Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea.

BACKGROUND: Therapy-related myeloid neoplasm (T-MN) rarely occurs among cancer survivors, and was characterized by poor prognosis. T-MN has germline predisposition in a considerable proportion. Here, clinical characteristics and germline/somatic variant profiles in T-MN patients were investigated, and the findings were compared with those of previous studies. METHODS: A review of medical records, cytogenetic study, targeted sequencing by next-generation sequencing, and survival analysis were performed on 53 patients with T-MN at a single institution in Korea. RESULTS: The patients were relatively younger compared to T-MN patients in other studies. Our T-MN patients showed a high frequency of complex karyotypes, -5/del(5q), and -7/del(7q), which was similar to the Japanese study group but higher than the Australian study group. The most common primary disease was non-Hodgkin lymphoma, followed by breast cancer. The detailed distributions of primary diseases were different across study groups. Seven patients (13.2%) harbored deleterious presumed/potential germline variants in cancer predisposition genes (CPG) such as BRIP1, CEBPA, DDX41, FANCM, NBN, NF1, and RUNX1. In the somatic variant profile, TP53 was the most frequently mutated gene, which was consistent with the previous studies about T-MN. However, the somatic variant frequency in our study group was lower than in other studies. Adverse factors for overall survival were male sex, older age, history of previous radiotherapy, previous longer cytotoxic therapy, and -5/del(5q). CONCLUSION: The findings of our study corroborate important information about T-MN patients. As well as a considerable predisposition to CPG, the clinical characteristics and somatic variant profile showed distinctive patterns. Germline variant testing should be recommended for T-MN patients. If the T-MN patients harbor pathogenic germline variants, the family members for stem cell donation should be screened for carrier status through germline variant testing to avoid donor-derived myeloid neoplasm. For the prediction of the prognosis in T-MN patients, sex, age, past treatment history, and cytogenetic findings can be considered.

Biocidal products: Opportunities in risk assessment, management, and communication.

In the coronavirus disease 2019 era, biocidal products are increasingly used for controlling harmful organisms, including microorganisms. However, assuring safety against adverse health effects is a critical issue from a public health standpoint. This study aimed to provide an overview of key aspects of risk assessment, management, and communication that ensure the safety of biocidal active ingredients and products. The inherent characteristics of biocidal products make them effective against pests and pathogens; however, they also possess potential toxicities. Therefore, public awareness regarding both the beneficial and potential adverse effects of biocidal products needs to be increased. Biocidal active ingredients and products are regulated under specific laws: the Federal Insecticide, Fungicide, and Rodenticide Act for the United States; the European Union (EU) Biocidal Products Regulation for the EU; and the Consumer Chemical Products and Biocide Safety Management Act for the Republic of Korea. Risk management also needs to consider the evidence of enhanced sensitivity to toxicities in individuals with chronic diseases, given the increased prevalence of these conditions in the population. This is particularly important for post-marketing safety assessments of biocidal products. Risk communication conveys information, including potential risks and risk-reduction measures, aimed at managing or controlling health or environmental risks. Taken together, the collaborative effort of stakeholders in risk assessment, management, and communication strategies is critical to ensuring the safety of biocidal products sold in the market as these strategies are constantly evolving.

Facet-Dependent Passivation for Efficient Perovskite Solar Cells.

Understanding the interplay between the surface structure and the passivation materials and their effects associated with surface structure modification is of fundamental importance; however, it remains an unsolved problem in the perovskite passivation field. Here, we report a surface passivation principle for efficient perovskite solar cells via a facet-dependent passivation phenomenon. The passivation process selectively occurs on facets, which is observed with various post-treatment materials with different functionality, and the atomic arrangements of the facets determine the alignments of the passivation layers. The profound understanding of facet-dependent passivation leads to the finding of 2-amidinopyridine hydroiodide as the material for a uniform and effective passivation on both (100) and (111) facets. Consequently, we achieved perovskite solar cells with an efficiency of 25.10% and enhanced stability. The concept of facet-dependent passivation can provide an important clue on unidentified passivation principles for perovskite materials and a novel means to enhance the performance and stability of perovskite-based devices.

Behavioral evidence for geomagnetic imprinting and transgenerational inheritance in fruit flies.

Certain long-distance migratory animals, such as salmon and sea turtles, are thought to imprint on the magnetic field of their natal area and to use this information to help them return as adults. Despite a growing body of indirect support for such imprinting, direct experimental evidence thereof remains elusive. Here, using the fruit fly as a magnetoreceptive model organism, we demonstrate that exposure to a specific geographic magnetic field during a critical period of early development affected responses to a matching magnetic field gradient later in life. Specifically, hungry flies that had imprinted on a specific magnetic field from 1 of 3 widely separated geographic locations responded to the imprinted field, but not other magnetic fields, by moving downward, a geotactic behavior associated with foraging. This same behavior occurred spontaneously in the progeny of the next generation: female progeny moved downward in response to the field on which their parents had imprinted, whereas male progeny did so only in the presence of these females. These results represent experimental evidence that organisms can learn and remember a magnetic field to which they were exposed during a critical period of development. Although the function of the behavior is not known, one possibility is that imprinting on the magnetic field of a natal area assists flies and their offspring in recognizing locations likely to be favorable for foraging and reproduction.

Deep Learning-Based Diagnostic System for Velopharyngeal Insufficiency Based on Videofluoroscopy in Patients With Repaired Cleft Palates.

Velopharyngeal insufficiency (VPI), which is the incomplete closure of the velopharyngeal valve during speech, is a typical poor outcome that should be evaluated after cleft palate repair. The interpretation of VPI considering both imaging analysis and perceptual evaluation is essential for further management. The authors retrospectively reviewed patients with repaired cleft palates who underwent assessment for velopharyngeal function, including both videofluoroscopic imaging and perceptual speech evaluation. The final diagnosis of VPI was made by plastic surgeons based on both assessment modalities. Deep learning techniques were applied for the diagnosis of VPI and compared with the human experts' diagnostic results of videofluoroscopic imaging. In addition, the results of the deep learning techniques were compared with a speech pathologist's diagnosis of perceptual evaluation to assess consistency with clinical symptoms. A total of 714 cases from January 2010 to June 2019 were reviewed. Six deep learning algorithms (VGGNet, ResNet, Xception, ResNext, DenseNet, and SENet) were trained using the obtained dataset. The area under the receiver operating characteristic curve of the algorithms ranged between 0.8758 and 0.9468 in the hold-out method and between 0.7992 and 0.8574 in the 5-fold cross-validation. Our findings demonstrated the deep learning algorithms performed comparable to experienced plastic surgeons in the diagnosis of VPI based on videofluoroscopic velopharyngeal imaging.

Protein interactome and cell-type expression analyses reveal that cytoplasmic FMR1-interacting protein 1 (CYFIP1), but not CYFIP2, associates with astrocytic focal adhesion.

The two members of the cytoplasmic FMR1-interacting protein family, CYFIP1 and CYFIP2, are evolutionarily conserved multifunctional proteins whose defects are associated with distinct types of brain disorders. Even with high sequence homology between CYFIP1 and CYFIP2, several lines of evidence indicate their different functions in the brain; however, the underlying mechanisms remain largely unknown. Here, we performed reciprocal immunoprecipitation experiments using CYFIP1-2 × Myc and CYFIP2-3 × Flag knock-in mice and found that CYFIP1 and CYFIP2 are not significantly co-immunoprecipitated with each other in the knock-in brains compared with negative control wild-type (WT) brains. Moreover, CYFIP1 and CYFIP2 showed different size distributions by size-exclusion chromatography of WT mouse brains. Specifically, mass spectrometry-based analysis of CYFIP1-2 × Myc knock-in brains identified 131 proteins in the CYFIP1 interactome. Comparison of the CYFIP1 interactome with the previously identified brain region- and age-matched CYFIP2 interactome, consisting of 140 proteins, revealed only eight common proteins. Investigations using single-cell RNA-sequencing databases suggested non-neuronal cell- and neuron-enriched expression of Cyfip1 and Cyfip2, respectively. At the protein level, CYFIP1 was detected in both neurons and astrocytes, while CYFIP2 was detected only in neurons, suggesting the predominant expression of CYFIP1 in astrocytes. Bioinformatic characterization of the CYFIP1 interactome, and co-expression analysis of Cyfip1 with astrocytic genes, commonly linked CYFIP1 with focal adhesion proteins. Immunocytochemical analysis and proximity ligation assay suggested partial co-localization of CYFIP1 and focal adhesion proteins in cultured astrocytes. Together, these results suggest a CYFIP1-specific association with astrocytic focal adhesion, which may contribute to the different brain functions and dysfunctions of CYFIP1 and CYFIP2. Cover Image for this issue: https://doi.org/10.1111/jnc.15410.

Current trends in read-across applications for chemical risk assessments and chemical registrations in the Republic of Korea.

Read-across, an alternative approach for hazard assessment, has been widely adopted when in vivo data are unavailable for chemicals of interest. Read-across is enabled via in silico tools such as quantitative structure activity relationship (QSAR) modeling. In this study, the current status of structure activity relationship (SAR)-based read-across applications in the Republic of Korea (ROK) was examined considering both chemical risk assessments and chemical registrations from different sectors, including regulatory agencies, industry, and academia. From the regulatory perspective, the Ministry of Environment (MOE) established the Act on Registration and Evaluation of Chemicals (AREC) in 2019 to enable registrants to submit alternative data such as information from read-across instead of in vivo data to support hazard assessment and determine chemical-specific risks. Further, the Ministry of Food and Drug Safety (MFDS) began to consider read-across approaches for establishing acceptable intake (AI) limits of impurities occurring during pharmaceutical manufacturing processes under the ICH M7 guideline. Although read-across has its advantages, this approach also has limitations including (1) lack of standardized criteria for regulatory acceptance, (2) inconsistencies in the robustness of scientific evidence, and (3) deficiencies in the objective reliability of read-across data. The application and acceptance rate of read-across may vary among regulatory agencies. Therefore, sufficient data need to be prepared to verify the hypothesis that structural similarities might lead to similarities in properties of substances (between source and target chemicals) prior to adopting a read-across approach. In some cases, additional tests may be required during the registration process to clarify long-term effects on human health or the environment for certain substances that are data deficient. To improve the quality of read-across data for regulatory acceptance, cooperative efforts from regulatory agencies, academia, and industry are needed to minimize limitations of read-across applications.

Read-across approaches: current applications and regulatory acceptance in Korea, Japan, and China.

The aim of this paper was to investigate the current status of read-across approaches in the Republic of Korea, Japan, and China in terms of applications and regulatory acceptance. In the Republic of Korea, over the last 6 years, approximately 8% of safety data records used for chemical registrations were based upon read-across, and a guideline published on the use of read-across results in 2017. In Japan, read-across is generally accepted for screening hazard classification of toxicological endpoints according to the Chemical Substances Control Law (CSCL). In China, read-across data, along with data from other animal alternatives are accepted as a data source for chemical registrations, but could be only considered when testing is not technically feasible. At present, read-across is not widely used for chemical registrations and regulatory acceptance of read-across may differ among countries in Asia. With consideration of the advantages and limitations of read-across, it is expected that read-across may soon gradually be employed in Asian countries. Thus, regulatory agencies need to prepare for this progression.

Strong SARS-CoV-2 Antibody Response After Booster Dose of BNT162b2 mRNA Vaccines in Uninfected Healthcare Workers.

Despite strict guidelines for coronavirus disease 2019 (COVID-19), South Korea is facing its fourth pandemic wave. In this study, by using an automated electrochemiluminescence immunoassay assay, we tracked anti-spike protein receptor-binding domain (anti-S-RBD) antibody titer from the second dose to 2 weeks after the booster dose vaccination. After the second dose, 234 participants had their anti-S-RBD antibody titers decrease over time. We also showed the booster dose (the third dose) increased antibody titer by average 14 (min-max, 2-255)-fold higher compared to the second dose among the 211-booster group participants, therefore, the booster dose could be recommended for low responders to the second dose. Our findings showed a distinct humoral response after booster doses of BNT162b2 mRNA vaccines and may provide further evidence of booster vaccination efficacy. These data will also be helpful in vaccination policy decisions that determine the need for the booster dose.

Applicability Evaluation of Surface and Sub-Surface Defects for Railway Wheel Material Using Induced Alternating Current Potential Drops.

The majority of catastrophic wheelset failures are caused by surface opening fatigue cracks in either the wheel tread or wheel inner. Since failures in railway wheelsets can cause disasters, regular inspections to check for defects in wheels and axles are mandatory. Currently, ultrasonic testing, acoustic emissions, and the eddy current testing method are regularly used to check railway wheelsets in service. Yet, in many cases, despite surface and subsurface defects of the railroad wheels developing, the defects are not clearly detected by the conventional non-destructive inspection system. In the present study, a new technique was applied to the detection of surface and subsurface defects in railway wheel material. The results indicate that the technique can detect surface and subsurface defects of railway wheel specimens using the distribution of the alternating current (AC) electromagnetic field. In the wheelset cases presented, surface cracks with depths of 0.5 mm could be detected using this method.

PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance.

PSMD14, a subunit of the 19S regulatory particles of the 26S proteasome, was recently identified as a potential prognostic marker and therapeutic target in diverse human cancers. Here, we show that the silencing and pharmacological blockade of PSMD14 in MDA-MB 435S breast cancer cells induce paraptosis, a non-apoptotic cell death mode characterized by extensive vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. The PSMD14 inhibitor, capzimin (CZM), inhibits proteasome activity but differs from the 20S proteasome subunit-inhibiting bortezomib (Bz) in that it does not induce aggresome formation or Nrf1 upregulation, which underlie Bz resistance in cancer cells. In addition to proteasome inhibition, the release of Ca2+ from the ER into the cytosol critically contributes to CZM-induced paraptosis. Induction of paraptosis by targeting PSMD14 may provide an attractive therapeutic strategy against cancer cells resistant to proteasome inhibitors or pro-apoptotic drugs.

Enhanced Tumor Imaging Using Glucosamine-Conjugated Polyacrylic Acid-Coated Ultrasmall Gadolinium Oxide Nanoparticles in Magnetic Resonance Imaging.

Owing to a higher demand for glucosamine (GlcN) in metabolic processes in tumor cells than in normal cells (i.e., GlcN effects), tumor imaging in magnetic resonance imaging (MRI) can be highly improved using GlcN-conjugated MRI contrast agents. Here, GlcN was conjugated with polyacrylic acid (PAA)-coated ultrasmall gadolinium oxide nanoparticles (UGONs) (davg = 1.76 nm). Higher positive (brighter or T1) contrast enhancements at various organs including tumor site were observed in human brain glioma (U87MG) tumor-bearing mice after the intravenous injection of GlcN-PAA-UGONs into their tail veins, compared with those obtained with PAA-UGONs as control, which were rapidly excreted through the bladder. Importantly, the contrast enhancements of the GlcN-PAA-UGONs with respect to those of the PAA-UGONs were the highest in the tumor site owing to GlcN effects. These results demonstrated that GlcN-PAA-UGONs can serve as excellent T1 MRI contrast agents in tumor imaging via GlcN effects.

Highly Sensitive Immuno-CRISPR Assay for CXCL9 Detection.

CRISPR-based detection of target DNA or RNA exploits a dual function, including target sequence-specific recognition followed by trans-cleavage activity of a collateral ssDNA linker between a fluorophore (F) and a quencher (Q), which amplifies a fluorescent signal upon cleavage. In this work, we have extended such dual functionality in a modified immunoassay format to detect a target protein, CXCL9, which is markedly elevated in the urine of kidney transplant recipients undergoing acute rejection episodes. To establish the "immuno-CRISPR" assay, we used anti-CXCL9 antibody-DNA barcode conjugates to target CXCL9 and amplify fluorescent signals via Cas12a-based trans-cleavage activity of FQ reporter substrates, respectively, and in the absence of an isothermal amplification step. To enhance detection sensitivity, the DNA barcode system was engineered by introducing multiple Cas12a recognition sites. Use of biotinylated DNA barcodes enabled self-assembly onto streptavidin (SA) to generate SA-DNA barcode complexes to increase the number and density of Cas12a recognition sites attached to biotinylated anti-CXCL9 antibody. As a result, we improved the rate of CXCL9 detection approximately 8-fold when compared to the use of a monomeric DNA barcode. The limit of detection (LOD) for CXCL9 using the immuno-CRISPR assay was 14 pg/mL, which represented an ∼7-fold improvement when compared to traditional HRP-based ELISA. Selectivity was shown with a lack of crossover reactivity with the related chemokine CXCL1. Finally, we successfully evaluated the presence of CXCL9 in urine samples from 11 kidney transplant recipients using the immuno-CRISPR assay, resulting in 100% accuracy to clinical CXCL9 determination and paving the way for use as a point-of-care noninvasive biomarker for the detection of kidney transplant rejection.

Correction: LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons.

[This corrects the article DOI: 10.1371/journal.pbio.1002516.].

Chemophobia and knowledge of toxicological principles in South-Korea: perceptions of trace chemicals in consumer products.

Many consumer products are manufactured or synthesized from chemicals. However, consumers may be hesitant to purchase consumer products that are perceived as synthetic or derived with chemical substances. Prior studies suggested a preference for chemicals of natural origin and an irrational fear of synthetic chemicals, a phenomenon that is referred to as chemophobia. The aim of this study was two-fold as follows: to (1) investigate the levels of knowledge with respect to toxicological principles, chemophobia, and trust in stakeholders in South Korea and (2) experimentally test the effect of information provision on acceptance and willingness-to-buy for the specific case of trace chemicals in consumer products. For this purpose, an online survey and experiment was conducted with consumers in South Korea. Data suggested that in South Korea chemophobia correlated with an individual's knowledge regarding toxicological principles. Accordingly, a small intervention providing information on the dose-response mechanism increased consumers' acceptance of the presence of trace chemicals and subsequent willingness to purchase the products in this study. In conclusion, this investigation stresses the importance of educating the public regarding basic principles of toxicology to avoid chemophobia, while simultaneously discussing other factors that need to be taken into account such as attitudes and trust in communicators.

Sea Fog Dissipation Prediction in Incheon Port and Haeundae Beach Using Machine Learning and Deep Learning.

Sea fog is a natural phenomenon that reduces the visibility of manned vehicles and vessels that rely on the visual interpretation of traffic. Fog clearance, also known as fog dissipation, is a relatively under-researched area when compared with fog prediction. In this work, we first analyzed meteorological observations that relate to fog dissipation in Incheon port (one of the most important ports for the South Korean economy) and Haeundae beach (the most populated and famous resort beach near Busan port). Next, we modeled fog dissipation using two separate algorithms, classification and regression, and a model with nine machine learning and three deep learning techniques. In general, the applied methods demonstrated high prediction accuracy, with extra trees and recurrent neural nets performing best in the classification task and feed-forward neural nets in the regression task.

Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease.

Mitochondria play many important biological roles, including ATP production, lipid biogenesis, ROS regulation, and calcium clearance. In neurons, the mitochondrion is an essential organelle for metabolism and calcium homeostasis. Moreover, mitochondria are extremely dynamic and able to divide, fuse, and move along microtubule tracks to ensure their distribution to the neuronal periphery. Mitochondrial dysfunction and altered mitochondrial dynamics are observed in a wide range of conditions, from impaired neuronal development to various neurodegenerative diseases. Novel imaging techniques and genetic tools provide unprecedented access to the physiological roles of mitochondria by visualizing mitochondrial trafficking, morphological dynamics, ATP generation, and ultrastructure. Recent studies using these new techniques have unveiled the influence of mitochondria on axon branching, synaptic function, calcium regulation with the ER, glial cell function, neurogenesis, and neuronal repair. This review provides an overview of the crucial roles played by mitochondria in the CNS in physiological and pathophysiological conditions.

Association Between Postoperative Body Temperature and All-Cause Mortality After Off-Pump Coronary Artery Bypass Graft Surgery: A Retrospective Observational Study.

BACKGROUND: Inadvertent perioperative hypothermia is common in patients undergoing off-pump coronary artery bypass grafting (OPCAB). We investigated the association between early postoperative body temperature and all-cause mortality in patients undergoing OPCAB. METHODS: We reviewed the electronic medical records of 1714 patients who underwent OPCAB (median duration of follow-up, 47 months). Patients were divided into 4 groups based on body temperature at the time of intensive care unit admission after surgery (moderate-to-severe hypothermia, <35.5°C; mild hypothermia, 35.5°C-36.5°C; normothermia, 36.5°C-37.5°C; and hyperthermia, ≥37.5°C). Cox proportional hazards models were used to assess the association between body temperature and all-cause mortality. The association between early postoperative changes in body temperature and all-cause mortality was also assessed by dividing the patients into 4 categories according to the body temperature measured at postoperative intensive care unit admission and the average body temperature during the first 3 postoperative days. RESULTS: Compared to the normothermia group, the adjusted hazard ratios of all-cause mortality were 2.030 (95% confidence interval, 1.407-2.930) in the moderate-to-severe hypothermia group and 1.445 (95% confidence interval, 1.113-1.874) in the mild hypothermia group. Patients who were hypothermic at postoperative intensive care unit admission but attained normothermia thereafter were at a lower risk of all-cause mortality compared to patients who did not regain normothermia (adjusted hazard ratio, 0.631; 95% confidence interval, 0.453-0.878), while they were still at a higher risk of all-cause mortality than those who were consistently normothermic (adjusted hazard ratio, 1.435; 95% confidence interval, 1.090-1.890). CONCLUSIONS: Even mild early postoperative hypothermia was associated with all-cause mortality after OPCAB. Patients who regained normothermia postoperatively were at lower risk of all-cause mortality compared to those who did not.

Risk communication for labeling all ingredients in consumer products.

The labeling of all ingredients contained in consumer products has been requested by consumers concerned regarding their safety. Consequently, regulatory agencies have set guidelines for industries on how to provide safety information regarding the ingredients in their products. However, discordant opinions were raised from stakeholders, resulting in the formation of a risk communication forum among industries, regulatory agencies, consumer groups, and academia. There are several methods that might be utilized to provide ingredient information to consumers: (1) listing all ingredients on the label of products, (2) providing major ingredients on the label of products, (3) presenting all ingredients on the websites of each manufacturer, and (4) listing major ingredients on the label of products and the remainder of ingredients (not on the label) on the websites. Each method might have its own advantages and disadvantages with respect to providing the information regarding the names of the ingredients used in consumer products to the consumers. A continuous risk communication forum might be an effective tool to facilitate an improved understanding of chemical information, toxicological science, regulatory guidelines, labeling methods, and consumers' concern. This study suggests that risk communication efforts may be helpful and a good opportunity for stakeholders to exchange opinions and reach a harmonious conclusion on labeling of consumer products ingredients.

In Vivo Positive Magnetic Resonance Imaging Applications of Poly(methyl vinyl ether-alt-maleic acid)-coated Ultra-small Paramagnetic Gadolinium Oxide Nanoparticles.

The study of ultra-small paramagnetic gadolinium oxide (Gd2O3) nanoparticles (NPs) as in vivo positive (T1) magnetic resonance imaging (MRI) contrast agents is one of the most attractive fields in nanomedicine. The performance of the Gd2O3 NP imaging agents depends on the surface-coating materials. In this study, poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) was used as a surface-coating polymer. The PMVEMA-coated paramagnetic ultra-small Gd2O3 NPs with an average particle diameter of 1.9 nm were synthesized using the one-pot polyol method. They exhibited excellent colloidal stability in water and good biocompatibility. They also showed a very high longitudinal water proton spin relaxivity (r1) value of 36.2 s-1mM-1 (r2/r1 = 2.0; r2 = transverse water proton spin relaxivity) under a 3.0 tesla MR field which is approximately 10 times higher than the r1 values of commercial molecular contrast agents. High positive contrast enhancements were observed in in vivo T1 MR images after intravenous administration of the NP solution sample, demonstrating its potential as a T1 MRI contrast agent.