K2S2O8-mediated direct C-H heteroarylation/hydroxylation of indolin-2-ones with quinoxalin-2(1H)-ones.

Herein, a K2S2O8-mediated direct heteroarylation and hydroxylation reaction between quinoxalin-2(1H)-ones with a C(sp2)-H bond and indolin-2-ones with a C(sp3)-H bond via an oxidative cross-coupling reaction has been reported. We have successfully established a feasible and concise reaction system that represents the first example of free-radical-promoted heteroarylation and hydroxylation reaction on the C-3 position of oxindole. A series of 3-substituted 3-hydroxyoxindoles are obtained in 0-83% yield using this methodology.

Role of TRPM2 in brain tumours and potential as a drug target.

Ion channels are ubiquitously expressed in almost all living cells, and are the third-largest category of drug targets, following enzymes and receptors. The transient receptor potential melastatin (TRPM) subfamily of ion channels are important to cell function and survival. Studies have shown upregulation of the TRPM family of ion channels in various brain tumours. Gliomas are the most prevalent form of primary malignant brain tumours with no effective treatment; thus, drug development is eagerly needed. TRPM2 is an essential ion channel for cell function and has important roles in oxidative stress and inflammation. In response to oxidative stress, ADP-ribose (ADPR) is produced, and in turn activates TRPM2 by binding to the NUDT9-H domain on the C-terminal. TRPM2 has been implicated in various cancers and is significantly upregulated in brain tumours. This article reviews the current understanding of TRPM2 in the context of brain tumours and overviews the effects of potential drug therapies targeting TRPM2 including hydrogen peroxide (H2O2), curcumin, docetaxel and selenium, paclitaxel and resveratrol, and botulinum toxin. It is long withstanding knowledge that gliomas are difficult to treat effectively, therefore investigating TRPM2 as a potential therapeutic target for brain tumours may be of considerable interest in the fields of ion channels and pharmacology.

TRPM2-AS inhibits the growth, migration, and invasion of gliomas through JNK, c-Jun, and RGS4.

Gliomas are a group of brain cancers with high mortality and morbidity. Understanding the molecular mechanisms is important for the prevention or treatment of gliomas. The present study was to investigate the effects and mechanisms of long noncoding RNA TRPM2-AS in gliomas proliferation, migration, and invasion. We first compared the levels of TRPM2-AS in 111 patients with glioma to that of the normal control group by a quantitative polymerase chain reaction. The results indicated a significant increase of TRPM2-AS in patients with glioma (2.43 folds of control, p = .0135). MTT methods, wound healing assays, transwell analysis, and clone formation analysis indicated the overexpression of TRPM2-AS promoted the proliferation, migration, and invasion of U251 and U87 cells, while downregulation of TRPM2-AS inhibited the cell proliferation, migration, and invasion significantly (p < .05). To further uncover the mechanisms, bioinformatics analysis was conducted on the expression profiles, GSE40687 and GSE4290, from the Gene Expression Omnibus database. One hundred fifty-six genes were differentially expressed in both datasets (FC > 2.0; p = .05). Among these differentially expressed genes, the level of RGS4 messenger RNA was drastically regulated by TRPM2-AS. Further western-blot analysis indicated the increase of RGS4 protein expression and decrease of p-JNK/JNK and p-c-Jun/c-Jun ratio after TRPM2-AS overexpression. On the other hand, inhibition of TRPM2-AS by small interfering RNA suppressed the expression of RGS4 and promoted the ratios of p-JNK/JNK and p-c-Jun/c-Jun. The present work indicated the mechanisms of the participation of TRPM2-AS in the progression of gliomas might, at least partly, be related to JNK, c-Jun, and RGS4. Our work provided new insights into the underlying mechanisms of glioma cellular functions.

A Novel Putative Role of TNK1 in Atherosclerotic Inflammation Implicating the Tyk2/STAT1 Pathway.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations. The present study was to investigate the anti-inflammatory functions and mechanisms of TNK1 in atherosclerosis. METHODS: The ApoE(-/-) mice and human carotid endarterectomy (CEA) atherosclerotic plaques were used to investigate the differential expression of TNK1. The ApoE(-/-) mice were fed with high-fat diet (HFD) or normal-fat diet (NFD) for 8 weeks; the aorta was separated and stained with oil red O to evaluate the formation of atherosclerosis. TNK1 in mice aorta was measured by qPCR. The human CEA were obtained and identified as ruptured and stable plaques. The level of TNK1 was measured by qPCR and Western-blot staining. Further studies were conducted in THP-1 cells to explore the anti-inflammatory effects of TNK1. We induced the formation of macrophages by incubating THP-1 cells with PMA (phorbol 12-myristate 13-acetate). Afterwards, oxidized low-density lipoprotein (oxLDL) was used to stimulate the inflammation, and the secretion of inflammatory factors was measured by ELISA and qPCR. The levels of TNK1, total STAT1 and Tyk2, and the phosphorylation of STAT1 and Tyk2 were measured by western blot to uncover the mechanisms of TNK1. RESULTS: The oil red O staining indicated obvious deposition of lipid on the aorta of ApoE(-/-) mice after 8-week HFD treatment. The TNK1 level was much higher in both the HFD-fed ApoE(-/-) mice aorta arch and the ruptured human CEA plaques. We found that TNK1 was highly expressed in THP-1 cells, compared to other atherosclerotic related cells (HUVEC, HBMEC, and HA-VSMC), indicating TNK1 might be involved in the inflammation. Suppressing the expression of TNK1 by shTNK1 inhibited the oxLDL-induced secretion of inflammatory factors, such as IL-12, IL-6, and TNF-α. ShTNK1 also inhibited the uptake of lipid and decreased the cellular cholesterol content in THP-1 cells. Furthermore, the shTNK1 suppressed the oxLDL-induced phosphorylation of Tyk2 and STAT1. CONCLUSION: TNK1 participated in the inflammation in atherosclerosis. shTNK1 suppressed the oxLDL-induced inflammation and lipid deposition in THP-1 cells. The mechanism might be related to the Tyk2/STAT signal pathway.

Long Noncoding RNA LINC00657 Acting as a miR-590-3p Sponge to Facilitate Low Concentration Oxidized Low-Density Lipoprotein-Induced Angiogenesis.

Angiogenesis in atherosclerotic plaque promotes plaque growth, causes plaque hemorrhage, and violates plaque stability. LINC00657 is a long noncoding RNA highly conserved and abundantly expressed in vascular endothelial cells. The present study was designed to investigate the effects and mechanisms of LINC00675 on low concentrations of oxidized low-density lipoprotein (oxLDL)-induced angiogenesis. Cell proliferation, transwell, wound healing, and tube formation assays were conducted to detect the effects of low concentrations of oxLDL on angiogenesis; the results discovered that oxLDL promoted cell proliferation, migration, and tube formation. oxLDL also upregulated LINC00657 expression. Inhibition of LINC00657 by siRNA significantly suppressed oxLDL-induced endothelial cell proliferation, migration, and tube formation. Bioinformatic assay indicated six binding sites in the LINC00657 sequence to miR-590-3p. The upregulation of LINC00657 was related to the downregulation of miR-590-3p in oxLDL-treated endothelial cells; while downregulation of LINC00657 resulted in upregulation of miR-590-3p. The antiangiogenesis effects of si-LINC00657 were partly abrogated by miR-590-3p inhibitor. Further dual-luciferase assay found miR-590-3p inhibited the expression of hypoxia-inducible factor 1α (HIF-1α) by binding to the position of 689-696 in HIF-1α 3'-untranslated region directly. MiR-590-3p also inhibited the oxLDL-induced upregulation of HIF-1α, vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). These results suggested that in oxLDL-treated endothelial cells, LINC00657 acted as a miR-590-3p sponge to attenuate the suppression of miR-590-3p on HIF-1α, and to promote angiogenesis through VEGF, MMP-2, and MMP-9. The present study provided new insight into the roles of LINC00657 and miR-590-3p in preventing oxLDL-induced angiogenesis and may provide a novel strategy for atherosclerosis treatment.

Pharmacological approaches promoting stem cell-based therapy following ischemic stroke insults.

Stroke can lead to long-term neurological deficits. Adult neurogenesis, the continuous generation of newborn neurons in distinct regions of the brain throughout life, has been considered as one of the appoaches to restore the neurological function following ischemic stroke. However, ischemia-induced spontaneous neurogenesis is not suffcient, thus cell-based therapy, including infusing exogenous stem cells or stimulating endogenous stem cells to help repair of injured brain, has been studied in numerous animal experiments and some pilot clinical trials. While the effects of cell-based therapy on neurological function during recovery remains unproven in randomized controlled trials, pharmacological agents have been administrated to assist the cell-based therapy. In this review, we summarized the limitations of ischemia-induced neurogenesis and stem-cell transplantation, as well as the potential proneuroregenerative effects of drugs that may enhance efficacy of cell-based therapies. Specifically, we discussed drugs that enhance proliferation, migration, differentiation, survival and function connectivity of newborn neurons, which may restore neurobehavioral function and improve outcomes in stroke patients.

Effect of Oridonin on Cytochrome P450 Expression and Activities in HepaRG Cell.

Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 µmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay. In general, ordonin has induced effects on the major member of CYP450s mRNA and protein expression, as well as on the enzyme activity in human HepaRG cells, especially on CYP3A4 and CYP2C9. To our knowledge, this is the first systematic research about the inductive effects of oridonin on the major member of CYP450s in human cell line. These results may provide at least partly of the basis for potential drug-drug interactions and oridonin should be used with caution to avoid potential risk.

Meta-Analysis on the Association between Brain-Derived Neurotrophic Factor Polymorphism rs6265 and Ischemic Stroke, Poststroke Depression.

BACKGROUND: Ischemic stroke is a multifactorial neurologic injury that causes mortality and disability worldwide. Poststroke depression is the most important neuropsychiatric consequence of stroke. Brain-derived neurotrophic factor is a neurotrophin family member that plays key role in regulating neuron survival and differentiation. Studies found a polymorphism in brain-derived neurotrophic factor gene (rs6265) may associate with the ischemic stroke and poststroke depression risk. However, the results are inconclusive and inconsistent. METHODS: In the present meta-analysis, the database PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI, and Chinese Biomedical Literature Database were searched until July 9, 2017. RESULTS: Seven studies with 1287 cases and 1032 controls were included for the meta-analysis of ischemic stroke, and five studies with 272 cases and 503 controls were included for poststroke depression. The results indicated that the GG genotype of brain-derived neurotrophic factor is related to a significantly lower risk of ischemic stroke in the homozygous and dominant models (odds ratio = .57 and .80, respectively). No significant relation was found between rs6265 and poststroke depression. CONCLUSIONS: Thus, brain-derived neurotrophic factor rs6265 might be recommended as a predictor of susceptibility of ischemic stroke. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity between studies and low sample size. Further studies are needed to evaluate the associations between rs6265 and poststroke depression, especially in Caucasians, with large sample size.

Rs4265085 in GPER1 gene increases the risk for unexplained recurrent spontaneous abortion in Dai and Bai ethnic groups in China.

Oestrogen receptors are implicated in the pathogenesis of recurrent spontaneous abortion (RSA). Non-genomic oestrogen responses can be mediated by GPER. The prevalence of polymorphisms in GPER1 gene in RSA was assessed in 747 Chinese women from Yunnan province (171 Bai, 258 Chinese Han, 234 Dai, 33 Achang and 51 Jingpo patients). Snapshot technology was used for genotyping the polymorphisms of the GPER1 gene. The rs4265085G was significantly increased in the Dai and Bai groups versus controls (Dai: P < 0.0001, Padj < 0.0001, OR 95% CI 2.34 [1.79 to 3.05]; Bai: P = 0.0004, Padj = 0.0012, OR 95% CI 1.71 [1.27 to 2.31]); recessive model of rs4265085 in the Dai (P = 0.003, Padj = 0.009, OR 95% CI 2.71 [1.38 to 5.30]); Bai (P < 0.0001, Padj < 0.0001, OR 95% CI 3.37 [1.93 to 5.91]). Haplotype frequencies containing rs10269151G-rs4265085G-rs11544331C were separately significantly different in Dai and Bai ethnic groups (Dai: P = 0.0002, Padj = 0.001, OR 95% CI = 2.12 [1.43 to 3.17]; Bai: P = 0.005, Padj = 0.025, OR 95% CI = 1.82 [1.18 to 2.78]) compared with controls. The intron variant rs4265085 may confer risk for RSA in Dai and Bai ethnic groups.

NF-κB-Regulated miR-99a Modulates Endothelial Cell Inflammation.

Objective. The present study was performed to investigate the effects and mechanisms of miR-99a on LPS-induced endothelial cell inflammation, as well as the regulation of NF-κB on miR-99a production. Methods and Results. ELISA showed that LPS treatment significantly promoted the secretion of inflammatory factors (TNF-α, IL-6, IL-1ß, and MCP-1). LPS treatment also inhibited miR-99a production and promoted mTOR expression and NF-κB nuclear translocation. Overexpression of miR-99a suppressed the LPS-induced TNF-α, IL-6, IL-1ß, and MCP-1 overproduction, mTOR upregulation, and NF-κB nuclear translocation. The PROMO software analysis indicated NF-κB binding site in the -1643 to -1652 region of miR-99a promoter. Dual luciferase reporter analysis, electrophoretic mobility shift assays (EMSA), and chromosome immunoprecipitation (ChIP) assays demonstrated that NF-κB promoted the transcription of miR-99a by binding to the -1643 to -1652 region of miR-99a promoter. Further studies on HUVECs verified the regulatory effects of NF-κB on miR-99a production. Conclusion. MiR-99a inhibited the LPS-induced HUVECs inflammation via inhibition of the mTOR/NF-κB signal. NF-κB promoted miR-99a production by binding to the -1643 to -1652 region of miR-99a promoter. Considering the importance of endothelial inflammation on cardiovascular diseases, such as atherosclerosis, our results may provide a new insight into the pathogenesis and therapy of atherosclerosis.

Meta-Analysis of miR-146a Polymorphisms Association with Coronary Artery Diseases and Ischemic Stroke.

Coronary artery disease (CAD) and ischemic stroke (IS) are manifestations of atherosclerosis, with a high death rate. miR-146a is a microRNA that participates in the progress of CAD and IS. A single nucleotide polymorphism (SNP) in the precursor of miR-146a, rs2910164, was found to be associated with the risks of CAD and IS. However, the results were inconsistent and inconclusive. A meta-analysis was performed to assess the relationship of rs2910164 and CAD as well as IS susceptibility. The database Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) were searched for related studies. Crude odds ratios with 95% confidence intervals were used to investigate the strength of the association by random- or fixed-effect model. A total of eight studies, with 3138 cases and 3097 controls were identified for the meta-analysis. The results shows that rs2910164 is associated with the risk of CAD significantly in allelic model (OR = 0.86), homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying the GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large sample size group and in Koreans, under homozygous and dominant models. In conclusion, the current meta-analysis suggests lower risks of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS.

Analysis of Niemann-Pick C1-like 1 (NPC1L1) genetic polymorphisms and haplotypes in Chinese Han population.

Niemann-Pick C1-like 1 (NPC1L1i) protein is the key transporter responsible for dietary cholesterol absorption. Recent studies indicated that several functional polymorphisms of NPC1L1 were associated with coronary heart disease (CHD) and response to ezetimibe therapy. The aim of the present study was to analyze the allele frequency and haplotype distribution of NPC1L1 polymorphisms in Chinese Hans and to compare them with those of other ethnic populations reported before. Blood samples were collected from 424 unrelated Chinese Hans (246 males and 178 females). Ten NPC1L1 polymorphisms (-762T > C, -133A > G, -18C > A, 1721C > T, 1735C > G, 1764T > C, 1767G > A, 27677T > C, 25342A > C and 28650A > G) were genotyped by direct sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Among the variants, the minor allele frequency of -762T > C and 1735C > G were 35.0% and 37.0%, respectively. Furthermore, these two polymorphisms were highly linked with a D' value of 0.80. The observed frequencies of two major haplotypes were 59.1% for T-762/C1735 and 30.1% for C-762/G1735, respectively. The frequencies of the rest variants were extremely low (1.8% for - 133G, 1.5% for -18A, 0.9% for 1721T and only 0.2% for 27677C allele, respectively) or even not detected (1764T > C, 1767G > A, 25342A > C and 28650A > G) in our study population. Comparison with other ethnic populations revealed a remarkable genetic variability in the incidences of NPC1L1 polymorphisms. The frequencies of NPC1L1 polymorphisms in Chinese Hans are comparable to Japanese population but totally different from Caucasians, African-Americans and Hispanic individuals. This is the first study to report the ethnic difference in the frequencies of NPC1L1 functional polymorphisms in detail. -762T > C and 1735C > G are two prevalent NPC1L1 variants which need further studies to explore their clinical impact on CHD prevalence and response to ezetimibe therapy in Chinese Hans.

Puerarin protects endothelial cells from oxidized low density lipoprotein induced injuries via the suppression of LOX-1 and induction of eNOS.

Oxidized low density lipoprotein (oxLDL) induced injury of endothelial cells is considered to be the first step in the pathogenesis of atherosclerosis. This study aimed to investigate some of the effects and mechanisms of puerarin on oxLDL-induced endothelial injuries. We measured cell viability, and the release of lactate dehydrogenase (LDH), nitric oxide (NO), and interleukin-8 (IL-8) to evaluate the protective effects of puerarin. Intracellular reactive oxygen species (ROS) were detected using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The expression of lectin-like low-density lipoprotein receptor-1 (LOX-1), endothelial nitric oxide synthase (eNOS), cyclooxygenase 2 (COX-2), p38MAPK, and protein kinase B (PKB) phosphorylation, nuclear factor-κB (NF-κB) nuclear translocation, and inhibitor of κB (IκB) degradation were detected using quantitative real-time PCR or Western blot. The results showed that oxLDL significantly decreased cell viability, increased LDH and IL-8 release, inhibited NO production, and induced COX-2 expression. Pretreatment with puerarin led to a strong inhibition of these effects. OxLDL stimulated the expression of LOX-1, the overproduction of ROS, the phosphorylation of p38MAPK, the dephosphorylation of PKB, activation of NF-κB, and the degradation of IκB. These oxLDL-induced effects were suppressed after puerarin pretreatment. These results suggest that puerarin inhibits oxLDL-induced endothelial cell injuries, at least in part, via inhibition of the LOX-1-mediated p38MAPK-NF-κB inflammatory and the PKB-eNOS signaling pathways.

Unstable simple volatiles and gas chromatography-tandem mass spectrometry analysis of essential oil from the roots bark of Oplopanax horridus extracted by supercritical fluid extraction.

Volatile oil from the root bark of Oplopanax horridus is regarded to be responsible for the clinical uses of the title plant as a respiratory stimulant and expectorant. Therefore, a supercritical fluid extraction method was first employed to extract the volatile oil from the roots bark of O. horridus, which was subsequently analyzed by GC/MS. Forty-eight volatile compounds were identified by GC/MS analysis, including (S,E)-nerolidol (52.5%), τ-cadinol (21.6%) and S-falcarinol (3.6%). Accordingly, the volatile oil (100 g) was subjected to chromatographic separation and purification. As a result, the three compounds, (E)-nerolidol (2 g), τ-cadinol (62 mg) and S-falcarinol (21 mg), were isolated and purified from the volatile oil, the structures of which were unambiguously elucidated by detailed spectroscopic analysis including 1D- and 2D-NMR techniques.

Induction of human CYP3A4 by huperzine A, ligustrazine and oridonin through pregnane X receptor-mediated pathways.

The pregnane X receptor (PXR) is a key regulator of CYP3A4, which is involved in catalyzing the metabolic conversion of a number of endogenous substrates. In this study, we screened 22 compounds isolated from traditional Chinese herbal medicines using luciferase reporter gene assays for inspecting their capabilities in inducing PXR-mediated transactivation of CYP3A4 expression. In addition, the mRNA and protein expressions of CYP3A4 and PXR as well as the enzymatic activites of CYP3A4 were analyzed by real-time PCR, Western blot analysis and UPLC-MS/MS-based metabolite assay in LS174T cells. Huperzine A, ligustrazine and oridonin were identified to be the inducers of CYP3A4. These compounds induced the CYP3A4 reporter luciferase activity, and up-regulated CYP3A4 mRNA and protein levels significantly. Besides, huperzine A, ligustrazine and oridonin significantly up-regulated enzymatic activities of CYP3A4. However, the three compounds showed no effects on PXR mRNA and protein expression. To our knowledge, it is the first identification of these three compounds as PXR activators to induce CYP3A4. These results indicate that huperzine A, ligustrazine and oridonin induced CYP3A4 expression and activation via PXR dependent pathways, and might contribute to drug-drug interactions.

LINC-PINT plays an anti-tumor role in nasopharyngeal carcinoma by binding to XRCC6 and affecting its function.

BACKGROUND: LINC-PINT was downregulated in nasopharyngeal carcinoma (NPC) and correlated with treatment efficiency of NPC. However, the underlying mechanism of LINC-PINT in NPC has not yet been fully explored. METHOD: We used CellTiter luminescent assay, clone formation assay, Hoechst staining, and SYTO-9/PI staining to examine cell viability and cell apoptosis regulated by LINC-PINT in NPC cells. Xenograft tumor model, HE staining, Ki67 staining, and TUNEL assay were conducted to assess the role of LINC-PINT in vivo. Bioinformatics and RNA immunoprecipitation assay was performed to identify the binding protein of LINC-PINT. Fluorescence in situ hybridization and immunofluorescence were utilized to measure the colocalization of XRCC6 with LINC-PINT and DNA-PKcs. Mito-Tracker red CMXRos staining was used to label mitochondria in cells specifically. RESULT: We found LINC-PINT was downregulated in many tumors (including NPC) and associated with poor prognosis. The cell viability was significantly inhibited and cell apoptosis was remarkably promoted in LINC-PINT overexpressed cells in contrast to control cells. The growth of tumor xenografts was significantly suppressed and the tumor weight was significantly decreased in LINC-PINT overexpression group compared to the control group. Correspondingly, the positive Ki67 foci was decreased while TUNEL foci was increased in LINC-PINT overexpression group. Mechanically, we verified XRCC6 as a new binding protein of LINC-PINT through RNA binding domains prediction, RIP and colocalization of LINC-PINT and XRCC6. By binding to XRCC6, LINC-PINT interfered the formation of DNA-PK complex, regulated mitochondria accumulation status and affected the modification of apoptosis proteins, leading to more cell apoptosis. CONCLUSION: Our study provided the first evidence that LINC-PINT promotes cell apoptosis in NPC by binding to XRCC6 and affecting its function.

Explainable ensemble learning method for OCT detection with transfer learning.

The accuracy and interpretability of artificial intelligence (AI) are crucial for the advancement of optical coherence tomography (OCT) image detection, as it can greatly reduce the manual labor required by clinicians. By prioritizing these aspects during development and application, we can make significant progress towards streamlining the clinical workflow. In this paper, we propose an explainable ensemble approach that utilizes transfer learning to detect fundus lesion diseases through OCT imaging. Our study utilized a publicly available OCT dataset consisting of normal subjects, patients with dry age-related macular degeneration (AMD), and patients with diabetic macular edema (DME), each with 15 samples. The impact of pre-trained weights on the performance of individual networks was first compared, and then these networks were ensemble using majority soft polling. Finally, the features learned by the networks were visualized using Grad-CAM and CAM. The use of pre-trained ImageNet weights improved the performance from 68.17% to 92.89%. The ensemble model consisting of the three CNN models with pre-trained parameters loaded performed best, correctly distinguishing between AMD patients, DME patients and normal subjects 100% of the time. Visualization results showed that Grad-CAM could display the lesion area more accurately. It is demonstrated that the proposed approach could have good performance of both accuracy and interpretability in retinal OCT image detection.

CircMYBL1 suppressed acquired resistance to osimertinib in non-small-cell lung cancer.

Circular RNAs (circRNAs) play an important role in the development of acquired resistance to many anticancer drugs. We developed the Non-Small-Cell Lung Cancer (NSCLC) cell lines with acquired resistance to osimertinib, a third-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and evaluated the different expression profiles of circRNAs in osimertinib-sensitive and -resistant NSCLC cell lines using RNA sequencing (RNA-Seq). The expression of selected differentially expressed circRNAs was verified using quantitative real-time PCR (qRT-PCR) in paired osimertinib-sensitive and -resistant NSCLC cell lines, and in plasma samples of osimertinib-sensitive and -resistant NSCLC patients. We found that circMYBL1(has_circ_0136924) was downregulated after acquired resistance to osimertinib, inhibiting circMYBL1 expression facilitated the proliferation, migration, and invasion in osimertinib-sensitive NSCLC cells. CircMYBL1 may be a novel molecular biomarker and therapeutic target for osimertinib-resistant NSCLC.

Assessing causal associations of bile acids with obesity indicators: A Mendelian randomization study.

Maintaining a balanced bile acids (BAs) metabolism is essential for lipid and cholesterol metabolism, as well as fat intake and absorption. The development of obesity may be intricately linked to BAs and their conjugated compounds. Our study aims to assess how BAs influence the obesity indicators by Mendelian randomization (MR) analysis. Instrumental variables of 5 BAs were obtained from public genome-wide association study databases, and 8 genome-wide association studies related to obesity indicators were used as outcomes. Causal inference analysis utilized inverse-variance weighted (IVW), weighted median, and MR-Egger methods. Sensitivity analysis involved MR-PRESSO and leave-one-out techniques to detect pleiotropy and outliers. Horizontal pleiotropy and heterogeneity were assessed using the MR-Egger intercept and Cochran Q statistic, respectively. The IVW analysis revealed an odds ratio of 0.94 (95% confidence interval: 0.88, 1.00; P = .05) for the association between glycolithocholate (GLCA) and obesity, indicating a marginal negative causal association. Consistent direction of the estimates obtained from the weighted median and MR-Egger methods was observed in the analysis of the association between GLCA and obesity. Furthermore, the IVW analysis demonstrated a suggestive association between GLCA and trunk fat percentage, with a beta value of -0.014 (95% confidence interval: -0.027, -0.0004; P = .04). Our findings suggest a potential negative causal relationship between GLCA and both obesity and trunk fat percentage, although no association survived corrections for multiple comparisons. These results indicate a trend towards a possible association between BAs and obesity, emphasizing the need for future studies.

Unveiling the causal link between metabolic factors and ovarian cancer risk using Mendelian randomization analysis.

Background: Metabolic abnormalities are closely tied to the development of ovarian cancer (OC), yet the relationship between anthropometric indicators as risk indicators for metabolic abnormalities and OC lacks consistency. Method: The Mendelian randomization (MR) approach is a widely used methodology for determining causal relationships. Our study employed summary statistics from the genome-wide association studies (GWAS), and we used inverse variance weighting (IVW) together with MR-Egger and weighted median (WM) supplementary analyses to assess causal relationships between exposure and outcome. Furthermore, additional sensitivity studies, such as leave-one-out analyses and MR-PRESSO were used to assess the stability of the associations. Result: The IVW findings demonstrated a causal associations between 10 metabolic factors and an increased risk of OC. Including "Basal metabolic rate" (OR= 1.24, P= 6.86×10-4); "Body fat percentage" (OR= 1.22, P= 8.20×10-3); "Hip circumference" (OR= 1.20, P= 5.92×10-4); "Trunk fat mass" (OR= 1.15, P= 1.03×10-2); "Trunk fat percentage" (OR= 1.25, P= 8.55×10-4); "Waist circumference" (OR= 1.23, P= 3.28×10-3); "Weight" (OR= 1.21, P= 9.82×10-4); "Whole body fat mass" (OR= 1.21, P= 4.90×10-4); "Whole body fat-free mass" (OR= 1.19, P= 4.11×10-3) and "Whole body water mass" (OR= 1.21, P= 1.85×10-3). Conclusion: Several metabolic markers linked to altered fat accumulation and distribution are significantly associated with an increased risk of OC.