Publications by authors named "Dongfeng Pan"

41 Publications

Oxygen Substituted Nucleosides Combined with Proton Beam Therapy: Therapeutic Transmutation In Vitro.

Int J Part Ther 2021 19;7(4):11-18. Epub 2021 Mar 19.

Georgetown University, Radiation Medicine, Washington, DC, USA.

Purpose: Proton therapy precisely delivers radiation to cancers to cause damaging strand breaks to cellular DNA, kill malignant cells, and stop tumor growth. Therapeutic protons also generate short-lived activated nuclei of carbon, oxygen, and nitrogen atoms in patients as a result of atomic transmutations that are imaged by positron emission tomography (PET). We hypothesized that the transition of O to F in an O-substituted nucleoside irradiated with therapeutic protons may result in the potential for combined diagnosis and treatment for cancer with proton therapy.

Materials And Methods: Reported here is a feasibility study with a therapeutic proton beam used to irradiate HO to a dose of 10 Gy produced by an 85 MeV pristine Bragg peak. PET imaging initiated >45 minutes later showed an F decay signal with T of ∼111 minutes.

Results: The O to F transmutation effect on cell survival was tested by exposing SQ20B squamous carcinoma cells to physiologic O-thymidine concentrations of 5 μM for 48 hours followed by 1- to 9-Gy graded doses of proton radiation given 24 hours later. Survival analyses show radiation sensitization with a dose modification factor (DMF) of 1.2.

Conclusions: These data support the idea of therapeutic transmutation in vitro as a biochemical consequence of proton activation of O to F in substituted thymidine enabling proton radiation enhancement in a cancer cell. O-substituted molecules that incorporate into cancer targets may hold promise for improving the therapeutic window of protons and can be evaluated further for postproton therapy PET imaging.
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http://dx.doi.org/10.14338/IJPT-D-20-00036.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019575PMC
March 2021

Corilagin induces apoptosis and autophagy in NRF2‑addicted U251 glioma cell line.

Mol Med Rep 2021 May 24;23(5). Epub 2021 Mar 24.

Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA.

Corilagin, extracted from the Euphorbiaceae and plants, inhibits the growth of a number of types of tumors. Compared with temozolomide, the traditional chemotherapy drug, corilagin has demonstrated stronger antitumor activity. However, the pharmaceutical mechanism of corilagin in glioma remains unclear. Nuclear factor erythroid 2 like 2 (NFE2L2 or NRF2) is positively associated with several types of tumor including glioma. In the present study, NRF2 expression was higher in glioma tissues compared with non‑glioma specimens. Therefore, it was hypothesized that corilagin targets NRF2 regulation of U251 cell apoptosis. The present study used Hoechst 33258 staining to demonstrate that corilagin induced glioma cell apoptosis and observed that the expression of the apoptosis‑related gene Bcl‑2 was reduced. In addition, corilagin induced autophagy and promoted the conversion of light chain 3 (LC3) protein from LC3Ⅰ to LC3II. NRF2 expression was downregulated by corilagin stimulation. Furthermore, the gene expression pattern following knockdown of NRF2 in U251 cells using siRNA was consistent with corilagin stimulation. Therefore, it was preliminarily concluded that corilagin induces apoptosis and autophagy by reducing NRF2 expression.
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http://dx.doi.org/10.3892/mmr.2021.11959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974271PMC
May 2021

Corilagin induces human glioblastoma U251 cell apoptosis by impeding activity of (immuno)proteasome.

Oncol Rep 2021 Apr 2;45(4):1-11. Epub 2021 Mar 2.

Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA.

Glioma is a type of common primary intracranial tumor, which is difficult to treat. It has been confirmed by research that corilagin (the primary active constituent of the matsumura leafflower herb) has significant antitumor effect. In particular, our previous research demonstrated that corilagin effectively promotes apoptosis of glioma U251 cells and has a synergistic effect when used with temozolomide. However, the mechanism by which corilagin causes apoptosis in U251 cells has yet to be investigated. Proteasomes are catalytic centers of the ubiquitin‑proteasome system, which is the major protein degradation pathway in eukaryotic cells; they are primarily responsible for the degradation of signal molecules, tumor suppressors, cyclins and apoptosis inhibitors and serve an important role in tumor cell proliferation and apoptosis. The present study investigated the pro‑apoptotic effect of corilagin on glioma U251 cells and confirmed that decreased proteasome activity and expression levels serve an important role in corilagin‑induced U251 cell apoptosis.
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http://dx.doi.org/10.3892/or.2021.7985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905533PMC
April 2021

Florescence Imaging Lung Cancer with a Small Molecule MHI-148.

J Fluoresc 2020 Dec 11;30(6):1523-1530. Epub 2020 Aug 11.

Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China.

MHI-148 is a type of heptamethine cyanine dye that can cross the cytoplasmic membrane of lung cancer cells. Here we tested the cytotoxic, in vivo imaging of MHI-148 in lung-cancer nude mice model. Ex vivo imaging was also been measured by testing the major tissue fluorescence intensity. And, the small molecular compound MHI-148 had low cytotoxicity which could be visualized at 1 h post-injection in tumor. From ex vivo fluorescence imaging, the tumor showed the highest uptake of MHI-148 among all the selected organs expect for the time point of 2 h. MHI-148 could be used for effective imaging in lung cancer tissue with good stability and specificity, which suggested that MHI-148 could be an effective tumor clinical imaging agent.
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http://dx.doi.org/10.1007/s10895-020-02605-zDOI Listing
December 2020

Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study.

Lancet Oncol 2020 07 29;21(7):904-913. Epub 2020 May 29.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Patients with cancer are a high-risk population in the COVID-19 pandemic. We aimed to describe clinical characteristics and outcomes of patients with cancer and COVID-19, and examined risk factors for mortality in this population.

Methods: We did a retrospective, multicentre, cohort study of 205 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and with a pathological diagnosis of a malignant tumour in nine hospitals within Hubei, China, from Jan 13 to March 18, 2020. All patients were either discharged from hospitals or had died by April 20, 2020. Clinical characteristics, laboratory data, and cancer histories were compared between survivors and non-survivors by use of χ test. Risk factors for mortality were identified by univariable and multivariable logistic regression models.

Findings: Between Jan 13 and Mar 18, 2020, 205 patients with cancer and laboratory-confirmed SARS-CoV-2 infection were enrolled (median age 63 years [IQR 56-70; range 14-96]; 109 [53%] women). 183 (89%) had solid tumours and 22 (11%) had haematological malignancies. The median duration of follow-up was 68 days (IQR 59-78). The most common solid tumour types were breast (40 [20%] patients), colorectal (28 [14%]), and lung cancer (24 [12%]). 54 (30%) of 182 patients received antitumour therapies within 4 weeks before symptom onset. 30 (15%) of 205 patients were transferred to an intensive care unit and 40 (20%) died during hospital admission. Patients with haematological malignancies had poorer prognoses than did those with solid tumours: nine (41%) of 22 patients with haematological malignancies died versus 31 (17%) of 183 patients with solid tumours (hazard ratio for death 3·28 [95% CI 1·56-6·91]; log rank p=0·0009). Multivariable regression analysis showed that receiving chemotherapy within 4 weeks before symptom onset (odds ratio [OR] 3·51 [95% CI 1·16-10·59]; p=0·026) and male sex (OR 3·86 [95% CI 1·57-9·50]; p=0·0033) were risk factors for death during admission to hospital.

Interpretation: Patients with cancer and COVID-19 who were admitted to hospital had a high case-fatality rate. Unfavourable prognostic factors, including receiving chemotherapy within 4 weeks before symptom onset and male sex, might help clinicians to identify patients at high risk of fatal outcomes.

Funding: National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S1470-2045(20)30310-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259917PMC
July 2020

The spatiotemporal distribution of human brucellosis in mainland China from 2007-2016.

BMC Infect Dis 2020 Mar 27;20(1):249. Epub 2020 Mar 27.

Department of Epidemiology and Biostatistics, School of Public Health and management, Ningxia Medical University, Yinchuan, 750001, China.

Background: Despite the considerable efforts made to address the issue of brucellosis worldwide, its prevalence in dairy products continues to be difficult to estimate and represents a key public health issue around the world today. The aim of the present study was to better understand the epidemiology of this disease in mainland China. We set out to investigate the yearly spatial distribution and possible hotspots of the disease.

Methods: Human brucellosis data from mainland China between 2007 and 2016 were collected from the China Information System for Disease Control and Prevention. A geographic information system ArcGIS10.3 (ESRI, Redlands) was used to identify potential changes in the spatial and temporal distribution of human brucellosis in mainland China during the study period. These distributions were evaluated using three-dimensional trend analysis and spatial autocorrelation analyse. A gravity-center was used to analyse the migration track of human brucellosis.

Results: A total of 399,578 cases of human brucellosis were reported during the 10-year study period. The monthly incidence of brucellosis in China demonstrates clear seasonality. Spring and summer are the peak seasons, while May is the peak month for brucellosis. Three-dimensional trend analysis suggests that brucellosis is on the rise from south to north, and that the epidemic situation in northern China is more severe. Between 2007 and 2016, the overall migration distance of the brucellosis incidence gravity-center was 906.43 km, and the direction was southwest. However, the overall gravity center of brucellosis was still in the northern part of China. In the global autocorrelation analysis, brucellosis in China demonstrated a non-random distribution between 2013 and 2014, with spatial autocorrelation (Z > 1.96, P < 0.05) and a clustering trend, while no clustering trend was found from 2007 to 2012 or from 2015 to 2016. In the local autocorrelation analysis, a Low-Low cluster phenomenon was found in the south of China in 2013 and 2014.

Conclusion: Human brucellosis remains a widespread challenge, particularly in northern China. The hotspots highlight potential high-risk areas which may require special plans and resources for monitoring and controlling the disease.
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http://dx.doi.org/10.1186/s12879-020-4946-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099799PMC
March 2020

Single-Photon Emission Computed Tomography Imaging Using Formyl Peptide Receptor 1 Ligand Can Diagnose Aortic Aneurysms in a Mouse Model.

J Surg Res 2020 07 12;251:239-247. Epub 2020 Mar 12.

Department of Surgery, University of Florida, Gainesville, Florida. Electronic address:

Background: Our previous studies showed that neutrophil infiltration and activation plays an important role in the pathogenesis of abdominal aortic aneurysms (AAA). However, there is a lack of noninvasive, inflammatory cell-specific molecular imaging methods to provide early diagnosis of AAA formation. Formyl peptide receptor 1 (FPR1) is rapidly upregulated on neutrophils during inflammation. Therefore, it is hypothesized that the use of cinnamoyl-F-(D)L-F-(D)L-F-K (cFLFLF), a PEGylated peptide ligand that binds FPR1 on activated neutrophils, would permit accurate and noninvasive diagnosis of AAA via single-photon emission computed tomography (SPECT) imaging.

Materials And Methods: Male C57BL/6 (wild-type) mice were treated with topical elastase (0.4 U/mL type 1 porcine pancreatic elastase) or heat-inactivated elastase (control), and aortic diameter was measured by video micrometry. Comparative histology was performed on Day 14 to assess neutrophil infiltration in aortic tissue. We performed near-infrared fluorescence imaging using c-FLFLF-Cy7 probe on Days 7 and 14 postelastase treatment and measured fluorescence intensity ex vivo in excised aortic tissue. A separate group of animals were injected with Tc-c-FLFLF 2 h before SPECT imaging on Day 14 using a SPECT/computed tomography/positron emission tomography trimodal scanner. Coexpression of neutrophils with c-FLFLF was also performed on aortic tissue by immunostaining on Day 14.

Results: Aortic diameter was significantly increased in the elastase group compared with controls on Days 7 and 14. Simultaneously, a marked increase in neutrophil infiltration and elastin degradation as well as decrease in smooth muscle integrity were observed in aortic tissue after elastase treatment compared with controls. Moreover, a significant increase in fluorescence intensity of c-FLFLF-Cy7 imaging probe was also observed in elastase-treated mice on Day 7 (approximately twofold increase) and Day 14 (approximately 2.5-fold increase) compared with respective controls. SPECT imaging demonstrated a multifold increase in signal intensity for Tc-cFLFLF radiolabel probe in mice with AAA compared with controls on Day 14. Immunostaining of aortic tissue with c-FLFLF-Cy5 demonstrated a marked increase in coexpression with neutrophils in AAA compared with controls.

Conclusions: cFLFLF, a novel FPR1 ligand, enables quantifiable, noninvasive diagnosis and progression of AAAs. Clinical application of this inflammatory, cell-specific molecular probe using SPECT imaging may permit early diagnosis of AAA formation, enabling targeted therapeutic interventions and preventing impending aortic rupture.
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http://dx.doi.org/10.1016/j.jss.2020.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540921PMC
July 2020

Amino Acid-Mediated Metabolism: A New Power to Influence Properties of Stem Cells.

Stem Cells Int 2019 5;2019:6919463. Epub 2019 Dec 5.

Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA.

The self-renewal and differentiation potentials of stem cells are dependent on amino acid (AA) metabolism. We review the literature on the metabolic preference of both cancer and noncancer stem cells. The balance in AA metabolism is responsible for maintaining the functionality of noncancer stem cells, and altering the levels of AAs can influence the malignant biological behavior of cancer stem cells. AAs are considered nutrients participating in metabolism and playing a critical role in maintaining the activity of normal stem cells and the effect of therapy of cancer stem cells. Targeting AA metabolism helps inhibit the stemness of cancer stem cells and remodels the function of normal stem cells. This review summarizes the metabolic characteristics and regulation pathways of AA in different stem cells, not only from the nutritional perspective but also from the genomic perspective that have been reported in the recent five years. In addition, we briefly survey new therapeutic modalities that may help eradicate cancer stem cells by exploiting nutrient deprivation. Understanding AA uptake characteristics helps researchers define the preference for AA in different stem cells and enables clinicians make timely interventions to specifically target the cell behavior.
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http://dx.doi.org/10.1155/2019/6919463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915148PMC
December 2019

SPECT imaging of lung ischemia-reperfusion injury using [Tc]cFLFLF for molecular targeting of formyl peptide receptor 1.

Am J Physiol Lung Cell Mol Physiol 2020 02 4;318(2):L304-L313. Epub 2019 Dec 4.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.

Primary graft dysfunction after lung transplantation, a consequence of ischemia-reperfusion injury (IRI), is a major cause of morbidity and mortality. IRI involves acute inflammation and innate immune cell activation, leading to rapid infiltration of neutrophils. Formyl peptide receptor 1 (FPR1) expressed by phagocytic leukocytes plays an important role in neutrophil function. The cell surface expression of FPR1 is rapidly and robustly upregulated on neutrophils in response to inflammatory stimuli. Thus, we hypothesized that use of [Tc]cFLFLF, a selective FPR1 peptide ligand, would permit in vivo neutrophil labeling and noninvasive imaging of IRI using single-photon emission computed tomography (SPECT). A murine model of left lung IRI was utilized. Lung function, neutrophil infiltration, and SPECT imaging were assessed after 1 h of ischemia and 2, 12, or 24 h of reperfusion. [Tc]cFLFLF was injected 2 h before SPECT. Signal intensity by SPECT and total probe uptake by gamma counts were 3.9- and 2.3-fold higher, respectively, in left lungs after ischemia and 2 h of reperfusion versus sham. These values significantly decreased with longer reperfusion times, correlating with resolution of IRI as shown by improved lung function and decreased neutrophil infiltration. SPECT results were confirmed using Cy7-cFLFLF-based fluorescence imaging of lungs. Immunofluorescence microscopy confirmed cFLFLF binding primarily to activated neutrophils. These results demonstrate that [Tc]cFLFLF SPECT enables noninvasive detection of lung IRI and permits monitoring of resolution of injury over time. Clinical application of [Tc]cFLFLF SPECT may permit diagnosis of lung IRI for timely intervention to improve outcomes after transplantation.
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http://dx.doi.org/10.1152/ajplung.00220.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052676PMC
February 2020

Microbiota-Produced -Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.

Diabetes 2019 07 22;68(7):1415-1426. Epub 2019 Apr 22.

Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease.
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http://dx.doi.org/10.2337/db18-1307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609982PMC
July 2019

A Novel Modality for Functional Imaging in Acute Intervertebral Disk Herniation via Tracking Leukocyte Infiltration.

Mol Imaging Biol 2017 Oct;19(5):703-713

Department of Orthopaedic Surgery, University of Virginia, Rm B051, Cobb Hall, 135 Hospital Dr., Charlottesville, VA, 22908, USA.

Purpose: Inflammation plays a key role in the progression of intervertebral disk (IVD) herniation and associated low back pain. However, real-time spatial diagnosis of inflammation associated with acute disk herniation has not been investigated. We sought to detect local neutrophil and macrophage infiltration near disk herniation via the formyl peptide receptor 1 (FPR1)-mediated molecular imaging in a disk puncture mouse model to elucidate pathophysiological process of disk herniation.

Procedures: Disk herniation was induced in mouse with an established needle puncture procedure. Degenerative change of disk and infiltration of neutrophils and macrophages were detected with Safranin-O, hematoxylin and eosin (H&E), and immunohistochemical staining after injury. FPR1-specific imaging probes cFLFLF-PEG-Cy7 and [Tc]HYNIC-PEG-cFLFLF were administered systemically to sham and disk injury mice. Leukocyte infiltration was tracked by in vivo near-infrared fluorescence (NIRF) and single-photon emission tomography (SPECT) imaging. The peptide-receptor binding specificity was further investigated with FPR1 mice via ex vivo NIRF scan and in vitro binding assays.

Results: Safranin-O staining exhibited disorganized disk structure and loss of proteoglycan after puncture. Massive inflammatory cells were observed in the anterior region of punctured annulus in the injury group. The majority of neutrophils were detected at 1 through 3 days, while infiltration of macrophages appeared the most at 7 days after injury. NIRF and SPECT images revealed preferential accumulation of cFLFLF probes in herniation site in wild-type mice but not in FPR1 mice. Binding of the cFLFLF peptide to FPR1 was also observed in RAW 267.4 cells and macrophages isolated from wild-type mice, whereas much less signal was observed in macrophages from FPR1 mice. The presence of macrophage infiltration was also detected in human-herniated disk samples by immunohistochemistry.

Conclusion: For the first time, leukocyte infiltration around acute disk herniation site was detected directly and non-invasively in a timely fashion using FPR1-targeted molecular imaging modalities. Such functional imaging of disk herniation via infiltrated leukocytes would advance the understanding of etiology and facilitate drug delivery and treatment monitoring of disk herniation.
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http://dx.doi.org/10.1007/s11307-016-1038-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495619PMC
October 2017

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE.

Basic Res Cardiol 2016 11 19;111(6):62. Epub 2016 Sep 19.

Department of Surgery, University of Virginia, P.O. Box 800709, Charlottesville, VA, 22908, USA.

The spleen plays a critical role in post-infarct myocardial remodeling. However, the role of the spleen in exacerbating myocardial infarction (MI) during acute ischemia/reperfusion (I/R) injury is unknown. The present study tests the hypothesis that splenic leukocytes are activated by substances released from ischemic myocardium to subsequently exacerbate myocardial injury during reperfusion. The left coronary artery in C57BL/6 mice underwent various durations of occlusion followed by 60 min of reperfusion (denoted as min/min of I/R) with or without splenectomy prior to I/R injury. Splenectomy significantly decreased myocardial infarct size (IS) in 40'/60' and 50'/60' groups (p < 0.05); however, it had no effect on IS in 10'/60', 20'/60' and 30'/60' groups (p = NS). In the 20'/60' group, infusion of 40-min ischemic heart homogenate (40-IHH) upon reperfusion increased IS by >threefold versus infusion of 10-IHH (p < 0.05). Splenectomy abolished the infarct-exacerbating effect of 40-IHH, which was restored by splenic leukocyte adoptive transfer (SPAT). Furthermore, depletion of HMGB1 in the 40-IHH group abolished its infarct-exacerbating effect (p < 0.05), and 40-IHH failed to increase IS in both RAGE(-/-) mice and splenectomized wild-type mice with SPAT from RAGE(-/-) mice. The injection of 40-IHH significantly increased formyl peptide receptor 1 (FPR1) expression in sham spleens when compared to 10-IHH-treated sham and control mice. cFLFLF, a specific FPR1 antagonist, reduced myocardial neutrophil infiltration and abrogated the infarct-exacerbating effect of 40-IHH during reperfusion. A cardio (HMGB1)-splenic (RAGE receptor) signaling axis exists and contributes to myocardial infarct exacerbation during reperfusion after prolonged ischemic insults by activating splenic leukocytes. The FPR1 is a potential therapeutic target for inhibiting the cardio-splenic axis that augments infarct size during post-ischemic reperfusion.
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http://dx.doi.org/10.1007/s00395-016-0583-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385142PMC
November 2016

Hepatoprotection and hepatotoxicity of Heshouwu, a Chinese medicinal herb: Context of the paradoxical effect.

Food Chem Toxicol 2017 Oct 30;108(Pt B):407-418. Epub 2016 Jul 30.

School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong. Electronic address:

Heshouwu (Polygonum multiflorum Thunb.) has been a common Chinese medicine and a folk Taoist medicine for over a thousand years. There are two drug forms, Shengshouwu (Polygoni Multiflori Radix) and Zhiheshouwu (Polygoni Multiflori Radix Prapaerata) in the Chinese Pharmacopoeia. In this review, we retrieved articles with such keywords as Heshouwu, liver protection and liver toxicity in the databases of PubMed and the China National Knowledge Infrastructure (CNKI). Hepatoprotection and hepatotoxicity of Shengshouwu and Zhiheshouwu in vitro and in vivo, and their clinical settings and adverse drug reactions (ADR) were summarized, analyzed and critically reviewed. In bench research, both drug forms had effects against nonalcoholic fatty liver disease, oxidation, fibrosis, cirrhosis, and liver cancer. Clinically, Heshouwu was used for treating fatty liver disease (FLD), hyperlipidemia, cirrhosis and hepatitis B. In contrast, both drug forms could lead to drug-induced liver injury and even death in vitro, in vivo and in clinical settings. In addition, the active components of both drug forms had hepatic benefits and toxicity in interaction with emodin, physcion, and probably 2,3,5,4'-tetrahydroxy-stilbene-2-O-beta-d-glucoside (TSG). In conclusion, Heshouwu exhibited both hepatoprotection and hepatotoxicity. It is essential to evaluate the advantages and disadvantages when Heshouwu is in clinical use.
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http://dx.doi.org/10.1016/j.fct.2016.07.035DOI Listing
October 2017

A review of UHMWPE wear-induced osteolysis: the role for early detection of the immune response.

Bone Res 2016 12;4:16014. Epub 2016 Jul 12.

Department of Orthopaedic Surgery, University of Virginia , Charlottesville, VA, USA.

In a world where increasing joint arthroplasties are being performed on increasingly younger patients, osteolysis as the leading cause of failure after total joint arthroplasty (TJA) has gained considerable attention. Ultra-high molecular weight polyethylene wear-induced osteolysis is the process by which prosthetic debris mechanically released from the surface of prosthetic joints induces an immune response that favors bone catabolism, resulting in loosening of prostheses with eventual failure or fracture. The immune response initiated is innate in that it is nonspecific and self-propagating, with monocytic cells and osteoclasts being the main effectors. To date, detecting disease early enough to implement effective intervention without unwanted systemic side effects has been a major barrier. These barriers can be overcome using newer in vivo imaging techniques and modules linked with fluorescence and/or chemotherapies. We discuss the pathogenesis of osteolysis, and provide discussion of the challenges with imaging and therapeutics. We describe a positron emission tomography imaging cinnamoyl-Phe-(D)-Leu-Phe-(D)-Leu-Phe-Lys module, specific to macrophages, which holds promise in early detection of disease and localization of treatment. Further research and increased collaboration among therapeutic and three-dimensional imaging researchers are essential in realizing a solution to clinical osteolysis in TJA.
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http://dx.doi.org/10.1038/boneres.2016.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941197PMC
July 2016

Neurofibromatosis type 1 associated with pheochromocytoma and gastrointestinal stromal tumors: A case report and literature review.

Oncol Lett 2016 Jul 1;12(1):637-643. Epub 2016 Jun 1.

Department of Pathology, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region 750002, P.R. China.

Neurofibromatosis type 1 (NF1) is a genetic disorder associated with neurofibromin 1 () gene mutation, which generates an increased risk of variety of tumor types. The current study reports a case involving NF1, pheochromocytoma (PHEO) and gastrointestinal stromal tumors (GIST). A 56-year-old man presented with abdominal pain and polypnea. Clinical investigation revealed multiple diffuse soft-tissue lesions throughout his body, and pigmented macules on the skin. Imaging analyses revealed thoracic scoliosis, multiple subcutaneous nodules in the abdomen and trunk, and a 7.0×7.7×8.9-cm oval-shaped, cystic mass in the left upper abdominal cavity. Immunohistochemical staining indicated that S-100 protein and synaptophysin were highly expressed in adrenal gland neoplasm, whilst CD117 and CD34 were highly expressed in small intestine tumors. The overall clinical and pathological finding suggested a diagnosis of NF1, giant PHEO and small intestinal stromal tumor. In addition, a literature review was conducted to identify the specific clinical features of patients with this condition. Only 11 similar cases have been reported worldwide. In the present study, paroxysmal hypertension occurred in the majority of patients, and GISTs tended to be located in the small intestine. In addition, the present study demonstrated that many of the patients had a poor prognosis. Therefore, the present study indicates that NF1-PHEO-GIST is a special type tumor with varied clinical symptoms, which may be associated with an increased risk for poor prognosis; however, more studies are required to confirm this.
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http://dx.doi.org/10.3892/ol.2016.4670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907302PMC
July 2016

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy.

J Biomed Opt 2016 05;21(5):50901

University of Virginia, Department of Radiology, Charlottesville, Virginia 22908, United States.

A class of near-infrared fluorescence (NIRF) heptamethine cyanine dyes that are taken up and accumulated specifically in cancer cells without chemical conjugation have recently emerged as promising tools for tumor imaging and targeting. In addition to their fluorescence and nuclear imaging-based tumor-imaging properties, these dyes can be developed as drug carriers to safely deliver chemotherapy drugs to tumors. They can also be used as effective agents for photodynamic therapy with remarkable tumoricidal activity via photodependent cytotoxic activity. The preferential uptake of dyes into cancer but not normal cells is co-operatively mediated by the prevailing activation of a group of organic anion-transporting polypeptides on cancer cell membranes, as well as tumor hypoxia and increased mitochondrial membrane potential in cancer cells. Such mechanistic explorations have greatly advanced the current application and future development of NIRF dyes and their derivatives as anticancer theranostic agents. This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.
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http://dx.doi.org/10.1117/1.JBO.21.5.050901DOI Listing
May 2016

Metformin therapy associated with survival benefit in lung cancer patients with diabetes.

Oncotarget 2016 Jun;7(23):35437-45

Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.

The purpose of this study is to summarize the currently available evidence regarding the concerned issue by performing a comprehensive meta-analysis. Relevant publications reporting the association of metformin use with survival of lung cancer patients with diabetes were electronically searched to identify eligible studies. The meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures for disease-free survival(DFS) and overall survival(OS) estimates. A total of 17 individual studies from 10 publications were included in the meta-analysis. Overall, the results revealed a significant association of metformin use with a better survival of lung cancer patients with diabetes(for DFS: HR = 0.65, 95%CI = 0.52-0.83; for OS: HR = 0.78, 95%CI = 0.64-0.93). The subgroup analyses showed similar association in Asian region(for DFS:HR = 0.69, 95%CI = 0.59-0.80; for OS: HR = 0.55, 95%CI = 0.46-0.67) but not in Western region. Such association was also presented in small cell lung cancer (for DFS: HR = 0.54, 95%CI = 0.38-0.77; for OS: HR = 0.52, 95%CI = 0.39-0.69) and in non-small cell lung cancer(for DFS: HR = 0.70, 95%CI = 0.51-0.96; for OS: HR = 0.75, 95%CI = 0.58- 0.97). Analyses stratified by treatment strategy showed a reduction in the risk of cancer-related mortality in patients receiving chemotherapy(for DFS: HR = 0.71, 95%CI = 0.64-0.83; for OS: HR = 0.58, 95%CI = 0.47-0.71) but not in patients receiving chemoradiotherapy. The meta-analysis demonstrated that metformin use was significantly associated with a favorable survival outcome of lung cancer patients with diabetes.
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http://dx.doi.org/10.18632/oncotarget.8881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085241PMC
June 2016

Improving Therapeutic Potential of Farnesylthiosalicylic Acid: Tumor Specific Delivery via Conjugation with Heptamethine Cyanine Dye.

Mol Pharm 2017 01 16;14(1):1-13. Epub 2016 Dec 16.

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California 90048, United States.

The RAS and mTOR inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS) is a promising anticancer agent with moderate potency, currently undergoing clinical trials as a chemotherapeutic agent. FTS has displayed its potential against a variety of cancers including endocrine resistant breast cancer. However, the poor pharmacokinetics profile attributed to its high hydrophobicity is a major hindrance for its continued advancement in clinic. One of the ways to improve its therapeutic potential would be to enhance its bioavailability to cancer tissue by developing a method for targeted delivery. In the current study, FTS was conjugated with the cancer-targeting heptamethine cyanine dye 5 to form the FTS-dye conjugate 11. The efficiency of tumor targeting properties of conjugate 11 against cancer cell growth and mTOR inhibition was evaluated in vitro in comparison with parent FTS. Cancer targeting of 11 in a live mouse model of MCF7 xenografts was demonstrated with noninvasive, near-infrared fluorescence (NIRF) imaging. The results from our studies clearly suggest that the bioavailability of FTS is indeed improved as indicated by log P values and cancer cell uptake. The FTS-dye conjugate 11 displayed higher potency (IC = 16.8 ± 0.5 μM) than parent FTS (IC = ∼51.3 ± 1.8 μM) and inhibited mTOR activity in the cancer cells at a lower concentration (12.5 μM). The conjugate 11 was shown to be specifically accumulated in tumors as observed by in vivo NIRF imaging, organ distribution, and ex vivo tumor histology along with cellular level confocal microscopy. In conclusion, the conjugation of FTS with cancer-targeting heptamethine cyanine dye improved its pharmacological profile.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815365PMC
January 2017

[Expression of the pulmonary surfactant in rat with paraquat-induced acute lung injury].

Zhonghua Yi Xue Za Zhi 2015 Dec;95(46):3762-5

Department of Emergency Medicine, Ningxia People's Hospital, Yinchuan 750021, China.

Objective: To explore the expression of pulmonary surfactant in rats with paraquat-induced acute lung injury.

Methods: A total of 36 SD rats were randomly divided into the control group (n=6) and paraquat group at 6, 12, 24, 48, 72 h five time points, each time points 6 rats. All of the rats were injected with paraquat (80 mg/kg) for once. The specimens were collected at 0 h (instant) after paraquat intoxication in the control group, and at the corresponding point in time in the paraquat each time point groups. The pathology changes of lung tissue were observed by HE staining, thiobarbituric acid method was used to detect malondialdehyde (MDA) level, and Western blot method was used to analyze the relative expression of surfactant protein (SP)-A and SP-D in bronchoalveolar lavage fluid (BALF) with time.

Results: As compared to control, the levels of MDA in BALF were significantly higher at 6, 24, 48 h after paraquat intoxication ((4.19 ± 0.12), (3.33 ± 0.08), (3.52 ± 0.08) vs (2.82 ± 0.15) nmol/mg, all P<0.01), no significantly different at 12, 72 h ((2.76 ± 0.13), (2.79 ± 0.10) nmol/mg, both P>0.05); the relative expression of SP-A in BALF were significantly higher at 6 h after paraquat intoxication (1.32 ± 0.19 vs 1.00 ± 0.19, P<0.01), lower at 24, 48 h (0.43 ± 0.07, 0.67 ± 0.08, both P<0.01), and no significantly different at 12, 72 h (0.98 ± 0.15, 0.79 ± 0.18, both P>0.05); the relative expression of SP-D in BALF were significantly higher at 6, 12 h after paraquat intoxication (1.54 ± 0.33, 1.64 ± 0.37 vs 1.00 ± 0.23, both P<0.01), no significantly different at 24, 48 h (1.07 ± 0.19, 0.97 ± 0.15, both P>0.05), and reached the peak at 72 h (2.15 ± 0.26, P<0.01); the expression of MDA, SP-A and SP-D were characterized by the state of fluctuation with increased first, reduced after, and finally increased.

Conclusion: The expression of SP-A, SP-D increase at the early stage of the paraquat-induced acute lung injury in rat, which can reflect the degree of lung injury.
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December 2015

Multimodal formyl peptide receptor 1 targeted inflammation imaging probe: cFLFLF-MHI-DOTA.

Bioorg Med Chem Lett 2016 Feb 12;26(3):1052-1055. Epub 2015 Dec 12.

Department of Radiology & Medical Imaging, University of Virginia, Charlottesville, VA 22908, United States. Electronic address:

Formyl peptide receptor 1 (FPR1) targeting multimodal probe cFLFLFK-MHI-DOTA for leukocyte based inflammation imaging is described. The compound consists of three domains, (a) cFLFLF peptide for FPR1 recognition and binding for activated leukocyte, (b) heptamethine cyanine dye (MHI) for near infrared fluorescence (NIRF) detection and imaging, and (c) metal chelator DOTA ligand that could form complex with a radiometal for nuclear (PET/SPECT) imaging or with a paramagnetic metal for MRI imaging. Detailed synthesis, characterization and in vitro evaluation are reported. The availability of dual mode inflammation imaging probe would allow in vivo gross level imaging of inflammation foci as well as ex vivo microscopic level cellular imaging for role played by innate immune cells in inflamed tissue.
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http://dx.doi.org/10.1016/j.bmcl.2015.12.029DOI Listing
February 2016

Targeting formyl peptide receptor 1 of activated macrophages to monitor inflammation of experimental osteoarthritis in rat.

J Orthop Res 2016 09 12;34(9):1529-38. Epub 2016 Jan 12.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, 22903.

Macrophages play a crucial role in the pathogenesis of osteoarthritis (OA). In this study, the feasibility of a formyl peptide receptor 1 (Fpr1)-targeting peptide probe cFLFLF-PEG-(64) Cu via positron emission tomography (PET) imaging was investigated for detection of macrophage activity during development of OA. Monoiodoacetate (MIA) was intraarticularly injected into the knee joint of Sprague-Dawley rats to induce OA. Five days later, cFLFLF-PEG-(64) Cu (∼7,400 kBq/rat) was injected into the tail vein and microPET/CT imaging was performed to assess the OA inflammation by detecting infiltration of macrophages by Fpr1 expression. In addition, a murine macrophage cell line RAW264.7 and two fluorescent probes cFLFLF-PEG-cyanine 7 (cFLFLF-PEG-Cy7) and cFLFLF-PEG-cyanine 5 (cFLFLF-PEG-Cy5) were used to define the binding specificity of the peptide to macrophages. It was found with the MIA model that the maximal standard uptake values (SUVmax ) for right (MIA treated) and left (control) knees were 17.96 ± 5.45 and 3.00 ± 1.40, respectively. Histological evaluation of cryomicrotome sections showed that Fpr1 expression, cFLFLF-PEG-Cy5 binding, and tartrate-resistant acid phosphatase activity were elevated in the injured synovial membranes. The in vitro experiments demonstrated that both fluorescent peptide probes could bind specifically to RAW264.7 cells, which was blocked by cFLFLF but not by the scramble peptide. The findings highlighted the use of cFLFLF-PEG-(64) Cu/PET as an effective method potentially applied for detection and treatment evaluation of OA. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1529-1538, 2016.
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http://dx.doi.org/10.1002/jor.23148DOI Listing
September 2016

Recognition of Immune Response for the Early Diagnosis and Treatment of Osteoarthritis.

J Immunol Res 2015 3;2015:192415. Epub 2015 May 3.

Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Osteoarthritis is a common and debilitating joint disease that affects up to 30 million Americans, leading to significant disability, reduction in quality of life, and costing the United States tens of billions of dollars annually. Classically, osteoarthritis has been characterized as a degenerative, wear-and-tear disease, but recent research has identified it as an immunopathological disease on a spectrum between healthy condition and rheumatoid arthritis. A systematic literature review demonstrates that the disease pathogenesis is driven by an early innate immune response which progressively catalyzes degenerative changes that ultimately lead to an altered joint microenvironment. It is feasible to detect this infiltration of cells in the early, and presumably asymptomatic, phase of the disease through noninvasive imaging techniques. This screening can serve to aid clinicians in potentially identifying high-risk patients, hopefully leading to early effective management, vast improvements in quality of life, and significant reductions in disability, morbidity, and cost related to osteoarthritis. Although the diagnosis and treatment of osteoarthritis routinely utilize both invasive and non-invasive strategies, imaging techniques specific to inflammatory cells are not commonly employed for these purposes. This review discusses this paradigm and aims to shift the focus of future osteoarthritis-related research towards early diagnosis of the disease process.
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http://dx.doi.org/10.1155/2015/192415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433702PMC
March 2016

PET imaging detection of macrophages with a formyl peptide receptor antagonist.

Nucl Med Biol 2015 Apr 6;42(4):381-6. Epub 2014 Dec 6.

Department of Radiology & Medical Imaging, University of Virginia, Charlottesville, VA 22908. Electronic address:

Macrophages are a major inflammatory cell type involved in the development and progression of many important chronic inflammatory diseases. We previously found that apolipoprotein E-deficient (Apoe(-/-)) mice with the C57BL/6 (B6) background develop type 2 diabetes mellitus (T2DM) and accelerated atherosclerosis when fed a Western diet and that there are increased macrophage infiltrations in pancreatic islets and aorta. The formyl peptide receptor 1 (FPR1) is abundantly expressed on the surface of macrophages. The purpose of this study was to evaluate the applicability of cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF), a natural FPR1 antagonist, to detection of macrophages in the pancreatic islets and aorta. (64)Cu labeled cFLFLF and (18)F-fluorodeoxyglucose (FDG) were administered to mice with or without T2DM. Diabetic mice showed an increased (18)FDG uptake in the subcutaneous fat compared with control mice, but pancreatic uptake was minimal for either group. In contrast, diabetic mice exhibited visually noticeable more cFLFLF-(64)Cu retention in pancreas and liver than control mice. The heart and pancreas isolated from diabetic mice contained more macrophages and showed stronger PET signals than those of control mice. Flow cytometry analysis revealed the presence of macrophages but not neutrophils in pancreatic islets. Real-time PCR analysis revealed much higher FPR1 expression in pancreatic islets of diabetic over control mice. Autoradiography and immunohistochemical analysis confirmed abundant FPR1 expression in atherosclerotic lesions. Thus, (64)Cu-labeled cFLFLF peptide is a more effective PET agent for detecting macrophages compared to FDG.
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http://dx.doi.org/10.1016/j.nucmedbio.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405787PMC
April 2015

Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1α/OATPs signaling axis.

Oncotarget 2014 Oct;5(20):10114-26

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259409PMC
http://dx.doi.org/10.18632/oncotarget.2464DOI Listing
October 2014

[99mTc]cFLFLF for Early Diagnosis and Therapeutic Evaluation in a Rat Model of Acute Osteomyelitis.

Mol Imaging Biol 2015 Jun;17(3):337-44

Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China,

Purpose: Early diagnosis and therapeutic monitoring of acute osteomyelitis (AO) is challenging. Here, we use a polyethylene glycol (PEG)ylated chemotactic peptide cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF) conjugated with hydrazinonicotinamide (HYNIC) and labeled with Tc-99m ([(99m)Tc]cFLFLF) to image AO in a rat model and to validate its efficacy in early diagnosis and therapeutic evaluation of AO.

Procedures: Forty rats were divided into eight groups of five each. Groups A, B, C, G, and H were AO models, and D, E, and F were sham controls. Groups A and D underwent [(99m)Tc]cFLFLF scintigraphy, groups B and E underwent [(99m)Tc]methylene diphosphonate ([(99m)Tc]MDP) bone scan, and groups C and F underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET)/computed tomography (CT) scan. [(99m)Tc]cFLFLF biodistribution was assessed in group G. The response to antibiotic therapy was evaluated using [(99m)Tc]cFLFLF scintigraphy in group H. Conventional radiographs were obtained following scintigraphy. Ratios of infected or sham-operated tibia to the opposite tibia (T/B) were calculated. Immediately after the imaging studies, infected tibias were excised and underwent histopathological analysis and immunohistochemistry staining.

Results: AO was present in all rats of groups A, B, C, G, and H. Total histological scores were not significantly different among groups A, B, and C (F = 0.34, p = 0.71). The biodistribution results revealed significant uptake and excellent retention of [(99m)Tc]cFLFLF in the infected tibia. [(99m)Tc]cFLFLF scintigraphy and [(99m)Tc]MDP bone scan both detected AO. The mean T/B ratio of [(99m)Tc]cFLFLF scintigraphy 1 h postinjection was 2.09-fold higher than that of [(99m)Tc]MDP bone scan (t = 13.81, p <0.001). The mean T/B ratio of [(18)F]FDG PET/CT scan was not significantly different from the control group F (t = 2.17, p = 0.062). [(99m)Tc]cFLFLF scintigraphy revealed a significant attenuation of inflammation in group H following a 3-week antibiotic treatment, which was verified by histopathological analysis and immunohistochemistry staining.

Conclusion: Our results suggest that the specificity and image quality of [(99m)Tc]cFLFLF are superior to those of the [(99m)Tc]MDP and [(18)F]DFG imaging probes currently used for early diagnosis of AO. Furthermore, [(99m)Tc]cFLFLF was able to effectively evaluate the therapeutic response to antibiotic treatment of AO. Our data suggest that [(99m)Tc]cFLFLF is a promising imaging agent for detection of infectious diseases.
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http://dx.doi.org/10.1007/s11307-014-0787-3DOI Listing
June 2015

Near-infrared fluorescence and nuclear imaging and targeting of prostate cancer.

Transl Androl Urol 2013 Sep;2(3):254-264

Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Despite advances in the treatment of castration-resistant and bone metastatic prostate cancer (PCa), there is still no clear demonstration that PCa growth and metastases can be unambiguously detected. We review recent advances including our own development of near-infrared fluorescence (NIRF) and near-infrared nuclear (NIRN) imaging approaches. We validated our results in experimental models of PCa bone and soft tissue metastases including PCa colonization at metastatic sites by injecting PCa cells either intratibially or intracardiacally. We describe our experience using noninvasive imaging and targeting modalities to probe PCa tumors grown at metastatic sites, molecular studies to understand the multiple molecular and cellular processes within tumor cells and their interactions with the tumor microenvironment, and targeting tumor growth at metastatic bone site. In this review, current knowledge and emerging technologies based on NIRF and NIRN disciplines will be summarized. Additionally the mechanisms of differential uptake of these agents by normal and cancerous cells will be described.
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http://dx.doi.org/10.3978/j.issn.2223-4683.2013.09.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180428PMC
September 2013

Imaging integrin αvβ 3 and NRP-1 positive gliomas with a novel fluorine-18 labeled RGD-ATWLPPR heterodimeric peptide probe.

Mol Imaging Biol 2014 Dec;16(6):781-92

Department of Nuclear Medicine, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Rd., Xiamen, 361003, China,

Purpose: Radiolabeled Arg-Gly-Asp (RGD) and Ala-Thr-Trp-Leu-Pro-Pro-Arg (ATWLPPR) peptide analogs have received interests for their capability to serve as radiopharmaceuticals for imaging integrin αvβ3 and Neuropilin-1 (NRP-1) positive tumors, respectively. In this study, we developed a RGD-ATWLPPR heterodimeric peptide which contained both RGD and ATWLPPR motifs in one molecular probe. The aim of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-ATWLPPR heterodimeric peptide labeled with fluorine-18 (F-18).

Procedures: A RGD-ATWLPPR heterodimer was synthesized from c(RGDyK) and ATWLPPR through a glutamate linker. The peptide was radiolabeled by reacting the [(18)F]fluoride-aluminum complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The receptor-binding characteristics and tumor-targeting efficacy of [(18)F]FAl-NOTA-RGD-ATWLPPR were tested in vitro and in vivo.

Results: RGD-ATWLPPR had affinity for both integrin αvβ3 and NRP-1 in vitro. [(18)F]FAl-NOTA-RGD-ATWLPPR displayed significantly higher tumor uptake than [(18)F]FAl-NOTA-RGD and [(18)F]FAl-NOTA-ATWLPPR, both in vitro and in vivo. The uptake of the F-18 labeled heterodimer by an U87MG tumor was inhibited only partially in the presence of an excess amount of unlabeled RGD or ATWLPPR but was blocked completely in the presence of both RGD and ATWLPPR. Compared with the monomeric RGD and ATWLPPR peptides, [(18)F]FAl-NOTA-RGD-ATWLPPR showed improved in vivo pharmacokinetics, resulting in a more preferable imaging quality.

Conclusions: [(18)F]FAl-NOTA-RGD-ATWLPPR exhibited significantly improved receptor-targeting properties both in vitro and in vivo compared with the F-18 labeled RGD or ATWLPPR monomers. The improved targeting and localization exhibited by the RGD-ATWLPPR heterodimer provide a foundation for further investigations of its applicability in clinical tumor imaging.
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http://dx.doi.org/10.1007/s11307-014-0761-0DOI Listing
December 2014

Novel cancer-targeting SPECT/NIRF dual-modality imaging probe (99m)Tc-PC-1007: synthesis and biological evaluation.

Bioorg Med Chem Lett 2013 Dec 1;23(23):6350-4. Epub 2013 Oct 1.

Department of Radiology and Medical Imaging, University of Virginia, Rm 263, 480 Ray C. Hunt Drive, Snyder Building, Charlottesville, VA 22908, USA.

Synthesis, characterization, in vitro and in vivo biological evaluation of a heptamethine cyanine based dual-mode single-photon emission computed tomography (SPECT)/near infrared fluorescence (NIRF) imaging probe (99m)Tc-PC-1007 is described. (99m)Tc-PC-1007 exhibited preferential accumulation in human breast cancer MCF-7 cells. Cancer-specific SPECT/CT and NIRF imaging of (99m)Tc-PC-1007 was performed in a breast cancer xenograft model. The probe uptake ratio of tumor to control (spinal cord) was calculated to be 4.02±0.56 at 6 h post injection (pi) and 8.50±1.41 at 20 h pi (P<0.0001). Pharmacokinetic parameters such as blood clearance and organ distribution were assessed.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710472PMC
December 2013

Heptamethine cyanine based (64)Cu-PET probe PC-1001 for cancer imaging: synthesis and in vivo evaluation.

Nucl Med Biol 2013 Apr 1;40(3):351-60. Epub 2013 Feb 1.

Department of Radiology, University of Virginia, Charlottesville, VA 22908, USA.

Purpose: Development of a heptamethine cyanine based tumor-targeting PET imaging probe for noninvasive detection and diagnosis of breast cancer.

Methods: Tumor-specific heptamethine-cyanine DOTA conjugate complexed with Cu-64 (PC-1001) was synthesized for breast cancer imaging. In vitro cellular uptake studies were performed in the breast cancer MCF-7 and noncancerous breast epithelial MCF-10A cell lines to establish tumor specificity. In vivo time-dependent fluorescence and PET imaging of breast tumor xenografts in mice were performed. Blood clearance, biodistribution, and tumor-specific uptake and plasma binding of PC-1001 were quantified. Tumor histology (H&E staining) and fluorescence imaging were examined.

Results: PC-1001 displayed similar fluorescence properties (ε=82,880cm(-1)M(-1), Ex/Em=750/820nm) to the parental dye. Time-dependent cellular accumulation indicated significantly higher probe uptake (>2-fold, 30min) in MCF-7 than MCF-10A cells and the uptake was observed to be mediated by organic anion transport peptides (OATPs) system. In vivo studies revealed that PC-1001 has desirable accumulation profile in tumor tissues, with tumor versus muscle uptake of about 4.3 fold at 24h and 5.8 fold at 48h post probe injections. Blood half-life of PC-1001 was observed to be 4.3±0.2h. Microscopic fluorescence imaging of harvested tumor indicated that the uptake of PC-1001 was restricted to viable rather than necrotic tumor cells.

Conclusions: A highly efficient tumor-targeting PET/fluorescence imaging probe PC-1001 is synthesized and validated in vitro in MCF-7 breast cancer cells and in vivo in mice breast cancer xenograft model.
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http://dx.doi.org/10.1016/j.nucmedbio.2013.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643142PMC
April 2013

A novel near-infrared fluorescence imaging probe for in vivo neutrophil tracking.

Mol Imaging 2012 Sep-Oct;11(5):372-82

Department of Radiology, The University of Virginia, Charlottesville, VA 22908, USA.

The development and validation of a multiscopic near-infrared fluorescence (NIRF) probe, cinnamoyl-F-(D)L-F-(D)L-F-PEG-cyanine7 (cFlFlF-PEG-Cy7), that targets formyl peptide receptor on neutrophils using a mice ear inflammation model is described. Acute inflammation was induced in mice by topical application of phorbol-12-myristate-13-acetate to left ears 24 hours before probe administration. Noninvasive NIRF imaging was longitudinally performed up to 24 hours following probe injection. The in vivo neutrophil-targeting specificity of the probe was characterized by a blocking study with preadministration of excess nonfluorescent peptide cFlFlF-PEG and by an imaging study with a scrambled peptide probe cLFFFL-PEG-Cy7. NIRF imaging of mice injected with cinnamoyl-L-F-F-F-L-PEG-cyanine7 (cFlFlF-PEG-Cy7) revealed that the fluorescence intensity for inflamed left ears was approximately fourfold higher than that of control right ears at 24 hours postinjection. In comparison, the ratios acquired with the scrambled probe and from the blocking study were 1.5- and 2-fold at 24 hours postinjection, respectively. Moreover, a microscopic immunohistologic study confirmed that the NIRF signal of cFlFlF-PEG-Cy7 was associated with activated neutrophils in the inflammatory tissue. With this probe, in vivo neutrophil chemotaxis could be correlatively imaged macroscopically in live animals and microscopically at tissue and cellular levels.
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September 2013