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PDF file, 779K, Figure S1. Expressionofp-KIT,p-AKT,andp-ERK increased according to the increased SCF concentrationin two KIT-expressingcelllines. Figure S2. Expression of KIT, p-KIT, p-AKT, and p-ERK after SCF treatment in two tumor cell lines with KIT mutation. FigureS3.Quantification of Westernblotting results for Fig.1E. FigureS4. Membranous KITexpression of DLD-1 was determined by FACS. Figure S5. Mutant KIT is not degraded after SCF treatment. Figure S6. FACS analysis of p-AKT and p-ERK expressing colon cancer cells treated with SCF and PMA. Figure S7. FACS analysis of KIT expression in the DLD-1 cells transfectedwith wild-type (Rab11-WT) or dominant-negative mutant form of Rab11 (Rab11-S25N). Figure S8. Effects of imatinibon CRC cells expressing KIT. FigureS9. DLD-1 cell number and invasion were increased after SCF and PMA treatment. FigureS10. Expression of SCF mRNA expression in CRC cell lines. Figure S11.Colon cancers expressing WT-KIT constantly generated activated KIT-SCF signaling as a result of KIT recycling in a condition of endogenous PKC-delta activation.

PDF file, 160K, Supplementary Table 1. Primer and siRNA sequences Supplementary Table 2. Clinicopathological characteristics of 250 colorectal cancers according to KIT expression.

Purpose: Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about the functional role of SCF-dependent KIT activation in colon cancer pathogenesis. We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis.Experimental Design: Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation.Results: We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated. We also showed the involvement of activated PKC-δ in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-δ and that expression of KIT is correlated with poor patient survival (P = 0.004).Conclusions: Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-δ–mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT. Clin Cancer Res; 19(18); 4961–71. ©2013 AACR.

Although the neuroinvasiveness of SARS-CoV-2 has been extensively studied, the correlation between virus infectivity and brain maturation remained unclear. Here, using human-induced pluripotent stem cells-derived three-dimensional cerebral organoids (CBOs), we present the first quantitative data for long-term kinetics of SARS-CoV-2 propagation in brain for 20 days post-infection. We showed that mature brains are more susceptible to SARS-CoV-2 than immature counterparts, evident from increased viral replication rate and higher TUNEL + cells proportion. Transcriptome profiling identified enhancement of corticogenesis and gliogenesis and indicated enrichments in translation machinery- and lipid metabolism-associated genes in mature brain, suggesting the major factors conferring the robust infectivity of SARS-CoV-2. The role of cholesterol in promoting viral replication was confirmed by the reduced number of infected cells in lipid lowering-drugs condition. Together, this study highlights that permissiveness of the brains to SARS-CoV-2 is greatly enhanced with their maturation and suggests cholesterol as a new target for suppressing viral replication.

As living liver transplantation has become a standard treatment method with a high success rate, many studies have investigated the experiences of living liver donors; however, their results have not been integrated. This qualitative meta-synthesis aimed to explore the life experiences of living liver donors to provide an in-depth understanding of meaningful common experiences. A comprehensive search on qualitative studies published in English or Korean was conducted in October 2021. The PRISMA statement was used for reporting each phase of the literature search, and MAXQDA2020 software was used for data analysis. Data synthesis was conducted using the three-step thematic synthesis method suggested by Thomas and Harden. Ten articles met the inclusion criteria. The analysis revealed five main themes: "Becoming an earnest donor," "Transitioning from a potential donor to an actual donor," "Difficulties in returning to normal life," "Re-examining the meaning of donation," and "Wishes for prospective donors." The study emphasizes that living liver donors need medical attention and intervention from multilateral perspectives as well as the need for systematic change in the society to enhance support for donors. This review provides comprehensive insights on how individuals became the living liver donor and the important aspects of living donation and other considerations in an integrated manner. Transplant teams, including nurses and coordinators, should have a comprehensive understanding of physical, psychological, and social experiences of donors ranging from decision-making to post donation health management.

PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.

Background People with disabilities are vulnerable to chronic diseases such as hypertension. In South Korea, over half of the population living with a physical disability suffer from hypertension. Understanding the typology of hypertension self-management patterns will assist with behavioural interventions for people with physical disabilities. Thus, this study aims to identify the typology of hypertension self-management behavioural patterns, the factors associated with the latent classes, and to recognise potential at-risk populations by comparing potential health outcomes among hypertensive adults with physical disabilities. Methods Data of 1551 participants were extracted from the 2017 National Survey of Disabled Persons. Latent classes were analysed using five indicators of self-management: smoking, alcohol consumption, physical activity, diet, and weight control. Determinants of self-management patterns, such as general characteristics, health-related factors, and social relationships, were identified using multinomial logistic regression. Further, health measures, such as health profile, psychological health, and patient experience, were compared. Results The following three latent classes were identified: “high self-management” group (40.8%), “harmful habitual behaviour” group (20.6%), and “inactive behaviour” group (38.6%). Compared with the high self-management group, the predictors of belonging to the harmful habitual behaviour group were being male, young, and single. Being female, employed, severely disabled, dependent, and unsatisfied with friendships were predictors of the inactive behaviour group. Those in the inactive behaviour group had a poor health-related quality of life, poor subjective health, depression, and unmet medical needs. Conclusions This study provides evidence that there are mutually exclusive subgroups of patients with hypertension regarding self-management patterns, identifies an array of predictive factors in each latent class membership, and distinguishes a high-risk group by comparing the health measures among patients with hypertension with physical disabilities. Analysing subgroups may assist in identifying and meeting the diverse needs of self-management support in hypertensive patients with physical disabilities.

Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC

Summary Because glioblastoma (GBM) exhibits high heterogeneity, it is desirable to use patient-derived cells from the first stage of screening for GBM drug discovery. Here, we describe a protocol to culture patient-derived GBM cells on the extracellular matrix-coated plates to allow high-throughput screening. Further, we detail approaches to identify the mechanism of action (MOA) of the selected effective drug through proteomics. This protocol will be useful for researchers interested in drug screening and the MOA of drugs. For complete details on the use and execution of this protocol, please refer to Nam et al. (2021)., Graphical abstract, Highlights • Methods for patient-derived GBM cell culture • Automated high-throughput screening methods using chemical libraries • Quantitative mass spectrometry to elucidate mechanism of action of drugs • Methods to perform data analysis from mass spectrometry, Because glioblastoma (GBM) exhibits high heterogeneity, it is desirable to use patient-derived cells from the first stage of screening for GBM drug discovery. Here, we describe a protocol to culture patient-derived GBM cells on the extracellular matrix-coated plates to allow high-throughput screening. Further, we detail approaches to identify the mechanism of action (MOA) of the selected effective drug through proteomics. This protocol will be useful for researchers interested in drug screening and the MOA of drugs.