Sex-specific survival gene mutations are discovered as clinical predictors of clear cell renal cell carcinoma.

Although sex differences have been reported in patients with clear cell renal cell carcinoma (ccRCC), biological sex has not received clinical attention and genetic differences between sexes are poorly understood. This study aims to identify sex-specific gene mutations and explore their clinical significance in ccRCC. We used data from The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC), The Renal Cell Cancer-European Union (RECA-EU) and Korean-KIRC. A total of 68 sex-related genes were selected from TCGA-KIRC through machine learning, and 23 sex-specific genes were identified through verification using the three databases. Survival differences according to sex were identified in nine genes (ACSS3, ALG13, ASXL3, BAP1, JADE3, KDM5C, KDM6A, NCOR1P1, and ZNF449). Female-specific survival differences were found in BAP1 in overall survival (OS) (TCGA-KIRC, p = 0.004; RECA-EU, p = 0.002; and Korean-KIRC, p = 0.003) and disease-free survival (DFS) (TCGA-KIRC, p = 0.001 and Korean-KIRC, p = 0.000004), and NCOR1P1 in DFS (TCGA-KIRC, p = 0.046 and RECA-EU, p = 0.00003). Male-specific survival differences were found in ASXL3 (OS, p = 0.017 in TCGA-KIRC; and OS, p = 0.005 in RECA-EU) and KDM5C (OS, p = 0.009 in RECA-EU; and DFS, p = 0.016 in Korean-KIRC). These results suggest that biological sex may be an important predictor and sex-specific tailored treatment may improve patient care in ccRCC.

Discovery and Validation of Survival-Specific Genes in Papillary Renal Cell Carcinoma Using a Customized Next-Generation Sequencing Gene Panel.

PURPOSE: Papillary renal cell carcinoma (PRCC), the second most common kidney cancer, is morphologically, genetically, and molecularly heterogeneous with diverse clinical manifestations. Genetic variations of PRCC and their association with survival are not yet well-understood. This study aimed to identify and validate survival-specific genes in PRCC and explore their clinical utility. MATERIALS AND METHODS: Using machine learning, 293 patients from the Cancer Genome Atlas-Kidney Renal Papillary Cell Carcinoma (TCGA-KIRP) database were analyzed to derive genes associated with survival. To validate these genes, DNAs were extracted from the tissues of 60 Korean PRCC patients. Next generation sequencing was conducted using a customized PRCC gene panel of 202 genes, including 171 survival-specific genes. Kaplan-Meier and Log-rank tests were used for survival analysis. Fisher's exact test was performed to assess the clinical utility of variant genes. RESULTS: A total of 40 survival-specific genes were identified in the TCGA-KIRP database through machine learning and statistical analysis. Of them, 10 (BAP1, BRAF, CFDP1, EGFR, ITM2B, JAK1, NODAL, PCSK2, SPATA13, and SYT5) were validated in the Korean-KIRP database. Among these survival gene signatures, three genes (BAP1, PCSK2, and SPATA13) showed survival specificity in both overall survival (OS) (p = 0.00004, p = 1.38 × 10-7, and p = 0.026, respectively) and disease-free survival (DFS) (p = 0.00002, p = 1.21 × 10-7, and p = 0.036, respectively). Notably, the PCSK2 mutation demonstrated survival specificity uniquely in both the TCGA-KIRP (OS: p = 0.010 and DFS: p = 0.301) and Korean-KIRP (OS: p = 1.38 × 10-7 and DFS: p = 1.21 × 10-7) databases. CONCLUSIONS: We discovered and verified genes specific for the survival of PRCC patients in the TCGA-KIRP and Korean-KIRP databases. The survival gene signature, including PCSK2 commonly obtained from the 40 gene signature of TCGA and the 10 gene signature of the Korean database, is expected to provide insight into predicting the survival of PRCC patients and developing new treatment.

L-serine restored lysosomal failure in cells derived from patients with BPAN reducing iron accumulation with eliminating lipofuscin.

Defective mitochondria and autophagy, as well as accumulation of lipid and iron in WDR45 mutant fibroblasts, is related to beta-propeller protein-associated neurodegeneration (BPAN). In this study, we found that enlarged lysosomes in cells derived from patients with BPAN had low enzyme activity, and most of the enlarged lysosomes had an accumulation of iron and oxidized lipid. Cryo-electron tomography revealed elongated lipid accumulation, and spectrometry-based elemental analysis showed that lysosomal iron and oxygen accumulation superimposed with lipid aggregates. Lysosomal lipid aggregates superimposed with autofluorescence as free radical generator, lipofuscin. To eliminate free radical stress by iron accumulation in cells derived from patients with BPAN, we investigated the effects of the iron chelator, 2,2'-bipyridine (bipyridyl, BIP). To study whether the defects in patient-derived cells can be rescued by an iron chelator BIP, we tested whether the level of iron and reactive oxygen species (ROS) in the cells and genes related to oxidative stress were rescued BIP treatment. Although BIP treatment decreased some iron accumulation in the cytoplasm and mitochondria, the accumulation of iron in the lysosomes and levels of cellular ROS were unaffected. In addition, the change of specific RNA levels related to free radical stress in patient fibroblasts was not rescued by BIP. To alleviate free radical stress, we investigated whether l-serine can regulate abnormal structures in cells derived from patients with BPAN through the regulation of free radical stress. l-serine treatment alleviated increase of enlarged lysosomes and iron accumulation and rescued impaired lysosomal activity by reducing oxidized lipid accumulation in the lysosomes of the cells. Lamellated lipids in the lysosomes of the cells were identified as lipofuscin through correlative light and electron microscopy, and l-serine treatment reduced the increase of lipofuscin. These data suggest that l-serine reduces oxidative stress-mediated lysosomal lipid oxidation and iron accumulation by rescuing lysosomal activity.

A Composite Blood Biomarker Including AKR1B10 and Cytokeratin 18 for Progressive Types of Nonalcoholic Fatty Liver Disease.

BACKGRUOUND: We aimed to evaluate whether composite blood biomarkers including aldo-keto reductase family 1 member B10 (AKR1B10) and cytokeratin 18 (CK-18; a nonalcoholic steatohepatitis [NASH] marker) have clinically applicable performance for the diagnosis of NASH, advanced liver fibrosis, and high-risk NASH (NASH+significant fibrosis). METHODS: A total of 116 subjects including healthy control subjects and patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were analyzed to assess composite blood-based and imaging-based biomarkers either singly or in combination. RESULTS: A composite blood biomarker comprised of AKR1B10, CK-18, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) showed excellent performance for the diagnosis of, NASH, advanced fibrosis, and high-risk NASH, with area under the receiver operating characteristic curve values of 0.934 (95% confidence interval [CI], 0.888 to 0.981), 0.902 (95% CI, 0.832 to 0.971), and 0.918 (95% CI, 0.862 to 0.974), respectively. However, the performance of this blood composite biomarker was inferior to that various magnetic resonance (MR)-based composite biomarkers, such as proton density fat fraction/MR elastography- liver stiffness measurement (MRE-LSM)/ALT/AST for NASH, MRE-LSM+fibrosis-4 index for advanced fibrosis, and the known MR imaging-AST (MAST) score for high-risk NASH. CONCLUSION: Our blood composite biomarker can be useful to distinguish progressive forms of NAFLD as an initial noninvasive test when MR-based tools are not available.

Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.

The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.

Association between social jetlag and chronic kidney disease among the Korean working population.

Social jetlag refers to the discrepancy between social time and the body's internal rhythm, which can lead to unfavorable health outcomes. However, no study has directly explored the relation between social jetlag and chronic kidney disease (CKD). This study aims to investigate the relationship between social jetlag and CKD in a representative population of South Korea. This study included 8259 currently economically active Korean population in the Korea National Health and Nutrition Examination Survey. Social jetlag was calculated as the difference between the midpoint of sleep time on weekdays and free days. The estimated glomerular filtration rate (eGFR) was calculated the by using the serum creatinine value according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Participants with an eGFR less than 60 ml/min/1.73 m2 were defined as CKD cases. The estimated glomerular filtration rate decreased as social jetlag increased. Multiple logistic regression analysis showed that the adjusted odds ratio (95% confidence interval) of CKD for 1-2 h of social jetlag was 0.926 (0.660-1.299), while the odds ratio for more than 2 h was 2.042 (1.328-3.139) when less than 1 h was used as reference. This study found that social jetlag and risk of CKD were significantly related in the Korean working population.

Data resource profile: the Korean Community Health Status Indicators (K-CHSI) database.

Korean Community Health Status Indicators (K-CHSI) is a model-based database containing annual data on health outcomes and determinants at the municipal level (si/gun/gu-level regions, including mid-sized cities, counties, and districts). K-CHSI's health outcomes include overall mortality, disease incidence, prevalence rates, and self-reported health. Health determinants were measured in 5 domains: socio-demographic factors, health behaviors, social environment, physical environment, and the healthcare system. The data sources are 71 public databases, including Causes of Death Statistics, Cancer Registration Statistics, Community Health Survey, Population Census, and Census on Establishments and Statistics of Urban Plans. This dataset covers Korea's 17 metropolitan cities and provinces, with data from approximately 250 municipal regions (si/gun/gu). The current version of the database (DB version 1.3) was built using 12 years of data from 2008 to 2019. All data included in K-CHSI may be downloaded via the Korea Community Health Survey site, with no login requirement (https://chs.kdca.go.kr/chs/recsRoom/dataBaseMain.do). K-CHSI covers extensive health outcomes and health determinants at the municipal level over a period of more than 10 years, which enables ecological and time-series analyses of the relationships among various health outcomes and related factors.

Plasma Aldo-Keto Reductase Family 1 Member B10 as a Biomarker Performs Well in the Diagnosis of Nonalcoholic Steatohepatitis and Fibrosis.

We found several blood biomarkers through computational secretome analyses, including aldo-keto reductase family 1 member B10 (AKR1B10), which reflected the progression of nonalcoholic fatty liver disease (NAFLD). After confirming that hepatic AKR1B10 reflected the progression of NAFLD in a subgroup with NAFLD, we evaluated the diagnostic accuracy of plasma AKR1B10 and other biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) and fibrosis in replication cohort. We enrolled healthy control subjects and patients with biopsy-proven NAFLD (n = 102) and evaluated the performance of various diagnostic markers. Plasma AKR1B10 performed well in the diagnosis of NASH with an area under the receiver operating characteristic (AUROC) curve of 0.834 and a cutoff value of 1078.2 pg/mL, as well as advanced fibrosis (AUROC curve value of 0.914 and cutoff level 1078.2 pg/mL), with further improvement in combination with C3. When we monitored a subgroup of obese patients who underwent bariatric surgery (n = 35), plasma AKR1B10 decreased dramatically, and 40.0% of patients with NASH at baseline showed a decrease in plasma AKR1B10 levels to below the cutoff level after the surgery. In an independent validation study, we proved that plasma AKR1B10 was a specific biomarker of NAFLD progression across varying degrees of renal dysfunction. Despite perfect correlation between plasma and serum levels of AKR1B10 in paired sample analysis, its serum level was 1.4-fold higher than that in plasma. Plasma AKR1B10 alone and in combination with C3 could be a useful noninvasive biomarker for the diagnosis of NASH and hepatic fibrosis.

Pregnancy loss and Income in the Republic of Korea using National Health Insurance Service Data, 2008-2014.

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.

Genome-Wide Analysis of MYB10 Transcription Factor in Fragaria and Identification of QTLs Associated with Fruit Color in Octoploid Strawberry.

The genus Fragaria encompass fruits with diverse colors influenced by the distribution and accumulation of anthocyanin. Particularly, the fruit colors of strawberries with different ploidy levels are determined by expression and natural variations in the vital structural and regulatory genes involved in the anthocyanin pathway. Among the regulatory genes, MYB10 transcription factor is crucial for the expression of structural genes in the anthocyanin pathway. In the present study, we performed a genome wide investigation of MYB10 in the diploid and octoploid Fragaria species. Further, we identified seven quantitative trait loci (QTLs) associated with fruit color in octoploid strawberry. In addition, we predicted 20 candidate genes primarily influencing the fruit color based on the QTL results and transcriptome analysis of fruit skin and flesh tissues of light pink, red, and dark red strawberries. Moreover, the computational and transcriptome analysis of MYB10 in octoploid strawberry suggests that the difference in fruit colors could be predominantly influenced by the expression of MYB10 from the F. iinumae subgenome. The outcomes of the present endeavor will provide a platform for the understanding and tailoring of anthocyanin pathway in strawberry for the production of fruits with aesthetic colors.

RIG-I Deficiency Promotes Obesity-Induced Insulin Resistance.

Inflammation and immunity are linked to the onset and development of obesity and metabolic disorders. Pattern recognition receptors (PRRs) are key regulators of inflammation and immunity in response to infection and stress, and they have critical roles in metainflammation. In this study, we investigated whether RIG-I (retinoic acid-inducible gene I)-like receptors were involved in the regulation of obesity-induced metabolic stress in RIG-I knockout (KO) mice fed a high-fat diet (HFD). RIG-I KO mice fed an HFD for 12 weeks showed greater body weight gain, higher fat composition, lower lean body mass, and higher epididymal white adipose tissue (eWAT) weight than WT mice fed HFD. In contrast, body weight gain, fat, and lean mass compositions, and eWAT weight of MDA5 (melanoma differentiation-associated protein 5) KO mice fed HFD were similar to those of WT mice fed a normal diet. RIG-I KO mice fed HFD exhibited more severely impaired glucose tolerance and higher HOMA-IR values than WT mice fed HFD. IFN-ß expression induced by ER stress inducers, tunicamycin and thapsigargin, was abolished in RIG-I-deficient hepatocytes and macrophages, showing that RIG-I is required for ER stress-induced IFN-ß expression. Our results show that RIG-I deficiency promotes obesity and insulin resistance induced by a high-fat diet, presenting a novel role of RIG-I in the development of obesity and metabolic disorders.

Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts.

Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.

Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy.

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

Versatile Nutraceutical Potentials of Watermelon-A Modest Fruit Loaded with Pharmaceutically Valuable Phytochemicals.

Watermelon (Citrulus lantus) is an important horticultural crop which belongs to the Curcubitaceae family. The nutraceutical potential of watermelon has been illustrated by several researchers, which makes it a better choice of functional food. Watermelon has been used to treat various ailments, such as cardio-vascular diseases, aging related ailments, obesity, diabetes, ulcers, and various types of cancers. The medicinal properties of watermelon are attributed by the presence of important phytochemicals with pharmaceutical values such as lycopene, citrulline, and other polyphenolic compounds. Watermelon acts as vital source of l-citrulline, a neutral-alpha amino acid which is the precursor of l-arginine, an essential amino acid necessary for protein synthesis. Supplementation of l-citrulline and lycopene displayed numerous health benefits in in vitro and in vivo studies. Similarly, the dietary intake of watermelon has proven benefits as functional food in humans for weight management. Apart from the fruits, the extracts prepared from the seeds, sprouts, and leaves also evidenced medicinal properties. The present review provides a comprehensive overview of benefits of watermelon for the treatment of various ailments.

Expression of Colorectal Cancer Antigenic Protein Fused to IgM Fc in Chinese Cabbage (Brassica rapa).

The epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen and a potential target for tumor vaccine. The EpCAM is a cell-surface glycoprotein highly expressed in colorectal carcinomas. The objective of the present study is to develop an edible vaccine system through Agrobacterium-mediated transformation in Chinese cabbage (Brassica rapa). For the transformation, two plant expression vectors containing genes encoding for the EpCAM recombinant protein along with the fragment crystallizable (Fc) region of immunoglobulin M (IgM) and Joining (J)-chain tagged with the KDEL endoplasmic reticulum retention motif (J-chain K) were constructed. The vectors were successfully transformed and expressed in the Chinese cabbage individually using Agrobacterium. The transgenic Chinese cabbages were screened using genomic polymerase chain reaction (PCR) in T0 transgenic plant lines generated from both transformants. Similarly, the immunoblot analysis revealed the expression of recombinant proteins in the transformants. Further, the T1 transgenic plants were generated by selfing the transgenic plants (T0) carrying EpCAM-IgM Fc and J-chain K proteins, respectively. Subsequently, the T1 plants generated from EpCAM-IgM Fc and J-chain K transformants were crossed to generate F1 plants carrying both transgenes. The presence of both transgenes was validated using PCR in the F1 plants. In addition, the expression of Chinese cabbage-derived EpCAM-IgM Fc × J-chain K was evaluated using immunoblot and ELISA analyses in the F1 plants. The outcomes of the present study can be utilized for the development of a potential anti-cancer vaccine candidate using Chinese cabbage.

Occupational disparities in survival in Korean women with cancer: a nationwide registry linkage study.

OBJECTIVES: We sought to examine occupational disparities in survival among Korean women diagnosed with cancer. DESIGN: Population-based, registry-linkage study. SETTING: South Korea. PARTICIPANTS: Our study population comprised female workers registered in the Korean national employment insurance programme during 1995-2000 and diagnosed with cancer between 1995 and 2008. A total of 61 110 women with cancer diagnoses was included in analysis. The occupation was categorised into four groups: (1) managers, professionals and technical workers, (2) clerks, (3) service/sales workers and (4) blue-collar workers. PRIMARY AND SECONDARY OUTCOME MEASURE: Study population were linked to the national death registry until 2009. HRs for mortality adjusting for age and year of diagnosis were calculated in the study sample and subgroups with 10 specific cancer sites including thyroid, breast, stomach, cervix, colon or lung cancer using managers, professionals and technical workers as the reference. RESULTS: Women in service/sales (HR 1.25, 95% CI 1.15 to 1.35) and blue-collar occupations (HR 1.34, 95% CI 1.25 to 1.44) had poorer survival for all cancer sites combined, while blue-collar workers showed poorer survival for lung (HR 1.41, 95% CI 1.14 to 1.77), breast (HR 1.28, 95% CI 1.06 to 1.54), cervical cancer (HR 1.42, 95% CI 1.02 to 2.06) and non-Hodgkin's lymphoma (HR 1.69, 95% CI 1.09 to 2.77) compared with women in professional and managerial positions. CONCLUSION: We found substantial and significant inequalities in overall survival by the occupational group among Korean women with cancer, even in the context of universal access to cancer screening and treatment.

Genome Editing of eIF4E1 in Tomato Confers Resistance to Pepper Mottle Virus.

Many of the recessive virus-resistance genes in plants encode eukaryotic translation initiation factors (eIFs), including eIF4E, eIF4G, and related proteins. Notably, eIF4E and its isoform eIF(iso)4E are pivotal for viral infection and act as recessive resistance genes against various potyviruses in a wide range of plants. In this study, we used Clustered Regularly Interspaced Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated targeted mutagenesis to test whether novel sequence-specific mutations at eIF4E1 in Solanum lycopersicum (tomato) cv. Micro-Tom could confer enhanced resistance to potyviruses. This approach produced heritable homozygous mutations in the transgene-free E1 generation. Sequence analysis of eIF4E1 from E0 transgenic plants expressing Cas9 and eIF4E-sgRNA transcripts identified chimeric deletions ranging from 11 to 43 bp. Genotype analysis of the eIF4E1-edited lines in E0, E1, and E2 transgenic tomato plants showed that the mutations were transmitted to subsequent generations. When homozygous mutant lines were tested for resistance to potyviruses, they exhibited no resistance to tobacco etch virus (TEV). Notably, however, several mutant lines showed no accumulation of viral particles upon infection with pepper mottle virus (PepMoV). These results indicate that site-specific mutation of tomato eIF4E1 successfully conferred enhanced resistance to PepMoV. Thus, this study demonstrates the feasibility of the use of CRISPR/Cas9 approach to accelerate breeding for trait improvement in tomato plants.

Evaluation of Manassantin A Tetrahydrofuran Core Region Analogues and Cooperative Therapeutic Effects with EGFR Inhibition.

Tumors adapt to hypoxia by regulating angiogenesis, metastatic potential, and metabolism. These adaptations mediated by hypoxia-inducible factor 1 (HIF-1) make tumors more aggressive and resistant to chemotherapy and radiation. Therefore, HIF-1 is a validated therapeutic target for cancer. In order to develop new HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural product manassantin A, we synthesized and evaluated manassantin A analogues with modifications in the tetrahydrofuran core region of manassantin A. Our structure-activity relationship study indicated that the α,α'-trans-configuration of the central ring of manassantin A is critical to HIF-1 inhibition. We also demonstrated that a combination of manassantin A with an epidermal growth factor receptor inhibitor shows cooperative antitumor activity (∼80% inhibition for combination vs ∼30% inhibition for monotherapy). Our findings will provide important frameworks for the future therapeutic development of manassantin A-derived chemotherapeutic agents.

γ-Glutamylcysteine- and Cysteinylglycine-Directed Growth of Chiral Gold Nanoparticles and their Crystallographic Analysis.

Chiral optical metamaterials with delicate structures are in high demand in various fields because of their strong light-matter interactions. Recently, a scalable strategy for the synthesis of chiral plasmonic nanoparticles (NPs) using amino acids and peptides has been reported. Reported herein, 3D chiral gold NPs were synthesized using dipeptide γ-Glu-Cys and Cys-Gly and analyzed crystallographically. The γ-Glu-Cys-directed NPs present a cube-like outline with a protruding chiral wing. In comparison, the NPs synthesized with Cys-Gly exhibited a rhombic dodecahedron-like outline with curved edges and elliptical cavities on each face. Morphology analysis of intermediates indicated that γ-Glu-Cys generated an intermediate concave hexoctahedron morphology, while Cys-Gly formed a concave rhombic dodecahedron. NPs synthesized with Cys-Gly are named 432 helicoid V because of their unique morphology and growth pathway.

Cancer Incidence by Occupation in Korea: Longitudinal Analysis of a Nationwide Cohort.

BACKGROUND: We performed this study to investigate the inequalities in site-specific cancer incidences among workers across different occupations in Korea. METHODS: Subjects included members of the national employment insurance. Incident cancers among 8,744,603 workers were followed from 1995 to 2007. Occupational groups were classified according to the Korean Standard Occupational Classification. Age-standardized incidence rate ratios were calculated. RESULTS: We found that men in service/sales and blue-collar occupations had elevated rates of esophageal, liver, laryngeal, and lung cancer. Among women, service/sales workers had elevated incidences of cervical cancer. Male prostate cancer, female breast, corpus uteri, and ovarian cancers, as well as male and female colorectal, kidney, and thyroid cancer showed lower incidences among workers in lower socioeconomic occupations. CONCLUSIONS: Substantial differences in cancer incidences were found depending on occupation reflecting socioeconomic position, in the Korean working population. Cancer prevention policy should focus on addressing these socioeconomic inequalities.