Extracellular vesicle proteins as breast cancer biomarkers: Mass spectrometry-based analysis.

Extracellular vesicles (EVs) are membrane-surrounded vesicles released by various cell types into the extracellular microenvironment. Although EVs vary in size, biological function, and components, their importance in cancer progression and the potential use of EV molecular species to serve as novel cancer biomarkers have become increasingly evident. Cancer cells actively release EVs into surrounding tissues, which play vital roles in cancer progression and metastasis, including invasion and immune modulation. EVs released by cancer cells are usually chosen as a gateway in the search for biomarkers for cancer. In this review, we mainly focused on molecular profiling of EV protein constituents from breast cancer, emphasizing mass spectrometry (MS)-based proteomic approaches. To further investigate the potential use of EVs as a source of breast cancer biomarkers, we have discussed the use of these proteins as predictive marker candidates. Besides, we have also summarized the key characteristics of EVs as potential therapeutic targets in breast cancer and provided significant information on their implications in breast cancer development and progression. Information provided in this review may help understand the recent progress in understanding EV biology and their potential role as new noninvasive biomarkers as well as emerging therapeutic opportunities and associated challenges.

SIRT1 regulates the localization and stability of telomerase protein by direct interaction.

Telomerase reverse transcriptase (TERT) not only upholds telomeric equilibrium but also plays a pivotal role in multiple non-canonical cellular mechanisms, particularly in the context of aging, cancer, and genomic stability. Though depletion of SIRT1 in mouse embryonic fibroblasts has demonstrated telomere shortening, the impact of SIRT1 on enabling TERT to regulate telomeric homeostasis remains enigmatic. Here, we reveal that SIRT1 directly interacts with TERT, and promotes the nuclear localization and stability of TERT. Reverse transcriptase (RT) domain of TERT and N-terminus of SIRT1 mainly participated in their direct interaction. TERT, concomitantly expressed with intact SIRT1, exhibits nuclear localization, whereas TERT co-expressed with N-terminal-deleted SIRT1 remains in the cytosol. Furthermore, overexpression of SIRT1 enhances the nuclear localization and protein stability of TERT, akin to overexpression of deacetylase-inactive SIRT1, whereas N-terminal-deleted SIRT1 has no effect on TERT. These findings suggest a novel regulatory role of SIRT1 for TERT through direct interaction. This interaction provides new insights into the fields of aging, cancer, and genome stability governed by TERT and SIRT1.

Evaluation of derived concentration guideline levels reflecting the site-specific data for the soil of the Korea research reactor unit 1 and 2.

The purpose of this study is to evaluate the derived concentration guideline levels for unrestricted site reuse the Korea research reactor unit 1 and 2. Distribution coefficients for Co-60 and Sr-90 were derived, and site-specific values of the KRR soil were applied for the DCGLs for the seven target nuclide. The distribution coefficients of Co-60 and Sr-90 were 6,128 and 86.0 mL/g. The DCGLs derived from the dose by age group were 0.053 Bq/g for Co-60 and 45.0 Bq/g for H-3.

Risk of hematologic malignant neoplasms from head CT radiation in children and adolescents presenting with minor head trauma: a nationwide population-based cohort study.

OBJECTIVES: The carcinogenic risks of CT radiation in children and adolescents remain debated. We aimed to assess the carcinogenic risk of CTs performed in children and adolescents with minor head trauma. METHODS: In this nationwide population-based cohort study, we included 2,411,715 patients of age 0-19 with minor head trauma from 2009 to 2017. We excluded patients with elevated cancer risks or substantial past medical radiation exposure. Patients were categorized into CT-exposed or CT-unexposed group according to claim codes for head CT. The primary outcome was development of hematologic malignant neoplasms. Secondary outcomes included development of malignant solid neoplasms and benign neoplasms in the brain. We measured the incidence rate ratio (IRR) and incidence rate difference (IRD) using G-computation with Poisson regression adjusting for age, sex, hospital setting, and the type of head trauma. RESULTS: Hematologic malignant neoplasms developed in 100 of 216,826 patients during 1,303,680 person-years in the CT-exposed group and in 808 of 2,194,889 patients during 13,501,227 person-years in the CT-unexposed group. For hematologic malignant neoplasms, the IRR was 1.29 (95% CI, 1.03-1.60) and the IRD was 1.71 (95% CI, 0.04-3.37) per 100,000 person-years at risk. The majority of excess hematologic malignant neoplasms were leukemia (IRR, 1.40 [98.3% CI, 1.05-1.87]; IRD, 1.59 [98.3% CI, 0.02-3.16] per 100,000 person-years at risk). There were no between-group differences for secondary outcomes. CONCLUSIONS: Radiation exposure from head CTs in children and adolescents with minor head trauma was associated with an increased incidence of hematologic malignant neoplasms. CLINICAL RELEVANCE STATEMENT: Our study provides a quantitative grasp of the risk conferred by CT examinations in children and adolescents, thereby providing the basis for cost-benefit analyses and evidence-driven guidelines for patient triaging in head trauma. KEY POINTS: • This nationwide population-based cohort study showed that radiation exposure from head CTs in children and adolescents was associated with a higher incidence of hematologic malignant neoplasms. • The incidence rate of hematologic malignant neoplasms in the CT-exposed group was 29% higher than that in the CT-unexposed group (IRR, 1.29 [95% CI, 1.03-1.60]), and there were approximately 1.7 excess neoplasms per 100,000 person-years at risk in the CT-exposed group (IRD, 1.71 [0.04-3.37]). • Our study provides a quantified grasp of the risk conferred by CT examinations in children and adolescents, while controlling for biases observed in previous studies via specifying CT indication and excluding patients with predisposing conditions for cancer development.

Assessment of Radiation Doses to the General Public around Nuclear Power Plants Based on Representative Person Concept.

ABSTRACT: The International Commission on Radiological Protection recommended that the representative person concept should be used in radiation dose assessment of the general public to specify exposed individuals. The objective of this study is to assess radiation doses of the residents around nuclear power plants (NPPs) in relation to the introduction of the representative person concept. Critical group candidates and representative agro-livestock product producing areas were selected around a NPP site by considering radioactive effluents and regional meteorological data, geographical information, etc. A total of five exposure scenarios, including adult (non-fishery, fishery, and commuter), 10-y-old, and 1-y-old groups, were selected for the dose assessment. Generally, radiation doses were higher for 1-y-old, 10-y-old, and adult groups, in that sequence. There was no significant difference among the radiation doses by occupation in adult groups. Radiation dose results calculated by applying the representative person concept and dose assessment method currently used in Korea were compared. Application of the representative person concept results in lower radiation dose by 68.2% due to consideration of actual residential and agro-livestock product producing areas for the radiation dose assessment, by 13.3% due to the application method of habit data for dose calculation, and by 33.3% due to representative value of the dose results. Finally, considering all the factors above, radiation dose calculated by the current dose assessment method was 8.16 × 10 -2 mSv y -1 , while that calculated using the representative person concept was 1.40 × 10 -2 mSv y - 1 (82.8% lower). The results of this study can be used as reference data when introducing the representative person concept to the regulatory systems in Korea.

PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer.

Tumor necrosis factor superfamily (TNFSF) resistance contributes to the development and progression of tumors and resistance to various cancer therapies. Tumor-intrinsic alterations involved in the adaptation to the TNFSF response remain largely unknown. Here, we demonstrate that protein kinase C substrate 80K-H (PRKCSH) abundance in lung cancers boosts oncogenic IGF1R activation, leading to TNFSF resistance. PRKCSH abundance is correlated with IGF1R upregulation in lung cancer tissues. Specifically, PRKCSH interacts with IGF1R and extends its half-life. The PRKCSH-IGF1R axis in tumor cells impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, leading to an imbalance between cell death and survival. PRKCSH deficiency augmented the antitumor effects of natural killer (NK) cells, representative TNFSF effector cells, in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. Our data suggest that PRKCSH plays a critical role in TNFSF resistance and may be a potential target to improve the efficacy of NK cell-based cancer therapy.

Nitrosylation of ß2-Tubulin Promotes Microtubule Disassembly and Differentiated Cardiomyocyte Beating in Ischemic Mice.

BACKGROUND: Beating cardiomyocyte regeneration therapies have revealed as alternative therapeutics for heart transplantation. Nonetheless, the importance of nitric oxide (NO) in cardiomyocyte regeneration has been widely suggested, little has been reported concerning endogenous NO during cardiomyocyte differentiation. METHODS: Here, we used P19CL6 cells and a Myocardiac infarction (MI) model to confirm NO-induced protein modification and its role in cardiac beating. Two tyrosine (Tyr) residues of ß2-tubulin (Y106 and Y340) underwent nitrosylation (Tyr-NO) by endogenously generated NO during cardiomyocyte differentiation from pre-cardiomyocyte-like P19CL6 cells. RESULTS: Tyr-NO-ß2-tubulin mediated the interaction with Stathmin, which promotes microtubule disassembly, and was prominently observed in spontaneously beating cell clusters and mouse embryonic heart (E11.5d). In myocardial infarction mice, Tyr-NO-ß2-tubulin in transplanted cells was closely related with cardiac troponin-T expression with their functional recovery, reduced infarct size and thickened left ventricular wall. CONCLUSION: This is the first discovery of a new target molecule of NO, ß2-tubulin, that can promote normal cardiac beating and cardiomyocyte regeneration. Taken together, we suggest therapeutic potential of Tyr-NO-ß2-tubulin, for ischemic cardiomyocyte, which can reduce unexpected side effect of stem cell transplantation, arrhythmogenesis.

P176S Mutation Rewires Electrostatic Interactions That Alter Maspin Functionality.

Maspin is known to regress tumors by inhibiting angiogenesis; however, its roles have been reported to be context- and sequence-dependent. Various proteins and cofactors bind to maspin, possibly explaining its conflicting roles. Moreover, polymorphic forms of maspin have also been linked to tumor regression and survival; for instance, maspin with Ser at 176 (maspin-S176) promotes tumors, while maspin with Pro at 176 (maspin-P176) has opposing roles in cancer pathogenesis. With the help of long molecular dynamics simulations, a possible link between polymorphic forms and tumor progression has been established. First, maspin is dynamically stable with either amino acid at the 176 position. Second, differential contacts have been observed among various regions; third, these contacts have significantly altered the electrostatic energetics of various residues; finally, these altered electrostatics of maspin-S176 and maspin-P176 rewire the polar contacts that abolished the allosteric control of the protein. By combining these factors, the altered electrostatics substantially affect the localization and preference of maspin-binding partners, thus culminating in a different maspin-protein(cofactor)-interaction landscape that may have been manifested in previous conflicting reports. Here, the underlying reason has been highlighted and discussed, which may be helpful for better therapeutic manipulation.

Characterization of Lipid Alterations by Oncogenic PIK3CA Mutations Using Untargeted Lipidomics in Breast Cancer.

Lipids play crucial biological roles in health and disease, including in cancers. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal promoter of cell growth and proliferation in various types of cancer. The somatic mutations in PIK3CA, the gene coding for the catalytic subunit p110α of PI3K, are frequently present in cancer cells, including breast cancer. Although the most prominent mutants, represented by single amino acid substitutions in the helical domain in exon 9 (E545K) and the kinase domain in exon 20 (H1047R) are known to cause a gain of PI3K function, activate AKT signaling and induce oncogenic transformation, the effect of these mutations on cellular lipid profiles has not been studied. We carried out untargeted lipidomics using liquid chromatography-tandem mass spectrometry to detect the lipid alterations in mammary gland epithelial MCF10A cells with isogenic knockin of these mutations. A total of 536 species of lipids were analyzed. We found that the levels of monosialogangliosides, signaling molecules known to enhance cell motility through PI3K/AKT pathway, were significantly higher in both mutants. In addition, triglycerides and ceramides, lipid molecules known to be involved in promoting lipid droplet production, cancer cell migration and invasion, were increased, whereas lysophosphatidylcholines and phosphatidylcholines that are known to inhibit cancer cell motility were decreased in both mutants. Our results provide novel insights into a potential link between altered lipid profile and carcinogenesis caused by the PIK3CA hotspot mutations. In addition, we suggest untargeted lipidomics offers prospects for precision/personalized medicine by unpacking new molecular substrates of cancer biology.

ECPAS/Ecm29-mediated 26S proteasome disassembly is an adaptive response to glucose starvation.

The 26S proteasome comprises 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in cells exist as free 20S complexes; however, our mechanistic understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation uncouples 26S holoenzymes into 20S and 19S subcomplexes. Subcomplex affinity purification and quantitative mass spectrometry reveal that Ecm29 proteasome adaptor and scaffold (ECPAS) mediates this structural remodeling. The loss of ECPAS abrogates 26S dissociation, reducing degradation of 20S proteasome substrates, including puromycylated polypeptides. In silico modeling suggests that ECPAS conformational changes commence the disassembly process. ECPAS is also essential for endoplasmic reticulum stress response and cell survival during glucose starvation. In vivo xenograft model analysis reveals elevated 20S proteasome levels in glucose-deprived tumors. Our results demonstrate that the 20S-19S disassembly is a mechanism adapting global proteolysis to physiological needs and countering proteotoxic stress.

Protective effects of an electrophilic metabolite of docosahexaenoic acid on UVB-induced oxidative cell death, dermatitis, and carcinogenesis.

Docosahexaenoic acid (DHA), a representative omega-3 (ω-3) polyunsaturated fatty acids, undergoes metabolism to produce biologically active electrophilic species. 17-Oxo-DHA is one such reactive metabolite generated from DHA by cyclooxygenase-2 and dehydrogenase in activated macrophages. The present study was aimed to investigate the effects of 17-oxo-DHA on ultraviolet B (UVB)-induced oxidative stress, inflammation, and carcinogenesis in mouse skin. UVB-induced epidermal cell death was ameliorated by topically applied 17-oxo-DHA. Topical application of 17-oxo-DHA onto hairless mouse skin inhibited UVB-induced phosphorylation of the proinflammatory transcription factor, STAT3 on tyrosine 705 (Tyr705). The 17-oxo-DHA treatment also reduced the levels of oxidative stress markers, 4-hydroxynonenal-modified protein, malondialdehyde, and 8-oxo-2'-deoxyguanosine. The protective effects of 17-oxo-DHA against oxidative damage in UVB-irradiated mouse skin were associated with activation of Nrf2. 17-Oxo-DHA enhanced the engulfment of apoptotic JB6 cells by macrophages, which was related to the increased expression of the scavenger receptor CD36. The 17-oxo-DHA-mediated potentiation of efferocytic activity of macrophages was attenuated by the pharmacologic inhibition or knockout of Nrf2. The pretreatment with 17-oxo-DHA reduced the UVB-induced skin carcinogenesis and tumor angiogenesis. It was also confirmed that 17-oxo-DHA treatment significantly inhibited the phosphorylation of the Tyr705 residue of STAT3 and decreased the expression of its target proteins in cutaneous papilloma. In conclusion, 17-oxo-DHA protects against UVB-induced oxidative cell death, dermatitis, and carcinogenesis. These effects were associated with inhibition of STAT3-mediated proinflammatory signaling and also activation of Nrf2 with subsequent upregulation of antioxidant and anti-inflammatory gene expression.

8-paradol from ginger exacerbates PINK1/Parkin mediated mitophagy to induce apoptosis in human gastric adenocarcinoma.

Gastric cancer (GC) occurs in the gastric mucosa, and its high morbidity and mortality make it an international health crisis. Therefore, novel drugs are needed for its treatment. The use of natural products and their components in cancer treatments has shown promise. Therefore, this study aimed to evaluate the effect of 8-paradol, a phenolic compound isolated from ginger (Zingiber officinale Roscoe), on GC and determine its underlying mechanisms of action. In this study, repeated column chromatography was conducted on ginger EtOH extract to isolate gingerol and its derivatives. The cytotoxicity of the eight ginger compounds underwent a (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) tetrazolium reduction (MTT) assay. 8-paradol showed the most potent cytotoxicity effect among the isolated ginger compounds. The underlying mechanism by which 8-paradol regulated specific proteins in AGS cells was evaluated by proteomic analysis. To validate the predicted mechanisms, AGS cells and thymus-deficient nude mice bearing AGS xenografts were used as in vitro and in vivo models of GC, respectively. The results showed that the 8-paradol promoted PINK1/Parkin-associated mitophagy, mediating cell apoptosis. Additionally, the inhibition of mitophagy by chloroquine (CQ) ameliorated 8-paradol-induced mitochondrial dysfunction and apoptosis, supporting a causative role for mitophagy in the 8-paradol-induced anticancer effect. Molecular docking results revealed the molecular interactions between 8-paradol and mitophagy-/ apoptosis-related proteins at the atomic level. Our study provides strong evidence that 8-paradol could act as a novel potential therapeutic agent to suppress the progression of GC by targeting mitophagy pathway.

Paraoxonase-2 contributes to promoting lipid metabolism and mitochondrial function via autophagy activation.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent immuno-metabolic disease that can progress to hepatic cirrhosis and cancer. NAFLD pathogenesis is extremely complex and is characterized by oxidative stress, impaired mitochondrial function and lipid metabolism, and cellular inflammation. Thus, in-depth research on its underlying mechanisms and subsequent investigation into a potential drug target that has overarching effects on these features will help in the discovery of effective treatments for NAFLD. Our study examines the role of endogenous paraoxonase-2 (PON2), a membrane protein with reported antioxidant activity, in an in vitro cell model of NAFLD. We found that the hepatic loss of PON2 activity aggravated steatosis and oxidative stress under lipotoxic conditions, and our transcriptome analysis revealed that the loss of PON2 disrupts the activation of numerous functional pathways closely related to NAFLD pathogenesis, including mitochondrial respiratory capacity, lipid metabolism, and hepatic fibrosis and inflammation. We found that PON2 promoted the activation of the autophagy pathway, specifically the mitophagy cargo sequestration, which could potentially aid PON2 in alleviating oxidative stress, mitochondrial dysfunction, lipid accumulation, and inflammation. These results provide a mechanistic foundation for the prospect of PON2 as a drug target, leading to the development of novel therapeutics for NAFLD.

Emerging role of LETM1/GRP78 axis in lung cancer.

The selective autophagy of damaged mitochondria is called mitophagy. Mitochondrial dysfunction, mitophagy, and apoptosis have been suggested to be interrelated in various human lung carcinomas. Leucine zipper EF-hand-containing transmembrane protein-1 (LETM1) was cloned in an attempt to identify candidate genes for Wolf-Hirschhorn syndrome. LETM1 plays a role in mitochondrial morphology, ion homeostasis, and cell viability. LETM1 has also been shown to be overexpressed in different human cancer tissues, including lung cancer. In the current study, we have provided clear evidence that LETM1 acts as an anchoring protein for the mitochondria-associated ER membrane (MAM). Fragmented mitochondria have been found in lung cancer cells with LETM1 overexpression. In addition, a reduction of mitochondrial membrane potential and significant accumulation of microtubule-associated protein 1 A/1B-light chain 3 punctate, which localizes with Red-Mito, was found in LETM1-overexpressed cells, suggesting that mitophagy is upregulated in these cells. Interestingly, glucose-regulated protein 78 kDa (GRP78; an ER chaperon protein) and glucose-regulated protein 75 kDa (GRP75) were posited to interact with LETM1 in the immunoprecipitated LETM1 of H460 cells. This interaction was enhanced in cells treated with carbonyl cyanide m-chlorophenylhydrazone, a chemical mitophagy inducer. Treatment of cells with honokiol (a GRP78 inhibitor) blocked LETM1-mediated mitophagy, and CRISPR/Cas9-mediated GRP75 knockout inhibited LETM1-induced autophagy. Thus, GRP78 interacts with LETM1. Taken together, these observations support the notion that the complex formation of LETM1/GRP75/GRP78 might be an important step in MAM formation and mitophagy, thus regulating mitochondrial quality control in lung cancer.

Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis.

Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.

FCH domain only 1 (FCHo1), a potential new biomarker for lung cancer.

Lung carcinoma is the main reason for cancer-associated deaths in the world. In a previous study, FCH domain only 1 (FCHo1) which is managed by protein kinase B (AKT), was shown to be activated in lung cancer. FCHo1 knockdown has previously been shown to cause cell death in lung cancer. However, the specific roles of FCHo1 in lung carcinoma remain elusive. Herein, we propose that FCHo1's intracellular mechanism targets the G1 to S phase transition, following the M phase. We demonstrated that F-BAR and mu homology domains exist separately in human lung tissues and that one truncated form is not detected in patients with lung cancer. Furthermore, quantitative global proteome analysis of FCHo1 indicated that the inhibition of G1/S phase transition and FCHo1 RNAi led to the death of cells in the G1/S phase. Noninvasive viral aerosol-mediated delivery of FCHo1 shRNA suppressed cancer progression in mice with non-small-cell lung cancer (NSCLC), suggesting that the delivery of FCHo1 shRNA could be a meaningful therapeutic strategy in lung cancer. Additional studies are needed to make clear the detailed mechanism of action of FCHo1.

Crosstalk Between the Immune System and Plant-Derived Nanovesicles: A Study of Allergen Transporting.

Background: Nanometer-sized membrane-surrounded vesicles from different parts of plants including fruits are gaining increasing attention due to their anti-inflammatory and anticancer effects demonstrated by in vitro and in vivo studies, and as nanovectors for molecular delivery of exogenous substances. These nanomaterials are very complex and contain a diverse arsenal of bioactive molecules, such as nucleic acids, proteins, and lipids. Our knowledge about the transport of allergens in vesicles isolated from plant food is limited today. Methods: Here, to investigate the allergenicity of strawberry-derived microvesicles (MVs), nanovesicles (NVs), and subpopulations of NV, we have set up a multidisciplinary approach. The strategy combines proteomics-based protein identification, immunological investigations, bioinformatics, and data mining to gain biological insights useful to evaluate the presence of potential allergens and the immunoglobulin E (IgE) inhibitory activity of vesicle preparations. Results: Immunological test showed that several proteins of strawberry-derived vesicles compete for IgE binding with allergens spotted on the FABER biochip. This includes the known strawberry allergens Fra a 1, Fra a 3, and Fra a 4, and also other IgE-binding proteins not yet described as allergens in this food, such as gibberellin-regulated proteins, 2S albumin, pectate lyase, and trypsin inhibitors. Proteomics identified homologous sequences of the three strawberry allergens and their isoforms in total protein extract (TPE) but only Fra a 1 and Fra a 4 in the vesicle samples. Label-free quantitative proteomic analysis revealed no significant enrichment of these proteins in strawberry vesicles with respect to TPE. Conclusion: Immunological tests and bioinformatics analysis of proteomics data sets revealed that MVs and NVs isolated from strawberries can carry functional allergens their isoforms as well as proteins potentially allergenic based on their structural features. This should be considered when these new nanomaterials are used for human nutraceutical or biomedical applications.

Rapid Androgen-Responsive Proteome Is Involved in Prostate Cancer Progression.

Androgen exerts its functions by binding with an androgen receptor (AR). It can activate many signaling pathways that are important to the progression of castration-resistant prostate cancer (CRPC). Here, we characterized the rapid proteomic changes seen at 5, 15, 30, and 60 min after the androgen treatment of VCaP cells via the tandem mass tag (TMT) labeling strategy. A total of 5529 proteins were successfully identified and quantified. Dynamic time profiling of protein expression patterns allowed us to identify five protein clusters involved in various stages of androgen-initiated signal transmission and processing. More details of protein functions and localization patterns, and our elucidation of an AR-interacting protein network, were obtained. Finally, we validated the expression level of AR-regulated proteins known to be significantly regulated in CRPC patients using the mouse xenograft model and patient samples. Our work offers a systematic analysis of the rapid proteomic changes induced by androgen and provides a global view of the molecular mechanisms underlying CRPC progression.

Occupational Radiation Exposure and Validity of National Dosimetry Registry among Korean Interventional Radiologists.

The national dose registry (NDR) contains essential information to help protect radiation workers from radiation-related health risks and to facilitate epidemiological studies. However, direct validation of the reported doses has not been considered. We investigated the validity of the NDR with a personal dosimeter monitoring conducted among Korean interventional radiologists. Among the 56 interventional radiologists, NDR quarterly doses were compared with actively monitored personal thermoluminescent dosimeter (TLD) doses as standard measures of validation. We conducted analyses with participants categorized according to compliance with TLD badge-wearing policies. A correlation between actively monitored doses and NDR doses was low (Spearman ρ = 0.06), and the mean actively monitored dose was significantly higher than the mean NDR dose (mean difference 0.98 mSv) in all participants. However, interventional radiologists who wore badges irregularly showed a large difference between actively monitored doses and NDR doses (mean difference 2.39 mSv), and participants who wore badges regularly showed no apparent difference between actively monitored doses and NDR doses (mean difference 0.26 mSv). This study indicated that NDR data underestimate the actual occupational radiation exposure, and the validity of these data varies according to compliance with badge-wearing policies. Considerable attention is required to interpret and utilize NDR data based on radiation workers' compliance with badge-wearing policies.