scholar. In every search engine another search was performed using various permutations of the following keywords: ultrasonography, ultrasound imaging, low back pain, back muscles, paraspinal muscles, multifidus, transverse abdominis, muscle size, spinal canal, sacroiliac joint and spondylolisthesis. Results: Magnetic resonance imaging (MRI) is widely used in evaluation of patients with LBP; however, high costs, limited availability and contraindications for its use have restricted MRI utilization. In a quest for a less expensive and readily available tool to investigate LBP, clinicians and researchers found ultrasonography (US) as an alternative. In this review we discuss the US application in diagnosis of some common causes of non-specific chronic LBP. Discussed topics include evaluation of spinal canal diameter, paraspinal and transabdominal muscles, sacroiliac joint laxity, pregnancy related LBP, sacroiliitis, and spondylolisthesis using US in patients with LBP. Conclusions: While the first researches on employing ultrasound in diagnosis of patients with LBP had been focused on spinal canal diameter, recent studies have been mostly performed to evaluate the role of transabdominal and paraspinal muscles on core stability and thereby LBP occurrence. On the other side, Doppler ultrasonography has recently played an important role in objective measurement of joint laxity as a common etiology for LBP. Doppler imaging also in pregnant patients with LBP has been recommended as a safe and sensitive method. As conclusion, according to recent and most prestigious studies, focusing more on transabdominal muscle thickness can be considered as future approach in investigations.Publication Fatalities Among Iranian High-altitude Outdoor Enthusiasts: Causes and Mechanisms(Tehran University of Medical Sciences, 2012) Kordi, Ramin; Rostami, Mohsen; Heidari, Pedram; Ameli, Sanaz; Foroughifard, Lotfali; Kordi, MahboobehPurpose: This study was performed to determine the possible causes and mechanisms of fatalities among Iranian mountaineers during climbing. Methods: By contacting several sources, deceased mountaineers were identified. Data about the causes and mechanism of death was retrospectively obtained using a standard questionnaire for each case. Results: A total of 29 deaths were identified from March 2006 to June 2010. Deceased subjects had a mean age of 39 years (SD: 12.8, Range: 20-67). Falling was the most common accident leading to death of outdoor enthusiasts (n = 14, 48%). Asphyxia (n = 6, 24%) was the most common cause of death among the subjects, followed by heart attack, internal bleeding, cerebral hemorrhage and hypothermia (17%, 17%, 17% and 10%, respectively). Conclusions: Our findings suggest that education of medical service providers of the climbing groups on facing victims in high altitude areas, where they have limited resources, can be particularly helpful. In addition, a national program to educate mountaineers might help to reduce fatalities.Publication The Student Committee of Sports Medicine Research Center: To Be Independent or Not to Be? That Is the Question(Tehran University of Medical Sciences, 2011) Rostami, Mohsen; Heidari, Pedram; Abdollahi, Mohammad; Kordi, Ramin