Showing papers by "Hye Jin Lee published in 2019"

Antibody and fragment-based PET imaging of CTLA-4+ T-cells in humanized mouse models.

Abstract: Imaging of immunotherapy targets using positron emission tomography (PET) can allow for noninvasive monitoring of their dynamic expression and may allow for patient stratification in the future. Therefore, two tracers targeting CTLA-4, one a full antibody and the other a F(ab')2 fragment, were radiolabeled with 64Cu and validated in humanized mouse models. Ipilimumab was digested to develop ipilimumab-F(ab')2, and both the intact antibody and the fragment were conjugated with NOTA to chelate 64Cu for PET. The tracers were administered to both control NBSGW mice and humanized mice (PBL mice, engrafted with human peripheral blood lymphocytes), and PET was conducted out to 48 h post-injection. PET region-of-interest analysis, ex vivo biodistribution studies, and tissue staining were used to confirm that the tracers specifically accumulated in CTLA-4+ tissues. Following injection of tracers (n = 3-5 per group), specific uptake was noted in the salivary gland tissues of the humanized mice. This uptake, a result of graft-versus-host disease onset, was proven to be due to human T-cells through staining of the tissues for human CD3 and CTLA-4. 64Cu-NOTA-ipilimumab demonstrated the highest absolute uptake in the salivary glands of PBL mice, peaking at 7.00 ± 2.19 %ID/g. In contrast, 64Cu-NOTA-ipilimumab-F(ab')2 uptake was 2.40 ± 0.86 %ID/g at the same time point. However, the F(ab')2 agent cleared from circulation more quickly than the intact antibody, providing higher salivary gland-to-blood ratios, which reached 1.78 ± 0.72 at 48 h post-injection, compared to 64Cu-NOTA-ipilimumab at 1.19 ± 0.49. Uptake of the tracers in the salivary glands of control mice, and the nonspecific tracer in the PBL mice, was lower at all time points as well. PET imaging with both 64Cu-NOTA-ipilimumab and 64Cu-NOTA-ipilimumab-F(ab')2 was able to localize CTLA-4+ tissues. These tracers may thus help elucidate the mechanisms of response to CTLA-4-targeted checkpoint immunotherapy treatments.

Antibody-based Tracers for PET/SPECT Imaging of Chronic Inflammatory Diseases

Abstract: Chronic inflammatory diseases are often progressive, resulting not only in physical damage to patients but also social and economic burdens, making early diagnosis of them critical. Nuclear medicine techniques can enhance the detection of inflammation by providing functional as well as anatomical information when combined with other modalities such as magnetic resonance imaging, computed tomography or ultrasonography. Although small molecules and peptides were mainly used for the treatment and imaging of chronic inflammatory diseases in the past, antibodies and their fragments have also been emerging for chronic inflammatory diseases as they show high specificity to their targets and can have various biological half-lives depending on how they are engineered. In addition, imaging with antibodies or their fragments can visualize the in vivo biodistribution of the probes or help monitor therapeutic responses, thereby providing physicians with a greater understanding of drug behavior in vivo and another means of monitoring their patients. In this review, we introduce various targets and radiolabeled antibody-based probes for the molecular imaging of chronic inflammatory diseases in preclinical and clinical studies. Targets can be classified into three different categories: 1) cell-adhesion molecules, 2) surface markers on immune cells, and 3) cytokines or enzymes. The limitations and future directions of using radiolabeled antibodies for imaging inflammatory diseases are also discussed.

Double amplified colorimetric detection of DNA using gold nanoparticles, enzymes and a catalytic hairpin assembly

Abstract: The authors describe an isothermal and ultrasensitive colorimetric DNA assay that consists of two amplification stages using enzymes and a catalytic hairpin assembly (CHA). The first step consists in the selective amplification of DNA using Klenow fragment and nicking enzyme. The second step consists in the amplification of the optical signal by using a catalytic hairpin assembly. After two amplification steps, the DNA reaction induces the aggregation of the red gold nanoparticles to give a blue color shift. The degree of aggregation can be quantified by measurement of the ratio of the UV-vis absorbances of the solutions at 620 and 524 nm which are the wavelengths of the aggregated gold nanoparticles and bare gold nanoparticles. The detection limit is as low as 3.1 fM. Due to the use of a specific enzyme, only the desired DNAs will be detected. The method can be applied to the determination of DNA of various lengths. Despite the presence of large amounts of wildtype DNA, it can readily detect a target DNA. Conceivably, the technique has a large potential because of its high sensitivity and selectivity.

Green synthesis and Characterization of ZnO-CoFe2O4 Semiconductor Photocatalysts Prepared Using Rambutan (Nephelium lappaceum L.) Peel Extract

Abstract: In this work, the semiconductor of ZnO-CoFe2O4 composites were prepared by green synthesis approach using rambutan peel extract (Nephelium lappaceum L.) as a capping agent. X-ray diffraction patterns of composites showed the main peaks of ZnO at 2θ = 31.8°, 34.5°, and 36.2° corresponding to hexagonal wurtzite structure and weak peak at 2θ = 35.4° for cubic structure of CoFe2O4. The formation of rice-like and small granular morphology were confirmed by scanning electron microscope (SEM) and transmission electron microscope (TEM), whereas the superparamagnetic behavior of the samples were determined by vibrating sample magnetometer (VSM). The spectrum of Fourier transform infrared (FTIR) and x-ray photoelectron spectroscopy (XPS) showed absorption bands related to a number of interactions and binding energy in the samples respectively. The photocatalytic performance of composites under solar light was evaluated for the degradation of Direct Red 81 and the dye from washing water of batik garments. The composites showed good photocatalytic activity with the degradation percentage reaching 99.6% for Direct Red 81 dye after 2 hours.

Dual-labeled pertuzumab for multimodality image-guided ovarian tumor resection.

Abstract: Pertuzumab is clinically employed in the treatment of cancers over-expressing human epidermal growth factor receptor 2 (HER2). Herein, we developed dual-labeled pertuzumab with a radionuclide (89Zr) and a near-infrared fluorophore (IRDye 800CW) to investigate the feasibility of utilizing dual-labeled monoclonal antibodies (mAbs) with numerous imaging modalities for preoperative imaging and image-guided surgery in ovarian cancer models. MAbs were dually-labeled with 89Zr and IRDye 800CW to generate 89Zr-Df-pertuzumab-800CW or 89Zr-Df-IgG-800CW. Serial positron emission tomography (PET) and near-infrared fluorescence (NIRF) images were acquired up to 72 hours after injection of dual-labeled mAbs to map the tracers' biodistributions. After the last time point, image-guided tumor resection was executed using different modalities (NIRF, Cerenkov luminescence [CL], and β particle imaging) and ex vivo studies including biodistribution assays and histology analysis were performed to confirm the in vivo imaging data. SKOV3 ovarian cancer cells showed high expression of HER2 and pertuzumab conjugated with Df and IRDye 800CW maintained its binding affinity for these cells. For PET imaging in subcutaneous xenograft ovarian cancer models, 89Zr-Df-pertuzumab-800CW showed a significantly higher tumor-to-muscle ratio compared to the nonspecific 89Zr-Df-IgG-800CW from 24 hours after injection through the last time point (72 h: 30.7 ± 7.4 vs. 7.5 ± 1.8, P < 0.01, n = 3-4). During image-guided surgery, three imaging modalities including NIRF, CL, and β particle imaging could detect ovarian cancer in both subcutaneous and orthotopic models and each exhibited its own imaging characteristics. In addition, ex vivo imaging and biodistribution studies as well as histology analysis corroborated the in vivo imaging results. Therefore, we concluded that this single radiolabeled tracer can provide all-in-one contrast for multiple imaging modalities. The dual-labeled mAbs may hold promise to be employed for image-guided tumor surgery as well as diagnosis and staging through balancing out the strengths and weaknesses of various modalities such as PET/CT, NIRF, CL, and β particle imaging.

Effects of Combined Upper Limb Robotic Therapy in Patients With Tetraplegic Spinal Cord Injury.

Abstract: Objective To confirm the effects of combined upper limb robotic therapy (RT) as compared to conventional occupational therapy (OT) in tetraplegic spinal cord injury (SCI) patients and to suggest the optimized treatment guidelines of combined upper limb RT. Methods After subject recruitment and screening for eligibility, the baseline evaluation for outcome measures were performed. We evaluated the Graded and Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP), the American Spinal Injury Association upper extremity motor score, grip and pinch strength, and the Spinal Cord Independence Measurement III (SCIM-III). In this study, the pre-tested participants were divided randomly into the RT and OT group. The utilized interventions included combined upper limb RT using ArmeoPower and Amadeo (RT group), or conventional OT (OT group) in addition to daily inpatient rehabilitation program. The participants underwent 40 minutes×3 sessions×5 weeks of interventions. Results A total of 30 tetraplegic SCI patients completed entire study program. After 5 weeks of intervention, both groups demonstrated increases in GRASSP-strength and SCIM-III. The manual muscle test scores of elbow flexion, elbow extension, 2-5th metacarpophalangeal extension, and SCIM-III subscores of bathing-upper, dressing-upper, and grooming as well as the GRASSP-qualitative prehension score were noted to have been significantly increased in the RT group as evaluated. The OT group showed improvements in the GRASSP-quantitative prehension score and some items in grip and pinch strength. There was no significant difference between the two groups in almost all measurements except for the SCIM-III bathing-upper subscore. Conclusion Combined upper limb RT demonstrated beneficial effects on the upper limb motor function in patients with tetraplegic SCI, which were comparable with conventional OT.

Ni(OH)2 Decorated Pt-Cu Octahedra for Ethanol Electrooxidation Reaction.

Abstract: Here we report the synthesis of 9 nm Ni(OH)2 decorated Pt-Cu octahedra (Ni(OH)2-PtCu) in one-pot synthesis for ethanol oxidation reaction (EOR) electrocatalysis in acidic electrolyte. To prepare Ni(OH)2-PtCu octahedra, CO gas was directly introduced in a reaction process as selective capping agents on the PtCu(111) facet. Ni(OH)2 was naturally deposited on the Pt-Cu octahedra during the synthesis. Carbon supported Ni(OH)2-PtCu (Ni(OH)2-PtCu/C) as an EOR catalyst showed enhanced CO tolerance due to the existence of oxophilic Ni(OH)2 on the surface of Pt-Cu, facilitating water dissolution to produce OH adsorption and to promote complete CO oxidation to CO2. In addition, Pt-Cu alloy composition also showed improvement of CO tolerance because of modified d-band structure of the Pt atoms, thereby weakening the binding strength of CO on the catalysts. Therefore, the Ni(OH)2-PtCu/C showed enhanced EOR activity and durability compared to the Pt-Cu octahedra and commercial Pt/C counterparts.

Voltammetric layer-by-layer biosensor featuring purine nucleoside phosphorylase and chitosan for inosine in human serum solutions

Abstract: A highly sensitive and selective voltammetric biosensing platform for the determination of inosine (INO) concentrations and further applications to biological sample solutions was developed. The biosensor configures a layer-by-layer (LbL) self-assembly of the positively charged chitosan (CS) and negatively charged purine nucleoside phosphorylase (PNP) on screen-printed carbon electrode (SPCE); PNP was chosen to improve the selectivity since it is INO selective while CS was used for the enzyme PNP loading. The electrocatalytic reaction of INO and PNP was studied using cyclic voltammetry (CV) and square wave voltammetry (SWV). Under the optimal condition with two-bilayer of the PNP and CS on the modified electrode (PNP-CS)2-SPCE, a linear dynamic range from 2 to 90 μM INO with a limit of detection of 0.3 μM was achieved when using SWV method. Finally, the developed biosensing platform was applied to the detection of INO in both normal human serum sample and myocardial infarction (MI) patient serum sample in addition to INO dietary supplements. The sensing results of normal human and MI patient serum samples were further compared to those obtained from liquid chromatography-mass spectrometry (LC-MS) and a commercial inosine assay kit.

Memory facilitation for emotional faces: Visual working memory trade-offs resulting from attentional preference for emotional facial expressions.

Abstract: Visual working memory (VWM) for faces is facilitated when they display negative facial expressions. The present study manipulated the emotional heterogeneity of the encoding display in a change detection task to examine whether VWM is enhanced by having a separate memory store or by a bias in the allocation of limited attentional resource. When the encoding display was emotionally heterogeneous, regardless of whether happy or fearful facial expressions were presented, memory for emotional faces increased while memory for neutral faces decreased, indicating a memory trade-off. To investigate whether this occurred as a result of preferential allocation of attentional resource towards emotional expressions over neutral ones, faces were shown sequentially in different quadrants of the display. The memory trade-off between happy and neutral faces disappeared but persisted between fearful and neutral faces at trailing serial positions. When blank intervals were inserted between faces to prevent fearful faces from having prolonged processing that consumes attentional resource that should be shared with neutral faces, the memory trade-off disappeared. Findings support the argument that emotional expressions facilitate VWM due to their bias in obtaining attentional resource but the exact mechanisms through which limited resource is allocated between happy and fearful expressions may differ.

Clinical efficacy of upper limb robotic therapy in people with tetraplegia: a pilot randomized controlled trial.

Abstract: In the original version of the article the authors incorrectly stated that: “One case study provided evidence of some improvements in motor performance and spasticity [19], while several other studies only provided evidence on the feasibility of UER as an assessment tool; however, the fact that the manufacturer funded these studies lessens their objectivity [15, 20–24].” This is not correct as the manufacturers did not fund the studies. The correct phrase therefore should have read: “One case study provided evidence of some improvements in motor performance and spasticity [19], while several other studies provided evidence focusing more on the feasibility of UER rather than the clinical efficacy [15, 20–24].” The authors would like to apologise for this error. This has been corrected in both the PDF and HTML versions of the Article.

Potential Applicabilities of Ammonia in Future Hydrogen Energy Supply Industries

Abstract: As a non-renewable energy source, fossil fuel causes environment problems, numerous efforts have been made for a global decarbonization, for example, the realization of Power 2 Gas (P2G) system as a definitive research goal. In particular, ammonia is regarded as an emerging source since it can be used as a hydrogen carrier and production alongside for fuel cell applications. In this mini-review, we summarized the properties of ammonia and further highlighted the worldwide research trend for its superb potential in hydrogen energy supply industries.

Sarcoidosis presenting pulmonary subsolid nodules that mimic lung adenocarcinoma in a patient with history of uveitis and arrhythmia: a case report.

Abstract: Sarcoidosis is an idiopathic systemic granulomatous disorder that can involve any organ, although the lung is the most commonly affected site; moreover, it may affect multiple organs simultaneously or serially over a long time span. Diagnosing sarcoidosis can be a challenge in cases presenting an isolated extra-thoracic lesion at the early stage of disease. Pulmonary nodular lesion, a rare radiologic finding, may also lead to delayed diagnosis of sarcoidosis. We reported a case of atypical pulmonary nodular sarcoidosis that was suspected as lung adenocarcinoma, which was diagnosed about 20 years after initial isolated extra-thoracic manifestation occurred.

Analysis of Human Serum Amyloid A-1 Concentrations Using a Lateral Flow Immunoassay with CdSe/ZnS Quantum Dots

Abstract: A lateral flow immunoassay platform utilizing antibody functionalized water soluble CdSe/ZnS semiconductor quantum dots (QDs) was developed for the analysis of human serum amyloid A-1 (hSAA1) in a buffer solution. hSAA1 was chosen as a target protein because it is regarded as a potential biomarker associated with early diagnosis and prognosis in patients of lung cancer. The immunoassay strip on a nitrocellulose membrane was fabricated by spraying two lines composed of a test line with a monoclonal antibody against hSAA1 (10G1) (anti hSAA1) and a control line of anti-chicken IgY. While the CdSe/ZnS QDs synthesized in an organic phase were transferred to a water phase by ligand exchange using carboxylic acid modified alkane thiol. The QDs was then conjugated to monoclonal antibody against hSAA1 (14F8) [anti hSAA1 (14F8)] and used as a fluorescent detection probe. The sequential lateral flow of hSAA1 in different concentration and QDs-anti hSAA1 (14F8) complex allowed to form the surface sandwich complex of anti hSAA1 (10G1)/hSAA1/QD-anti hSAA1 (14F8), which was then analyzed using fluorescence microscope. A 100 nM concentration of hSAA1 protein can be detected by naked eyes under an optimized lateral flow buffer condition with a sensing time of 5 mins.

Imaging CTLA-4+ T-cells in humanized mouse models

Abstract: 2 Objectives: Checkpoint immunotherapy treatments are showing great promise for cancer patients; however, the mechanisms and predictors of response are still largely mysteries, especially for CTLA-4-targeted treatments, which have particularly heterogeneous response patterns. Imaging of these immunotherapy targets using positron emission tomography (PET) can allow for noninvasive monitoring of their dynamic expression and biodistribution, and may allow for patient stratification in the future. Therefore, two tracers targeting human CTLA-4, one a full antibody and the other a F(ab’)2 fragment, were radiolabeled with 64Cu and validated in humanized mouse models. Methods: Ipilimumab was enzymatically digested to develop ipilimumab-F(ab’)2, and both the intact antibody and the fragment were conjugated with NOTA to chelate 64Cu for PET. Both tracers maintained their specificity for activated CTLA-4+ T-cells in vitro. The tracers were administered to both control NBSGW mice and humanized mice (PBL mice, which were engrafted with human peripheral blood lymphocytes), and PET was conducted out to 48 h post-injection. The onset of graft-versus-host disease in these humanized mice causes their salivary glands to dysfunction and sequestration of the foreign cells there, providing a localized site for exploration of CTLA-4+ tissue uptake. PET region-of-interest analysis, ex vivo biodistribution studies, and tissue staining were used to confirm that the tracers specifically accumulated in CTLA-4+ tissues. Results: Following intravenous injection of the respective tracers (n=3-5 per group), specific uptake was noted in the salivary gland tissues of the humanized mice. This uptake, as a result of graft-versus-host disease onset, was proven to be due to the presence of human T-cells through staining of the tissues for human CD3 and CTLA-4. 64Cu-NOTA-ipilimumab demonstrated the highest absolute uptake in the salivary glands of PBL mice, peaking at 7.00 ± 2.19 %ID/g, 24 h post-injection. In contrast, 64Cu-NOTA-ipilimumab-F(ab’)2 uptake was at 2.40 ± 0.86 %ID/g at the same time point. However, the F(ab’)2 agent cleared from circulation much more quickly than the intact antibody, providing higher salivary gland-to-blood ratios, which reached 1.78 ± 0.72 at 48 h post-injection, compared to 64Cu-NOTA-ipilimumab at 1.19 ± 0.49. Comparison with a nonspecific IgG, with a salivary gland-to-blood ratio of only 0.34 ± 0.08, verified the specificity of the salivary gland uptake with the targeted tracers. Uptake of the tracers in the salivary glands of control mice, and the nonspecific tracer in the PBL mice, was lower than that of the related targeted tracers at all imaging time points. Ex vivo studies verified all the trends found through PET analysis. Conclusions: PET imaging with both 64Cu-NOTA-ipilimumab and 64Cu-NOTA-ipilimumab-F(ab’)2 was able to localize CTLA-4+ tissues. These tracers may thus help elucidate the mechanisms of response to, and possibly toxicity from, CTLA-4-targeted checkpoint immunotherapy treatments.