Since the etiology of diabetic chronic kidney disease (CKD) is multifactorial, studies on DNA methylation for kidney function deterioration have rarely been performed despite the need for an epigenetic approach. Therefore, this study aimed to identify epigenetic markers associated with CKD progression based on the decline in the estimated glomerular filtration rate in diabetic CKD in Korea. An epigenome-wide association study was performed using whole blood samples from 180 CKD recruited from the KNOW-CKD cohort. Pyrosequencing was also performed on 133 CKD participants as an external replication analysis. Functional analyses, including the analysis of disease-gene networks, reactome pathways, and protein-protein interaction networks, were conducted to identify the biological mechanisms of CpG sites. A phenome-wide association study was performed to determine the associations between CpG sites and other phenotypes. Two epigenetic markers, cg10297223 on AGTR1 and cg02990553 on KRT28 indicated a potential association with diabetic CKD progression. Based on the functional analyses, other phenotypes (blood pressure and cardiac arrhythmia for AGTR1) and biological pathways (keratinization and cornified envelope for KRT28) related to CKD were also identified. This study suggests a potential association between the cg10297223 and cg02990553 and the progression of diabetic CKD in Koreans. Nevertheless, further validation is needed through additional studies.

It is unclear whether non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease. We examined the independent impact of NAFLD on the progression of the coronary artery calcification (CAC) score, a well-known marker of atherosclerosis progression. We examined 1,173 asymptomatic participants who underwent repeated CAC score measurement during routine health examinations. The subjects were categorised into four groups based on the presence (+) or absence (-) of NAFLD and metabolic syndrome (MetS). The progression of CAC score was defined as either incident CAC in a CAC-free population at baseline or an increase of ≥2.5 units between the baseline and the final square roots of the CAC scores of participants with detectable CAC at baseline. CAC progression was seen in 18.6% (98/526), 28.3% (77/272), 29.1% (30/103) and 32.0% (87/272) of the subjects with NAFLD(-)/MetS(-), NAFLD(+)/MetS(-), NAFLD(-)/MetS(+) and NAFLD(+)/MetS(+), respectively. The subjects with NAFLD(+)/MetS(+) and NAFLD(+)/MetS(-) had a significantly higher risk of CAC progression than those with NAFLD(-)/MetS(-) (multivariate-adjusted odds ratio [OR]: 1.76; 95% confidence interval [CI]: 1.18-2.62 and multivariate-adjusted OR: 1.53, 95% CI: 1.05-2.23, respectively). NAFLD is an independent risk factor for CAC progression, irrespective of the presence of MetS.

Established fear memory becomes vulnerable to disruption after memory retrieval and extinction; this labile state is critical for inhibiting the return of fear memory. However, the labile state has a very narrow time window after retrieval, and underlying molecular mechanisms are not well known. To that end, we isolated the hippocampus immediately after fear memory retrieval and performed proteomics. We identified Neurobeachin (NBEA), an autism-related regulator of synaptic protein trafficking, to be upregulated after contextual fear memory retrieval. NBEA protein expression was rapid and transient after fear memory retrieval at the synapse. Nbea mRNA was enriched at the synapses, and the rapid induction of NBEA expression was blocked by inhibition of the mammalian target of rapamycin (mTOR)-dependent signaling pathway. Mice with cornu ammonis 1 (CA1)-specific Nbea shRNA knockdown showed normal fear acquisition and contextual fear memory but impaired extinction, suggesting an important role of Nbea in fear memory extinction processes. Consistently, Nbea heterozygotes showed normal fear acquisition and fear memory recall but showed impairment in extinction. Our data suggest that NBEA is necessary either for induction of memory lability or for the physiological process of memory extinction.

Melanogenesis is the process of production of melanin pigments that are responsible for the colors of skin, eye, and hair and provide protection from ultraviolet radiation. However, excessive levels of melanin formation cause hyperpigmentation disorders such as freckles, melasma, and age spots. Liver X receptors (LXR) are nuclear oxysterol receptors belonging to the family of ligand-activated transcription factors and physiological regulators of lipid and cholesterol metabolism. In the skin, activation of LXRs stimulates differentiation of keratinocytes and augments lipid synthesis in sebocytes. However, the function of LXRs in melanogenesis has not been clearly elucidated. In addition, although beauvericin, a well-known mycotoxin primarily isolated from several fungi, has various biological properties, its involvement in melanogenesis has not been reported. Therefore, in this study, we examined the effects of beauvericin on melanogenesis and its molecular mechanisms. Beauvericin decreased melanin content and tyrosinase activity without any cytotoxicity. Beauvericin also reduced protein levels of MITF, tyrosinase, TRP1, and TRP2. In addition, beauvericin suppressed cAMP-PKA-CREB signaling and upregulated expression of LXR-α, resulting in the suppression of p38 MAPK. Our results indicate that beauvericin attenuates melanogenesis by regulating both cAMP/PKA/CREB and LXR-α/p38 MAPK pathways, consequently leading to a reduction of melanin levels.

Diffusion-weighted imaging (DWI) is proven useful to differentiate benign and malignant soft tissue tumors (STTs). Radiomics utilizing a vast array of extracted imaging features has a potential to uncover disease characteristics. We aim to assess radiomics using DWI can outperform the conventional DWI for STT differentiation. In 151 patients with 80 benign and 71 malignant tumors, ADCmean and ADCmin were measured on solid portion within the mass by two different readers. For radiomics approach, tumors were segmented and 100 original radiomic features were extracted on ADC map. Eight radiomics models were built with training set (n = 105), using combinations of 2 different algorithms-multivariate logistic regression (MLR) and random forest (RF)-and 4 different inputs: radiomics features (R), R + ADCmin (I), R + ADCmean (E), R + ADCmin and ADCmean (A). All models were validated with test set (n = 46), and AUCs of ADCmean, ADCmin, MLR-R, RF-R, MLR-I, RF-I, MLR-E, RF-E, MLR-A and RF-A models were 0.729, 0.753 0.698, 0.700, 0.773, 0.807, 0.762, 0.744, 0.773 and 0.807, respectively, without statistically significant difference. In conclusion, radiomics approach did not add diagnostic value to conventional ADC measurement for differentiating benign and malignant STTs.

HER2-positive luminal B breast cancer (BC), a subset of the luminal B subtype, is ER-positive and HER2-positive BC which is approximately 10% of all BC. However, HER2-positive luminal B BC has received less attention and is less represented in previous molecular analyses than other subtypes. Hence, it is important to elucidate the molecular biology of HER2-positive luminal B BC to stratify patients in a way that allows them to receive their respective optimal treatment. We performed molecular profiling using targeted next-generation sequencing on 94 HER2-positive luminal B BC to identify its molecular characteristics. A total of 134 somatic nonsynonymous mutations, including 131 nonsynonymous single nucleotide variants and three coding insertions/deletions were identified in 30 genes of 75 samples. PIK3CA was most frequently mutated (38/94, 40.4%), followed by TP53 (31/94, 33.0%), and others were detected at lower frequencies. Recurrent germline mutations of MLH1 V384D were found in 13.8% (13/94), with a significantly high TP53 mutations rate. The frequency of MLH1 V384D germline mutation in individuals with HER2-positive luminal B BC was significantly higher than that observed in the controls. All 13 cases were classified as microsatellite stable tumors. Tumor mutation burdens (TMB) were not significantly different between MLH1 V384D carrier and wild type. The concordant results of microsatellite instability (MSI) and TMB suggest that the haploinsufficiency of MLH1 plays a role as a tumor predisposition factor rather than a direct oncogenic driver. Our study identified, for the first time, that MLH1 V384D germline variant is frequently detected in HER2-positive luminal B BC. MLH1 V384D germline variant may not only contribute to gastrointestinal cancer predisposition but may also contribute to BC in East Asians.

With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. The value of immune markers, including programmed cell death ligand-1, programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-dominant containing-3 (TIM-3), is not well known. Using tissue microarrays of 396 patients who underwent surgery for oesophageal squamous cell carcinoma (ESCC), infiltrated T-cell subsets (CD3, CD8, and Foxp3) and checkpoint protein expression were scored. With a median follow-up of 24.8 months, CD3+ TIL subsets (50.0%) had longer median recurrence-free survival (RFS, 55.0 vs 21.4 months) and overall survival (OS, 77.7 vs 35.8 months). Patients with high ICOS expression (46.5%) had longer median RFS (53.9 vs 25.3 months) and OS (88.8 vs 36.9 months). For PD-1, RFS (hazard ratio [HR] 0.67) and OS (HR 0.66) were significantly longer in the high-expression group (45.2%). In the multivariate analysis, high TIM-3 expression (50.8%) had a significant relationship with shorter RFS (HR = 1.52) and OS (HR = 1.60). High CD3+ TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade.