Search

The designed 64Cu-QT-NPs, where 64Cu radioisotopes were isomorphically doped in the octahedral site of the QT lattice, were showed high labeling efficiency and stability, and selectively targeted to the tumor tissue due to the passive targeting effect.

Background The purpose of this study was to evaluate both the biodistribution and safety of 64Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Trastuzumab, a novel 64Cu-labeled positron emission tomography (PET) tracer for human epidermal growth factor receptor 2 (HER2) in patients with breast cancer. Methods PET images at 1, 24, and 48 h after 296 MBq of 64Cu-NOTA-Trastuzumab injection were obtained from seven patients with breast cancer. Both the primary tumors’ and metastatic lesions’ maximum standardized uptake value (SUVmax) was evaluated. The mean SUVmax (SUVmean) was evaluated in the other organs, including the blood pool, liver, kidney, muscle, spleen, bladder, and the lungs, as well as the bones. Moreover, the internal radiation dosimetry was calculated using the OLINDA/EXM software. Safety was assessed based on feedback regarding adverse reactions and safety-related issues within 1 month after 64Cu-NOTA-Trastuzumab administration. Results 64Cu-NOTA-Trastuzumab PET images showed that the overall SUVmean values in each organ negatively correlated with time. The liver’s average SUVmean values were measured at 5.3 ± 0.7, 4.8 ± 0.6, and 4.4 ± 0.5 on 1 h, 24 h, and 48 h after injection, respectively. The average SUVmean blood values were measured at 13.1 ± 0.9, 9.1 ± 1.2, and 7.1 ± 1.9 on 1 h, 24 h, and 48 h after injection, respectively. The SUVmax of HER2-positive tumors was relatively higher than HER2-negative tumors (8.6 ± 5.1 and 5.2 ± 2.8 on 48 h after injection, respectively). Tumor-to-background ratios were higher in the HER2-positive tumors than in the HER2-negative tumors. No adverse events related to 64Cu-NOTA-Trastuzumab were reported. The calculated effective dose with a 296 MBq injection of 64Cu-NOTA-Trastuzumab was 2.96 mSv. The highest absorbed dose was observed in the liver (0.076 mGy/MBq), followed by the spleen (0.063 mGy/MBq), kidney (0.044 mGy/MBq), and heart wall (0.044 mGy/MBq). Conclusions 64Cu-NOTA-Trastuzumab showed a specific uptake at the HER2-expressing tumors, thus making it a feasible and safe monitoring tool of HER2 tumor status in patients with breast cancer. Trial registration CRIS, KCT0002790. Registered 02 February 2018, https://cris.nih.go.kr

To evaluate the biodistribution of [18F]Florastamin, a novel 18F-labelled positron emission tomography (PET) tracer for prostate-specific membrane antigen (PSMA) for the diagnosis of prostate cancer. PET was performed for five healthy controls and 10 patients with prostate cancer at 0, 10, 30, 70, and 120 mins after injecting 370 MBq of [18F]Florastamin. The maximum standardised uptake value (SUVmax) was evaluated in the primary tumour. The mean SUVmax (SUVmean) was evaluated in normal organs. Furthermore, the residence time was evaluated by assessing radioactivity in each organ. The internal radiation dosimetry was calculated using the OLINDA/EXM software. The SUVmax in primary tumours increased with time. A favourable tumour to background ratio was also observed over time. Multiple lymph nodes and bone metastases were also evaluated and showed a similar pattern to SUVmax in the primary tumour. In one patient, a tiny lymph node metastasis was identified using [18F]Florastamin PET, which was not observed using other modalities, and was histologically confirmed. The highest absorbed dose was observed in the kidney (0.062 ± 0.015 mGy/MBq), followed by the bladder (0.032 ± 0.013 mGy/MBq), liver (0.022 ± 0.006 mGy/MBq), and salivary gland (0.018 ± 0.006 mGy/MBq). The effective dose with a 370 MBq injection of [18F]Florastamin was 1.81 mSv. No adverse events related to [18F]Florastamin were reported. We identified a novel PSMA-targeted PET ligand, [18F]Florastamin, for imaging prostate cancer. [18F]Florastamin showed a high SUVmax and relatively high tumour to background ratio in both primary tumour and metastatic lesions, which suggests its high sensitivity to detect tumours without any adverse events. KCT0003924 registered at https://cris.nih.go.kr/ .

Background: Trans-splicing ribozymes (TSR) are useful anticancer agents targeting cancer-specific transcripts and replacing the RNA to induce anticancer gene expression specifically and selectively...

The effects of packaging materials, package shape, and secondary packaging on the inactivation of indigenous mesophilic aerobic bacteria in Korean steamed rice cakes using in-package atmospheric dielectric barrier discharge cold plasma (ADCP) treatment were investigated. Inactivation of indigenous mesophilic aerobic bacteria by ADCP treatment (21 kV, 3 min) was significantly increased by 0.6 and 0.8 log CFU/g (p

Purpose: Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging–based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model. Experimental Design: We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. Results: Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype. Conclusions: Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.

This study was conducted to examine the effects of microwave cold plasma (CP) treatment on inactivation of polyphenol oxidase (PPO) of potato. The PPO activity and treatment variables were fit to first-order kinetics, the Weibull model, and the second-order model. The optimum CP-generation power and treatment time for inactivating PPO in the PPO extract were found to be 900 W and 40 min, respectively, which resulted in the highest inactivation of PPO (49.5%). PPO activity after CP treatment of potato slices decreased from 72.4% to 59.0% as the sample surface-to-volume ratio increased from 7.1 to 9.0. CP treatment delayed the browning of potato slices. Microwave CP treatment effectively inactivated PPO in potatoes, demonstrating the potential of CP treatment for controlling PPO activity in foods. PRACTICAL APPLICATION: This study demonstrated that microwave CP treatment, a nonthermal food processing technology, inactivates PPO activity in potatoes. The results showed that the inactivation effect of CP treatment on PPO corresponded to the surface-to-volume ratio of potato slices. Furthermore, this study proposed an enzyme inactivation model that is suitable for predicting the inactivation of PPO activity and confirmed that CP treatment delayed browning in potatoes.

Cachexia is a wasting syndrome associated with high mortality in cancer patients through inducing the failure of normal metabolism and reducing the efficacy of cancer treatment. Thus, it is critically important to diagnose cancer cachexia early. To provide background data for the diagnosis of cachexia, cancer cachectic factors were characterized in the present situation, including immunological cachectic changes during cachexia progression in a cancer cachexia mouse model. Major constitution of cachexia progression is known as the stages of pre-cachexia, cachexia, and refractory cachexia. In the pre-cachexia stage, the weights of immune-related organs, including the thymus and spleen were significantly. T cell populations in spleen were markedly reduced and cachectic cytokines consistently increased in a time-dependent manner. Immunosuppression by activation of cytotoxic T-lymphocyte-associated antigen 4 was induced earlier in CD4+ cells versus other T cell populations. Furthermore, monocyte chemoattractant protein 1 and interleukin-6 levels in the cachexia group were significantly increased at 3 days from C26 cell inoculation whereas significant carcass weight loss as a classical diagnostic marker occurred at 9 days from C26 cell inoculation. In conclusion, the initiation of cachectic immunological changes was observed prior to weight loss, during the pre-cachexia stage. Accordingly, these findings reveal that the monitoring of humoral and immunological factors may be more sensitive than weight loss for the initial diagnosis and treatment of cachexia.

The purpose of this study is to evaluate the efficacy of bone regeneration and volume maintenance of the three-dimensional (3D) structured biphasic calcium phosphate (BCP) block with porous hexahedron channels in a rabbit calvarial model. In this work, four circular defects (diameter: 8 mm) in calvarium of rabbits were randomly assigned to (1) negative control (control), (2) 3D hexahedron channel structured BCP block, (3) deproteinized bovine bone mineral particle, and (4) deproteinized porcine bone mineral particle. Animals were euthanized at 2 (n = 5) and 8 weeks (n = 5). Outcome measures included micro-computed tomography (CT) and histomorphometrical analysis. Results indicated that in micro-CT, BCP group showed the highest new bone volume with significant difference compared to control (p = 0.008) at 8 weeks. Histomorphometrically, total augmented area of BCP group was the highest with significant difference compared to control (p = 0.008) at 8 weeks. BCP group also maintained total volume of the original defect without collapsing. BCP block with 3D hexahedron channel structure seems to have favorable osteogenic and volume maintaining ability and highly porous structure might attribute to new bone formation. Further studies regarding the optimal internal structure and porosity of the BCP block bone substitute are needed. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2254-2262, 2019.

The antimicrobial effects of in-package cold plasma (CP) treatment on Korean rice cakes (KRC) were evaluated. The CP treatment (25 kV) inactivated indigenous mesophilic aerobic bacteria by 0.8–1.0 log CFU/g, irrespective of the position of KRC in the package. The addition of a shaking step during CP treatment increased the reduction in microbes by ~1 log CFU/g. The microbial inactivation efficiency increased significantly when the treatment time increased from 1 to 3 min. Microbial inactivation activity was highest for packages containing eight rice cakes. The optimized CP treatment achieved a 2.0 ± 0.1 log CFU/g reduction in indigenous bacteria. In addition, the optimum CP treatment inactivated indigenous yeast and molds and Salmonella in KRC by 1.7 ± 0.1 log CFU/g and 3.9 ± 0.3 log CFU/g, respectively. No significant changes in color and firmness were observed, and the surface temperature of KRC did not exceed 22 °C after CP treatment. Moreover, CP treatment damaged the cellular membrane of Salmonella, mainly by inducing lipid peroxidation. This study demonstrates the potential use of in-package CP treatment for the non-thermal microbial inactivation of KRC.

Integrity competitiveness is one of the most important competences of government, business, and the society to achieve Sustainable Development Goals (SDGs). Otherwise, invaluable investment money for development will be aimlessly wasted as a result of corruption, bribery, theft, and tax evasion, etc. To tackle the problems, we need to change the majority acting on circumstances into the majority practicing anti-corruption. Four change factors are essential for behavioral change: regulation for addressing both demand and supply sides of bribery, incentive for rewarding good compliance, technology for ruling out human discretionary power, and training of current and future workforces. They are closely linked with continuous efforts by international organizations such as OECD and UN. South Korea’s regulatory and policy change examples of each factor, aligned by their imperatives with global acknowledgement, clearly show that they can generate substantial outputs, outcomes, and impacts. They will enhance integrity competitiveness of public, private, and nonprofit sectors. Furthermore, their shared responsibility and collaborative partnership based on Responsible Government Conduct, Responsible Business Conduct (RBC), and recognition by civil society organizations on good compliance will set a faster and further path to reach SDGs.

This study investigated the effects of plasma-activated water (PAW) treatment parameters on the inactivation of indigenous mesophilic aerobic bacteria and coliform bacteria on steamed rice cake (SRC). PAW treatment was conducted by washing SRC with PAW, prepared by treating sterilized distilled water with surface dielectric barrier discharge plasma at 16 kV. The plasma discharge time and SRC mass significantly affected the efficacy of microbial inactivation. The optimum treatment conditions (28.7 min of discharge time, 29.0 min of treatment time, and 155.5 g of SRC) did not alter the color and firmness of the SRC. The results demonstrated that the antimicrobial activity of PAW was more due to the presence of plasma reactive species than due to low pH. Furthermore, PAW treatment inhibited the growth of indigenous mesophilic aerobic bacteria much more effectively than NaClO (0.2 g/L) solution treatments. This study demonstrated the potential of using PAW treatment to improve the microbiological stability of SRC.

This article evaluates the effects of in-package atmospheric dielectric barrier discharge cold plasma (ADCP) treatment on microbial inactivation, nitrate and nitrite contents, oral toxicity, and storage quality of protein-coated boiled chicken breast cubes (CBCs). ADCP treatment at 24 kV for 3 min inactivated natural mesophilic aerobic bacteria, Salmonella, and Tulane virus in CBCs by 0.7 &plusmn, 0.2, 1.4 &plusmn, 0.1 log CFU/cube, and 1.1 &plusmn, 0.2 log PFU/cube, respectively. ADCP treatment did not affect the nitrite content of CBCs (p &gt, 0.05). Furthermore, the hematological and blood biochemical parameters from toxicity tests indicated the toxicological safety of ADCP-treated CBCs. Microbial counts of natural bacteria and Salmonella in ADCP-treated CBCs were lower than the ADCP-untreated CBCs by 0.7&ndash, 0.9 and 1.4&ndash, 1.7 log CFU/cube, respectively, throughout post-treatment storage at 4 &deg, C for 21 d. ADCP treatment did not alter the pH, color, total volatile basic nitrogen, lipid oxidation, and tenderness of CBCs during storage at 4 and 24 &deg, C, and did not change the sensory properties of CBCs following a 3 d storage period at 4 &deg, C (p &gt, 0.05). Thus, ADCP treatment has the potential to be applied as a method to increase the microbiological safety of packaged ready-to-eat chicken products, leading to overall toxicological safety.

Background: The purpose of this study was to evaluate the biodistribution and safety of 64Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Trastuzumab, a novel 64Cu-labelled positron emission tomography (PET) tracer for human epidermal growth factor receptor 2 (HER2) in patients with breast cancer.Methods: PET images at 1, 24, and 48 hours after injection of 296 MBq of 64Cu-NOTA-Trastuzumab were obtained on seven patients with breast cancer. The maximum standardized uptake value (SUVmax) was evaluated in the tumors, including the primary tumor and metastatic lesions. The mean SUVmax (SUVmean) was evaluated in the normal organs including the blood pool, liver, kidney, muscle, spleen, bladder, lung, and bone. In addition, the internal radiation dosimetry was calculated using the OLINDA/EXM software. Safety was assessed by gathering the feedback of adverse reactions and safety-related issues within 1 month after 64Cu-NOTA-Trastuzumab administration.Results: The overall values of SUVmean in each normal organ decreased with time on 64Cu-NOTA-Trastuzumab PET images. The average values of SUVmean of the liver were measured at 5.3 ± 0.7, 4.8 ± 0.6, and 4.4 ± 0.5 on 1 hour, 24 hours, and 48 hours after injection. The average values of SUVmean of the blood were evaluated as 13.1 ± 0.9, 9.1 ± 1.2, and 7.1 ± 1.9 on 1 hour, 24 hours, and 48 hours after injection. The SUVmax of HER2-positive tumors showed relatively higher than that of HER2-negative tumors (8.6 ± 5.1 and 5.2 ± 2.8 on 48 hours after injection, respectively). Tumor to background ratios were calculated higher in the HER2-positive tumors than those of HER2-negative tumors. No adverse events related to 64Cu-NOTA-Trastuzumab were reported. The calculated effective dose with a 296 MBq injection of 64Cu-NOTA-Trastuzumab was 2.96 mSv. The highest absorbed dose was observed in the liver (0.076 mGy/MBq), followed by the spleen (0.063 mGy/MBq), kidney (0.044 mGy/MBq), and heart wall (0.044 mGy/MBq).Conclusions: 64Cu-NOTA-Trastuzumab showed specific uptake at the HER2-expressing tumors. It suggests that 64Cu-NOTA-Trastuzumab can be a feasible monitoring tool for HER2 tumor status in the patients with breast cancer with safe.Trial registration: CRIS, KCT0002790. Registered 02 February 2018, https://cris.nih.go.kr

Background The purpose of this study was to evaluate both the biodistribution and safety of 64Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Trastuzumab, a novel 64Cu-labeled positron emission tomography (PET) tracer for human epidermal growth factor receptor 2 (HER2) in patients with breast cancer. Methods PET images at 1, 24, and 48 h after 296 MBq of 64Cu-NOTA-Trastuzumab injection were obtained from seven patients with breast cancer. Both the primary tumors’ and metastatic lesions’ maximum standardized uptake value (SUVmax) was evaluated. The mean SUVmax (SUVmean) was evaluated in the other organs, including the blood pool, liver, kidney, muscle, spleen, bladder, and the lungs, as well as the bones. Moreover, the internal radiation dosimetry was calculated using the OLINDA/EXM software. Safety was assessed based on feedback regarding adverse reactions and safety-related issues within 1 month after 64Cu-NOTA-Trastuzumab administration. Results 64Cu-NOTA-Trastuzumab PET images showed that the overall SUVmean values in each organ negatively correlated with time. The liver’s average SUVmean values were measured at 5.3 ± 0.7, 4.8 ± 0.6, and 4.4 ± 0.5 on 1 h, 24 h, and 48 h after injection, respectively. The average SUVmean blood values were measured at 13.1 ± 0.9, 9.1 ± 1.2, and 7.1 ± 1.9 on 1 h, 24 h, and 48 h after injection, respectively. The SUVmax of HER2-positive tumors was relatively higher than HER2-negative tumors (8.6 ± 5.1 and 5.2 ± 2.8 on 48 h after injection, respectively). Tumor-to-background ratios were higher in the HER2-positive tumors than in the HER2-negative tumors. No adverse events related to 64Cu-NOTA-Trastuzumab were reported. The calculated effective dose with a 296 MBq injection of 64Cu-NOTA-Trastuzumab was 2.96 mSv. The highest absorbed dose was observed in the liver (0.076 mGy/MBq), followed by the spleen (0.063 mGy/MBq), kidney (0.044 mGy/MBq), and heart wall (0.044 mGy/MBq). Conclusions 64Cu-NOTA-Trastuzumab showed a specific uptake at the HER2-expressing tumors, thus making it a feasible and safe monitoring tool of HER2 tumor status in patients with breast cancer. Trial registration CRIS, KCT0002790. Registered 02 February 2018, https://cris.nih.go.kr

To evaluate the biodistribution of [PET was performed for five healthy controls and 10 patients with prostate cancer at 0, 10, 30, 70, and 120 mins after injecting 370 MBq of [The SUVWe identified a novel PSMA-targeted PET ligand, [KCT0003924 registered at https://cris.nih.go.kr/ .

Gulfweed-based edible materials were developed in forms of food film and coating. Gulfweed suspension was subjected to high-pressure homogenization (HPH) at 103, 138, and 193 MPa with 1, 2, and 3 passes, and mixed with 14, 30, 50, and 70% (w/w gulfweed) glycerol and 1% (w/w gulfweed) polysorbate 20 to produce a film-forming suspension. The particle size of the suspension decreased with increasing pressure from 103 to 193 MPa and pass number from 1 to 3. The HPH-treated gulfweed suspension behaved like a pseudo-plastic non-Newtonian fluid. High pressure and pass number generally decreased the suspension viscosity. Uniformity and compactness of the films increased with increasing pressure. The optimal conditions for forming a film with high stretchability, low water vapor permeability, low and water solubility, as well as for preparing bright-colored coated smoked salmon, were found to be 193 MPa, three passes of HPH, and a glycerol concentration of 70%. Coating smoked salmon with gulfweed suspension enhanced the redness without altering its texture and volatile properties. The method reported in this study may be useful for seaweed-based edible film production, increasing their potential application to various food products like red meats. PRACTICAL APPLICATION: Seaweeds have high nutritional and functional values, but they are not commonly used as food materials owing to their appearance and size. Therefore, it is important to develop methods to utilize seaweeds by overcoming appearance and size limitations. A self-standing film/coating using gulfweed was developed in this study, making use of commercially available high-pressure homogenization technology. The method developed herein might enable increased applications of gulfweed and possibly other seaweeds to food products such as films, rolls, or coatings.

Defect-specific bone regeneration using 3-dimensional (3D) printing of block bone has been developed. Polycaprolactone (PCL) is biocompatible polymer that can be used as 3D scaffold. The aim of this study is to assess the biocompatibility and osteogenic efficacy of 3D printed PCL scaffold and to evaluate the effectiveness of β-tricalcium phosphate (β-TCP) addition in PCL scaffold. In this work, four circular defects (diameter: 8 mm) in rabbit calvarium were randomly assigned to (1) negative control (control), (2) PCL block (PCL), (3) PCL mixed with 10 wt% β-TCP (PCL/β-TCP), and (4) PCL/β-TCP plus collagen membrane (PCL/β-TCP + M). Animals were euthanized at 2 (n = 5) and 8 weeks (n = 5). Results indicated that in micro-CT, PCL/β-TCP + M showed the highest total augmented volume and new bone volume at 8 weeks, but there was no significant difference among four groups. Histomorphometrically, PCL, PCL/β-TCP, and PCL/β-TCP + M showed the significantly higher total augmented area compared to the control. PCL/β-TCP + M showed the highest new bone area but not statistically higher than the control. New bone formation deep inside the scaffold was observed only in β-TCP added scaffold. PCL showed high biocompatibility with great volume maintenance. Addition of β-TCP to PCL seemed to increase hydrophilicity and osteoconductivity. Developments in 3D-printed PCL material are expected. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1254-1263, 2019.

The purpose of this study was to develop 64Cu-labeled trastuzumab with improved pharmacokinetics for human epidermal growth factor receptor 2 (HER2). Methods: Trastuzumab was conjugated with SCN-Bn-NOTA and radiolabeled with 64Cu. Serum stability and immunoreactivity of 64Cu-NOTA-trastuzumab were tested. Small-animal PET imaging and biodistribution studies were performed in a HER2-positive breast cancer xenograft model (BT-474). The internal dosimetry for experimental animals was determined using the image-based approach with the Monte Carlo N-particle code. Results:64Cu-NOTA-trastuzumab was prepared with high radiolabeling yield and radiochemical purity (>98%) and showed high stability in serum and good immunoreactivity. Uptake of 64Cu-NOTA-trastuzumab was highest at 48 h after injection as determined by PET imaging and biodistribution results in BT-474 tumors. The blood radioactivity concentrations of 64Cu-NOTA-trastuzumab decreased biexponentially with time in both mice with and mice without BT-474 tumor xenografts. The calculated absorbed dose of 64Cu-NOTA-trastuzumab was 0.048 mGy/MBq for the heart, 0.079 mGy/MBq for the liver, and 0.047 mGy/MBq for the spleen. Conclusion:64Cu-NOTA-trastuzumab was effectively targeted to the HER2-expressing tumor in vitro and in vivo, and it exhibited a relatively low absorbed dose due to a short residence time. Therefore, 64Cu-NOTA-trastuzumab could be applied to select the right patients and right timing for HER2 therapy, to monitor the treatment response after HER2-targeted therapy, and to detect distal or metastatic spread.

// In Ho Song 1, * , Youn Noh 2, * , Junhye Kwon 2 , Jae Ho Jung 3 , Byung Chul Lee 3 , Kwang Il Kim 1 , Yong Jin Lee 1 , Joo Hyun Kang 1 , Chae Seo Rhee 4 , Chul Hee Lee 4 , Tae Sup Lee 1 and Ik Joon Choi 2, 5 1 Division of RI Convergence Research, Research Institute of Radiological and Medical Sciences (RIRAMS), Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, Republic of Korea 2 Division of Radiological and Clinical Research, Korea Cancer Center Hospital (KCCH), Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, Republic of Korea 3 Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea 4 Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea 5 Department of Otorhinolaryngology-Head and Neck Surgery, Korea Cancer Center Hospital (KCCH), Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Tae Sup Lee, email: nobelcow@kirams.re.kr Ik Joon Choi, email: ijchoiorl@gmail.com Keywords: immuno-PET, radioimmunotherapy, cetuximab, EGFR, head and neck squamous cell carcinoma Received: June 16, 2017 Accepted: August 04, 2017 Published: September 08, 2017 ABSTRACT The epidermal growth factor receptor (EGFR) is one of the most comprehensively studied molecular targets in head and neck squamous cell carcinoma (HNSCC). However, inherent and acquired resistance are serious problems and are responsible for limited clinical efficacy and tumor recurrence. In this study, we evaluated the feasibility of immuno-positron emission tomography (PET) imaging and radioimmunotherapy (RIT) with 64 Cu-/ 177 Lu-PCTA-cetuximab in cetuximab-resistant SNU-1066 HNSCC xenografted model. The cellular uptake of 64 Cu/ 177 Lu-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA)-cetuximab showed good correlation with western blot and flow cytometry analysis in EGFR expression level of various HNSCC cells. 177 Lu-PCTA-cetuximab selectively killed cetuximab-resistant SNU-1066 cells in vitro . 64 Cu-/ 177 Lu-PCTA-cetuximab specifically accumulated in SNU-1066 tumor and those uptakes were peaked at 48 h and 7 day, respectively in biodistribution, PET and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. RIT with single dose of 177 Lu-PCTA-cetuximab exhibited significant tumor regression and markedly reduced 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) uptake, compared to other groups. Proliferation index were dramatically decreased and apoptotic index increased in RIT group. These results suggest that a diagnostic and therapeutic convergence radiopharmaceutical, 64 Cu-/ 177 Lu-PCTA-cetuximab has the potential of target selection using immuno-PET imaging and targeted therapy by RIT in EGFR expressing cetuximab-resistant HNSCC tumors.

Introduction Macrophages play a key role in atherosclerotic plaque formation in atherosclerosis, but its detailed understanding has poorly investigated until now. Thus, we sought to demonstrate a noninvasive technique for macrophage tracking to atherosclerotic lesions in apolipoprotein E −/− (ApoE −/− ) mice with an imaging system based on sodium iodide symporter (NIS) gene coupled with 99m Tc-single-photon emission computed tomography (SPECT). Methods and results Macrophage cells (RAW264.7) were stably transduced with retrovirus expressing NIS gene (RAW-NIS). In RAW-NIS cells, uptake of 125 I was higher than the parental cells. [ 18 F]FDG signals in the aorta at 30weeks on an ApoE −/− mice with high cholesterol diet were higher (1.7±0.12% injected dose (ID)) than those in control group (0.84±0.06% ID). Through 99m Tc-SPECT/computed tomography (CT), in the RAW-NIS cell injected group, the 99m Tc-pertechnetate uptake in aorta was higher than control groups. However, according to atorvastatin treatment, RAW-NIS cell recruitment reduced to the aorta. Area of 99m Tc-pertechnetate uptake was positively correlated with immunostaining results against macrophage antigen (CD68). Cholesterol and low-density lipoprotein levels of atorvastatin-treated group showed lower than those of atorvastatin-untreated group, but did not reach statistical difference. Conclusions This novel approach to tracking macrophages to atherosclerotic plaques in vivo can be applied for studies of arterosclerotic vascular disease.

Cucurbit[6]uril (CB[6])-based polymer nanocapsules (CB[6]PNs) were used as a multimodal platform for cancer-targeted in vivo bioimaging. By taking advantage of the strong and robust host–guest interaction between CB[6] and spermidine (spmd) under in vivo conditions, the surface of the CB[6]PNs was non-covalently modified with various spmd-conjugated functionalities in a modular manner. The CB[6]PNs modified with imaging probes and targeting ligands showed tumor targeted PET and NIR imaging in mice. This proof of concept demonstrates the potential of non-covalently modified nanomaterials in real world in vivo systems.

Signaling by small guanosine triphosphatases (GTPase), Rap1/Rac1, is one of the major pathways controlling cancer cell migration and tumor metastasis. Thymosin beta-4 (Tβ4), an actin-sequestering protein, has been shown to increase migration of cancer cells. Episodes of hypoxia and re-oxygenation (H/R) are an important phenomenon in tumor microenvironment (TME). We investigated whether Tβ4 could play as an intermediary to crosstalk between Rac1- and Rap1- GTPase activation under hypoxia/reoxygenation (H/R) conditions. Inhibition of Tβ4 expression using transcription activator-like effector nucleases (TALEN) significantly decreased lung metastasis of B16F10 cells. Rac1 and Rap1 activity, as well as cancer cell migration, increased following induction of Tβ4 expression in normoxia- or H/R-experienced cells, but were barely detectable in Tβ4-depleted cells. Rap1-regulated Rac1 activity was decreased by a dominant negative Rap1 (Rap1N17), and increased by 8-(4-chloro-phenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (CPT), a Rap1 activator. In contrast, a Rac1-specific inhibitor, NSC23766, and dominant negative Rac1 (Rac1N17) enhanced Tβ4 expression and aberrant Rap1 activity. While NSC23766 and Rac1N17 incompletely inhibited tumor metastasis in vivo, and H/R-experienced cancer cell migration in vitro, more efficient attenuation of cancer cell migration was accomplished by simultaneous inactivation of Rap1 and Rac1 with Rap1N17 and Rac1N17, respectively. These data suggest that a combination therapy targeting both Rap1 and Rac1 activity may be an effective method of inhibiting tumor metastasis.

A new microbial decontamination system combining washing with a natural antimicrobial solution and coating with a carnauba wax (CW)-based antimicrobial coating was developed and its effects on mandarin storability were investigated. Mandarins were washed with an antimicrobial solution and/or coated with grapefruit seed extract-CW (GSE/CW). Values for the disease incidence of Penicillium digitatum in untreated mandarins; mandarins coated with GSE/CW without washing; and mandarins coated with GSE/CW after washing with a fumaric acid (FA) solution of slightly acidic electrolyzed water, a highly activated calcium oxide (CaO) aqueous solution, or CaO solution followed by FA solution were 96.0, 70.0, 78.8, 50.0, and 72.2%, respectively. GSE/CW coating after CaO washing was most effective in inhibiting P. digitatum growth during storage at 25 °C. Compared to untreated samples, GSE/CW coating alone or after CaO washing retained CO2 generation, firmness, and total polyphenol content of mandarins at 25 °C. Such treatments also effectively maintained mandarin pH, ascorbic acid concentration, and antioxidant capacity at both 4 and 25 °C. Moreover, GSE/CW coating after CaO washing more effectively inhibited P. digitatum growth at 25 °C and maintained ascorbic acid concentration and antioxidant capacity at 4 and 25 °C than GSE/CW coating alone. The microbial decontamination system integrating CaO washing and GSE/CW coating demonstrates potential for improving mandarin storability by inhibiting P. digitatum growth and improving the preservation of quality properties and sensory characteristics. PRACTICAL APPLICATION: This is the first study to develop a microbial decontamination system involving both washing with a natural antimicrobial solution and carnauba wax coating containing grapefruit seed extract to improve the storability of fruits. This system demonstrated a primary effect of inhibiting fungi that cause mandarin surface decay at 25 °C via the highly activated calcium oxide wash and secondary effects of delaying quality degradation and inhibiting fungal growth by the action of the antimicrobial coating. These effects led to improvements in mandarin storability, along with enhanced visual appeal while not affecting taste, flavor, or texture.

The aim of this study was to assess the clinical activity and toxicity of 131I-rituximab as consolidation therapy for patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone). Patients who had been diagnosed with advanced stage (Ann Arbor III or IV) or bulky stage II DLBCL and achieved complete or partial response after six to eight cycles of R-CHOP were enrolled. A total of 16 patients were enrolled and treated with a single dose of 131I-rituximab as consolidation therapy after the completion of six or eight cycles of R-CHOP between December 2005 and June 2011. This trial was terminated before the scheduled enrollment owing to low recruitment. Among the 16 patients who were treated with consolidative 131I-rituximab, 6 achieved complete response (CR) after three cycles of R-CHOP, and another 9 patients further achieved CR after the completion of six or eight cycles of R-CHOP. During the median follow-up period of 73 months, only four patients (25 %) experienced relapse. Two-year relapse-free survival was 88 %, and 5-year relapse-free survival was 81 %. Grade 3 or 4 treatment-related toxicity occurred in four patients and included neutropenia and thrombocytopenia. 131I-rituximab showed promising efficacy as consolidation treatment for patients with DLBCL. A future randomized phase III study to confirm our results is warranted.

There is increasing evidence that cancer contains cancer stem cells (CSCs) that are capable of regenerating a tumor following chemotherapy or radiotherapy. CD44 and CD133 are used to identify CSCs. This study investigated non-invasive in vivo monitoring of CD44-positive cancer stem-like cells in breast cancer by γ-irradiation using molecular image by fusing the firefly luciferase (fLuc) gene with the CD44 promoter. We generated a breast cancer cell line stably expressing fLuc gene by use of recombinant lentiviral vector controlled by CD44 promoter (MCF7-CL). Irradiated MCF7-CL spheres showed upregulated expression of CD44 and CD133, by immunofluorescence and flow cytometry. Also, gene expression levels of CSCs markers in irradiated spheres were clearly increased. CD44+ CSCs increased fLuc expression and tumor growth in vivo and in vitro. When MCF7-CL was treated with siCD44 and irradiated, CD44 expression was inhibited and cell survival ratio was decreased. MCF7-CL subsets were injected into the mice and irradiated by using a cobalt-60 source. Then, in vivo monitoring was performed to observe the bioluminescence imaging (BLI). When breast cancer was irradiated, relative BLI signal was increased, but tumor volume was decreased compared to non-irradiated tumor. These results indicate that increased CD44 expression, caused by general feature of CSCs by irradiation and sphere formation, can be monitored by using bioluminescence imaging. This system could be useful to evaluate CD44- expressed CSCs in breast cancer by BLI in vivo as well as in vitro for radiotherapy.

A few recent reports have indicated that metastatic growth of several human cancer cells could be promoted by radiotherapy. C6-L cells expressing the firefly luciferase (fLuc) gene were implanted subcutaneously into the right thigh of BALB/c nu/nu mice. C6-L xenograft mice were treated locally with 50-Gy γ-irradiation (γ-IR) in five 10-Gy fractions. Metastatic tumors were evaluated after γ-IR by imaging techniques. Total RNA from non-irradiated primary tumor (NRPT), γ-irradiated primary tumor (RPT), and three metastatic lung nodule was isolated and analyzed by microarray. Metastatic lung nodules were detected by BLI and PET/CT after 6-9 weeks of γ-IR in 6 (17.1%) of the 35 mice. The images clearly demonstrated high [18F]FLT and [18F]FDG uptake into metastatic lung nodules. Whole mRNA expression patterns were analyzed by microarray to elucidate the changes among NRPT, RPT and metastatic lung nodules after γ-IR. In particular, expression changes in the cancer stem cell markers were highly significant in RPT. We observed the metastatic tumors after γ-IR in a tumor-bearing animal model using molecular imaging methods and analyzed the gene expression profile to elucidate genetic changes after γ-IR.

This study was aimed to evaluate the effect of (124)I-labeling with hexadecyl-4-iodobenzoate (HIB) on gene expression related to cell cycle, DNA repair, transcription, proliferation and differentiation of adipose-derived stem cells (ADSCs). [(124)I]HIB showed high labeling efficiency with ADSCs (51.3±1.3%, 0.3-2.0 Bq/cell) and there is no morphological change of ADSCs. In the microarray analysis of gene expression pattern, differences were not observed between non-labeled and [(124)I]HIB-labeled ADSCs. We demonstrated that (124)I-labeling with HIB did not affect the biological properties of ADSCs.

This study investigated the efficacy of atmospheric dielectric barrier discharge in-package cold plasma treatment (ADCPT) in inactivating Escherichia coli O157:H7, Salmonella, Listeria monocytogenes, and Tulane virus (TV) in whey protein-coated boiled chicken breast (BCB) cubes. The optimal ADCPT conditions for Salmonella inactivation were determined, and the effects of ADCPT on lipid oxidation and color were also evaluated. The optimal ADCPT voltage and time for Salmonella inactivation were found to be 39 kV and 3.5 min, respectively, resulting in a reduction of 3.7 log CFU/cube. Further, these conditions effectively inactivated E. coli O157:H7 (3.9 log CFU/cube), L. monocytogenes (3.5 log CFU/cube), and TV (2.2 PFU/cube). A second-order polynomial model can be used to explain the inactivation of Salmonella. ADCPT did not significantly affect the values of thiobarbituric acid reactive substance or color of BCB. Thus, these results suggest that ADCPT is an effective method for enhancing the microbiological safety of ready-to-eat packaged BCB by inactivating major foodborne pathogens and human norovirus without affecting the lipid oxidation and color of BCB.

This study investigated the effects of washing and packaging combined treatments on satsuma mandarin (Citrus unshiu Marc.) quality during storage at 4 °C and 25 °C. The treatments involved the combinations of washing using calcium oxide (CaO, 0.2%) solution, carnauba wax coating with grapefruit seed extract (1%) (CW coating), and modified atmosphere packaging (MAP) using O2–CO2–N2 (9.9%, 2.1%, and 88.0%, respectively). The growth of P. digitatum was inhibited across all samples at 4 °C and 25 °C. CaO washing delayed the increase in mandarin CO2 generation during storage at both temperatures and the decrease in antioxidant capacity at 4 °C. CW coating retarded the increase in CO2 generation and the decrease in firmness and antioxidant capacity at both temperatures. MAP delayed the decrease in ascorbic acid concentration at 25 °C and the increase in CO2 generation at 4 °C and 25 °C and also retarded the reduction in antioxidant capacity with or without CaO washing at both temperatures. The combination of three treatments effectively delayed decreases in firmness, ascorbic acid concentration, and antioxidant capacity, and retarded increases in the CO2 generation of mandarins during storage, which demonstrates the potential effectiveness of combined treatments in extending the shelf life of mandarins.

We evaluated the effect of plasma-activated water (PAW) on the populations of foodborne pathogens and food-spoilage microorganisms on Korean rice cake. PAW was produced by treating distilled water with two atmospheric dielectric-barrier discharges (51.7 W, 14.4 kHz, air discharge) for 20 min. The inactivation effect of PAW on indigenous microorganism and inoculated Escherichia coli O157:H7, Salmonella Typhimurium, Listeria monocytogenes, Penicillium chrysogenum and Candida albicans on Korean rice cake were measured and their effect on the color and texture values of the samples were determined. PAW treatment for 20 min reduced the numbers of the three foodborne pathogens by about 2.0 log CFU/g. PAW treatment for 20 min reduced the numbers of total aerobes, P. chrysogenum, and C. albicans by 2.78, 1.97, and 1.00 log CFU/g, respectively. The antimicrobial effect of PAW was not significantly different from 0.2 ppm of sodium hypochlorite solution, which is used in Korean rice cake production. PAW treatment did not affect the color, texture, or pH of Korean rice cake. Therefore, PAW treatment can be used as an alternative method to reduce safety risk and spoilage of Korean rice cake without deteriorating its quality.

Epidermal growth factor receptor (EGFR) is overexpressed and considered as a proper molecular target for diagnosis and targeted therapy of esophageal squamous cell carcinoma (ESCC). This study evaluated the usefulness of PET imaging biomarkers with 64Cu-PCTA-cetuximab and 18F-FDG-PET for anti-EGFR immunotherapy in ESCC models. In vivo EGFR status and glucose metabolism by cetuximab treatment were evaluated using 64Cu-PCTA-cetuximab and 18F-FDG-PET, respectively. Therapeutic responses with imaging biomarkers were confirmed by western blot and immunohistochemistry. TE-4 and TE-8 tumors were clearly visualized by 64Cu-PCTA-cetuximab, and EGFR expression on TE-8 tumors showed 2.6-fold higher uptake than TE-4. Tumor volumes were markedly reduced by cetuximab in TE-8 tumor (92.5 &plusmn, 5.9%), but TE-4 tumors were refractory to cetuximab treatment. The SUVs in 64Cu-PCTA-cetuximab and 18F-FDG-PET images were statistically significantly reduced by cetuximab treatment in TE-8 but not in TE-4. 64Cu-PCTA-cetuximab and 18F-FDG-PET images were well correlated with EGFR and pAkt levels. 64Cu-PCTA-cetuximab immuno-PET had a potential for determining EGFR level and monitoring therapeutic response by anti-EGFR therapy. 18F-FDG-PET was also attractive for monitoring efficacy of anti-EGFR therapy. In conclusion, PET imaging biomarkers may be useful for selecting patients that express target molecules and for monitoring therapeutic efficacy of EGFR-targeted therapy in ESCC patients.

Purpose The aim of the present study was to evaluate the biocompatibility and barrier function of mussel adhesive protein (MAP)-loaded collagen membranes in guided bone regeneration (GBR). Methods Eight male New Zealand white rabbits were used. Four circular defects (diameter: 8 mm) were created in the calvarium of each animal. The defects were randomly assigned to 1) a negative control group, 2) a cyanoacrylate (CA)-loaded collagen membrane group (the CA group), 3) a MAP-loaded collagen membrane group (the MAP group), and 4) a group that received a polycaprolactone block with MAP-loaded collagen membrane (the MAP-PCL group). Specimens were harvested at 2 weeks (n=4) and 8 weeks (n=4) postoperatively for observational histology and histometric analysis. Results In the histologic analysis, MAP was completely absorbed without any byproducts. In contrast, some of the CA adhesive remained, showing an inflammatory reaction, at 8 weeks. In the MAP-PCL group, the MAP-loaded collagen membranes served as a barrier membrane despite their fast degradation in GBR. No significant difference was found in the amount of new bone between the MAP-PCL and MAP groups (1.82±0.86 mm2 and 2.60±0.65 mm2, respectively). Conclusions The MAP-loaded collagen membrane functioned efficiently in this rabbit calvarial GBR model, with excellent biocompatibility. Further research is needed to assess clinical applications in defect types that are more challenging for GBR than those used in the current model., Graphical Abstract

The purpose of this study was to develop