Functional variants of the pentraxin 3 gene are associated with the metastasis and progression of prostate cancer.

Age, ethnic background and genetic components have been identified as the established risks for prostate cancer (PCa). Pentraxin 3 (PTX3), originally identified as a pattern-recognition molecule for defence against infectious agents, has multiple functions in tissue repair and in the regulation of cancer-associated inflammation. In this study, we sought to investigate the impact of PTX3 gene variants on the development of PCa. Genotypes of four common single-nucleotide polymorphisms (SNPs) of PTX3 gene, including rs1840680, rs2305619, rs3816527 and rs2120243, were profiled among 705 PCa patients and 705 ethnicity-matched controls. In this study, we found that patients who carry at least one minor allele (C) of rs3816527 (AC and CC) tended to develop advanced forms of diseases (clinical large T stage, OR, 1.593, p = 0.032; pathologically-confirmed nodal spread, OR, 1.987, p = 0.011; metastatic tumour, OR, 3.896, p = 0.032) as compared with those homologous for the major allele (AA). Further stratification analysis showed that such association of rs3816527 with lymphatic and distal metastasis of PCa was accentuated in the younger age group (≤65 at diagnosis) but not seen in the older age group (>65 at diagnosis), suggesting an age-specific effect of PTX3 variants. Prediction of PTX3 protein structure implied that polymorphism may alter the quaternary organization and oligomerization of PTX3 protein. Moreover, our gene silencing experiments and survey of public datasets revealed that elevation of PTX3 levels in PCa was required for cell migration and associated with tumour metastasis. Our results highlight an association of PTX3 rs3816527 with the progression of PCa.

The Anti-Metastatic Action of Oxyresveratrol via Suppression of Phosphoryl-ERK/-PKCα-Mediated Sp1/MMP1 Signaling in Human Renal Carcinoma Cells.

Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.

Contribution of Matrix Metalloproteinase-7 Genotypes to Endometriosis Risk in Taiwan.

BACKGROUND/AIM: The activity and expression of matrix metalloproteinase-7 (MMP7) have been found to be upregulated in the late stages of endometriosis. However, the contribution of MMP7 genotype to endometriosis has seldom been examined. This study aimed to investigate the role of MMP7 promoter A-181G (rs11568818) and C-153T (rs11568819) genotypes in determining personal susceptibility to endometriosis in a Taiwanese cohort. PATIENTS AND METHODS: In this hospital-based case-control study, MMP7 genotypes were analyzed in 153 endometriosis and 636 individuals without endometriosis using typical polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The statistical analysis revealed that MMP7 rs11568818 genotypes were differentially distributed between the endometriosis and control groups (p for trend=0.0048). Specifically, the MMP7 rs11568818 homozygous variant GG was associated with endometriosis risk compared to the wild-type AA genotype (OR=4.59, 95% CI=1.46-14.48, p=0.0136). However, the MMP7 rs11568818 heterozygous variant AG was not associated with endometriosis risk (OR=1.57, 95% CI=0.97-2.53, p=0.0854). The frequency of than variant allele G of MMP7 rs11568818 was 12.7% in the endometriosis group, significantly higher than the 7.2% observed in the control group (OR=1.90, 95% CI=1.27-2.82, p=0.0021). CONCLUSION: MMP7 rs11568818 GG genotype was found to be a novel marker for endometriosis risk in Taiwanese.

Renoprotective effect of rosmarinic acid by inhibition of indoxyl sulfate-induced renal interstitial fibrosis via the NLRP3 inflammasome signaling.

We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1ß/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1ß showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1ß/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1ß, collagen I, fibronectin and α-SMA, and TGF- ß 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.

Asiatic acid inhibits osteosarcoma cell migration and invasion via the AKT/Sp1/MMP1 axis.

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti-tumor, anti-inflammatory, and anti-oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non-toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down-regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA-induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti-invasive effect of AA on osteosarcoma cells via the p-AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma.

Tricetin suppresses the cell migration and BMP-6 expression through p38 signaling pathways in human retinal pigment epithelium cells.

Proliferative vitreoretinopathy (PVR) is a visual-threatening disease, which cause from the migration of retinal pigment epithelium (RPE). Tricetin, a family of flavonoids, can inhibit the metastasis of several cancers. Herein, we aim to evaluate the possible effect of tricetin on inhibiting ARPE-19 cells migration. The Boyden chamber assay, wound healing assay, RNA sequencing, and Western blot analysis were applied in our experiment. The results revealed that tricetin inhibited the cell migration abilities of ARPE-19 cells. Moreover, using RNA sequencing technology, we revealed that tricetin repressed bone morphogenetic protein-6 (BMP-6) gene expressions in ARPE-19 cells. Overexpression of BMP-6 resulted in significant restoration of cell migration capabilities of tricetin-treated ARPE-19 cells. Furthermore, tricetin suppressed the phosphorylation of the p38 signaling pathway. Moreover, blocking the p38 pathway also inhibits BMP-6 expression and migration in the ARPE-19 cells. In conclusion, this study revealed that tricetin inhibits the ARPE-19 cell migration mainly via the suppression of BMP-6 expression and p38 signaling pathway.

Curcumin Analog L48H37 Induces Apoptosis in Human Oral Cancer Cells by Activating Caspase Cascades and Downregulating the Inhibitor of Apoptosis Proteins through JNK/p38 Signaling.

L48H37 is a synthetic curcumin analog that has anticancer potentials. Here, we further explored the anticancer effect of L48H37 on oral cancer cells and its mechanistic acts. Cell cycle distribution was assessed using flow cytometric analysis. Apoptosis was elucidated by staining with PI/Annexin V and activation of the caspase cascade. Cellular signaling was explored using apoptotic protein profiling, Western blotting, and specific inhibitors. Our findings showed that L48H37 significantly reduced the cell viability of SCC-9 and HSC-3 cells, resulting in sub-G1 phase accumulation and increased apoptotic cells. Apoptotic protein profiling revealed that L48H37 increased cleaved caspase-3, and downregulated cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) in SCC-9 cells, and the downregulated cIAP1 and XIAP in both oral cancer cells were also demonstrated by Western blotting. Meanwhile, L48H37 triggered the activation of caspases and mitogen-activated protein kinases (MAPKs). The involvement of c-Jun N-terminal kinase (JNK) and p38 MAPK (p38) in the L48H37-triggered apoptotic cascade in oral cancer cells was also elucidated by specific inhibitors. Collectively, these findings indicate that L48H37 has potent anticancer activity against oral cancer cells, which may be attributed to JNK/p38-mediated caspase activation and the resulting apoptosis. This suggests a potential benefit for L48H37 for the treatment of oral cancer.

MAOB expression correlates with a favourable prognosis in prostate cancer, and its genetic variants are associated with the metastasis of the disease.

Monoamine oxidase B (MAOB), a neurotransmitter-degrading enzyme, was reported to reveal conflicting roles in various cancers. However, the functional role of MAOB and impacts of its genetic variants on prostate cancer (PCa) is unknown. Herein, we genotyped four loci of MAOB single-nucleotide polymorphisms (SNPs), including rs1799836 (A/G), rs3027452 (G/A), rs6651806 (A/C) and rs6324 (G/A) in 702 PCa Taiwanese patients. We discovered that PCa patients carrying the MAOB rs6324 A-allele exhibited an increased risk of having a high initial prostate-specific antigen (iPSA) level (>10 ng/mL). Additionally, patients with the rs3027452 A-allele had a higher risk of developing distal metastasis, particularly in the subpopulation with high iPSA levels. In a subpopulation without postoperative biochemical recurrence, patients carrying the rs1799836 G-allele had a higher risk of developing lymph node metastasis and recurrence compared to those carrying the A-allele. Furthermore, genotype screening in PCa cell lines revealed that cells carrying the rs1799836 G-allele expressed lower MAOB levels than those carrying the A-allele. Functionally, overexpression and knockdown of MAOB in PCa cells respectively suppressed and enhanced cell motility and proliferation. In clinical observations, correlations of lower MAOB expression levels with higher Gleason scores, advanced clinical T stages, tumour metastasis, and poorer prognosis in PCa patients were noted. Our findings suggest that MAOB may act as a suppressor of PCa progression, and the rs3027452 and rs1799836 genetic variants of MAOB are linked to PCa metastasis within the Taiwanese population.

Ellagic acid ameliorates renal fibrogenesis by blocking epithelial-to-mesenchymal transition.

Objectives: Ellagic acid (EA), a kind of polyphenol found in numerous fruits and vegetables, has anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-fibrotic effects against a variety of diseases, but its role in mediating renal fibrogenesis remains unknown. Materials and Methods: We used an in vivo mouse unilateral ureteral obstruction (UUO) model and an in vitro model with HK-2 cell lines treated with EA and transforming growth factor ß1 (TGF-ß1). The expression of epithelial-to-mesenchymal transition (EMT)-related proteins of UUO mice was examined using immunohistochemical staining. Liver function and renal function were evaluated using biochemical testing. Western blot analysis was used to determine the proteins related to EMT, and MTT assay was used to determine cell viability. Results: In UUO mice fed EA, both microscopical examination with immunohistochemical staining and western blotting protein analysis showed reduced expression of fibrotic (α-SMA, fibronectin, and collagen I)- and EMT (vimentin and N-cadherin)-related proteins, compared with sham control. In HK-2 cells treated with TGF-ß1, EA decreased motility as well as expression of α-SMA, collagen-I, fibronectin, N-cadherin, and vimentin. Conclusion: EA reduced the progression of the morphological transformations and concomitantly suppressed the expression of fibrotic- and EMT-related proteins in vitro and in vivo. These findings improved our understanding of the role of EA in suppressing renal fibrogenesis and demonstrated the promising role EA may play in the management of chronic kidney disease.

Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

A longitudinal epidemiology study of fluoroquinolone-nonsusceptible Klebsiella pneumoniae reveals an increasing prevalence of qnrB and qnrS in Taiwan.

BACKGROUND: Our objective was to investigate the prevalence of plasmid-mediated quinolone resistance (PMQR) genes in fluoroquinolone-nonsusceptible Klebsiella pneumoniae (FQNSKP) in Taiwan, 1999-2022. METHODS: A total of 938 FQNSKP isolates were identified from 1966 isolates. The presence of PMQR and virulence genes, antimicrobial susceptibility, capsular types, and PMQR-plasmid transferability were determined. RESULTS: An increasing number of PMQR-containing FQNSKP isolates were observed over the study period. Our results showed that 69.0% (647 isolates) of FQNSKP isolates contained at least one PMQR gene, and 40.6%, 37.0%, and 33.9% of FQNSKP carried aac(6')-Ib-cr, qnrB, and qnrS, respectively. None of FQNSKP carried qepA and qnrC. The most common combination of PMQR genes was aac(6')-Ib-cr and qnrB (12.3%). The presence of PMQR genes is strongly related to resistance to aminoglycoside, cephalosporin, tetracycline, and sulfamethoxazole/trimethoprim in FQNSKP. The capsular serotype K64 is the most common serotype we tested in both the non-PMQR and PMQR FQNSKP isolates, while K20 showed a higher prevalence in PMQR isolates. The magA and peg-344 genes showed a significantly higher prevalence rate in non-PMQR isolates than in PMQR isolates. Eleven isolates that carried the PMQR and carbapenemase genes were identified; however, three successful transconjugants showed that the PMQR and carbapenemase genes were not located on the same plasmid. CONCLUSIONS: Our results indicated an increasing prevalence of PMQR genes, especially qnrB and qnrS, in FQNSKP in Taiwan. Moreover, the distribution of PMQR genes was associated with capsular serotypes and antimicrobial resistance gene and virulence gene distribution in FQNSKP.

HO-3867, a curcumin analog, elicits cell apoptosis and p38-mediated caspase activation in hepatocellular carcinoma.

HO-3867, a synthetic curcumin analog, has displayed various tumor-suppressive characteristics and improved bioabsorption over its parent compound. However, its influences on the development of hepatocellular carcinoma (HCC) are poorly defined. To address this, we tested the anticarcinogenic impact of HO-3867 and investigated the underlying mechanisms in fighting liver cancer. Our result demonstrated that HO-3867 reduced the viability of HCC cells, accompanied by promotion of cell cycle arrest at the sub-G1 stage and apoptotic responses. Furthermore, a distinctive profile of apoptosis associated proteins, encompassing elevated heme oxygenase-1 (HO-1) level and caspase activation, was detected in HO-3867-stimulated HCC cells. In addition, such HO-3867-mediated elevation in caspase activation was dampened by pharmacological suppression of p38 activities. Taken together, our findings unveiled that HO-3867 triggered cell cycle arrest and apoptotic events in liver cancer, involving a p38-mediated activation of caspase cascades. These data highlighted a usefulness of curcumin or its analogs on the management of hepatocarcinogenesis.

Corosolic acid inhibits metastatic response of human renal cell carcinoma cells by modulating ERK/MMP2 signaling.

Corosolic acid (CA), a plant-derived pentacyclic triterpenoid, has potent anti-inflammatory, anti-metabolic, and anti-neoplastic actions against a variety of human cancers. However, the specific mechanism by which CA inhibits the progression of renal cell carcinoma (RCC) is yet unclear. We found that CA (≤8 µM) had no influence on either the growth or viability of RCC cell lines (786-O, ACHN, and Caki-1) or normal HK2 cells. However, in a dose-dependent manner, CA prevented the invasion and migration of RCC cells. Human protease array analysis showed that CA reduced MMP2 expression. At increasing concentrations of CA, the expression of MMP2 was dose-dependently reduced, as shown by western blot and RT-PCR analyses as well as immunofluorescence staining. CA also stimulated ERK1/2 phosphorylation in 786-O and Caki-1 cells. Transfection of CA-treated RCC cells with siRNA-ERK restored MMP2 protein expression and the motility and invasion capabilities of RCC cells. Molecular docking study results showed that CA and MMP2 interact strongly. These findings elucidate the mechanism by which CA prevents RCC cells from migrating and invading, and these findings indicate that CA may be a potential anti-metastatic therapy for RCC.

Loss of MTA2-mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK-MMP7 axis.

The expression of metastasis tumor-associated protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) is associated with hepatocellular carcinoma (HCC) progression. However, the functional effect and mechanism through which MTA2 regulates PTK7-mediated HCC progression remains unclear. Here, we found that MTA2 knockdown significantly down-regulated PTK7 expression in HCC cells (SK-Hep-1 and PLC/PRF/5). Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases show that the PTK7 expression level was higher in HCC tissues than in normal liver tissues. In HCC patients, the PTK7 expression level clearly correlated with tumor stage and grade, lower overall survival (OS) correlated positively with MTA2 level, and PTK7 expression acted as a downstream factor for MTA2 expression. In addition, matrix metalloproteinase 7 (MMP7) expression was closely regulated by PTK7, and the mRNA and protein expression levels of MTA2 and PTK7 correlated positively with lower OS. MMP7 downregulation by PTK7 knockdown clearly decreased the migration and invasion abilities of HCC cells. In HCC cells, recombinant human MMP7 reversed the PTK7 knockdown-induced suppression of migration and invasion. Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF-573228, PF) synergistically contributed to PTK7 knockdown-inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2-FAK-MMP7 axis and may be a diagnostic value for HCC patients.

Morin inhibits osteosarcoma migration and invasion by suppressing urokinase plasminogen activator through a signal transducer and an activator of transcription 3.

Osteosarcoma, the most common primary bone cancer that affects adolescents worldwide, has the early metastatic potential to be responsible for high mortality rates. Morin has a multipurpose role in numerous cancers, whereas little is known about its role in osteosarcoma migration and invasion. Therefore, we hypothesized that morin suppresses the invasive activities and the migratory potential of human osteosarcoma cells. Our results showed that morin reduced migration and invasion capabilities in human osteosarcoma U2OS and HOS cells. Moreover, morin inhibited the urokinase plasminogen activator (uPA) expression through a signal transducer and an activator of transcription-3 (STAT3) phosphorylation. After STAT3 overexpression, the decrease of the migratory potential and uPA expression caused by 100 µM of morin in U2OS cells was countered, indicating that STAT3 contributes to the antimetastatic property of morin in human osteosarcoma cells by reducing uPA. In conclusion, morin may be a potential candidate for the antimetastatic treatment of human osteosarcoma.

Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation.

Magnolin (MGL), a compound derived from the magnolia plant, has inhibitory effects on tumor cell invasion and growth. His study aims to explore the antitumor effect and underlying molecular mechanism of MGL against human cervical cancer. We found that MGL inhibited the proliferation, migration, and invasiveness of cervical cancer cells in vitro and in vivo. The underlying mechanism was shown to involve MGL-induced inhibition of JNK/Sp1-mediated MMP15 transcription and translation. Overexpression of JNK/Sp1 resulted in significant restoration of MMP15 expression and the migration and invasion capabilities of MGL-treated cervical cancer cells. MGL modulated the cervical cancer microenvironment by inhibiting cell metastasis via targeting IL-10/IL-10 receptor B (IL-10RB) expression, thereby attenuating JNK/Sp1-mediated MMP15 expression. Analysis of the gut microbiota of mice fed MGL revealed a significant augmentation in Lachnospiraceae bacteria, known for their production of sodium butyrate. In vivo experiments also demonstrated synergistic inhibition of cervical cancer cell metastasis by MGL and sodium butyrate co-administration. Our study provides pioneering evidence of a novel mechanism by which MGL inhibits tumor growth and metastasis through the IL-10/IL-10RB targeting of the JNK/Sp1/MMP15 axis in human cervical cancer cells.

Utilizing Graph Neural Networks for Breast Cancer Prognosis Prediction with High-dimensional Genomic Data.

An accurate prediction of breast cancer is essential to help physicians make appropriate treatment recommendations to reduce the chance of excessive treatment, avoiding unnecessary anxiety for patients. Cancer prognosis is highly related to patients' genomic features, which are high-dimensional in nature. In this study, we utilize a systems biology feature selector for dimension reduction to select 20 prognostic biomarkers that are considered closely related to breast cancer prognosis from the high dimensional RNA Sequencing (RNA-Seq) data. Furthermore, we establish a graph neural network (GNN) and a multi-layer perception (MLP) graph-level readout method to better extract the underlying gene interactions from the corresponding gene interaction network (GIN). With the help of GINs, the model performs the best among all baseline models, especially in the area under the precision-recall curve (AUPRC) by as large as 23%. The results demonstrate that our approach using GNNs can successfully extract high-dimensional and complicated interactions within genomic data.

Meta-EHR: A meta-learning approach for electronic health records with a high imbalanced ratio and missing rate.

Data imbalance is a practical and crucial issue in deep learning. Moreover, real-world datasets, such as electronic health records (EHR), often suffer from high missing rates. Both issues can be understood as noises in data that may lead to bad generalization results for standard deep-learning algorithms. This paper introduces a novel meta-learning approach to deal with these noise issues in an EHR dataset for a binary classification task. This meta-learning approach leverages the information from a selected subset of balanced, low-missing rate data to automatically assign proper weight to each sample. Such weights would enhance the informative samples and suppress the opposites during training. Furthermore, the meta-learning approach is model-agnostic for deep learning-based architectures that simultaneously handle the high imbalanced ratio and high missing rate problems. Through experiments, we demonstrate that this meta-learning approach is better in extreme cases. In the most extreme one, with an imbalance ratio of 172 and a 74.6% missing rate, our method outperforms the original model without meta-learning by as much as 10.3% of the area under the receiver-operating characteristic curve (AUROC) and 3.2% of the area under the precision-recall curve (AUPRC). Our results mark the first step towards training a robust model for extremely noisy EHR datasets.

X-RIM: Extreme Recurrent Independent Mechanisms for Noise-resistant and Interpretable Stroke Risk Prediction.

Stroke is a leading cause of mortality and long-term disability worldwide. An accurate stroke risk prediction is crucial for its early detection and prevention. Using deep learning to exploit patients' time-series electronic health records (EHRs) has been shown as a promising and efficient solution for such a prediction. Although time-series data could be more informative than a single cross-section in time, real-world time-series EHRs usually have a significantly high missing rate due to irregular patient visits. This could undermine sequential data's benefits unless a proper deep-learning model design is adopted. Furthermore, deep models have long been challenged for their interpretability, which is especially crucial for medical applications. In this study, we propose an extreme design based on the concept of recurrent independent mechanisms (RIM), termed extreme RIM (X-RIM). With no need for imputation, X-RIM utilizes the information of each input feature's temporal records through independent recurrent modules. Experiments on real-world data from the National Taiwan University Hospital showed that, in terms of the area under the precision-recall curve (AUPRC), the area under the receiver-operating characteristics curve (AUROC), and Youden Index, X-RIM (AUPRC: 0.210; AUROC: 0.764; Youden: 0.373) outperformed the classic risk score CHA2DS2-VASc (AUPRC: 0.103; AUROC: 0.650; Youden: 0.223) and other benchmarks in stroke risk prediction. Additional experiments also indicate that individual feature contributions to a prediction could be evaluated intuitively under X-RIM's independent structure to enhance interpretability.

Alpha-mangostin alleviate renal interstitial fibrosis via suppression of TGF-ß1/Smad/ERK signaling axis in vitro and in vivo.

α-mangostin (α-MG), a natural derivative of coumarin, exhibits anti-inflammatory, antioxidant and anti-fibrotic effects. This study aimed to determine the effect of α-MG treatment in mediating the process of renal interstitial fibrosis. We found that α-MG could alleviate tubule-interstitial damage and decrease fibrotic (α-smooth muscle actin [α-SMA], fibronectin, and collagen I), and epithelial-mesenchymal transition (EMT) protein (N-cadherin, Snail, Slug, TGF-ß1 and vimentin) expression in unilateral ureteral obstruction (UUO) mice with chronic kidney disease. α-MG significantly decreased motility as well as inhibited expression of fibrotic- and EMT-related proteins in TGF-ß1-induced HK2 cells. To clarify the molecular mechanisms of α-MG in reducing renal interstitial fibrosis, we used a MEK inhibitor (U0126) or Smad inhibitor (SB431542) cotreatment with α-MG. This is the first study is to demonstrate the antifibrotic effects of α-MG by targeting the TGF-ß1/ERK/Smad-mediated EMT signaling pathway, is even more effective against renal interstitial fibrosis.