Protease Activity: Meeting Its Theranostic Potential

This themed issue provides up-to-date review and research articles covering the theranostic applications in the combined fields of protease research, diagnostics and drug development

Role of Immunohistochemistry in Fine Needle Aspiration and Core Needle Biopsy of Thyroid Nodules

Objectives Immunohistochemistry (IHC) has been used for the diagnosis of indeterminate results in fine needle aspiration (FNA) of thyroid nodules. However, the role of IHC in core needle biopsy (CNB) is not clear and the efficacy of testing for molecular markers following CNB has not been evaluated. The aim of this study is to compare the role of IHC staining in CNB with that in FNA when examining thyroid nodules and to compare the sensitivity and usefulness of different molecular markers. Methods Consecutive cases of thyroid FNA and CNB accompanied by IHC from 2004 to 2014 were included in this study with retrospective review of medical record. The rate of remaining nondiagnostic result (unsatisfactory, atypia of undetermined significance or follicular lesion of undetermined significance [AUS/FLUS]) and rate of strong expression of each molecular marker according to the diagnosis were evaluated. Results IHC was more frequently performed in CNB with multiple molecular markers compared to FNA (38.1% vs. 2.8%, 3 or 4 markers [Gal-3, HBME-1, CK19, and CD56] vs. 1 marker [Gal-3]). In the CNB group, 11.3% remained as AUS/FLUS after IHC, and the rate remaining nondiagnostic was significantly less than in the FNA group (42.9%). Gal-3 and CK19 showed higher specificity and expressed mainly in conventional type of papillary carcinoma and HBME-1 showed higher sensitivity for the diagnosis of carcinoma with expression in both conventional type and follicular variant papillary thyroid carcinoma. Conclusion With these data, we could conclude that IHC was more effective following CNB than following FNA

Temperature-dependent ff-electron evolution in CeCoIn5_5 via a comparative infrared study with LaCoIn5_5

We investigated CeCoIn$_5$ and LaCoIn$_5$ single crystals, which have the same HoCoGa$_5$-type tetragonal crystal structure, using infrared spectroscopy. However, while CeCoIn$_5$ has 4$f$ electrons, LaCoIn$_5$ does not. By comparing these two material systems, we extracted the temperature-dependent electronic evolution of the $f$ electrons of CeCoIn$_5$. We observed that the differences caused by the $f$ electrons are more obvious in low-energy optical spectra at low temperatures. We introduced a complex optical resistivity and obtained a magnetic optical resistivity from the difference in the optical resistivity spectra of the two material systems. From the temperature-dependent average magnetic resistivity, we found that the onset temperature of the Kondo effect is much higher than the known onset temperature of Kondo scattering ($\simeq$ 200 K) of CeCoIn$_5$. Based on momentum-dependent hybridization, the periodic Anderson model, and a maximum entropy approach, we obtained the hybridization gap distribution function of CeCoIn$_5$ and found that the resulting gap distribution function of CeCoIn$_5$ was mainly composed of two (small and large) components (or gaps). We assigned the small and large gaps to the in-plane and out-of-plane hybridization gaps, respectively. We expect that our results will provide useful information for understanding the temperature-dependent electronic evolution of $f$-electron systems near Fermi level.Comment: 23 pages, 8 figure

Optimal Trajectory and En-Route Contingency Planning for Urban Air Mobility Considering Battery Energy Levels

Copyright © 2022 by Seulki Kim, Caleb Harris, Cedric Y. Justin, and Dimitri Mavris . Published by the American Institute of Aeronautics and Astronautics, Inc., with permission.Presented at the AIAA Aviation Forum, June 27-July 1, 2022, Chicago, IL & VirtualUrban Air Mobility (UAM) is an electric propelled, vertical takeoff and landing (eVTOL) aircraft envisioned for transporting passengers and goods within metropolitan areas. Planning UAM flights will not be easy as unexpected wind turbulence from high-altitude structures may impact the vehicles operating at a low altitude. Furthermore, considering the short travel time of the UAM, smart and safe decision-making will be challenging, particularly in off-nominal situations that force the aircraft to divert to an alternate destination instead of landing at the initially planned destination. To overcome these challenges, this research proposes automated pre-flight and in-flight contingency planning systems to assist in both normal and irregular UAM operations. A planner in the pre-flight planning system optimizes an aerial trajectory between the scheduled origin and destination, avoiding restricted high-level structures and estimating energy levels. In the contingency planning system, an in-flight replanner produces several optimal trajectories from where the diversion is declared to each alternate destination candidate. A diversion decision-making tool then scores a list of candidates and selects the best site for diversion. Real-world operational scenarios in the city of Miami are presented to demonstrate the capability of the proposed framework

Emergency Planning for Aerial Vehicles by Approximating Risk with Aerial Imagery and Geographic Data

Presented at the AIAA SCITECH 2022 ForumUrban Air Mobility and Advanced Air Mobility require the certification of novel electrified, vertical takeoff and landing, and autonomous aerial vehicles. These vehicles will operate at lower altitudes, in more dense environments, and with limited recovery abilities. Therefore, emergency landing scenarios must be considered broadly to understand the risks in some situations of flight failures. This work provides a preflight planning tool to assist these vehicles when emergency landing is required in crowded environments by fusing geographic data about the population, geometric data from lidar scans, and semantic data about land cover from aerial imagery. The Pix2Pix Conditional GAN is trained on Washington D.C. datasets to predict eight classifications at a 1m resolution. The information from this detection phase is transformed into a costmap, or riskmap, to use in planning the path to the safest landing locations. Multiple combinations of the cost layers are investigated in three test scenarios. The Rapidly Exploring Random Tree (RRT) algorithm efficiently searches for an alternative path that minimizes risk during emergency landing. The tool is demonstrated through three scenarios in the D.C. area. The objective is that the tool allows for the safe operation of UAM and AAM vehicles through crowded regions by providing confidence to the local population and federal regulators

The association of serum irisin with anthropometric, metabolic, and bone parameters in obese children and adolescents

BackgroundIrisin is an adipomyokine secreted by muscle and adipose cells, and it plays a role in glucose, fat, and bone metabolism. This study aimed to determine the correlation of serum irisin levels with anthropometric, metabolic, and bone parameters in obese children and adolescents.MethodsThis single-center study included 103 Korean children and adolescents: 54 (52.4%) obese participants with a body mass index (BMI) ≥95th percentile and 49 (47.6%) healthy controls with BMI within the 15th to 85th percentile. Various parameters were measured, including fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride and glucose (TyG) index, lipid profile, alkaline phosphatase (ALP), osteocalcin, and 25(OH)-Vitamin D levels. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA) in 33 healthy subjects.ResultsSerum irisin was significantly higher in the obese group than in the control group (mean 18.1 ± 3.5 vs. 16.2 ± 2.0 ng/mL; p = 0.001). Serum irisin level was positively correlated with chronological age (r = 0.28; p = 0.004), height SDS (r = 0.24; p = 0.02), BMI SDS (r = 0.37; p < 0. 001), fasting glucose (r = 0.27; p = 0.007), fasting insulin (r = 0.23; p = 0.03), HOMA-IR (r = 0.21; p = 0.04), osteocalcin (r = 0.27; p = 0.006) and negatively correlated with HDL cholesterol (r = -0.29; p = 0.005). All these correlations were evident in obese subjects but not in healthy subjects. ALP and 25(OH)-Vitamin D were unrelated to irisin levels. Among 33 healthy subjects, total body-less head (TBLH) BMD Z-score was positively correlated with serum irisin (r = 0.39; p = 0.03), osteocalcin (r = 0.40; p = 0.02), fasting insulin (r = 0.39; p = 0.04), and HOMA-IR (r = 0.38; p = 0.047).ConclusionThis study demonstrated an association between irisin levels and glucose, lipid, and bone parameters in children and adolescents. Our findings suggest that irisin has a potential role in metabolic disorders and bone health in obese children and adolescents

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Acquired resistance mechanisms to capmatinib, a MET inhibitor in MET-amplified non-small cell lung cancer cells

학위논문 (석사)-- 서울대학교 대학원 : 종양생물학전공, 2017. 2. 김동완.Purpose: Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been elucidated. Capmatinib (INC280, Novartis) is a highly potent and selective small molecule MET-TKI. To understand the mechanisms of resistance to MET-TKIs and establish therapeutic strategies, we developed an in vitro model using capmatinib-resistant cell lines (EBC-CR1, CR2, and CR3) derived from the MET-amplified NSCLC cell line EBC-1. Methods: We established capmatinib-resistant NSCLC cell lines from the MET-amplified NSCLC cell line EBC-1 and identified alternative signaling pathways using 3mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative PCR and cell proliferation assayactivation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the EBC-CR1, -CR2, and -CR3 resistant cell lines. Results: We found that epidermal growth factor (EGFR) mRNA expression and protein activation were increased in EBC-CR1–3 cells compared to EBC-1 cells. EBC-CR1 cells showed EGFR-dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells, which overexpressed the EGFR-MET heterodimer, responded dramatically to the combination of capmatinib and the phosphoinositide-3 kinase catalytic subunit α (PIK3CA) inhibitor afatinib. In addition, EBC-CR3 cells, which had activated EGFR along with amplified PIK3CA, were sensitive to the combination of afatinib and the PI3Kα inhibitor BYL719. Conclusions: Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be an effective therapeutic strategy in MET-TKI-resistant NSCLC patients.1. Introduction 1 2. Materials and methods 3 3. Results 8 3.1 Establishment of EBC-1 cells with acquired resistance to capmatinib 8 3.2 Acquired resistant mechanisms to capmatinib were associated with EGFR kinase pathway 12 3.3 Increased MET and EGFR heterodimerization caused acquired resistance to MET-TKI 20 3.4 Acquired resistance to EGFR-TKI beyond MET-TKI resistance 25 4. Discussion 30 5. Reference 37 6. Abstract in Korean 40Maste