Elucidating immunological characteristics of the adenoma-carcinoma sequence in colorectal cancer patients in South Korea using a bioinformatics approach.

Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan-Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.

Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8+ T cells in murine models of inflammation.

The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors.

BACKGROUND: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rß)high CD8+ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+ cells within the tumor and the tumor-draining lymph nodes (tdLN). METHODS: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry. RESULTS: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD39highTIM-3+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors. CONCLUSIONS: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+ T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.

Large-scale integrative analysis of juvenile idiopathic arthritis for new insight into its pathogenesis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear. METHODS: To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk. RESULTS: We have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks. CONCLUSION: Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.

S6K1 deficiency in tumor stroma impairs lung metastasis of melanoma in mice.

Accumulating data suggest that ribosomal protein S6 kinase 1 (S6K1), an effector in the mammalian target of rapamycin (mTOR) pathway, plays pleiotropic roles in tumor progression. However, to date, while the tumorigenic function of S6K1 in tumor cells has been well elucidated, its role in the tumor stroma remains poorly understood. We recently showed that S6K1 mediates vascular endothelial growth factor A (VEGF-A) production in macrophages, thereby supporting tumor angiogenesis and growth. As macrophage-derived VEGF-A is crucial for both tumor cell intravasation and extravasation across the vascular endothelium, our previous findings suggest that stromal S6K1 signaling is required for tumor metastatic spread. Therefore, we aimed to determine the impact of host S6K1 depletion on tumor metastasis using a murine model of pulmonary metastasis (S6k1-/- mice implanted with B16F10 melanoma). The ablation of S6K1 in the host microenvironment significantly reduced the metastasized B16F10 melanoma cells on the lung surface in both spontaneous and intravenous lung metastasis mouse models without affecting the incidence of metastasis to distant lymph nodes. In addition, stromal S6K1 loss decreased the number of tumor cells circulating in the peripheral blood of mice bearing B16F10 xenografts without affecting the vascular leakage induced by VEGF-A in vivo. These observations demonstrate that S6K1 signaling in host cells other than endothelial cells is required to modulate the host microenvironment to facilitate the metastatic spread of tumors via blood circulation, thus revealing its novel role in the tumor stroma during tumor progression.

Factors Associated with Acute Kidney Injury Occurrence and Prognosis in Rhabdomyolysis at the Emergency Department.

Background and Objectives: This study aimed to analyze patients with rhabdomyolysis who presented to emergency departments and identify their distribution of related disease and prognostic factors. Materials and Methods: A retrospective cohort study was conducted on patients with rhabdomyolysis who presented to emergency departments over a 10-year period. Patient data, including patients' demographic variables (sex and age), mode of arrival, final diagnosis, statin use, rhabdomyolysis trigger factors, and levels of serum creatine phosphokinase (CPK), myoglobin, creatinine, sodium, potassium, phosphate, calcium, and lactate, were analyzed. Univariate and multivariate logistic regression analyses were conducted to identify the predictive factors of acute kidney injury (AKI). Results: Among the patients, 268 (65.6%) were found to have trigger factors without underlying diseases. Furthermore, 115 (28.2%) patients developed AKI. This comprehensive study sheds light on the diverse factors influencing the occurrence of AKI in rhabdomyolysis and provides insights into AKI predictive markers. Furthermore, we analyzed the cases by dividing them into six groups: occurrence of AKI, occurrence of infection, and simple or complex rhabdomyolysis. CPK time course was found to be important in clinical prognosis, such as AKI occurrence, dialysis or not, and mortality. Conclusions: Age, statin use, elevated creatinine and lactate levels, and initial serum CPK level emerged as significant predictors of AKI. CPK time course was also found to be an important factor in predicting the clinical outcomes of patients with rhabdomyolysis.

Efficacy of smartphone application-based multi-domain cognitive training in older adults without dementia.

Background: As the population ages and the prevalence of dementia increases, there is a growing emphasis on the importance of cognitive training to prevent dementia. A smartphone application-based cognitive training software program, BeauBrain Trainer (BBT), has been developed to provide better access to cognitive training for older adults. Numerous studies have revealed the effectiveness of cognitive training using a cognitive assessment tool. However, relatively few studies have evaluated brain activation using brain imaging as a result of improved cognitive function. Methods: All participants were required to download the BBT, an Android-based application for cognitive training, onto their own smartphone or tablet computer and to engage in cognitive training at home. Older adults without dementia were enrolled in this study, including 51 participants in the intervention group and 50 participants in the control group. The BBT comprised a set of 12 cognitive tasks, including two tasks in each of the following six cognitive domains: attention, language, calculation, visuospatial function, memory, and frontal/executive function. Each cognitive task was divided into four blocks based on its level of difficulty. A 16-week cognitive training was designed to carry out cognitive tasks using a total of 48 blocks (12 tasks × 4 levels) for at least 1.5 h per day, 5 days per week. All participants in the intervention group were given BBT tasks that gradually increased in difficulty level, which they submitted through a smartphone application daily for 16 weeks. The researchers monitored the participants' task performance records on the website and encouraged participants to engage in cognitive training through regular contact. This study was conducted to investigate the improvement in cognitive function and the activation pattern of the frontal cortex in older adults participating in smartphone application-based cognitive training. The cognitive assessment tool was the BeauBrain cognitive screening test (CST), a tablet-based computerized cognitive screening test. The activation pattern of the frontal cortex was measured using functional near-infrared spectroscopy (fNIRS). Additionally, this study aimed to determine the positive effects of cognitive training on everyday functioning and psychological states using a questionnaire. Results: Of 101 participants, 85 older adults without dementia (84.1%) who completed the study protocol were included in the statistical analysis. There were 41 participants (80.3%) in the intervention group and 44 participants (88.0%) in the control group. A two-way repeated-measures analysis of variance (ANOVA) was used to compare the cognitive scores over a 16-week period between the intervention and control groups. According to the CST results, the intervention group exhibited a statistically significant increase in the language subtest scores, specifically the phonemic word fluency test, compared to those of the control group. The fNIRS results revealed greater activation in the dorsolateral prefrontal cortex during the STROOP incongruent task in the intervention group than did the control group. However, the effectiveness of cognitive training was not observed across a variety of rating scales, including everyday functioning, depression, self-efficacy, attention, and subjective memory complaints. Conclusion: This study revealed that a smartphone-based cognitive training application led to improvements in phonemic generative naming ability and activation of the prefrontal cortex in older adults without dementia. This study is meaningful because it confirmed that cognitive training is partially effective in enhancing frontal lobe function. It also provided information on the brain mechanisms related to the effects of cognitive training using fNIRS.

Activation of Lysosomal Function Ameliorates Amyloid-ß-Induced Tight Junction Disruption in the Retinal Pigment Epithelium.

Accumulation of pathogenic amyloid-ß disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-ß, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-ß by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-ß with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-ß oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-ß in vitro and in vivo. Furthermore, clearance of amyloid-ß by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.

Formation Process of SiF6@Cu2L4 Chiral Cage Pairs in a Glass Vessel: Catechol Oxidation Catalysis and Chiral Recognition.

Self-assembly of CuX2 (X- = BF4-, PF6-, and SbF6-) with a pair of chiral bidentate ligands, (1R,2S)-(+)- and (1S,2R)-(-)-1-(nicotinamido)-2,3-dihydro-1H-inden-2-yl-nicotinate (r,s-L or s,r-L), in a mixture solvent including ethanol in a glass vessel gives rise to SiF62--encapsulated Cu2L4 chiral cage products. The SiF62- anion from the reaction of X- with SiO2 of the glass-vessel surface acts as a cage template or cage bridge. One of the products, [SiF6@Cu2(SiF6)(s,r-L)4]·3CHCl3·4EtOH, is one of the most effective heterogeneous catalysts for the oxidation of 3,5-di-tert-butylcatechol. Furthermore, an l-DOPA/d-DOPA pair is recognizable by the cyclic voltammetry (CV) signals of its combination with chiral cages [SiF6@Cu2(BF4)2(s,r- or r,s-L)4]·4CHCl3·2EtOH pair and [SiF6@Cu2(SiF6)(s,r- or r,s-L)4]·3CHCl3·4EtOH pair.

Couple-Oriented Interventions for Mental Health: A Scoping Review.

The purpose of this research was to systematically examine and collate evidence on couple-oriented interventions for mental health to identify trends in the literature, review research strategies, and suggest directions for future research. A systematic search included studies relating to couple-oriented interventions for preventing mental disorders and/or promoting mental health. We identified a total of 52 studies, which included 55 articles. Our findings revealed that interventions were delivered through various modes, including face-to-face, telephone, and online, with the majority of couple-oriented interventions operating in conjoint sessions. The most common intervention was for selective prevention targeting patients with cancer and their partners. This review provided evidence of the applicability of theoretical frameworks, dyad analysis, and measurements associated with couple-oriented interventions. Findings can help family nurse practitioners and health care professionals advance strategies to develop and implement evidence-based, couple-oriented interventions for primary prevention of mental disorders and the promotion of mental health.

Comparison of Check-All-That-Apply (CATA), Rate-All-That-Apply (RATA), Flash Profile, Free Listing, and Conventional Descriptive Analysis for the Sensory Profiling of Sweet Pumpkin Porridge.

With significant progress in the use of rapid descriptive methodologies as alternatives to conventional descriptive analysis (DA), several consumer-based approaches have emerged. In this study, we compared four such methodologies-check-all-that-apply (CATA), rate-all-that-apply (RATA), flash profile (FP), and free listing (FL)-for sensory profiling to DA, using six sweet pumpkin porridges. The DA involved eight trained panelists, whereas each consumer evaluation engaged 60 untrained consumers. Overall, the performance of the consumer methods was similar to the DA, and it could effectively profile differences in consumer perceptions of sensory attributes, as evident from high regressor vector (RV) values (>0.89). RATA exhibited the highest similarity to the DA (Rv = 0.96), featuring quicker and less tedious processes compared with FP or FL. Novel combined methods for sensory characterization using the strengths of these four approaches are warranted. This includes leveraging the simplicity and versatility of CATA or RATA coupled with the capacity of FP or FL to capture spontaneous perceptions of products by consumers.

Online coaching blended couple-oriented intervention for preventing depression among Korean middle adulthood: A feasibility study.

Depression and marital satisfaction have a reciprocal cause-and-effect relationship. Thus, couple relationships should be considered to maximize the effectiveness of couple-oriented interventions for depression. Moreover, developing culturally tailored couple-oriented interventions is critical for improving cultural acceptability and enhancing the perceived effectiveness of the interventions. A new culturally tailored MindGuide Couple intervention was developed to prevent Korean middle adulthood depression and enhance couple relationships using intervention mapping. This feasibility study used a single-arm, pre- and post-test, and 2-month follow-up design to explore the reach, acceptability, and preliminary effectiveness of this preventive intervention. Reach was assessed by recruitment, retention, and completion rates; acceptability was measured based on helpfulness, suitability, and satisfaction; and preliminary effectiveness was measured by depression (CES-D), positive and negative affect (PANAS), satisfaction with life (SWLS), couple satisfaction (CSI), and healthy relationship between spouses (FRAS). Fifteen middle-aged couples participated in four psychoeducational and asynchronous online modules and four synchronous coaching sessions via videoconferencing for 5-7 weeks. Data were analyzed using descriptive statistics and repeated measures with analysis of variance. With a 94.1% completion rate, the participants demonstrated high satisfaction with the online coaching blended intervention and reported that it was helpful and easy to use. Both husbands and wives showed significant differences over time in depression, couple satisfaction, and healthy relationships between spouses. This feasibility study demonstrated the successful reach, acceptability, and potential effectiveness of this preventive intervention. Additionally, we suggest the importance of culturally tailored and online coaching blended couple-oriented intervention for preventing depression and promoting healthy couple relationships.

Single breath-hold CINE imaging with combined simultaneous multislice and region-optimized virtual coils.

PURPOSE: To investigate the feasibility of combining simultaneous multislice (SMS) and region-optimized virtual coils (ROVir) for single breath-hold CINE imaging. METHOD: ROVir is a recent virtual coil approach that allows reduced-field of view (FOV) imaging by localizing the signal from a region-of-interest (ROI) and/or suppressing the signal from unwanted spatial regions. In this work, ROVir is used for reduced-FOV SMS bSSFP CINE imaging, which enables whole heart CINE with a single breath-hold acquisition. RESULTS: Reduced-FOV CINE with either SMS-only or ROVir-only resulted in significant aliasing, with severely reduced image quality when compared to the full FOV reference CINE, while the visual appearance of aliasing was substantially reduced with the proposed SMS+ROVir. The end diastolic volume, end systolic volume, and ejection fraction obtained using the proposed approach were similar to the clinical reference (correlations of 0.92, 0.94, and 0.88, respectively with p < 0 . 05 $$ p<0.05 $$ in each case, and biases of 0.1, 1.6 mL, and - 0 . 6 % $$ -0.6\% $$ , respectively). No statistically significant differences for these parameters were found with a Wilcoxon rank test (p = 0.96, 0.20, and 0.40, respectively). CONCLUSION: We demonstrated that reduced-FOV CINE imaging with SMS+ROVir enables single breath-hold whole-heart imaging without compromising visual image quality or quantitative cardiac function parameters.

Characteristics of a Rollable Dielectric Barrier Discharge Plasma and Its Effects on Spinach-Seed Germination.

We investigated the characteristics of a rollable dielectric barrier discharge (RDBD) and evaluate its effects on seed germination rate and water uptake. The RDBD source was composed of a polyimide substrate and copper electrode, and it was mounted in a rolled-up structure for omnidirectional and uniform treatment of seeds with flowing synthetic air gas. The rotational and vibrational temperatures were measured to be 342 K and 2860 K, respectively, using optical emission spectroscopy. The chemical species analysis via Fourier-transform infrared spectroscopy and 0D chemical simulation showed that O3 production was dominant and NOx production was restrained at the given temperatures. The water uptake and germination rate of spinach seeds by 5 min treatment of RDBD was increased by 10% and 15%, respectively, and the standard error of germination was reduced by 4% in comparison with the controls. RDBD enables an important step forward in non-thermal atmospheric-pressure plasma agriculture for omnidirectional seed treatment.

PLK1-mediated phosphorylation of ß-catenin enhances its stability and transcriptional activity for extracellular matrix remodeling in metastatic NSCLC.

Rationale: ß-catenin is a component for cell adhesion and a transcriptional coactivator in epithelial-mesenchymal transition (EMT). Previously we found that catalytically active PLK1 drives EMT in non-small cell lung cancer (NSCLC), upregulating extracellular matrix factors including TSG6, laminin γ2, and CD44. To understand the underlying mechanism and clinical significance of PLK1 and ß-catenin in NSCLC, their relationship and function in metastatic regulation were investigated. Methods: The clinical relevance between the survival rate of NSCLC patients and the expression of PLK1 and ß-catenin was analyzed by a KM plot. Immunoprecipitation, kinase assay, LC-MS/MS spectrometry, and site-directed mutagenesis were performed to reveal their interaction and phosphorylation. A lentiviral doxycycline-inducible system, Transwell-based 3D culture, tail-vein injection model, confocal microscopy, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated ß-catenin in the EMT of NSCLC. Results: Clinical analysis revealed that the high expression of CTNNB1/PLK1 was inversely correlated with the survival rates of 1,292 NSCLC patients, especially in metastatic NSCLC. In TGF-ß-induced or active PLK1-driven EMT, ß-catenin, PLK1, TSG6, laminin γ2, and CD44 were concurrently upregulated. ß-catenin is a binding partner of PLK1 in TGF-ß-induced EMT and is phosphorylated at S311. Phosphomimetic ß-catenin promotes cell motility, invasiveness of NSCLC cells, and metastasis in a tail-vein injection mouse model. Its upregulated stability by phosphorylation enhances transcriptional activity through nuclear translocation for the expression of laminin γ2, CD44, and c-Jun, therefore enhancing PLK1 expression by AP-1. Conclusions: Our findings provide evidence for the critical role of the PLK1/ß-catenin/AP-1 axis in metastatic NSCLC, implying that ß-catenin and PLK1 may serve as a molecular target and prognostic indicator of the therapeutic response in metastatic NSCLC patients.

Scalable, Highly Pure, and Diameter-Sorted Boron Nitride Nanotube by Aqueous Polymer Two-Phase Extraction.

Boron nitride nanotube (BNNT) has attracted recent attention owing to its exceptional material properties; yet, practical implementation in real-life applications has been elusive, mainly due to the purity issues associated with its large-scale synthesis. Although different purification methods have been discussed so far, there lacks a scalable solution method in the community. In this work, a simple, high-throughput, and scalable purification of BNNT is reported via modification of an established sorting technique, aqueous polymer two-phase extraction. A complete partition mapping of the boron nitride species is established, which enables the segregation of the highly pure BNNT with a major impurity removal efficiency of > 98%. A successful scaling up of the process is illustrated and provides solid evidence of its diameter sorting behavior. Last, towards its macroscopic assemblies, a liquid crystal of the purified BNNT is demonstrated. The effort toward large-scale solution purification of BNNT is believed to contribute significantly to the macroscopic realization of its exceptional properties in the near future.

Plk2-mediated phosphorylation and translocalization of Nrf2 activates anti-inflammation through p53/Plk2/p21cip1 signaling in acute kidney injury.

The Plk2 is a cellular stress-responsive factor that is induced in response to oxidative stress. However, the roles of Plk2 in acute kidney injury (AKI) have not been clarified. We previously found that Plk2 is an interacting factor of Nrf2 in response to cellular stress, since Plk2 is upregulated in the Nrf2-dependent network. Here, we show that the levels of p53, Plk2, p21cip1, and chromatin-bound Nrf2 were all upregulated in kidney tissues of mice or NRK52E cells treated with either cisplatin or methotrexate. Upregulation of Plk2 by p53 led to an increase of Nrf2 in both soluble and chromatin fractions in cisplatin-treated NRK52E cells. Consistently, depletion of Plk2 suppressed the levels of Nrf2. Of note, Plk2 directly phosphorylated Nrf2 at Ser40, which facilitated its interaction with p21cip1 and translocation into the nuclei for the activation of anti-oxidative and anti-inflammatory factors in response to AKI. Together, these findings suggest that Plk2 may serve as an anti-oxidative and anti-inflammatory regulator through the phosphorylation and activation of Nrf2 to protect kidney cells from kidney toxicants and that Plk2 and Nrf2 therefore work cooperatively for the protection and survival of kidney cells from harmful stresses.

Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes.

We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation-phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA-protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2-4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

Delayed feeding of a high-sucrose diet led to increased body weight by affecting the circadian rhythm of body temperature and hepatic lipid-metabolism genes in rats.

Skipping breakfast is an irregular feeding behavior, typically in young people. In our previous study, we established a 4 h-delayed feeding protocol for rats as a breakfast-skipping model and showed that the 4 h-delayed feeding of a high-fat diet led to body weight gain in rats. Excess sucrose induces metabolic syndrome and fatty liver. Recently, excess sucrose intake has received increased attention. Young people generally consume more sugar than adults do. In the present study, we investigated whether a 4 h-delayed feeding promoted high-sucrose diet-induced abnormalities in lipid metabolism, such as fatty liver and obesity in rats. The 4 h-delayed feeding rats showed increased body weight gain, although it did not induce fatty liver and hyperlipidemia compared to normal feeding rats. Serum insulin concentration during the feeding period was higher than in the control rats, suggesting that slight insulin resistance was induced by the 4 h-delayed feeding. The surge in body temperature was also delayed by 4 h in response to the 4 h-delayed feeding. This delay would result in less energy expenditure to increase body weight. The oscillations of hepatic lipid and glucose metabolism-related gene expression were delayed by almost 2-4 h, and the clock genes were delayed by approximately 2 h. The 4 h-delayed feeding induced weight gain by affecting body temperature, insulin resistance, and circadian oscillation of lipid metabolism-related genes in rats fed a high-sucrose diet, suggesting that a high sucrose intake with breakfast skipping leads to obesity.