Simple and accurate genomic classification model for distinguishing between human and pig Staphylococcus aureus.

Staphylococcus aureus (S. aureus) can cause various infections in humans and animals, contributing to high morbidity and mortality. To prevent and control cross-species transmission of S. aureus, it is necessary to understand the host-associated genetic variants. We performed a two-stage genome-wide association study (GWAS) including initial screening and further validation to compare genomic differences between human and pig S. aureus, aiming to identify host-associated determinants. Our multiple GWAS analyses found six consensus significant k-mers associated with host species, providing novel genetic evidence for distinguishing human from pig S. aureus. The best k-mer predictor achieved a high classification accuracy of 98.12% on its own and had extremely high resolution similar to the SNPs-based phylogeny, offering a very simple target for predicting the cross-species transmission risk of S. aureus. The final k-mer model revealed that 90% of S. aureus isolates from farm workers were predicted as livestock origin, suggesting a high risk of cross-species transmission. Bayesian inference revealed different cross-species transmission directions, with the human-to-pig transmission for ST5 and the pig-to-human transmission for ST398. Our findings provide a simple and accurate k-mer model for identifying and predicting the cross-species transmission risk of S. aureus.

The effect of endocrine-disrupting chemicals in follicular fluid: The insights from oocyte to fertilization.

Endocrine-disrupting chemicals (EDCs) exhibited the detriment in female reproductive health. Our objective was to investigate the individual and mixture effects of EDCs present in follicular fluid, the environment in which oocytes grow and develop, on early reproductive outcomes. We recruited 188 women seeking reproduction examination from the Study of Exposure and Reproductive Health (SEARCH) cohort between December 2020 and November 2021. We assessed the concentrations of 7 categories of 64 EDCs in follicular fluid, and measured early reproductive outcomes, including retrieved oocytes, mature oocytes, normal fertilized oocytes, and high-quality embryos. In this study Monomethyl phthalate (MMP) (2.17 ng/ml) were the compounds found in the highest median concentrations in follicular fluid. After adjusting for multiple testing, multivariate regression showed that multiple EDCs were significantly negatively associated with early assisted reproduction outcomes. For example, MMP showed a significant negative correlation with the number of high quality embryos (ß: -0.1, 95 % CI: -0.15, -0.04). Specifically, eight types of EDCs were significantly negatively associated with four early assisted reproductive outcomes (ß range: -0.2 âˆ¼ -0.03). In the mixed exposure model, we found that mixtures of EDC were significantly negatively correlated with all four outcomes. In the quantile g-computation (QGCOMP) model, for each interquartile range increase in the concentration of EDC mixtures, the number of oocytes retrieved, mature oocytes, normally fertilized oocytes, and high-quality embryos decreased by 0.46, 0.52, 0.77, and 1.2, respectively. Moreover, we identified that phthalates (PAEs) predominantly contributed to the negative effects. Future research should validate our findings.

Peripheral ulcerative keratitis secondary to tuberculosis: A case report and literature review.

RATIONALE: Compared with intraocular tuberculosis, ocular tuberculosis with ocular surface involvement is rare. Corneal involvement in ocular tuberculosis may include interstitial keratitis or peripheral ulcerative keratitis. We report a case of peripheral ulcerative keratitis directly caused by tuberculosis. PATIENT CONCERNS: A 20-year-old man complained of vision loss and pain in the left eye that had lasted for 1 week. A slit lamp examination of the left eye showed a corneal epithelial defect, interstitial corneal edema, and a white irregular infiltrative lesion and ulcer (with the dimension of 2 × 2.5 mm) in the inferior temporal region. DIAGNOSES: The corneal ulcer was scraped, and the Mycobacterium tuberculosis deoxyribonucleic acid polymerase chain reaction was positive. INTERVENTIONS AND OUTCOMES: After a month of oral antituberculosis treatment, the corneal ulcer resolved, and the intraocular inflammation improved. LESSONS: Peripheral ulcerative keratitis secondary to tuberculosis can be directly caused by M tuberculosis.

PSAT1 Promotes Metastasis via p-AKT/SP1/ITGA2 Axis in Estrogen Receptor-Negative Breast Cancer Cell.

BACKGROUND: Accumulating evidence indicates that PSAT1 not only reprogrammed metabolic function but also exhibits "moonlighting" functions in promoting tumor malignancy. However, the underlying molecular mechanisms of PSAT1 promoting ER-negative breast cancer cell migration need further investigation. METHODS: Briefly, the PSAT1 and ITGA2 expression in cells and tissues was detected using qRT-PCR, immunofluorescence staining and western blot assay. The effect of PSAT1 and ITGA2 was verified both in vitro and in vivo. RNA-seq analysis explored a series of differently expressed genes. The regulation between SP1 and ITGA2 was investigated by ChIP analysis. RESULTS: We reported PSAT1 was highly expressed in ER-breast cancer tissues and tumor cells and positively correlated with metastasis. Moreover, RNA-seq analysis explored a series of differently expressed genes, including ITGA2, in PSAT1 overexpressed cells. Mechanistically, PSAT1 facilitated breast cancer metastasis via the p-AKT/SP1/ITGA2 axis. We further elucidated that PSAT1 promoted the entry of SP1 into the nucleus through the upregulation of p-AKT and confirmed ITGA2 is a target of SP1. In addition, enhanced cell migration was remarkably reversed by ITGA2 depletion or p-AKT inhibitor treatment. CONCLUSION: This study clarified the mechanism of PSAT1 in promoting ER-negative breast cancer metastasis, which may provide mechanistic clues for attenuating breast cancer metastasis.

Perfluoroalkyl and Polyfluoroalkyl Substances in Relation to the Participant-Reported Total Pregnancy and Live Birth Numbers among Reproductive-Aged Women in the United States.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), widely utilized in various industries, may pose potential reproductive well-being risks. However, the research on the impact of PFAS exposures on pregnancy and live birth rates remains scarce. To address this gap, we conducted a cross-sectional study using the data from the United States National Health and Nutrition Examination Survey (NHANES) collected between 2013 and 2018. We focused on six PFAS compounds measured in the serum of women aged 20 to 50 years, employing the Poisson regression, Quantile G-composition (Qgcomp), and Weighted Quantile Sum (WQS) regression models. Adjusting for age, racial/ethnic origin, educational level, marital status, family income, body mass index (BMI), menarche age, birth control pill use, and other female hormone consumption, the Poisson regression identified significant negative associations between the individual PFAS exposures and pregnancy and live birth numbers (p < 0.05 for all 24 null hypotheses for which the slope of the trend line is zero). The Qgcomp analysis indicated that a one-quartile increase in the mixed PFAS exposures was associated with reductions of 0.09 (95% CI: -0.15, -0.03) in the pregnancy numbers and 0.12 (95% CI: -0.19, -0.05) in the live birth numbers. Similarly, the WQS analysis revealed that a unit increase in the WQS index corresponded to decreases of 0.14 (95% CI: -0.20, -0.07) in the pregnancy numbers and 0.14 (95% CI: -0.21, -0.06) in the live birth numbers. Among the six specific PFAS compounds we studied, perfluorononanoic acid (PFNA) had the most negative association with the pregnancy and live birth numbers. In conclusion, our findings suggest that PFAS exposures are associated with lower pregnancy and live birth numbers among women of reproductive age.

Mixed effects of ambient air pollutants on oocyte-related outcomes: A novel insight from women undergoing assisted reproductive technology.

Air pollution is widely acknowledged as a significant risk factor for human health, especially reproductive health. Nevertheless, many studies have disregarded the potentially mixed effects of air pollutants on reproductive outcomes. We performed a retrospective cohort study involving 8048 women with 9445 cycles undergoing In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI) in China, from 2017 to 2021. A land-use random forest model was applied to estimate daily residential exposure to air pollutants, including sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and fine particulate matter (PM2.5). Individual and joint associations between air pollutants and oocyte-related outcomes of ART were evaluated. In 90 days prior to oocyte pick-up to oocyte pick-up (period A), NO2, O3 and CO was negatively associated with total oocyte yield. In the 90 days prior to oocyte pick-up to start of gonadotropin medication (Gn start, period B), there was a negative dose-dependent association of exposure to five air pollutants with total oocyte yield and mature oocyte yield. In Qgcomp analysis, increasing the multiple air pollutants mixtures by one quartile was related to reducing the number of oocyte pick-ups by -2.00 % (95 %CI: -2.78 %, -1.22 %) in period A, -2.62 % (95 %CI: -3.40 %, -1.84 %) in period B, and -0.98 % (95 %CI: -1.75 %, -0.21 %) in period C. During period B, a 1-unit increase in the WQS index of multiple air pollutants exposure was associated with fewer number of total oocyte (-1.27 %, 95 %CI: -2.16 %, -0.36 %) and mature oocyte (-1.42 %, 95 %CI: -2.41 %, -0.43 %). O3 and NO2 were major contributors with adverse effects on the mixed associations. Additionally, period B appears to be the susceptible window. Our study implies that exposure to air pollution adversely affects oocyte-related outcomes, which raises concerns about the potential adverse impact of air pollution on women's reproductive health.

Depression and the Risk of Dementia and All-Cause Mortality Among Japanese Older Adults: A 9-Year Longitudinal Study From JAGES.

BACKGROUND: This study aims to investigate the association and dose-response relationship between depression, dementia, and all-cause mortality based on a national cohort study of older adults in Japan. METHODS: We conducted a longitudinal study of 44,546 participants ≥65 years from 2010-2019 Japanese Gerontological Evaluation Study. The Geriatric Depression Scale-15 was used to assess depressive symptoms and the long-term care insurance was used to assess dementia. Fine-Gray models and Cox proportional hazard models were used to explore the effect of depression severity on the incidence of dementia and all-cause mortality, respectively. Causal mediation analysis were used to explore the extent of association between dementia-mediated depression and all-cause mortality. RESULTS: We found that both minor and major depressive symptoms were associated with the increased cumulative incidence of dementia and all-cause mortality, especially major depressive symptoms (p < .001). The multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia were 1.25 (1.19-1.32) for minor depressive symptoms and 1.42 (1.30-1.54) for major depressive symptoms in comparison to non-depression; p for trend < .001. The multivariable-adjusted HRs and 95% CIs for all-cause mortality were 1.27 (1.21-1.33) for minor depressive symptoms and 1.51 (1.41-1.62) for major depressive symptoms in comparison to non-depression; p for trend < .001. Depression has a stronger impact on dementia and all-cause mortality among the younger group. In addition, dementia significantly mediated the association between depression and all-cause mortality. DISCUSSION: Interventions targeting major depression may be an effective strategy for preventing dementia and premature death.

Influence of nutritional supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccines.

BACKGROUND: Because of the significantly higher demand for nutrients during pregnancy, pregnant women are more likely to have nutrient deficiencies, which may adversely affect maternal and fetal health. The influence of nutritional supplements on the immune effects of inactivated SARS-CoV-2 vaccines during pregnancy is not clear. METHODS: In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 y in Guangdong, China. The general demographic characteristics of pregnant women and their use of nutritional supplements were investigated, and the serum antibody levels induced by inactivated SARS-CoV-2 vaccines were measured. A logistic regression model was used to analyze the association between nutritional supplements and SARS-CoV-2 antibody levels. RESULTS: Of the 873 pregnant women enrolled, 825 (94.5%) took folic acid during pregnancy, 165 (18.9%) took iron supplements, and 197 (22.6%) took DHA. All pregnant women received at least one dose of inactivated SARS-CoV-2 vaccine, and the positive rates of serum SARS-CoV-2 neutralizing antibodies (NAbs) and immunoglobulin G (IgG) antibodies were 44.7% and 46.4%, respectively. After adjustment for confounding factors, whether pregnant women took folic acid, iron supplements, or DHA did not influence NAb positivity or IgG positivity (P > 0.05). Compared with pregnant women who did not take folic acid, the odds ratios (ORs) for the presence of SARS-CoV-2 NAb and IgG antibody in pregnant women who took folic acid were 0.67 (P = 0.255; 95% CI, 0.34-1.32) and 1.24 (P = 0.547; 95% CI, 0.60-2.55), respectively. Compared with pregnant women who did not take iron supplements, the ORs for the presence of NAb and IgG antibody in pregnant women who took iron supplements were 1.16(P = 0.465; 95% CI, 0.77-1.76) and 0.98 (P = 0.931; 95% CI, 0.64-1.49), respectively. Similarly, the ORs for NAb and IgG antibody were 0.71 (P = 0.085; 95% CI, 0.49-1.04) and 0.95 (P = 0.801; 95% CI, 0.65-1.38) in pregnant women who took DHA compared with those who did not. CONCLUSIONS: Nutritional supplementation with folic acid, iron, or DHA during pregnancy was not associated with antibody levels in pregnant women who received inactivated SARS-CoV-2 vaccines.

Immune response and safety of inactivated SARS-CoV-2 vaccines during pregnancy: a real-world observational study.

BACKGROUND: As pregnant women are excluded from clinical trials of inactivated SARS-CoV-2 vaccines, it is important to assess the immune response in women receiving the vaccination while unknowingly pregnant. METHODS: In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 years. Serum antibody levels induced by inactivated vaccines were determined. Adverse events were collected by self-reported survey after vaccination. Logistic regression model and restricted cubic spline model were used to investigate the association of factors with antibody positivity. RESULTS: As the doses of the vaccine increase, neutralizing antibody (NAb) positivity was 98.3%, 39.5%, and 9.5% in pregnant women, respectively. The dose of vaccine and duration since vaccination were associated with NAb positivity. The OR of two and three doses of vaccines were 7.20 and 458.33 (P < 0.05). NAb levels and duration since vaccination showed a linear relationship in pregnant women vaccinated two doses, with a decrease to a near seropositivity threshold at 22 weeks. Adverse events were mainly mild or moderate after vaccinated during pregnancy, with no increase in incidence compared with whom vaccinated during pre-pregnancy. CONCLUSIONS: The use of inactivated vaccines during pregnancy induced favorable immune persistence, and the incidence of adverse events did not increase.

Variations of bile bacterial community alongside gallstone disease progression and key taxa involved in poor outcomes after endoscopic surgery.

Gallstone disease is a prevalent biliary disease worldwide, and bacteria play vital roles in the disease development and progression, as well as the prognosis after endoscopic surgery. However, there have been limited studies to explore the key taxa involved. In this study, bile samples from healthy controls (HCs, liver donors without hepatobiliary disease) and three diseased groups, namely patients with gallbladder stones (GBS), patients with common bile duct stones (CBDS), and patients with stricture in the common bile duct (SCBD), were collected and analyzed. Bacterial community characterization based on 16S rRNA amplicon sequencing showed that bacterial diversities did not change significantly alongside gallstone disease development and progression. The predominant phyla in each group were Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota, representing over 80% in abundance of the biliary bacteria community. Specifically, the abundance of Proteobacteria decreased greatly while that of Firmicutes and Bacteroidota increased greatly in the diseased groups when compared to that in HCs. Moreover, linear discriminant analysis identified several genera highly represented in the diseased groups. Among them, Klebsiella, Prevotella, Pseudomonas and Veillonella are persistent in both the HCs group and the diseased groups, indicating an enrichment of local bile bacteria in the diseased bile; while Lachnoanerobaculum, Atopobium, Oribacterium, and Stomatobaculum, those aligned to oral cavity taxa, are persistent in the diseased groups but are transient in the HCs group, and their abundances sequentially increased with the disease development and progression (HCs→GBS→CBDS→SCBD), implying a translocation and colonization of the oral cavity bacteria in the diseased bile. Moreover, co-occurrence network analysis revealed that bacterial infection (e.g., Photobacterium and Plesiomonas) from the intestine was developed during endoscopic surgery with reduced bile bacteria diversity. The results of this study revealed that the bile bacterial community is relatively stable and dominated by a few persistent taxa. Moreover, we hypothesized that translocation and colonization of specific bacteria from the oral cavity happens alongside gallstone disease development and progression, and bacterial infection from the intestinal tract results in poor outcomes after endoscopic surgery.

Novel prognostic nomograms in cervical cancer based on analysis of 1075 patients.

OBJECTIVE: To explore the factors affecting the prognosis of cervical cancer (CC), and to construct and evaluate predictive nomograms to guide individualized clinical treatment. METHODS: The clinicopathological and follow-up data of CC patients from June 2013 to December 2019 in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were retrospectively analyzed. Log-rank test was used for univariate survival analysis, and Cox multivariate regression was used to identify independent prognostic factors, based on which nomogram models were established and evaluated in multiple aspects. RESULTS: Patients were randomly assigned into the training (n = 746) and validation sets (n = 329). Survival analysis of the training set identified cervical myometrial invasion, parametrial involvement, and malignant tumor history as prognosticators of postoperative DFS and pathological type, cervical myometrial invasion, and history of STD for OS. C-index was 0.799 and 0.839 for the nomograms for DFS and OS, respectively. Calibration curves and Brier scores also indicated high performance. Importantly, decision curve analysis suggested great clinical applicability of these nomograms. CONCLUSIONS: In this study, we analyzed a cohort of 1075 CC patients and identified DFS- or OS-associated clinicohistologic characteristics. Two nomograms were subsequently constructed for DFS and OS prognostication, respectively, and showed high performance in terms of discrimination, calibration, and clinical applicability. These models may facilitate individualized treatment and patient selection for clinical trials. Future investigations with larger cohorts and prospective designs are warranted for validating these prognostic models.

Drought Assessment Based on Data Fusion and Deep Learning.

Drought is a major factor affecting the sustainable development of society and the economy. Research on drought assessment is of great significance for formulating drought emergency policies and drought risk early warning and enhancing the ability to withstand drought risks. Taking the Yellow River Basin as the object, this paper utilizes data fusion, copula function, entropy theory, and deep learning, fuses the features of meteorological drought and hydrological drought into a drought assessment index, and establishes a long short-term memory (LSTM) network for drought assessment, based on deep learning theory. The results show that (1) after extracting the features of meteorological drought and hydrological drought, the drought convergence index (DCI) built on the fused features by copula function can accurately reflect the start and duration of the drought; (2) the drought assessment indices were effectively screened by judging the causality of the drought system, using the transfer entropy; (3) drawing on the idea of deep learning, LSTM for drought assessment, which was established on DCI and the drought assessment factors, can accurately assess the drought risks of the Yellow River Basin.

Long-term corneal recovery by simultaneous delivery of hPSC-derived corneal endothelial precursors and nicotinamide.

Human pluripotent stem cells (hPSCs) hold great promise for the treatment of various human diseases. However, their therapeutic benefits and mechanisms for treating corneal endothelial dysfunction remain undefined. Here, we developed a therapeutic regimen consisting of the combination of hPSC-derived corneal endothelial precursors (CEPs) with nicotinamide (NAM) for effective treatment of corneal endothelial dysfunction. In rabbit and nonhuman primate models, intracameral injection of CEPs and NAM achieved long-term recovery of corneal clarity and thickness, similar with the therapeutic outcome of cultured human corneal endothelial cells (CECs). The transplanted human CEPs exhibited structural and functional integration with host resident CECs. However, the long-term recovery relied on the stimulation of endogenous endothelial regeneration in rabbits, but predominantly on the replacing function of transplanted cells during the 3-year follow-up in nonhuman primates, which resemble human corneal endothelium with limited regenerative capacity. Mechanistically, NAM ensured in vivo proper maturation of transplanted CEPs into functional CECs by preventing premature senescence and endothelial-mesenchymal transition within the TGF-ß-enriched aqueous humor. Together, we provide compelling experimental evidence and mechanistic insights of simultaneous delivery of CEPs and NAM as a potential approach for treating corneal endothelial dysfunction.

Poly(ADP-ribose) polymerase inhibitor PJ34 protects against UVA-induced oxidative damage in corneal endothelium.

Fuchs endothelial corneal dystrophy (FECD) is one of the main causes for corneal endothelial blindness, which is characterized by the progressive decline of corneal endothelial cells. Poly (ADP-ribose) polymerase (PARP) was reported to be involved in cell death and apoptosis of several diseases. However, the role of PARP1 in the progression of FECD remains elusive. In the present study, we reported that UVA irradiation caused the corneal endothelial damage and corneal edema in mice, which was accompanied with the elevated activity of PARP1 and PAR. The PARP1 inhibitor PJ34 resolved the corneal edema and protected corneal endothelium from UVA-induced oxidative damage, mitochondrial dysfunction, and cell apoptosis. Mechanistically, PARP1 inhibition exerted its anti-apoptotic effects through downregulation of the phosphorylation levels of JNK1/2 and p38 MAPK and subsequently the increase of MKP-1. Our results suggest that PARP1 inhibition protects corneal endothelium from UVA-induced oxidative damage, which provides a potential alternative strategy for the therapy of FECD.

Transplantation of human induced pluripotent stem cell-derived neural crest cells for corneal endothelial regeneration.

BACKGROUND: The corneal endothelium maintains corneal hydration through the barrier and pump function, while its dysfunction may cause corneal edema and vision reduction. Considering its development from neural crest cells (NCCs), here we investigated the efficacy of the human induced pluripotent stem cell (hiPSC)-derived NCCs for corneal endothelial regeneration in rabbits. METHODS: Directed differentiation of hiPSC-derived NCCs was achieved using the chemically defined medium containing GSK-3 inhibitor and TGF-ß inhibitor. The differentiated cells were characterized by immunofluorescence staining, FACS analysis, and in vitro multi-lineage differentiation capacity. For in vivo functional evaluation, 1.0 × 106 hiPSC-derived NCCs or NIH-3 T3 fibroblasts (as control) combined with 100 µM Y-27632 were intracamerally injected into the anterior chamber of rabbits following removal of corneal endothelium. Rabbit corneal thickness and phenotype changes of the transplanted cells were examined at 7 and 14 days with handy pachymeter, dual-immunofluorescence staining, and quantitative RT-PCR. RESULTS: The hiPSC-derived NCCs were differentiated homogenously through 7 days of induction and exhibited multi-lineage differentiation capacity into peripheral neurons, mesenchymal stem cells, and corneal keratocytes. After 7 days of intracameral injection in rabbit, the hiPSC-derived NCCs led to a gradual recovery of normal corneal thickness and clarity, when comparing to control rabbit with fibroblasts injection. However, the recovery efficacy after 14 days deteriorated and caused the reappearance of corneal edema. Mechanistically, the transplanted cells exhibited the impaired maturation, cellular senescence, and endothelial-mesenchymal transition (EnMT) after the early stage of the in vivo directional differentiation. CONCLUSIONS: Transplantation of the hiPSC-derived NCCs rapidly restored rabbit corneal thickness and clarity. However, the long-term recovery efficacy was impaired by the improper maturation, senescence, and EnMT of the transplanted cells.

Multiple roles of FGF10 in the regulation of corneal endothelial wound healing.

Corneal endothelial dysfunction usually induces corneal haze and oedema, which seriously affect visual function. The main therapeutic strategy for this condition is corneal transplantation, but the use of this strategy is limited by the shortage of healthy donor corneas. Compared with corneal transplantation, drug intervention is less invasive and more accessible; thus, finding an effective pharmaceutical alternative for cornea transplantation is critical for the treatment of corneal endothelial dysfunction. In this study, we established a rabbit scratch model to investigate the effect of fibroblast growth factor 10 (FGF10) on corneal endothelial wound healing. Results showed that FGF10 injection accelerated the recovery of corneal transparency and increased the protein expression levels of ZO1, Na+/K+-ATPase and AQP-1. Moreover, FGF10 significantly inhibited the expression levels of endothelial-to-mesenchymal transition proteins and reduced the expression levels of the proinflammatory factors IL-1ß and TNF-α in the anterior chamber aqueous humour. FGF10 also enhanced the Na+/K+-ATPase activity by enhancing mitochondrial function as a result of its direct interaction with its conjugate receptor. Thus, FGF10 could be a new pharmaceutical preparation as treatment for corneal endothelial dysfunction.

LncRNA TINCR favors tumorigenesis via STAT3-TINCR-EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer.

The long noncoding RNA (lncRNA) TINCR has recently been found to be associated with the progression of human malignancies, but the molecular mechanism of TINCR action remains elusive, particularly in breast cancer. The oncogenic role of TINCR was examined in vitro and in vivo in breast cancer. Next, the interaction between TINCR, DNMT1, and miR-503-5p methylation was explored. Moreover, the mechanism by which TINCR enhances EGFR expression and downstream signaling via an RNA-RNA interaction was comprehensively investigated. Furthermore, upstream transcriptional regulation of TINCR expression by STAT3 was examined by performing chromatin immunoprecipitation. Finally, feedback signaling in the STAT3-TINCR-EGFR downstream cascade was also investigated. TINCR is upregulated in human breast cancer tissues, and TINCR knockdown suppresses tumorigenesis in vitro and in vivo. Mechanistically, TINCR recruits DNMT1 to the miR-503-5p locus promoter, which increases the methylation and suppresses the transcriptional expression of miR-503-5p. Furthermore, TINCR also functions as a competing endogenous RNA to upregulate EGFR expression by sponging miR-503-5p. In addition, TINCR stimulates JAK2-STAT3 signaling downstream from EGFR, and STAT3 reciprocally enhances the transcriptional expression of TINCR. Our findings broaden the current understanding of the diverse manners in which TINCR functions in cancer biology. The newly identified STAT3-TINCR-EGFR-feedback loop could serve as a potential therapeutic target for human cancer.

ABTB2 Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer.

Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.

Laminin 511 Precoating Promotes the Functional Recovery of Transplanted Corneal Endothelial Cells.

Corneal endothelial dysfunction is a major cause of corneal blindness and is mainly treated by corneal transplantation. However, the global shortage of donor cornea hampers its application. Intracameral injection of cultured primary corneal endothelial cells (CECs) was recently confirmed in clinical trials. However, abnormal adhesion of the grafted CECs affects the application of this strategy. In this study, we explored if laminin 511 (LN511) improves the therapeutic function of the intracameral CEC injection for corneal endothelial dysfunction. To mimic the late stage of corneal endothelial diseases, intense scraping was developed to remove CECs and extracellular matrix of the posterior Descemet's membrane (DM) without DM removal in rabbits. Then, Dulbecco's phosphate-buffered saline (DPBS) and LN511 were intracamerally injected as the control and intervention groups, respectively. We found that the injected LN511 could settle and form a coating on the posterior surface of DM. After CEC transplantation, corneal clarity of rabbits in the LN511 group was rapidly recovered within 7 days, whereas the corneal recovery took 14 days in the DPBS group. Corneal thickness of LN511 group decreased to 413.3 ± 20.8 µm 7 days after operation, which was significantly lower than 1086.3 ± 78.6 µm of DPBS group (p < 0.01). Moreover, for the grafted CECs, LN511 promoted the rapid adhesion, tight junction formation, and expression of Na+/K+-ATPase and ZO-1. In vitro analysis revealed that the functions of LN511 on the cultured human CECs mechanistically depended on the cell density and the nuclear-cytoplasmic translocation of the Yes-associated protein. Our study demonstrated that LN511 precoating promoted the adhesion of the transplanted CECs and enhanced the functional regeneration of the corneal endothelium. Thus, our data suggested that the strategy of LN511 precoating and CECs' intracameral injection could be a potential method for the therapy of corneal endothelial dysfunction. Impact statement Intracameral injection of cultured corneal endothelial cells (CECs) is a potential alternative therapy for corneal endothelial dysfunction and has been proven to be effective in clinical trials. However, abnormal adhesion of the grafted CECs affects its application. In this study, intense scraping was developed to remove CECs and extracellular matrix of the posterior Descemet's membrane (DM) without DM removal for the therapy of late stage of corneal endothelial diseases. Laminin 511 was intracamerally injected to form a coating, improve the posterior DM, enhance the adhesion of the grafted CECs, and promote the functional regeneration of CEC transplantation through Yes-associated protein signaling.