Atosiban Combined with Ritodrine for Late Threatened Abortion or Threatened Premature Labor Patients with No Response to Ritodrine: A Clinical Trial.

BACKGROUND Premature labor is an important cause of infant death and long-term disability. This study aimed to explore the safety and effectiveness of combining the tocolytic agents atosiban and ritodrine to extend gestation. MATERIAL AND METHODS The study included 52 patients with late threatened abortion and threatened premature labor between 20°â¸7 and 336⸍7 weeks' gestation who were administrated continuous tocolytic agents for 48 h. Patients were divided into a research group receiving ritodrine combined with atosiban, owing to having no response to ritodrine alone (n=30), and a control group receiving ritodrine alone (n=22). The mean infusion rate and duration of tocolytic administration, gestation extension, pregnancy outcomes, and adverse effects were recorded. Routine blood tests, including C-reactive protein, and cultures for leukorrhea, candida, and mycoplasma were performed before and 1 week after treatment. RESULTS Patients receiving ritodrine with atosiban had a mean gestation extension of 42.53±31.70 days. The extension of gestation of the research group was statistically shorter than that of the control group (P<0.05). The fetal loss rate, newborn birth weight, and Apgar score at 1 min were similar between the 2 groups (all, P>0.05). The research group had a lower incidence of palpitations than the control group (P<0.05). CONCLUSIONS For patients with late threatened abortion or threatened premature labor not controlled with ritodrine alone, ritodrine combined with atosiban extends gestation and improves pregnancy outcomes. For patients with abnormal uterine contractions, routine testing for reproductive tract infection should be performed. When infection is present, anti-infective therapy should be administered.

SO2 derivatives induce dysfunction in human trophoblasts via inhibiting ROS/IL-6/STAT3 pathway.

BACKGROUND: Epidemiological studies have revealed that sulfur dioxides (SO2) can increase the risk of pregnancy complications such as missed abortion in the first trimester, stillbirth, preterm birth, small for gestational age, gestational diabetes mellitus and preeclampsia, but the mechanisms underlying these findings remains unknown. What is known, however, is that trophoblasts, a type of fetal cell exerting vital immunologic functions to maintain a successful pregnancy, are usually involved in the pathogenic mechanism of pregnancy complications. OBJECTIVE: To study the effect of SO2 derivatives (bisulfite and sulfite, 1:3 M/M) on the function of trophoblasts. METHODS: Swan.71 trophoblast cells were treated with various concentrations of SO2 derivatives to determine the effect of SO2 derivatives on cellular viability by CKK8. Flow cytometry was performed to analyze the effect of SO2 derivatives on apoptosis, cell cycle and intracellular ROS. Wound healing assay and transwell assay were conducted to examine the migration and invasion of Swan.71 cells. Inflammation-related cytokines in the supernatant (IL-1ß, IL-6, IL-8, IL-10 and TNF-α) were measured by IMMULITE®1000 Systems (SIEMENS). The expression level of NLRP3, Caspase1, MMP9, MMP2, STAT3, and p-STAT3 were evaluated by Western Blotting. RESULTS: Exposure to SO2 derivatives significantly decreased cellular viability, arrested cell cycle at S/G2/M phase and induced cell apoptosis of Swan.71 trophoblasts. In addition, the migration and invasion of Swan.71 cell were significantly inhibited. SO2 derivatives also significantly increased IL-1ß secretion while it is NLRP3/Caspase1 independent. IL-6 secretion was significant inhibited accompanied by decreased STAT3 phosphorylation and expression of MMP2 and MMP9. The intracellular ROS level was significantly suppressed by SO2 derivatives. CONCLUSION: SO2 derivatives exert toxic effects on trophoblasts which results in: suppressing cellular viability and intracellular ROS level, interfering with cell proliferation through arresting cell cycle, inducing cell apoptosis, disturbing inflammation-related cytokines secretion and inhibiting motility. Decreased ROS/IL-6/STAT3 levels play a role in inhibited cell viability, cell cycle arrest, apoptosis and defective motility.

Fasudil inhibits LPS-induced migration of retinal microglial cells via regulating p38-MAPK signaling pathway.

PURPOSE: To investigate the effect and possible molecular mechanisms of fasudil on retinal microglial (RMG) cell migration. METHODS: Primary cultured RMG cells were incubated with lipopolysaccharide (LPS), fasudil, and/or SB203580 (a p38 inhibitor). RMG cell motility was determined with the scratch wound assay and the Transwell migration assay. The phosphorylation of p38 and levels of matrix metalloproteinase 2 (MMP-2) and MMP-9 were measured with western blot. RESULTS: In the scratch-induced migration assay, as well as in the Transwell migration assay, the results indicated that LPS stimulated the migratory potential of RMG cells and fasudil significantly reduced LPS-stimulated RMG cell migration in a concentration-dependent manner. However, fasudil had no effect on RMG cell migration in the absence of LPS stimulation. Moreover, fasudil reduced the level of phosphor-p38 mitogen-activated protein kinase (p-p38-MAPK) in a concentration-dependent manner, without effects on the levels of phospho-p44/42 (p-ERK1/2) and phospho-c-Jun N-terminal kinase (p-JNK). Cotreatment with SB203580 (a p38 inhibitor) and fasudil resulted in the synergistic reduction of MMP-2, MMP-9, and p-p38-MAPK, as well as a reduction in the LPS-stimulated migration capabilities of the RMG cells, suggesting fasudil suppresses the LPS-stimulated migration of RMG cells via directly downregulating the p38-MAPK signaling pathway. CONCLUSIONS: Our studies indicated that fasudil inhibited LPS-stimulated RMG cell migration via suppression of the p38-MAPK signaling pathway.

Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion.

AIM: Abnormal natural killer (NK) cell activity has been suggested to be a high-risk factor associated with unexplained recurrent spontaneous abortion (URSA). Intralipid, like immunoglobulin, is able to lower the activity of NK cells, which has been reported to be useful for improving URSA outcomes in pregnancy. This study aimed to determine whether intralipid could be used as an alternative treatment to intravenous immunoglobulin (IVIG) which is expensive and has many side-effects. METHODS: A prospective, randomized clinical trial was conducted from December 2010 to December 2012. Eligible participants were matched and sorted randomly into the intralipid and the IVIG group. The primary outcome was the rate of successful pregnancy. In addition, comparisons of peripheral NK cell activities were accessed by flow cytometry. Moreover, the effects of intralipid on trophoblasts were investigated using a Matrigel assay with the JEG-3 cell line. RESULTS: Seventy-six patients in the intralipid group and 78 in the IVIG group completed the trial. There were no statistically significant differences in successful pregnancy rates between the two groups (92.1 vs 88.2 %, P = 0.415). The reduced NK cell concentrations revealed the cytotoxic effects of the treatments in both groups. The invasive ability of JEG-3 cells was inhibited during co-culture with patient PBMCs. However, the inhibitory effect could be alleviated if the patient PBMCs were stimulated with intralipid. CONCLUSIONS: Intralipid can be used as an alternative treatment to IVIG for URSA, and its potential mechanism of action may occur by regulating NK cell function and promoting trophoblast invasion.

Effects of emergency cervical cerclage on pregnancy outcome: a retrospective study of 158 cases.

The aim of this study was to evaluate the effectiveness and safety of emergency cervical cerclage in women with advanced cervical dilatation and bulging of fetal membranes. The study included 158 women who underwent emergency cervical cerclage because of cervix dilatation and protruding membranes in mid-trimester at Sun Yat-sen Memorial Hospital of Sun Yat-sen University. Pregnancy outcomes and pregnancy outcome related to clinical features were analyzed retrospectively. Analysis revealed that the placement of emergency cerclage led to the delivery of live infants with a success rate of 82.28%. The mean interval between cerclage and delivery was 52.16.±26.62 days, with a mean gestation at delivery of 30.3±4.7 weeks and a mean birth weight of 1934.69±570.37 g. No severe maternal complications such as maternal death, hematosepsis, and hysterorrhexis occurred after the operation. Two women (1.25%) had laceration of the cervix, 1 woman (0.61%) suffered pulmonary edema, and 2 women (1.25%) developed deep vein thrombosis (DVT). There were significant correlations between the pregnancy outcome and risk factors, including any presenting symptoms, cervical dilatation, postoperative white blood cell count, and C-reactive protein (CRP) value. No significant difference was found in women with good vs. poor outcome in terms of maternal age and obstetric histories. Emergency cervical cerclage is effective in prolonging pregnancy and improving neonatal outcome in women with cervical incompetence. It should be considered a viable option for women with a dilated cervix in mid-trimester.

Chitosan-based hydrogel incorporated with polydopamine and protoporphyrin for photothermal-oxidation sterilization of bacteria-infected wound therapy.

Phototherapy has emerged as a potential treatment strategy for bacteria-infected wounds, but the inadequate bacteria-capturing ability and excessive damage to normal tissues from single phototherapy are huge limitations. To solve the issues, herein we report the design of chitosan-based hydrogel with bacteria capturing and combined photothermal/photodynamic sterilization functions. Such hydrogel is prepared by mixing chitosan (CS) as matrix, protoporphyrin (PpIX) as photosensitizer and polydopamine (PDA) as photothermal agent and then chemically cross-linking CS with glutaraldehyde. The resulting CS-PpIX-PDA hydrogel possesses a porous architecture (average pore porosity = 60.9 %), excellent swelling capabilities (swelling ratio = 1855 %) and rheological property (G' > G″). The hydrogel can effectively produce reactive oxygen species (ROS) under 660 nm light irradiation due to the photodynamic effect of PpIX. Owing to the presence of PDA, the hydrogel displays a photoabsorption range between 600 and 1500 nm and can generate maximal temperature of 60 °C within 10 min under 808 nm laser illumination (0.6 W/cm2) through photothermal effect. Besides, under synergetic illumination of 808/660 nm laser, CS-PpIX-PDA hydrogel can induce the death of 99.9999 % of E. coli and 99.99999 % of S. aureus. Importantly, when coated on the wound site, the hydrogel exhibits a remarkable bacteria-trapping ability due to its porous structure and the presence of amino groups on chitosan. Under the excitation of 660/808 nm, the combined photothermal and photodynamic effects can effectively eradicate bacteria. Simultaneously, the hydrogel also demonstrates anti-inflammatory properties and upregulates Heat Shock Protein 90 (HSP90) expression, thereby promoting collagen deposition and facilitating wound healing. Therefore, the study may provide some new insights into the development of multifunctional hydrogel for photothermal-oxidation sterilization of bacteria-infected wound therapy.

Investigating into microbiota in the uterine cavity of the unexplained recurrent pregnancy loss patients in early pregnancy.

INTRODUCTION: The majority of unexplained recurrent pregnancy loss (URPL) cases have been attributed to immune abnormalities. Inappropriate changes in microbiota could lead to immune disorders. However, the specific role of uterine cavity microbiota in URPL remains unclear, and only a limited number of related studies are available for reference. METHODS: We utilized double-lumen embryo transfer tubes to collect uterine cavity fluid samples from pregnant women in their first trimester. Subsequently, we conducted 16S rRNA sequencing to analyze the composition and abundance of the microbiota in these samples. RESULTS: For this study, we enlisted 10 cases of URPL and 28 cases of induced miscarriages during early pregnancy. Microbial communities were detected in all samples of the URPL group (100 %, n = 10), whereas none were found in the control group (0 %, n = 28). Among the identified microbes, Lactobacillus and Curvibacter were the two most dominant species. The abundance of Curvibacter is correlated with the number of NK cells in peripheral blood (r = -0.759, P = 0.018). DISCUSSION: This study revealed that during early pregnancy, Lactobacillus and Curvibacter were the predominant colonizers in the uterine cavity of URPL patients and were associated with URPL. Consequently, alterations in the dominant microbiota may lead to adverse pregnancy outcomes.

Erythrocyte-Membrane-Camouflaged Magnetic Nanocapsules With Photothermal/Magnetothermal Effects for Thrombolysis.

Venous/arterial thrombosis poses significant threats to human health. However, drug-enabled thrombolysis treatment often encounters challenges such as short half-life and low bioavailability. To address these issues, the design of erythrocyte-membrane (EM) camouflaged nanocapsules (USIO/UK@EM) incorporating ultra-small iron oxide (USIO) and urokinase (UK) drug, which exhibits remarkable photothermal/magnetothermal effects and drug delivery ability for venous/arterial thrombolysis, is reported. USIO, UK, and EM are coextruded to fabricate USIO/UK@EM with average sizes of 103.7 nm. As USIO/UK@EM possesses wide photoabsorption and good magnetic properties, its solution demonstrates a temperature increase to 41.8-42.9 °C within 5 min when exposed to an 808 nm laser (0.33 mW cm-2) or alternating magnetic field (AMF). Such photothermal/magnetothermal effect along with UK confers impressive thrombolytic rates of 82.4% and 74.2%, higher than that (≈15%) achieved by UK alone. Further, the EM coating extends the circulating half-life (t1/2 = 3.28 h). When USIO/UK@EM is administered to mice and rabbits, tail vein thrombus in mice and femoral artery thrombus in rabbits can be dissolved by the synergetic effect of thermothrombolysis and UK. Therefore, this study not only offers insights into the rational design of multifunctional biomimetic nanocapsules but also showcases a promising thrombolysis strategy utilizing nanomedicine.

[Coagulation and prothrombotic state parameters: clinical analysis in early pregnancy].

OBJECTIVE: To assess the changes in coagulation, thrombosis, anti-coagulation and fibrinolysis during early pregnancy. METHODS: A total of 105 gravidas with monocytic pregnancies between 10 and 12 weeks gestational age at Sun Yat-sen Memorial Hospital, Sun Yat-sen University during April 2005 to June 2009 were recruited for study group and another 82 non-pregnant women as control group. Coagulation parameters, including thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin (PT) and fibrinogen (Fg), were measured. We also tested the prothrombotic state parameters, including prothrombin fragment 1+2 (F1+2), thrombomodulin (TM), thrombin-antithrombin complex (TAT), antithrombin III(AT-III), GMP140, thromboxane B2 (TXB2), plasminogen activator inhibitor (PAI-2; performed by enzyme-linked immunosorbent assay) and D-dimer (D2; tested by latex turbidimetric immunoassay). RESULTS: Fg (4.00 vs 2.52 g/L), F1+2 (0.66 vs 0.31 nmol/L), TAT (179.95 vs 39.46 µg/L), GMP140 (9.42 vs 19.13 µg/L), D2 (201.51 vs 125.02 µg/L) and PAI-2 (0.047 vs 0.006 g/L) were statistically different between the study and control groups (P < 0.01). CONCLUSIONS: The coagulation, fibrinolysis and anti-fibrinolysis functions of healthy pregnant women become enhanced during early pregnancy while anti-coagulation function slightly increases. These four basic functions are balanced at a higher level so that the activation of platelets stays at a lower level.

Single-cell transcriptomics implicates the FEZ1-DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence.

Limbal stem/progenitor cells (LSC) represent the source of corneal epithelium renewal. LSC proliferation and differentiation are essential for corneal homeostasis, however, the regulatory mechanism remains largely unexplored. Here, we performed single-cell RNA sequencing and discovered proliferation heterogeneity as well as spontaneously differentiated and senescent cell subgroups in multiply passaged primary LSC. Fasciculation and elongation protein zeta 1 (FEZ1) and Dickkopf-1 (DKK1) were identified as two significant regulators of LSC proliferation and senescence. These two factors were mainly expressed in undifferentiated corneal epithelial cells (CECs). Knocking down the expression of either FEZ1 or DKK1 reduced cell division and caused cell cycle arrest. We observed that DKK1 acted as a downstream target of FEZ1 in LSC and that exogenous DKK1 protein partially prevented growth arrest and senescence upon FEZ1 suppression in vitro. In a mouse model of corneal injury, DKK1 also rescued the corneal epithelium after recovery was inhibited by FEZ1 suppression. Hence, the FEZ1-DKK1 axis was required for CEC proliferation and the juvenile state and can potentially be targeted as a therapeutic strategy for promoting recovery after corneal injury.

Association of metastatic nodal size with survival in non-surgical non-small cell lung cancer patients: Recommendations for clinical N staging.

Background: This study aims to analyze the prognostic significance of the metastatic lymph node (mLN) size in non-small cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT) to provide some information for the optimization of clinical nodal (cN) staging. Methods: A retrospective study with 325 NSCLC patients was conducted between January 2011 and December 2018 at two participating institutes. We evaluated the potential relationship between the mLN size and the survival to propose a potential revised nodal (rN) staging. Results: Kaplan-Meier analyses showed significant differences in the overall survival (OS) based on the cN staging and the size of mLNs (N0, ≤2 cm, and >2 cm). We found that the nodal size correlated statistically with the response to CRT. The HRs of OS for patients with bulky mLNs increase significantly compared with patients in the non-bulky mLNs group in the cN2-3 group. Interestingly, the HRs of patients with bulky cN2 disease and non-bulky cN3 disease were similar to each other. We classified the patients into five subsets: N0, rN1(cN1), rN2(non-bulky cN2), rN3a(bulky cN2, and non-bulky cN3), and rN3b(bulky cN3). In our study, the rN stage showed better prognostic discrimination than the 8th IASLC cN staging and was an independent prognostic factor for survival. Conclusions: In addition to the anatomic location, the size of mLNs correlated statistically with the response to CRT and should be incorporated into the cN staging system to predict survival more accurately.

Lymph node metastasis is not associated with survival in patients with clinical stage T4 esophageal squamous cell carcinoma undergoing definitive radiotherapy or chemoradiotherapy.

Background: Clinical T4 stage (cT4) esophageal tumors are difficult to be surgically resected, and definitive radiotherapy (RT) or chemoradiotherapy (dCRT) remains the main treatment. The study aims to analyze the association between the status of lymph node (LN) metastasis and survival outcomes in the cT4 stage esophageal squamous cell carcinoma (ESCC) patients that underwent treatment with dCRT or RT. Methods: This retrospective study analyzed the clinical data of 555 ESCC patients treated with dCRT or RT at the Shandong Cancer Hospital and the Liaocheng People's Hospital from 2010 to 2017. Kaplan-Meier and Cox regression analyses was performed to determine the relationship between LN metastasis and survival outcomes of cT4 and non-cT4 ESCC patients. The chi-square test was used to evaluate the differences in the local and distal recurrence patterns in the ESCC patients belonging to various clinical T stages. Results: The 3-year survival rates for patients with non-cT4 ESCC and cT4 ESCC were 47.9% and 30.8%, respectively. The overall survival (OS) and progression-free survival (PFS) rates were strongly associated with the status of LN metastasis in the entire cohort (all P < 0.001) and the non-cT4 group (all P < 0.001) but not in the cT4 group. The local recurrence rates were 60.7% for the cT4 ESCC patients and 45.1% for the non-cT4 ESCC patients (P < 0.001). Multivariate analysis showed that clinical N stage (P = 0.002), LN size (P = 0.007), and abdominal LN involvement (P = 0.011) were independent predictors of favorable OS in the non-cT4 group. However, clinical N stage (P = 0.824), LN size (P = 0.383), and abdominal LN involvement (P = 0.337) did not show any significant correlation with OS in the cT4 ESCC patients. Conclusions: Our data demonstrated that the status of LN metastasis did not correlate with OS in the cT4 ESCC patients that received dCRT or RT. Furthermore, the prevalence of local recurrence was higher in the cT4 ESCC patients.

Association of thyroid peroxidase antibodies with the rate of first-trimester miscarriage in euthyroid women with unexplained recurrent spontaneous abortion.

Background: Unexplained recurrent spontaneous abortion is a serious reproductive problem of unknown etiology. Thyroid peroxidase antibodies (TPO-Ab) may be associated with pregnancy outcomes in unexplained recurrent spontaneous abortion with normal thyroid function. Objective: This study aimed to investigate the relationship between TPO-Ab and the first trimester miscarriage rate/live birth rate in women of unexplained recurrent spontaneous abortion with normal thyroid function. Methods: We retrospectively analyzed the clinical data of 297 women who met our strict inclusion criteria, comparing the first trimester miscarriage rate/live birth rate between the TPO-Ab positive and TPO-Ab negative groups. For the same purpose, we also performed subgroup analysis. Results: Of the included women, 76 (25.6%) were TPO-Ab positive, and 221 (74.4%) were negative. First trimester miscarriage rate differed between the two groups (36.8% vs 24.0%, RR = 1.54, 95% CI: 1.05-2.24, P = 0.030). In the younger subgroup (<35 years) and the primary RSA subgroup, First trimester miscarriage rate was also higher in the TPO-Ab positive group (33.3% vs 19.0%, RR = 1.75, 95% CI: 1.07-2.87, P = 0.030; 36.5% vs 21.7%, RR = 1.69, 95% CI: 1.10-2.58, P = 0.020). While the live birth rate was lower in women with TPO-Ab positive, the difference did not reach statistical significance, even in the subgroup analysis. Conclusion: Our results suggest that TPO-Ab is associated with first trimester miscarriage rate in euthyroid women with unexplained recurrent spontaneous abortion.

dsRNA Induced IFNß-MMP13 Axis Drives Corneal Wound Healing.

Purpose: Cornea, the outermost transparent layer of the eye, is the first line of defense against external threats. Following injury, the wound healing response is crucial to corneal repair and regeneration, yet its underlying mechanism is poorly understood. Our study was designed to investigate the role of dsRNA and its regulatory network in corneal wound healing. Methods: A corneal wound healing model was established via the surgical removal of half of the corneal surface and adjoining limbus. RNase III was then used to clarify the role of dsRNA in corneal wound closure and RNA-seq was performed to investigate the mechanism of dsRNA in the healing process. Related gene expression was assessed using immunofluorescence staining, qPCR, and Western blot. Flow cytometry and scratch assay were used to analyze the proliferation and migration of limbal stem/progenitor cells (LSCs) in vitro and functional analysis of the target genes was completed using the corneal wound healing model. Results: Corneal wound healing was delayed and impaired when the dsRNAs were removed or damaged following RNase III digestion. The dsRNAs released following corneal damage activate type I interferon (IFN-I) signaling, primarily IFNß, via the corneal epithelium and neutralizing IFNß or blocking IFN-I signaling delays corneal wound closure. Moreover, our data identified MMP13 as a downstream effector of IFNß where its expression promotes LSC proliferation and enhances corneal epithelial reconstruction in vivo. Conclusions: The dsRNA induced IFNß-MMP13 axis plays a key role in corneal wound healing.

Cis-regulatory chromatin loops analysis identifies GRHL3 as a master regulator of surface epithelium commitment.

Understanding the regulatory network of cell fate acquisition remains a major challenge. Using the induction of surface epithelium (SE) from human embryonic stem cells as a paradigm, we show that the dynamic changes in morphology-related genes (MRGs) closely correspond to SE fate transitions. The marked remodeling of cytoskeleton indicates the initiation of SE differentiation. By integrating promoter interactions, epigenomic features, and transcriptome, we delineate an SE-specific cis-regulatory network and identify grainyhead-like 3 (GRHL3) as an initiation factor sufficient to drive SE commitment. Mechanically, GRHL3 primes the SE chromatin accessibility landscape and activates SE-initiating gene expression. In addition, the evaluation of GRHL3-mediated promoter interactions unveils a positive feedback loop of GRHL3 and bone morphogenetic protein 4 on SE fate decisions. Our work proposes a concept that MRGs could be used to identify cell fate transitions and provides insights into regulatory principles of SE lineage development and stem cell-based regenerative medicine.

Cotransplantation of Limbal Epithelial and Stromal Cells for Ocular Surface Reconstruction.

Purpose: To propose an improved stem cell-based strategy for limbal stem cell deficiency (LSCD) treatment. Design: Experimental randomized or parallel-group animal study. Subjects: Fifty adult male New Zealand white rabbits. Methods: Human limbal stem/progenitor cells (LSCs) and limbal stromal stem/progenitor cells (LSSCs) were cultured in serum-free conditions and further differentiated into corneal epithelial cells and keratocytes, respectively. All cell types were characterized with lineage-specific markers. Gene expression analysis was performed to identify the potential function of LSSCs in corneal regeneration. Two LSCD models of rabbits for transplantations were used: transplantation performed at the time of limbal and corneal epithelial excision (LSCD model) and transplantation performed after clinical signs were induced in an LSCD model (pLSCD model). The pLSCD model better mimics the pathologic changes and symptoms of human LSCD. Rabbit models received LSC or LSC plus LSSC treatment. Corneal epithelial defects, neovascularization, and opacity were assessed every 3 weeks for 24 weeks. ZsGreen-labeled LSSCs were used for short-term tracking in vivo. Main Outcome Measures: Rates of corneal epithelial defect area, corneal neovascularization and opacity scores, graft survival rate, and immunofluorescence staining of specific markers. Results: Both LSC transplantation and LSC plus LSSC cotransplantation effectively repaired the corneal surface in the LSCD model. These 2 strategies showed no significant differences in terms of graft survival rate or epithelial repair. However, corneal opacity was observed in the LSC group (in 3 of 8 rabbits), but not in the LSC plus LSSC group. Notably, when treating LSCD rabbits with distinguishable stromal opacification and neovascularization, cotransplantation of LSCs and LSSCs exhibited significantly better therapeutic effects than transplantation of LSCs alone, with graft survival rates of 87.5% and 37.5%, respectively. The implanted LSSCs could differentiate into keratocytes during the wound-healing process. RNA sequencing analysis showed that the stromal cells produced not only a collagen-rich extracellular matrix to facilitate reconstruction of the lamellar structure, but also niche factors that accelerated epithelial cell growth and inhibited angiogenesis and inflammation. Conclusions: These findings highlight the support of stromal cells in niche homeostasis and tissue regeneration, providing LSC plus LSSC cotransplantation as a new treatment strategy for corneal blindness.

Comprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity.

The insights into how genome topology couples with epigenetic states to govern the function and identity of the corneal epithelium are poorly understood. Here, we generate a high-resolution Hi-C interaction map of human limbal stem/progenitor cells (LSCs) and show that chromatin multi-hierarchical organisation is coupled to gene expression. By integrating Hi-C, epigenome and transcriptome data, we characterize the comprehensive 3D epigenomic landscapes of LSCs. We find that super-silencers mediate gene repression associated with corneal development, differentiation and disease via chromatin looping and/or proximity. Super-enhancer (SE) interaction analysis identified a set of SE interactive hubs that contribute to LSC-specific gene activation. These active and inactive element-anchored loop networks occur within the cohesin-occupied CTCF-CTCF loops. We further reveal a coordinated regulatory network of core transcription factors based on SE-promoter interactions. Our results provide detailed insights into the genome organization principle for epigenetic regulation of gene expression in stratified epithelia.

Short-term response might influence the treatment-related benefit of adjuvant chemotherapy after concurrent chemoradiotherapy for esophageal squamous cell carcinoma patients.

BACKGROUND: Whether adjuvant chemotherapy (AC) after concurrent chemoradiotherapy (CCRT) could provide benefit to esophageal squamous cell carcinoma (ESCC) patients is controversial. Therefore, we decided to investigate the potential benefit of AC after CCRT for ESCC and to identify biomarkers predictive of a clinical benefit. METHODS: We retrospectively analysed the clinical data of ESCC patients with clinical stage II-IVa who underwent CCRT. Then, we compared patients who received CCRT and AC (CCRT + AC group) with those who received CCRT alone (CCRT group). Propensity score analysis, subgroup analysis and an additional Cox regression model were conducted to analyse the predictive factors. The overall survival (OS) and progression-free survival (PFS) rates were taken as the endpoints. RESULTS: From January 2013 to December 2017, 244 patients were recruited (n = 131 for CCRT + AC; n = 113 for CCRT alone) for the analysis. After propensity score matching was performed (1:1 and 99 patients for each group) with consideration of the basic clinical characteristics, no significant differences were found in OS (HR = 1.024; 95% CI 0.737-1.423; P = 0.886) or PFS (HR = 0.809; 95% CI 0.582-1.126; P = 0.197) between the two groups. The good short-term response subgroup showed a better PFS and favoured CCRT + AC treatment (HR = 0.542; 95% CI 0.336-0.876; P = 0.008), the independent predictive role of which was confirmed in additional multivariate Cox regression analysis. CONCLUSIONS: Although AC did not significantly improve PFS and OS for all ESCC patients after CCRT, the short-term response to CCRT might help identify a subgroup that will benefit, which needs further prospective research to confirm.

Highly-efficient and easy separation of hexahedral sodium dodecyl sulfonate/δ-FeOOH colloidal particles for enhanced removal of aqueous thallium and uranium ions: Synergistic effect and mechanism study.

Thallium (Tl) and uranium (U) contaminants pose serious threats to the ecological environment and human health. In this research, a cost-effective feroxyhite (δ-FeOOH) dispersed with sodium dodecyl sulfonate (SDS) was prepared and a series of experiments were optimized to explore the removal mechanism of Tl+ and UO22+ from the effluent. The SDS/δ-FeOOH exhibited highly dispersed colloidal particles and showed significantly enhanced adsorption performance on the removal of Tl and U in the presence of H2O2 and pH of 7.0. Equilibrium uptakes of 99.5% and 99.7% were rapidly achieved for Tl+ and UO22+ within 10 min, respectively. The Freundlich isotherm model fitted well with the adsorption data of Tl and U. The maximum isotherm sorption capacity of SDS/δ-FeOOH for Tl+ and UO22+ was 182.9 and 359.6 mg/g, respectively. The sorption of Tl followed the pseudo-second-order kinetic model, whereas the sorption of U followed the pseudo-first-order kinetic model. The uptake of Tl and U by SDS/δ-FeOOH was notably inhibited at Na+, K+ concentrations over 5.0 mM, and a high content of dissolved organic matter (over 0.5 mg/L). The mechanistic study revealed that ion exchange, precipitation, and surface complexation were main mechanisms for the removal of Tl and U. The findings of this study indicate that stabilizer dispersion may serve as an effective strategy to facilitate the treatment of wastewater containing Tl and U by using δ-FeOOH.