miR-21-5p-loaded bone mesenchymal stem cell-derived exosomes repair ovarian function in autoimmune premature ovarian insufficiency by targeting MSX1.

RESEARCH QUESTION: What is the effect of micro-RNA (miR)-21-5p-loaded bone marrow mesenchymal stem cell-derived exosomes (miR-21-Exo) on autoimmune premature ovarian insufficiency (POI)? DESIGN: The Cell Counting Kit 8 (CCK8) assay, fluorescence-activated cell sorting, western blotting, quantitative reverse transcriptase (qRT)-PCR and enzyme-linked immunosorbent assay (ELISA) verified the effect of miR-21-Exo on interferon-γ (IFN-γ)-induced KGN cells. qRT-PCR, western blotting and dual-luciferase reporter gene assays verified that miR-21-Exo mediated Msh homeobox 1 (MSX1) regulation of the Notch signalling pathway and that miR-21 interacted directly with MSX1. The effects of miR-21-Exo on the ovaries were verified by monitoring of the oestrous cycle, haematoxylin and eosin staining, follicle counts, ELISA, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL), western blotting and qRT-PCR. RESULTS: The results showed that miR-21-Exo promoted IFN-γ-induced KGN cell proliferation and hormone synthesis, and inhibited apoptosis. Using dual-luciferase reporter gene assays, miR-21 and MSX1 were shown to have direct interactions. Moreover, the findings elucidated that miR-21-Exo inhibited cell apoptosis and promoted hormone synthesis by mediating MSX1 to regulate the Notch signalling pathway. miR-21-Exo restored the ovarian structure in a mouse model of autoimmune POI, promoted endocrine function and proliferation, and inhibited apoptosis and inflammation in vivo. CONCLUSIONS: This study demonstrates that miR-21-Exo regulates the MSX1-mediated Notch signalling pathway to inhibit granulosa cell apoptosis and improve hormone synthesis function, providing insight into a potential mechanism of molecular therapy for the treatment of autoimmune POI.

Exosomes derived from mesenchymal stem cells attenuate NLRP3-related pyroptosis in autoimmune premature ovarian insufficiency via the NF-κB pathway.

RESEARCH QUESTION: What is the effect of exosomes derived from bone marrow mesenchymal stem cells (MSC-Exos) on the pyroptosis and recovery of granulosa cells in autoimmune premature ovarian insufficiency (POI)? DESIGN: In vitro, KGN cells were exposed to interferon-gamma to simulate immune injury. Samples were collected after a 48 h incubation with MSC-Exos (30 µg/ml). The cell viability, secretion of oestrogen and expression of key molecules in pyroptosis and the nuclear factor kappa B (NF-κB) pathway were tested. In vivo, the BALB/c mouse model of autoimmune POI model induced by zona pellucida glycoprotein 3 was used. Fertility testing and sample collection were applied 4 weeks after the ovarian subcapsular injection of MSC-Exos (150 µg for each ovary). Hormone concentration measurements, follicle counting and pyroptotic pathway analyses were conducted for each group. RESULTS: In vitro, MSC-Exos significantly promoted the proliferation rate and secretion of oestrogen, while at the same time suppressing apoptosis and pyroptosis. In vivo, exosomal treatment normalized the irregular oestrous cycles, rescued the follicular loss and increased the pregnancy rate and number of offspring in POI mice. Elevated serum concentrations of oestrogen and anti-Müllerian hormone, as well as decreased concentrations of FSH and interleukin-1ß, were shown. Furthermore, MSC-Exos down-regulated the expression of the NLRP3/Casp1/GSDMD pathway and inhibited activation of the NF-κB pathway. CONCLUSIONS: These findings demonstrate for the first time that MSC-Exos exert a significant effect on restoring ovarian function in autoimmune POI in vivo and in vitro by suppressing the NLRP3/Casp1/GSDMD pathway and pyroptosis. The NF-κB pathway may contribute to the regulation of NLRP3-related pyroptosis.

Asymmetric Total Synthesis of (+)-Phainanoid A and Biological Evaluation of the Natural Product and Its Synthetic Analogues.

Here, we report our detailed efforts toward the synthesis of phainanoids, a novel class of dammarane-type triterpenoids with potent immunosuppressive activities and unique structural features. Systematic model studies have been carried out, and efficient approaches have been established to construct the benzofuranone-based 4,5-spirocycle, the D/E/F tricyclic core, the [4.3.1] propellane, and the 5,5-oxaspirolactone moieties. The asymmetric synthesis of (+)-phainanoid A has been achieved through kinetic resolution of the tricyclic core followed by diastereoselective installation of the A/B/C and G/H rings and fragment coupling with the enantioenriched I/J rings. In addition, novel estrone-derived phainanoid analogues have been prepared. The immunosuppressive and cell survival assays revealed that (+)-phainanoid A and some of its synthetic analogues can specifically inhibit stimulation-induced lymphocyte proliferation but not cell survival at their effective concentrations. Preliminary structure-activity relationship information has been obtained, which could inspire future design of immunosuppressive phainanoid analogues.

Regulatory T Cells Overexpressing Peli1 Show Better Efficacy in Repairing Ovarian Endocrine Function in Autoimmune Premature Ovarian Insufficiency.

Regulatory T (Treg) cell dysfunction is involved in the pathogenesis of autoimmune premature ovarian insufficiency (POI). Adoptive transfer of Treg cells has been shown to be effective in the treatment of autoimmune POI in mice. However, the therapeutic effect of Treg cell therapy is limited because the phenotype and function of Treg cells is not properly maintained when they are reinfused in an inflammatory environment. Therefore, enhancing the function of Treg cells using genetic engineering is of great significance for improving the efficacy of Treg cells in the treatment of immune diseases. In this study, we investigated the role of the E3 ubiquitinated ligase Pellino 1 (Peli1) in the proliferation and immunosuppressive function of Treg cells and the therapeutic effect of Treg cells overexpressing Peli1 on autoimmune POI. The results showed that the overexpression of Peli1 promoted cell proliferation and enhanced the immunosuppressive function of Treg cells in vitro. After the adoptive transfer of Treg cells overexpressing Peli1 in autoimmune POI mice, the apoptosis rate of ovarian granulosa cells declined. The levels of the inflammatory inhibitors interleukin 10 and transforming growth factor-ß as well as the ovarian hormone estradiol were elevated. The number of primordial, primary, secondary, and mature follicles was restored to a certain extent compared with those in control subjects. These results revealed that the adoptive transfer of Treg cells overexpressing Peli1 promoted its efficacy against zona pellucida protein 3 peptide-induced POI, which provides new insights into the treatment of autoimmune POI.

Association of ESR1 gene polymorphisms with the susceptibility to Hepatitis B virus infection and the clinical outcomes.

Estrogen receptor alpha (ESR1) has been implicated in the pathological process of Hepatitis B virus (HBV) infection and is probably an important determinant for gender differences. In this study, a total of 975 subjects including 368 healthy controls, 323 hepatocellular carcinoma (HCC) patients with HBsAg positive, and 284 HBV-infected subjects without HCC were included. Three single nucleotide polymorphisms of ESR1 (rs2234693, rs2077647, rs2228480) were detected to investigate the correlation between ESR1 polymorphisms and the susceptibility to HBV persistence and the clinical outcomes. The association of ESR1 polymorphisms with HCC prognosis was investigated in our cohort enrolling 376 HBV-HCC patients. The frequency of rs2234693 C allele was lower in chronic Hepatitis B (CHB) and liver cirrhosis (LC) than that in HCC patients in the males (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.41-0.96). rs2228480 A allele was associated with increased risk of LC (AOR = 2.20, 95% CI = 1.06-4.56) in HBV genotype C, and significantly decreased the risk of HCC recurrence (p = 0.010) and ESR1 mRNA level in tumor tissues (p = 0.032). Haplotype C-G-G was associated with significantly increased risk of HBV persistence (OR = 1.37, 95% CI = 1.08-1.73), while it was opposite for C-A-G and T-G-G (OR = 0.41, 95% CI = 0.27-0.62; OR = 0.53, 95% CI = 0.32-0.85, respectively). These results imply that combinations of these ESR1 polymorphisms may be valuable for the prediction of HBV persistence.

Network and covariate adjusted response-adaptive design for binary response.

Randomization is a distinguishing feature of clinical trials for unbiased assessment of treatment efficacy. With a growing demand for more flexible and efficient randomization schemes and motivated by the idea of adaptive design, in this article we propose the network and covariate adjusted response-adaptive (NCARA) design that can concurrently manage three challenges: (1) maximizing benefits of a trial by assigning more patients to the superior treatment group randomly; (2) balancing social network ties across treatment arms to eliminate potential network interference; and (3) ensuring balance of important covariates, such as age, gender, and other potential confounders. We conduct simulation with different network structures and a variety of parameter settings. It is observed that the NCARA design outperforms four alternative randomization designs in solving the above-mentioned problems and has comparable power and type I error for detecting true difference between treatment groups. In addition, we conduct real data analysis to implement the new design in two clinical trials. Compared to equal randomization (the original design utilized in the trials), the NCARA design slightly increases power, largely increases the percentage of patients assigned to the better-performing group, and significantly improves network and covariate balances. It is also noted that the advantages of the NCARA design are augmented when the sample size is small and the level of network interference is high. In summary, the proposed NCARA design assists researchers in conducting clinical trials with high-quality and high-efficiency.

2-DG Regulates Immune Imbalance on the Titanium Surface after Debridement.

Peri-implantitis requires clinical treatments comprised of mechanical and chemical debridement to remove bacterial biofilms. Bone regeneration on the titanium surface after debridement has been a topical issue of peri-implantitis treatments. Increasing evidence has revealed that the immune microenvironment plays a key role in regulating the bone regeneration process. However, it remains unclear what kind of immune microenvironment the titanium surface induces after debridement. In the study, model titanium surface after debridement was prepared via biofilm induction and mechanical and chemical debridement in vitro. Then, the macrophages and naïve CD4+ T lymphocytes were cultured on the titanium surface after debridement for immune microenvironment evaluation, with the original titanium surface as the control. Next, to regulate the immune microenvironment, 2-DG, a glycolysis inhibitor, was further incorporated to regulate macrophages and CD4+ T lymphocytes at the same time. Surface characterization results showed that the bacterial biofilms were completely removed, while the micro-morphology of titanium surface altered after debridement, and the element composition did not change. Compared with the original titanium disc, titanium surface after debridement can lead to the inflammatory differentiation of macrophages and CD4+ T lymphocytes. The percentage of M1 and Th17 inflammatory cells and the expression of their inflammatory factor genes are upregulated. However, 0.3 mmol of 2-DG can significantly reduce the inflammatory differentiation of both macrophages and CD4+ T lymphocytes and inhibit their expression of inflammatory genes. In conclusion, although bacterial biofilms were removed from titanium surface after debridement, the surface topography changes could still induce immune imbalance and form an inflammatory immune microenvironment. However, this inflammatory immune microenvironment can be effectively reversed by 2-DG in vitro, thus creating an immune microenvironment conducive to osteogenesis, which might provide a new perspective for future therapy of peri-implantitis.

Bidirectional Total Synthesis of Phainanoid A via Strategic Use of Ketones.

Here we report the total synthesis of phainanoid A, a unique dammarane-type triterpenoid (DTT), using an unusual bidirectional synthetic strategy. It features two transition-metal-mediated highly diastereoselective transformations to access the two challenging strained ring systems that branch toward opposite directions from the tricyclic core. This work also highlights the strategic use of ketones (or enol triflates) as versatile handles for rapid growth of molecular complexity in all key transformations, which paves the way for efficient preparations of complex and biologically significant DTTs.

Co-exposure to fluoride and arsenic disrupts intestinal flora balance and induces testicular autophagy in offspring rats.

While numerous studies have shown that fluoride or arsenic exposure may damage the reproductive system, there are few reports of co-exposure to fluoride and arsenic. In addition, the literature on autophagy and intestinal flora composition in reproductive toxicity studies of co-exposure to fluoride and arsenic is insufficient. In this study, we developed a rat model of fluoride and arsenic exposure via drinking water from pre-pregnancy to 90 days postnatal. Sprague-Dawley rats were randomly divided into sterile water control group, fluoride group (100 mg/L NaF), arsenic group (50 mg/L NaAsO2) and combined exposure group (100 mg/L NaF+50 mg/L NaAsO2). Our results showed that fluoride and arsenic exposure caused a reduction in testicular weight and significant pathological damage to tissue. We found that the levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were reduced to varying degrees. Meanwhile experiments showed that fluoride and arsenic exposure can modulate autophagic flux, causing increased levels of Beclin1 and LC3 expression and decreased p62 expression. Analogously, by performing 16S sequencing of rat feces, we found 24 enterobacterial genera that differed significantly among the groups. Furthermore, the flora associated with testicular injury were identified by correlation analysis of hormonal indices and autophagy alterations with intestinal flora composition at the genus level, respectively. In summary, our study shows that fluoride and arsenic co-exposure alters autophagic flux in the testis, causes testicular injury, and reveals an association between altered intestinal flora composition and testicular injury.

Proteomics and transcriptomics jointly identify the key role of oxidative phosphorylation in fluoride-induced myocardial mitochondrial dysfunction in rats.

The regulation of mitochondrial function, which is dominated by oxidative phosphorylation (OXPHOs), is important in fluoride induced cardiovascular disease. Based on the previous study of fluoride-induced mitochondrial structure and membrane potential abnormalities, this study integrated ITRAQ protein quantification and RNA-Seq methods to analyze the sequencing data of rat myocardial tissue under fluoride exposure (0, 30, 60 and 90 mg/L). A total of 22 differentially expressed genes associated with the OXPHOs pathway were screened by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) co-enrichment analysis, and were localizated by Interaction Network and calculated inter-genes and inter-omics correlations by Pearson correlation. In general, fluoride exposure can down-regulate genes related OXPHOs, particularly affecting the assembly of the complex I including Ndufa10, resulting in abnormal mitochondrial ATP synthesis and reduced myocardial energy supply. Most importantly, this study shows that the enriched information from the proteomics can explain the change process of energy production, but the specific molecules involved in energy supply cannot be obtained via transcriptomics information alone. Based on the results of transcriptional and protein analysis, our findings contribute to an innovative understanding of the pathways and molecular changes of myocardial injury induced by fluorosis.

Effects of arsenic exposure on lipid metabolism: a systematic review and meta-analysis.

Lipid metabolism dysfunction is a risk factor for cardiovascular diseases. Reportedly, arsenic exposure could affect lipid metabolism, but this finding remains controversial. Herein, we updated and reevaluated evidence regarding the relationship between arsenic exposure and lipid metabolism. Electronic and manual searches were performed to determine the effect of arsenic exposure on lipid metabolism from inception up to 30 November 2019. Overall, five studies were included in our meta-analysis. Two reviewers independently extracted information. Standardized mean difference (SMD) and 95% confidence intervals (CI) were used to analyze the combined effects of four indicators related to lipid metabolism (total cholesterol [TC], triglyceride [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL]). Afterwards, subgroup and sensitivity analyses were performed to explore the source of heterogeneity. Publication bias was tested using funnel plots and Begg's test. In this study, we observed that arsenic exposure can affect lipid metabolism by reducing serum HDL levels and increasing serum LDL levels. Following subgroup analysis, the arsenic concentration appeared to affect lipid metabolism. Funnel plot and Begg's test suggested no asymmetry. In conclusion, we recommend that potential influencing factors, including age, exposure time, and multiple concentration gradients, should be considered to further explore the relationship between arsenic exposure and lipid metabolism.

Deregulation of autophagy is involved in nephrotoxicity of arsenite and fluoride exposure during gestation to puberty in rat offspring.

Exposure to fluoride (F) or arsenite (As) through contaminated drinking water has been associated with chronic nephrotoxicity in humans. Autophagy is a regulated mechanism ubiquitous for the body in a toxic environment with F and As, but the underlying mechanisms of autophagy in the single or combined nephrotoxicity of F and As are unclear. In the present study, we established a rat model of prenatal and postnatal exposure to F and As with the aim of investigating the mechanism underlying nephrotoxicity of these pollutants in offspring. Rats were randomly divided into four groups that received NaF (100 mg/L), NaAsO2 (50 mg/L), or NaF (100 mg/L) with NaAsO2 (50 mg/L) in drinking water or clean water during pregnancy and lactation; after weaning, pups were exposed to the same treatment as their mothers until puberty. The results revealed that F and As exposure (alone or combined) led to significant increases of arsenic and fluoride levels in blood and bone, respectively. In this context, F and/or As disrupted histopathology and ultrastructure in the kidney, and also altered creatinine (CRE), urea nitrogen (BUN) and uric acid (UA) levels. Intriguingly, F and/or As uptake induced the formation of autophagosomes in kidney tissue and resulted in the upregulation of genes encoding autophagy-related proteins. Collectively, these results suggest that nephrotoxicity of F and As for offspring exposed to the pollutants from in utero to puberty is associated with deregulation of autophagy and there is an antagonism between F and As in the toxicity autophagy process.

ITRAQ-based proteomics reveals the potential mechanism of fluoride-induced myocardial contraction function damage.

Fluorosis is a worldwide public health problem, and its adverse effects on the heart have been confirmed by many studies. Abnormal myocardial contractions are often associated with impairment of cardiac function as a cause or consequence. We designed two-part experiments to search for biomarkers and clarify the underlying molecular mechanism of fluoride on myocardial contraction. First, we used Pressure-volume Loop analysis to evaluate changes in myocardial function indexes with multiple fluoride exposure levels in mice (0, 30, 70, and 150 mg/L) exposed for 4 weeks. The results showed that fluoride exposure affects the heart pump function and reduces cardiac contractility. Then, we established a rat model of fluoride exposure (0, 30, 60, and 90 mg/L) for 6 months to carry out proteomic analysis of fluoride-induced myocardial contractile injury. Hematoxylin-eosin (H&E) staining was used to determine the severity of myocardial injury, and myocardial tissue samples were submitted for isobaric tags for relative and absolute quantitation (ITRAQ) analysis. A total of 1607 proteins were successfully identified with 294 differentially expressed proteins (DEPs) in fluoride treated groups. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 12 DEPs were confirmed to be involved in pathways related to myocardial contraction. Furthermore, we constructed a protein-protein interaction (PPI) network for these 12 core DEPs to illustrate the role and location of each DEP in the myocardial contraction pathway. The results of this study are helpful for identify a potential mechanism and biomarkers of fluoride-induced myocardial contraction function damage, moreover, which can provide a new insight into the heart toxicity of fluoride in animals at the proteomics level.

Asymmetric Total Synthesis of Lancifodilactone G Acetate. 1. Diastereoselective Synthesis of CDEFGH Ring System.

The stereoselective construction of the CDEFGH ring system of lancifodilactone G is described. The key steps in this synthesis are (i) ring-closing metathesis for formation of the oxa-bridged eight-membered ring; (ii) an intramolecular Pauson-Khand reaction for construction of the sterically congested F ring; and (iii) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G.

Interaction of signal transducer and activator of transcription 3 polymorphisms with hepatitis B virus mutations in hepatocellular carcinoma.

UNLABELLED: Hepatitis B virus (HBV) mutations and signal transducer and activator of transcription 3 (STAT3) activation are closely associated with hepatocellular carcinoma (HCC). However, single nucleotide polymorphisms (SNPs) of STAT3 have not been implicated in HCC susceptibility. This study was designed to evaluate the effect of STAT3 SNPs and their interactions with HBV mutations on HCC risk. A total of 2,011 HBV-infected subjects (including 1,021 HCC patients) and 1,012 healthy controls were involved in this study. SNPs rs4796793 (-1697, C>G), rs2293152 (intron 11, C>G), and rs1053004 (3' untranslated region, T>C) were genotyped using quantitative polymerase chain reaction. HBV mutations were determined via direct sequencing. It was found that rs2293152 (GG versus CC) was significantly associated with HCC risk compared with the subjects without HCC, adjusting for age and sex (adjusted odds ratio [AOR], 1.30; 95% confidence interval [CI], 1.04-1.62). The impact of rs2293152 was greater in women compared with men. Compared with HCC-free HBV-infected subjects, rs2293152 GG was solely associated with HCC in women (AOR, 2.04; 95% CI, 1.15-3.61). rs2293152 GG was significantly associated with high viral load (≥1 × 10(4) copies/mL) (AOR, 1.37; 95%, CI 1.01-1.88) and increased frequencies of T1674C/G (AOR, 1.61; 95% CI, 1.06-2.46) and A1762T/G1764A (AOR, 1.64; 95% CI, 1.14-2.35). In multivariate regression analyses, multiplicative interaction of rs1053004 with T1674C/G significantly increased HCC risk, whereas rs2293152 and A1726C interaction reduced it, adjusting for covariates including HBV mutations in the enhancer II/basal core promoter/precore region; the interaction of rs4796793 with preS2 start codon mutation significantly increased HCC risk, adjusting for covariates including HBV mutations in the preS region. CONCLUSION: STAT3 SNPs appear to predispose the host with HBV mutations to hepatocarcinogenesis, and this effect may differ in men versus women. STAT3 SNPs may have applicability in future HCC surveillance algorithms. (Hepatology 2013;57:2369-2377).

Association of a potential functional pre-miR-218 polymorphism and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk.

BACKGROUND & AIMS: MicroRNA-218 (miR-218) can function as a tumour suppressor and inactivate cancer-promoting inflammation. However, role of miR-218 on hepatocellular carcinoma (HCC) remains unclear. To determine the contribution of miR-218 genetic predisposition and its interaction with hepatitis B virus (HBV) mutations to HCC risk. METHODS: rs11134527 located at putative promoter region of pre-miR-218 was genotyped in 1012 healthy controls, 302 hepatitis B surface antigen (HBsAg) seroclearance subjects and 2011 subjects with chronic HBV infection (1021 with HCC) using quantitative PCR. HBV mutation was determined by sequencing. RESULTS: rs11134527 variant genotypes in dominant model was associated with HCC risk compared with all HCC-free subjects [odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.04-1.43], HCC-free HBsAg-positive subjects (OR = 1.23, 95% CI = 1.02-1.50) and HBsAg seroclearance subjects (OR = 1.45, 95% CI = 1.08-1.96), adjusting for age and gender, and also associated with the generation of HBV preS deletion in men (adjusted OR = 1.85, 95% CI = 1.23-2.76). In multivariate regression analyses, rs11134527 in dominant model was associated with HCC risk (OR = 1.50, 95% CI = 1.05-2.13), whereas its multiplicative interaction with viral mutation T1674C/G was inversely associated with HCC risk (OR = 0.44, 95% CI = 0.21-0.96), adjusting for covariates including HBV mutations in the enhancer II-precore region; its interaction with HBV preS1 start codon mutation was associated with HCC risk (OR = 4.44, 95% CI = 1.27-15.55), adjusting for covariates including HBV mutations in the preS region. CONCLUSION: rs11134527 may be a novel genetic risk factor of HCC in HBV-exposed subjects, can facilitate HBV preS deletion generation and predispose the host to the effect of T1674C/G and preS1 start codon mutation in hepatocarcinogenesis.

[Associations of signal transducer and activators of transcription 3 polymorphism with the susceptibility to hepatitis B virus-related hepatocellular carcinoma].

OBJECTIVE: To evaluate the association of signal transducer and activators of transcription 3 (STAT3) -1096G/C polymorphism in promoter region with the susceptibility to HBsAg positive hepatocellular carcinoma (HCC). METHODS: A total of 632 patients with HCC and 723 HBV-infected subjects without HCC treated at Changhai Hospital of Shanghai from 2009 to 2012 were included in this case-control study. The polymorphism of STAT3 -1096 G/C was genotyped by Fluorescent probe-Real time quantitative PCR. Univariate analysis was used to calculate the odds ratio (OR) and its 95% confidence interval (CI). RESULTS: The frequency of genetic allele STAT3 -1096G/C (GC+CC) of control group and case group were 61.83% (447/723) and 60.60% (383/632), while difference of HCC risk was not found among different genotypes (OR = 0.95, 95%CI: 0.76-1.18). When stratified by sex, the frequency of genetic allele STAT3 -1096C (GC+CC) of control group and case group were 62.18% (314/505) and 61.75% (331/536) in men, 61.01% (133/218) and 54.17% (52/96) in women, respectively, while difference of HCC risk was not found among different genotypes (OR = 0.98, 95%CI: 0.77-1.26; OR = 0.76, 95%CI: 0.47-1.26, respectively). When stratified by HBV genotypes, the frequency of genetic allele STAT3 -1096C (GC+CC) of control group and case group were 61.45% (110/179) and 53.13% (34/64) in HBV genotype B, 62.87% (276/439) and 60.27% (226/375) in HBV genotype C, respectively, while difference of HCC risk was not found among different genotypes (OR = 0.71, 95%CI: 0.40-1.26; OR = 0.90, 95%CI: 0.68-1.19, respectively). CONCLUSION: STAT3 -1096G/C polymorphism was not associated with the susceptibility to HCC for the HBV-infected subjects without HCC.

Robust Principal Component Analysis Based on Fuzzy Local Information Reservation.

Principal Component Analysis (PCA) aims to acquire the principal component space containing the essential structure of data, instead of being used for mining and extracting the essential structure of data. In other words, the principal component space contains not only information related to the essential structure of data but also some unrelated information. This frequently occurs when the intrinsic dimensionality of data is unknown or when it has complex distribution characteristics such as multi-modalities, manifolds, etc. Therefore, it is unreasonable to identify noise and useful information based solely on reconstruction error. For this reason, PCA is unsuitable as a preprocessing technique for most applications, especially in noisy environment. To solve this problem, this paper proposes robust PCA based on fuzzy local information reservation (FLIPCA). By analyzing the impact of reconstruction error on sample discriminability, FLIPCA provides a theoretical basis for noise identification and processing. This not only greatly improves its robustness but also extends its applicability and effectiveness as a data preprocessing technique. Meanwhile, FLIPCA maintains consistent mathematical descriptions with traditional PCA while having few adjustable hyperparameters and low algorithmic complexity. Finally, we conducted comprehensive experiments on synthetic and real-world datasets, which substantiated the superiority of our proposed algorithm.

An optimized postsurgery follow-up strategy for patients with esophageal cancer: a cohort study.

BACKGROUND: After radical surgery, patients with esophageal cancer should undergo long-term surveillance of disease relapse. However, the optimal follow-up strategy remains to be explored. METHOD: A total of 4688 patients were recruited. Recursive partition analysis was applied to develop recurrence risk stratification for patients. The follow-up strategies of each stratification were developed based on monthly recurrence probability and validated by bootstrap validation and an external dataset. A Markov decision-analytic model was constructed to evaluate the cost-effectiveness of the follow-up strategies. RESULTS: Patients were stratified into four groups according to four pathological features. The authors applied a random survival forest to calculate the monthly recurrence probability of each group. Based on the temporal distribution of recurrences, the authors further established surveillance strategies for four groups. The strategies were validated as optimal protocols by bootstrap resampling and another dataset. Markov cost-effective analysis indicated that our recommended strategies outperformed the mainstream protocols from guidelines. Using less than 12 visits across the first 5 years on average, our follow-up strategies were more efficient than the NCCN recommended strategies (14 visits average). Our results also supported the computerized tomography from the neck to the upper abdomen as a routine examination and PETCT of distant metastasis for some groups with high risks. CONCLUSION: Our study provided data-driven evidence of personalized and economic follow-up strategies for esophageal cancer patients and shed light on follow-up optimization for other cancer types.

Identification and validation of autophagy-related genes in SSc.

Multiple organs are affected by the complex autoimmune illness known as systemic sclerosis (SSc), which has a high fatality rate. Genes linked to autophagy have been linked to the aetiology of SSc. It is yet unknown, though, whether autophagy-related genes play a role in the aetiology of SSc. After using bioinformatics techniques to examine two databases (the GSE76885 and GSE95065 datasets) and autophagy-related genes, we were able to identify 12 autophagy-related differentially expressed genes that are linked to the pathophysiology of SSc. Additional examination of the receiver operating characteristic curve revealed that SFRP4 (AUC = 0.944, P < 0.001) and CD93 (AUC = 0.904, P < 0.001) might be utilized as trustworthy biomarkers for the diagnosis of SSc. The SSc group's considerably greater CD93 and SFRP4 expression levels compared to the control group were further confirmed by qRT-PCR results. The autophagy-related genes SFRP4 and CD93 were found to be viable diagnostic indicators in this investigation. Our research sheds light on the processes by which genes linked to autophagy affect the pathophysiology of SSc.