Reduced PTPRS expression promotes epithelial-mesenchymal transition of Schwann cells in NF1-related plexiform neurofibromas.

Plexiform neurofibromas (PNFs) are a prevalent and severe phenotype associated with NF1, characterized by a high teratogenic rate and potential for malignant transformation. The growth and recurrence of PNFs are attributed to aberrant proliferation and migration of Nf1-deficient Schwann cells. Protein tyrosine phosphatase receptor S (PTPRS) is believed to modulate cell migration and invasion by inhibiting the EMT process in NF1-derived malignant peripheral nerve sheath tumors. Nevertheless, the specific role of PTPRS in NF1-derived PNFs remains to be elucidated. The study utilized the GEO database and tissue microarray to illustrate a decrease in PTPRS expression in PNF tissues, linked to tumor recurrence. Furthermore, the down- and over-expression of PTPRS in Nf1-deficient Schwann cell lines resulted in the changes of cell migration and EMT processes. Additionally, RTK assay and WB showed that PTPRS knockdown can promote EGFR expression and phosphorylation. The restoration of EMT processes disrupted by alterations in PTPRS levels in Schwann cells can be achieved through EGFR knockdown and EGFR inhibitor. Moreover, high EGFR expression has been significantly correlated with poor prognosis. These findings underscore the potential role of PTPRS as a tumor suppressor in the recurrence of PNF via the regulation of EGFR-mediated EMT processes, suggesting potential targets for future clinical interventions.

FOXM1 promotes neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor progression in a NUF2-dependent manner.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas characterized by poor prognosis and low drug response rates. Traditional chemo/radiotherapies show only mild benefits for patients with MPNSTs, and no targeted therapy is available in the clinic. A better understanding of the molecular background of MPNSTs is critical for the development of effective targeted therapies. Forkhead box M1 (FOXM1) has been implicated in the progression of many human malignancies, though its role in MPNSTs is unclear. In this study, using four Gene Expression Omnibus (GEO) datasets and a tissue microarray, we demonstrated that FOXM1 upregulation was associated with poor prognosis in patients with MPNSTs. FOXM1 overexpression and knockdown regulated the proliferation and colony formation of MPNST cells. Using bioinformatics analysis and luciferase reporter assays, we identified NUF2 as a direct downstream target of FOXM1. Both in vitro and in vivo experiments demonstrated that the induction of MPNST cell proliferation by FOXM1 was dependent on elevated NUF2 expression, as NUF2 knockdown abolished the FOXM1-induced proliferation of MPNST cells. Our study showed that the FOXM1-NUF2 axis mediates human MPNST progression and could be a potential therapeutic target.

A dual-readout sensing platform for the evaluation of cell viability integrating with optical and digital signals based on a closed bipolar electrode.

Cell viability is essential for predicting drug toxicity and assessing drug effects in drug screening. However, the over/underestimation of cell viability measured by traditional tetrazolium colorimetric assays is inevitable in cell-based experiments. Hydrogen peroxide (H2O2) secreted by living cells may provide more comprehensive information about the cell state. Hence, it is significant to develop a simple and rapid approach for evaluating cell viability by measuring the excreted H2O2. In this work, we developed a dual-readout sensing platform based on optical and digital signals by integrating a light emitting diode (LED) and a light dependent resistor (LDR) into a closed split bipolar electrode (BPE), denoted as BP-LED-E-LDR, for evaluating cell viability by measuring the H2O2 secreted from living cells in drug screening. Additionally, the customized three-dimensional (3D) printed components were designed to adjust the distance and angle between the LED and LDR, achieving stable, reliable and highly efficient signal transformation. It only took 2 min to obtain response results. For measuring the exocytosis H2O2 from living cells, we observed a good linear relationship between the visual/digital signal and logarithmic function of MCF-7 cell counts. Furthermore, the fitted half inhibitory concentration curve of MCF-7 to doxorubicin hydrochloride obtained by the BP-LED-E-LDR device revealed a nearly identical tendency with the cell counting kit-8 assay, providing an attainable, reusable, and robust analytical strategy for evaluating cell viability in drug toxicology research.

Laser treatment for Cafe-au-lait Macules: a systematic review and meta-analysis.

Nowadays, laser is the mainstay treatment for cafe-au-lait macules (CALMs), but no systematic review has been published to demonstrate the overall efficacy and it's still controversial which type of laser is optimal. Thus, we conduct the meta-analysis to evaluate the effectiveness and side effects of various types of lasers in treating CALMs. Original articles reporting the efficacy and side effects for CALMs in laser treatment were identified in PubMed, EMBASE, and Web of Science from 1983 to April 11, 2023. Using R software and the 'meta' package, meta-analysis was conducted for clearance and recurrence for evaluation of efficacy. And the occurrence of hypopigmentation and hyperpigmentation rate was pooled for safety evaluation. We used RoB2 and ROBINS-I tools to assess the risks of bias in RCT studies and non-RCT studies, respectively. The Grading of Recommendations, Assessment, Development and Evaluation system was used to assess the quality of the evidence. Nineteen studies involving 991 patients were included, which had a very low to moderate quality of evidence. The pooled 75% clearance rate was 43.3% (95% CI 31.8-54.7%, I2 = 96%), 50% clearance rate was 75% (95% CI 62.2-85.9%, I2 = 89%) and the recurrence rate was 13% (95% CI 3.2-26.5%, I2 = 88%). The pooled hypopigmentation and hyperpigmentation rates were 1.2% (95% CI 0.3-2.1%, I2 = 0%) and 1.2% (95% CI 0.3-2%, I2 = 0%), respectively. Subgroup analysis revealed that QS-1064-nm Nd:YAG laser treatment not only achieved more than 75% clearance rate in 50.9% of patients (95% CI 26.9-74.4%, I2 = 90%) but also resulted in the lowest hypopigmentation and hyperpigmentation rate of 0.5% (95% CI 0.0-2.5%, I2 = 26%) and 0.4% (95% CI 0.0-2.5%, I2 = 0%). To draw a conclusion, the laser treatment could reach an overall clearance rate of 50% for 75% of the patients with CALMs, for 43.3% of the patients, the clearance rate could reach 75%. When looking at different wavelength subgroups, QS-1064-nm Nd:YAG laser exhibited the best treatment capability. Laser of all the wavelength subgroups presented acceptable safety regarding of the low occurrence of side effects, namely, hypopigmentation and hyperpigmentation.

CX-4945 inhibits fibroblast-like synoviocytes functions through the CK2-p53 axis to reduce rheumatoid arthritis disease severity.

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs. METHODS: Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis. RESULTS: RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation. CONCLUSIONS: RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.

Knockdown of NCOR2 Inhibits Cell Proliferation via BDNF/TrkB/ERK in NF1-Derived MPNSTs.

(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the progression of MPNST remains unclear. (2) Methods: by GEO database, MPNST tissue microarray, and NF1-related tumour tissues and cell lines were used to explore NCOR2 expression level in the MPNSTs. The role and mechanism of NCOR2 in NF1-derived MPNSTs were explored by experiments in vivo and in vitro and by transcriptome high-throughput sequencing. (3) Results: NCOR2 expression is significantly elevated in NF1-derived MPNSTs and is associated with patient 10-year survival time. Knockdown of NCOR2 suppressed NF1-derived MPNST cell proliferation by blocking the cell cycle in the G0/G1 phase. Moreover, decreased NCOR2 expression could down-regulate MAPK signal activity through the BDNF/TrkB pathway. (4) Conclusions: our findings demonstrated that NCOR2 expression is significantly elevated in NF1-derived MPNSTs. NCOR2 knockdown can inhibit NF1-derived MPNST cell proliferation by weakened BDNF/TrkB/ERK signalling. Targeting NF1-derived MPNSTs with TrkB inhibitors, or in combination with ERK inhibitors, may be a novel therapeutic strategy for clinical trials.

ß-Klotho Promotes the Development of Intrauterine Adhesions via the PI3K/AKT Signaling Pathway.

Intrauterine adhesion (IUA) refers to injury to the basal layer of the endometrium, which can be caused by various factors. It is often accompanied by clinical symptoms such as abnormal menstruation, infertility, recurrent abortion, and periodic abdominal pain. In recent years, a number of studies have reported the effects of ß-Klotho (KLB) on the occurrence and development of human tumors and fibrotic diseases, but its relationship with endometrial fibroblasts and endometrial fibrosis has not been elucidated. In this study, we compared the expression of KLB in endometrial stromal cells (ESCs) from patients with IUA and normal controls. We constructed animal and cell models of IUA and conducted expression verification and functional experiments on KLB. We found that the expression of KLB was significantly increased in the ESCs of IUA patients and rat models compared with the controls. The overexpression of KLB could promote the proliferation and fibrosis of ESCs. In addition, the overexpression of KLB activated the PI3K/AKT signaling pathway in ESCs. Our study shows that KLB protein is highly expressed in the ESCs of patients with IUA and can enhance stromal cell proliferation and cell fibrosis by activating the PI3K/AKT pathway, thus promoting the development of IUA.

Efficacy and Safety of Trametinib in Neurofibromatosis Type 1-Associated Plexiform Neurofibroma and Low-Grade Glioma: A Systematic Review and Meta-Analysis.

Trametinib has been used in neurofibromatosis type 1 (NF1) patients, especially those with unresectable nerve tumors, but no systematic review based on the latest studies has been published. We conducted this meta-analysis to evaluate the effectiveness and safety of trametinib in treating NF1-related nerve tumors. Original articles reporting the efficacy and safety of trametinib in NF1 patents were identified in PubMed, EMBASE, and Web of Science up to 1 June 2022. Using R software and the 'meta' package, the objective response rates (ORRs) and disease control rates (DCRs) were calculated to evaluate the efficacy, and the pooled proportion of adverse events (AEs) was calculated. The Grading of Recommendations, Assessment, Development and Evaluation system was used to assess the quality of evidence. Eight studies involving 92 patients were included, which had a very low to moderate quality of evidence. The pooled ORR was 45.3% (95% CI: 28.9-62.1%, I2 = 0%), and the DCR was 99.8% (95% CI: 95.5-100%, I2 = 0%). The most common AEs was paronychia, with a pooled rate of 60.7% (95% CI: 48.8-72.7%, I2 = 0%). Our results indicate the satisfactory ability to stabilize tumor progression but a more limited ability to shrink tumors of trametinib in NF1-related nerve tumors. The safety profile of trametinib is satisfactory.

Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas which lack effective drugs. Loss of the RAS GTPase-activating protein NF1 and subsequent overactivation of mitogen-activated protein kinase kinase (MAPK) signaling exist nearly uniformly in MPNST, making MAPK inhibition a promising therapeutic intervention. However, the efficacy of MEK inhibitor (MEKi) monotherapy was limited in MPNST and the relative mechanisms remained largely unexplored. In this study, we generated three MEKi-resistant cell models and investigated the mechanisms of MEKi resistance using high-throughput transcriptomic sequencing. We discovered that cell apoptosis and cell cycle arrest induced by MEKi were rescued in MEKi-resistant cells and the upregulation of LAMA4/ITGB1/FAK/SRC signaling conferred resistance to MEKi. In addition, concurrent inhibition of MAPK signaling and FAK/SRC cascade could sensitize MPNST cells to MEKi. Our findings provide potential solutions to overcome MEKi resistance and effective combination therapeutic strategies for treating MPNSTs.

Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hinders the clinical application as well as the development of combination therapy. To guide further clinical studies, we evaluated different MEK inhibitors in terms of efficacy, safety, and mechanism of adaptive response in treating MPNSTs. Using a MPNST tissue microarray, we found that p-ERK could serve as a biomarker for predicting the prognosis of MPNST patients as well as an effective therapeutic target. Through in vitro and in vivo experiments, we identified trametinib as the most potent MEK inhibitor for the treatment of MPNSTs. Mechanistically, reduced reactivation of the MAPK pathway and compensatory activation of the parallel pathways contributed to better efficacy. Our results provide a basis for the further clinical application of MEK inhibitors as single agents or combinational therapies.

Fucosylation of anti-dsDNA IgG1 correlates with disease activity of treatment-naïve systemic lupus erythematosus patients.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a complex and heterogeneous autoimmune disease mediated by quantities of autoantibodies in which anti-double-stranded DNA (anti-dsDNA) antibodies are important. Besides, glycosylation is one of the most commonly post-translational modifications of antibodies. The association of anti-dsDNA antibodies glycosylation and SLE disease activity is still unknown. METHODS: We enrolled 101 consecutive treatment-naïve SLE patients with positive anti-dsDNA antibodies from the Department of Rheumatology and Immunology at Ruijin Hospital, Shanghai, between 2017 and 2019. Serum samples were used in this study. We analysed the glycosylation of anti-dsDNA IgG and total IgG subclasses according to systemic lupus erythematosus disease activity index (SLEDAI) scores. Statistical analysis and machine learning were performed to assess the correlation between glycosylation of anti-dsDNA IgG and total IgG with disease activity. FINDINGS: Serum samples from 86 patients could be detected with anti-dsDNA IgG glycopeptide and subclass of IgG glycoform. Cluster analysis showed that glycosylation of anti-dsDNA IgG and total IgG subclasses were different in SLE patients. Fucosylation, galactosylation, and sialylation levels of anti-dsDNA IgG1 were increased with SLEDAI scores (all p<0.05). The results of machine learning showed that all the glycoforms of anti-dsDNA IgG1 had better performance with lower standardised square error (SSE) than that of total IgG1, with anti-dsDNA IgG1 fucosylation level having the lowest SSE (0.009). INTERPRETATION: Our study indicated that glycosylation of anti-dsDNA IgG was different from that of total IgG and fucosylation of anti-dsDNA IgG1 correlated best with SLE disease activity. FUNDING: This work is supported by the National Key Research and Development Program of China (2018YFC0910303), National Natural Science Foundation of China (81801592, 82101876), Clinical Research Plan of SHDC (SHDC2020CR4011), Ruijin Hospital Youth Incubation Project (KY2021607) and Shanghai Pujiang Young Rheumatologists Training Program (SPROG202006).

Nomogram to predict an endometrial thickness above 7.5 mm in the frozen embryo transfer cycle of women with a thin endometrium.

RESEARCH QUESTION: Which characteristics of patients with a thin endometrium (endometrial thickness [EMT] ≤7.5 mm on human chorionic gonadotrophin [HCG] trigger day) suggest the possibility of an EMT >7.5 mm in the subsequent frozen cycle? DESIGN: Data were collected from the university-affiliated Centre for Reproductive Medicine between January 2013 and September 2019. Multivariable logistic regression was used to generate the final prediction model and construct the nomogram. Model performances were quantified by discrimination and calibration. RESULTS: The predictive variables that entered the final model were: hysteroscopic adhesiolysis history, polycystic ovary syndrome status, application of clomiphene in the ovarian stimulation process, the ovarian stimulation protocol and the endometrial preparation protocol. The receiver operating characteristic (ROC) curve for the final model and validation cohort was 0.760 (95% confidence interval [CI] 0.722-0.797) and 0.713 (95% CI 0.664-0.759), respectively. Discrimination performed well in both the modelling and validation cohorts. CONCLUSIONS: In women with a thin endometrium (EMT ≤7.5 mm on HCG trigger day), the absence of a hysteroscopic adhesiolysis history, the presence of polycystic ovary syndrome, the application of clomiphene in the ovarian stimulation process, the application of a gonadotrophin-releasing hormone agonist short protocol, mild stimulation protocol, natural cycle protocol, and natural cycle for endometrial preparation are prognostic for an increased possibility of an EMT >7.5 mm in the subsequent frozen cycle.

The Efficiency of Hydroxychloroquine for the Treatment of Primary Sjögren's Syndrome: A Systematic Review and Meta-Analysis.

Objectives: This meta-analysis was conducted to evaluate the effects of hydroxychloroquine (HCQ) in the treatment of primary Sjögren's syndrome (pSS). Methods: Nine databases were searched for data collection. We used clinical features, including involvement in superficial tissues and visceral systems, and experimental findings, including Schirmer's test, unstimulated salivary flow rate (uSFR), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and immunoglobulins (IgG, IgM and IgA) as major outcome measures. The Downs and Black quality assessment tool and RevMan 5.3 were used to assess the methodological quality and statistical analysis, respectively. Results: Thirteen studies with pSS patients, consisting of two randomized controlled studies, four retrospective studies and seven prospective studies were analyzed. Results showed that HCQ treatment significantly improved the oral symptoms of pSS patients compared to non-HCQ treatment (P = 0.003). Similar trends favoring HCQ treatment were observed for uSFR (p = 0.05), CRP (p = 0.0008), ESR (p < 0.00001), IgM (p = 0.007) and IgA (p = 0.05). However, no significant improvement was observed in other clinical features, including ocular involvement, fatigue, articular lesions, pulmonary, neurological and lymphoproliferative symptoms, renal organs and other experimental parameters in the HCQ treatment group compared to the non-HCQ treatment group. Conclusion: HCQ treatment showed moderate efficacy to improve oral symptoms, uSFR, ESR, CRP, IgM and IgA. However, HCQ could not alleviate organ-specific systemic involvement. Systematic Review Registration:We have registered on the PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], and the registration number is identifier [CRD42020205624].

Epigallocatechin-3 gallate regulates macrophage subtypes and immunometabolism to ameliorate experimental autoimmune encephalomyelitis.

Epigallocatechin-3 gallate (EGCG) is a polyphenolic component of tea and has potential curative effects in patients with autoimmune diseases. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). It remains unknown whether EGCG can regulate macrophage subtypes in MS. Here we evaluated the effects of EGCG in experimental autoimmune encephalomyelitis (EAE), MS mouse model. We found that EGCG treatment reduced EAE severity and macrophage inflammation in the CNS. Moreover, EAE severity was well correlated with the ratio of M1 to M2 macrophages, and EGCG treatment suppressed M1 macrophage-mediated inflammation in spleen. In vitro experiments showed that EGCG inhibited M1 macrophage polarization, but promoted M2 macrophage polarization. These effects were likely to be related to the inhibition of nuclear factor-κB signaling and glycolysis in macrophages by EGCG in macrophages. Overall, these findings provided important insights into the mechanisms through which EGCG may mediate MS.

Factors Influencing the Live Birth Rate Following Fresh Embryo Transfer Cycles in Infertile Women After Endometrioma Cystectomy.

Background: Reproductive outcomes after fresh in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycles are diverse in infertile women with a history of ovarian cystectomy for endometriomas. We aimed to develop a logistic regression model based on patients' characteristics including number of embryos transferred and stimulation protocols to predict the live birth rate in fresh IVF/ICSI-ET cycles for such patients. Methods: We recruited 513 infertile women with a history of ovarian cystectomy for endometriomas who underwent their first fresh ET with different stimulation protocols following IVF/ICSI cycles in our unit from January 2014 to December 2018. One or two embryo are implanted. Clinical and laboratory parameters potentially affecting the live birth rate following fresh ET cycles were analyzed. Univariable and multivariable analyses were performed to assess the relationship between predictive factors and live birth rate. Results: The overall live birth rate was 240/513 (46.8%). Multivariable modified Poisson regression models showed that two factors were significantly lowers the probability of live birth: female age ≥ 5 years (aOR 0.603; 95% CI 0.389-0.933; P = 0.023); BMI range 21-24.99 kg/m2 compared with BMI <21 kg/m2 (aOR 0.572; 95% CI 0.372-0.881, P = 0.011). And two factors significantly increased the probability of live birth: AFC >7 (aOR 1.591; 95% CI 1.075-2.353; P = 0.020); two embryos transferred (aOR 1.607; 95% CI 1.089-2.372; P = 0.017). Conclusions: For these infertile women who had undergone ovarian cystectomy for endometriosis, female age <35 years, AFC > 7, and two embryos transferred might achieve better clinical fresh IVF/ICSI-ET outcomes. BMI <21 kg/m2 or ≥25 kg/m2 might also have positive effects on the live birth rate, but different ovarian stimulation protocols had no significant effects. However, a larger sample size may be needed for further study.

IFN-γ contributes to the hepatic inflammation in HFD-induced nonalcoholic steatohepatitis by STAT1ß/TLR2 signaling pathway.

Growing research evidence suggests that elevated TLR2 is closely related to the occurrence and development of nonalcoholic steatohepatitis (NASH). However, a little is known about its regulatory mechanism. Here, we found that IFN-γ and TLR2 expression is significantly upregulated in NASH associated rat liver specimens. Meanwhile, IFN-γ positively regulated the expression of TLR2 and its target genes in NR8383 rat macrophage cells in dose- & time-dependent manner. Importantly, IFN-γ also regulated the related transcriptional factors pSTAT1 and IRF1. Moreover, we identified that the DNA fragment from -1000 to -200 bp of the TLR2 promoter region is responsible for STAT1 binding, especially the STAT1-BS3 (-591∼-573 bp). Further investigation verified that STAT1ß is essential in this process, rather than STAT1α. Overall, our findings suggest that IFN-γ promotes TLR2 transcription and its target genes expression by STAT1ß. This leads to the hepatic inflammation vicious cycle in NASH and provides new potential targets for treating NASH.

Integrated paper-based 3D platform for long-term cell culture and in situ cell viability monitoring of Alzheimer's disease cell model.

Reactive oxygen species including superoxide anion, hydrogen peroxide (H2O2) and hydroxyl radicals, as a conflicting class of biological metabolites in living organism, act crucial effect on Alzheimer's disease (AD). In this work, a facile integrated platform composed of a paper-based three-dimension (3D) cell culture system and an electrochemical sensor was developed for the construction of AD cell model in third dimensional structure and in situ cell viability monitoring by H2O2 released from PC12 cells cultured on paper scaffold were divided into three groups containing control group, amyloid beta peptide 25-35 (Aß25-35) group and Aß25-35+curcumin (Aß25-35+cur) group, respectively. In addition, the paper-based 3D platform displayed excellent properties, such as sensitivity, selectivity, reproducibility and stability. The levels of H2O2 expressed in PC12 cells of the three groups were monitored through a paper-based 3D platform. The viability of cells cultured on the 96-well plate was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Results of this paper-based platform are consistent with those of MTT, both displaying improved cell viability and decreased H2O2 production in Aß25-35+cur group compared to Aß25-35 group, which indicates that curcumin has effective cytoprotection. The paper-based 3D platform provides a convenient, economic and universal platform for in situ cell activity monitoring by key small molecules released from living cells.

Reproductive Outcomes of In Vitro Fertilization-Intracytoplasmic Sperm Injection after Transcervical Resection of Adhesions: A Retrospective Cohort Study.

STUDY OBJECTIVE: To investigate pregnancy and obstetric outcomes of patients with intrauterine adhesions (IUAs) after treatment with in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) and fresh embryo transplantation after transcervical resection of adhesions (TCRA). DESIGN: Retrospective cohort study. SETTING: University-based reproductive medical center. PATIENTS: A total of 535 patients with IUAs and with a history of TCRA and 1605 matched patients without a history of IUAs underwent IVF-ICSI and received fresh embryo transfers. INTERVENTIONS: Between January 2014 and December 2018, all patients underwent IVF-ICSI treatment and received fresh embryo transfers. MEASUREMENTS AND MAIN RESULTS: The patients in the TCRA group were matched with the control group according to strict criteria. Pregnancy and obstetric outcomes were compared. There were no significant differences in clinical pregnancies, ectopic pregnancies, live births, preterm births, and obstetric outcomes between the 2 groups (p >.05). However, the TCRA group had a higher risk of miscarriage than the control group (p = .048). CONCLUSION: TCRA improved the reproductive outcomes of patients with IUAs, but the risk of miscarriage was higher than that in the general population. To avoid miscarriage, careful monitoring is critical for pregnant patients with a history of TCRA who undergo embryo transfers during IVF treatment.

Fresh versus frozen embryo transfer in women with thin endometrium: a retrospective cohort study.

BACKGROUND: A thin endometrium affects embryo implantation. We designed a retrospective cohort study to analyze the differences of in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) outcomes between fresh embryo transfer (ET) and frozen ET in patients with a thin endometrium. METHODS: The present study comprised of 1,110 patients with a thin endometrium undergoing IVF-ICSI between January 2013 and December 2017 in our unit. Propensity score matching (PSM) was used to balance the influence of intergroup confounding factors and to compare the pregnancy outcomes of the matched patients in the two groups. The fresh embryo group and frozen embryo group consisted of 632 and 478 women, respectively. After PSM, 173 patients were included in the two groups, respectively. RESULTS: The frozen embryo group showed a higher live birth rate (31% vs. 18.4%, P<0.001; 30.6% vs. 19.7%, P=0.019), clinical pregnancy rate (40% vs. 26.4%, P<0.001; 38.7% vs. 25.4%, P=0.008), and biochemical pregnancy rate (46.2% vs. 32.9%, P<0.001; 44.5% vs. 31.8%, P=0.020) than the fresh embryo group before and after PSM. CONCLUSIONS: Our results demonstrated that for women with a thin endometrium who were undergoing IVF, the live birth rate, clinical pregnancy rate, and biochemical pregnancy rate after frozen ET were significantly higher than in the fresh ET group.