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Clinical responses to second generation androgen signaling inhibitors (e.g., enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) are variable and transient, and are associated with dose limiting toxicities, including rare but severe CNS effects. We hypothesized that changes to iron metabolism coincident with more advanced disease might be leveraged for tumor-selective delivery of antiandrogen therapy. Using the recently described chemical probes SiRhoNox and 18F-TRX in mCRPC models, we found elevated Fe2+ to be a common feature of mCRPC in vitro and in vivo. We next synthesized ferrous-iron activatable drug conjugates of second and third-generation antiandrogens and found these conjugates possessed comparable or enhanced antiproliferative activity across mCRPC cell line models. Mouse pharmacokinetic studies showed that these prototype antiandrogen conjugates are stable in vivo and limited exposure to conjugate or free antiandrogen in the brain. Our results reveal elevated Fe2+ to be a feature of mCRPC that might be leveraged to improve the tolerability and efficacy of antiandrogen therapy.

PurposeWith the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets.Experimental designCDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post-enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice.ResultsCDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4-2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4-2B xenografts.ConclusionsThe data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.

This study explored science-related variables that have an impact on the prediction of science achievement groups by applying the educational data mining (EDM) method of the random forest analysis to extract factors associated with students categorized in three different achievement groups (high, moderate, and low) in the Korean data from the 2015 Programme for International Student Assessment (PISA). The 57 variables of science activities and learning in school collected from PISA questionnaires for students and parents were analyzed. Variables related to students' past science activities, science teaching and learning methods, and environmental awareness were found to played important roles in predicting science achievement. When checking partial dependence plots for major variables, science activities and instructional strategies had a high probability of changing the prediction of an achievement group. This study focused on science-related contextual variables that can be improved through government policies and science teachers' efforts in the classroom.

This study analyzed the responses of Korean students to interest, confidence, value, and instructional clarity in science and mathematics. To achieve this, the raw data of the recent student survey of TIMSS were analyzed. A one-way ANOVA was performed, and a post hoc test was performed. Additionally, a cohort analysis was performed to determine the changes when the fourth-grade students reached the eighth grade. The study results are as follows. First, interest and confidence were higher in the fourth grade than in the eighth grade. Second, in most cases, the average response of Singaporean students was the most positive, but in terms of interest and confidence in science in the fourth grade, the Japanese response average was generally the highest. Third, the average scores of Korean students on wanting to have a job related to their subject and knowing what teachers expect from them were low in both science and mathematics.

Among the complex and diverse triggering and aggravating factors for sensitive skin syndrome, potential defects in skin barrier function are considered one of the most important ones. Previously, we have reported improvements in skin barrier function thanks to autophagy-activating peptide derivatives. Further investigation revealed that the activation of autophagy signaling in skin cells also attenuated inflammatory responses induced by UV irradiation or exposure to pollution. In this study, in vitro and ex vivo human skin explant models were used to evaluate the potential benefits of the autophagy-activating peptide, pentasodium tetracarboxymethyl palmitoyl didpeptide-12 (PTPD-12), on sensitive skin-related parameters. Clinical efficacy testing was also performed to confirm the skin barrier-improving and skin-soothing activities of the autophagy-activating peptide. As a result, significant reductions in inflammatory cytokine (IL-8 and TNF-α) and enzyme activity (PDE4) were observed in the in vitro system. Increased expression of barrier marker proteins by PTPD-12 in UV-irradiated human skin tissue was observed ex vivo. In a clinical study, delayed response to topical capsaicin-induced vascular activation, which represents enhanced epidermal permeability barrier function, was observed after 4 weeks of application of PTPD-12 in healthy volunteers. In another clinical study with sensitive skin carriers identified via a lactic acid stinging test, a significant reduction in trans-epidermal water loss (TEWL) and skin erythema index was observed after 4 weeks of PTPD-12 usage. These results suggest that the activation of autophagy can be a potential treatment regimen for sensitive skin syndrome, specifically in terms of skin barrier function enhancement and skin soothing. [ABSTRACT FROM AUTHOR]

Microwave ablation (MWA) is based on the energy absorbed by biological tissue through microwave emission, which raises the temperature of the tumor to perform the treatment. MWA has the advantage of causing minimal bleeding and treating deep tumors. In this study, MWA for various slot design situations in a microwave coaxial antenna (MCA) was simulated through numerical analysis. For the slot design, the number of slots and the distance between slots were determined by the analysis parameters. A tumor developed inside the liver tissue was implemented, and the temperature distribution of the tumor and surrounding liver tissue was calculated for all cases selected for numerical analysis. The Helmholtz electromagnetic equation was used to calculate the electromagnetic field inside the tissue, and the modified Pennes bioheat equation was used to calculate the temperature change in the tissue due to the emitted microwave. Treatment effects were quantitatively analyzed for each slot design condition through an apoptotic variable based on the calculated temperature distribution. Lastly, conditions that produce optimal treatment effects were derived depending on the number of slots. The analysis showed that as the distance between the slots increased from 0.5 to 3.5 mm, the optimal treatment effect was obtained when the number of slots was 4, 3, 3, and 2, respectively, and the microwave input power at that time was 3.0, 2.8, 2.6, and 3.0 W, respectively. This is expected to allow for more rigorous and more therapeutically effective MWA. [ABSTRACT FROM AUTHOR]

The stringent environmental regulations and growing awareness of the low-carbon economy are presenting immense challenges to metallurgical operations, one of the major sectors with high emissions. Hydrometallurgy has been identified as a lower-emission technology in comparison to the high-temperature smelting and melt-refining processes. The close monitoring of traditional hydrometallurgical operations, however, does not fulfil the criteria for a sustainable, low-emission process. Recently, biotechnology has emerged as a green alternative within the hydrometallurgical domain, albeit significantly different from the basics involved in the process. Although the application of microbial activity has been successfully established in chalcopyrite leaching and bio-oxidation of gold-bearing minerals, the acceptability of bio-hydrometallurgy for other minerals and materials is still limited due to a wide research gap to connect solution chemistry, microbial activity, and extractive metallurgy. In general, a large portion of the total chemical consumption occurs in pre-treatment and/or leaching operations; hence, the primary application of microorganisms at the forefront can significantly minimize the overall consumption. Demonstrated applications in waste printed circuit boards and spent automobile catalysts have curtailed excessive acid usage, while the energy-intensive baking/roasting of monazite is successfully altered by microbial processing. Furthermore, the remarkable reduction in carbon footprints by the green biotechnology application in hydrometallurgy has been evaluated, which indicates sustainability in process metallurgy.