Clinical effectiveness of a multitarget urine DNA test for urothelial carcinoma detection: a double-blinded, multicenter, prospective trial.

Urine-based testing is promising for noninvasive diagnosis of urothelial carcinoma (UC) but has suboptimal sensitivity for early-stage tumors. Herein, we developed a multitarget urine tumor DNA test, UI-Seek, for UC detection and evaluated its clinical feasibility. The prediction model was developed in a retrospective cohort (n = 382), integrating assays for FGFR3 and TERT mutations and aberrant ONECUT2 and VIM methylation to generate a UC-score. The test performance was validated in a double-blinded, multicenter, prospective trial (n = 947; ChiCTR2300076543) and demonstrated a sensitivity of 91.37% and a specificity of 95.09%. The sensitivity reached 75.81% for low-grade Ta tumors and exceeded 93% in high-grade Ta and higher stages (T1 to T4). Simultaneous identification of both bladder and upper urinary tract tumors was enabled with sensitivities exceeding 90%. No significant confounding effects were observed regarding benign urological diseases or non-UC malignancies. The test showed improved sensitivities over urine cytology, the NMP22 test, and UroVysion FISH alongside comparable specificities. The single-target accuracy was greater than 98% as confirmed by Sanger sequencing. Post-surgery UC-score decreased in 97.7% of subjects. Overall, UI-Seek demonstrated robust performance and considerable potential for the early detection of UC.

Artificial intelligence-assisted system for the assessment of Forrest classification of peptic ulcer bleeding: a multicenter diagnostic study.

BACKGROUND: Inaccurate Forrest classification may significantly affect clinical outcomes, especially in high risk patients. Therefore, this study aimed to develop a real-time deep convolutional neural network (DCNN) system to assess the Forrest classification of peptic ulcer bleeding (PUB). METHODS: A training dataset (3868 endoscopic images) and an internal validation dataset (834 images) were retrospectively collected from the 900th Hospital, Fuzhou, China. In addition, 521 images collected from four other hospitals were used for external validation. Finally, 46 endoscopic videos were prospectively collected to assess the real-time diagnostic performance of the DCNN system, whose diagnostic performance was also prospectively compared with that of three senior and three junior endoscopists. RESULTS: The DCNN system had a satisfactory diagnostic performance in the assessment of Forrest classification, with an accuracy of 91.2% (95%CI 89.5%-92.6%) and a macro-average area under the receiver operating characteristic curve of 0.80 in the validation dataset. Moreover, the DCNN system could judge suspicious regions automatically using Forrest classification in real-time videos, with an accuracy of 92.0% (95%CI 80.8%-97.8%). The DCNN system showed more accurate and stable diagnostic performance than endoscopists in the prospective clinical comparison test. This system helped to slightly improve the diagnostic performance of senior endoscopists and considerably enhance that of junior endoscopists. CONCLUSION: The DCNN system for the assessment of the Forrest classification of PUB showed satisfactory diagnostic performance, which was slightly superior to that of senior endoscopists. It could therefore effectively assist junior endoscopists in making such diagnoses during gastroscopy.

Chicken Interferon-Alpha and -Lambda Exhibit Antiviral Effects against Fowl Adenovirus Serotype 4 in Leghorn Male Hepatocellular Cells.

Hydropericardium hepatitis syndrome (HHS) is primarily caused by fowl adenovirus serotype 4 (FAdV-4), causing high mortality in chickens. Although vaccination strategies against FAdV-4 have been adopted, HHS still occurs sporadically. Furthermore, no effective drugs are available for controlling FAdV-4 infection. However, type I and III interferon (IFN) are crucial therapeutic agents against viral infection. The following experiments were conducted to investigate the inhibitory effect of chicken IFN against FadV-4. We expressed recombinant chicken type I IFN-α (ChIFN-α) and type III IFN-λ (ChIFN-λ) in Escherichia coli and systemically investigated their antiviral activity against FAdV-4 infection in Leghorn male hepatocellular (LMH) cells. ChIFN-α and ChIFN-λ dose dependently inhibited FAdV-4 replication in LMH cells. Compared with ChIFN-λ, ChIFN-α more significantly inhibited viral genome transcription but less significantly suppressed FAdV-4 release. ChIFN-α- and ChIFN-λ-induced IFN-stimulated gene (ISG) expression, such as PKR, ZAP, IRF7, MX1, Viperin, IFIT5, OASL, and IFI6, in LMH cells; however, ChIFN-α induced a stronger expression level than ChIFN-λ. Thus, our data revealed that ChIFN-α and ChIFN-λ might trigger different ISG expression levels, inhibiting FAdV-4 replication via different steps of the FAdV-4 lifecycle, which furthers the potential applications of IFN antiviral drugs in chickens.

NDV-induced autophagy enhances inflammation through NLRP3/Caspase-1 inflammasomes and the p38/MAPK pathway.

Newcastle disease (ND), caused by the Newcastle disease virus (NDV), is a highly virulent infectious disease of poultry. Virulent NDV can cause severe autophagy and inflammation in host cells. While studies have shown a mutual regulatory relationship between autophagy and inflammation, this relationship in NDV infection remains unclear. This study confirmed that NDV infection could trigger autophagy in DF-1 cells to promote cytopathic and viral replication. NDV-induced autophagy was positively correlated with the mRNA levels of inflammatory cytokines such as IL-1ß, IL-8, IL-18, CCL-5, and TNF-α, suggesting that NDV-induced autophagy promotes the expression of inflammatory cytokines. Further investigation demonstrated that NLRP3 protein expression, Caspase-1 activity, and p38 phosphorylation level positively correlated with autophagy, suggesting that NDV-induced autophagy could promote the expression of inflammatory cytokines through NLRP3/Caspase-1 inflammasomes and p38/MAPK pathway. In addition, NDV infection also triggered mitochondrial damage and mitophagy in DF-1 cells, but did not result in a large leakage of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), indicating that mitochondrial damage and mitophagy do not contribute to the inflammation response during NDV infection.

Stabilizing Li-O2 Batteries with Multifunctional Fluorinated Graphene.

As a full cell system with attractive theoretical energy density, challenges faced by Li-O2 batteries (LOBs) are not only the deficient actual capacity and superoxide-derived parasitic reactions on the cathode side but also the stability of Li-metal anode. To solve simultaneously intrinsic issues, multifunctional fluorinated graphene (CFx, x = 1, F-Gr) was introduced into the ether-based electrolyte of LOBs. F-Gr can accelerate O2- transformation and O2--participated oxygen reduction reaction (ORR) process, resulting in enhanced discharge capacity and restrained O2--derived side reactions of LOBs, respectively. Moreover, F-Gr induced the F-rich and O-depleted solid electrolyte interphase (SEI) film formation, which have improved Li-metal stability. Therefore, energy storage capacity, efficiency, and cyclability of LOBs have been markedly enhanced. More importantly, the method developed in this work to disperse F-Gr into an ether-based electrolyte for improving LOBs' performances is convenient and significant from both scientific and engineering aspects.

S1PR1 regulates NDV-induced IL-1ß expression via NLRP3/caspase-1 inflammasome.

Newcastle disease (ND) is an acute, febrile, and highly contagious disease caused by the Newcastle disease virus (NDV), an important pathogen harmful to domestic poultry. Virulent NDV strain infection induces IL-1ß expression and along with strong inflammatory response, ultimately results in death. Inhibition or overexpression of S1PR1, an important target for inflammatory disease treatment, regulates IL-1ß expression, suggesting that S1PR1 may alter the degree of the inflammatory response induced by NDV infection by regulating pro-inflammatory cytokine expression. However, the molecular mechanism by which S1PR1 regulates IL-1ß expression remains unclear. Here, we explore the expression and tissue distribution of S1PR1 after NDV infection and found that S1PR1 expression increased in the lungs, bursa of Fabricius, and DF-1. IL-1ß expression induced by NDV was increased following treatment of cells with the S1PR1-specific agonist, SEW2871. In contrast, IL-1ß expression induced by NDV was decreased after cells were treated with the S1PR1 inhibitor W146, suggesting that S1PR1 promotes NDV-induced IL-1ß expression. Further investigation demonstrated that NDV induced IL-1ß expression through p38, JNK/MAPK, and NLRP3/caspase-1 signaling molecules and S1PR1 affected the expression of IL-1ß by activating the NLRP3/caspase-1 inflammasome but had no significant effect on p38 and JNK/MAPK. Our study shows that NDV infection promotes S1PR1 expression and induces IL-1ß expression through p38, JNK/MAPK, and NLRP3/caspase-1 inflammasomes and that S1PR1 regulates IL-1ß expression mainly through the NLRP3/caspase-1 inflammasome.

Antibiotics use and risk of colorectal neoplasia: An updated meta-analysis.

PURPOSE: Accumulating evidence indicate that antibiotic use could induce microbiome dysbiosis, which was a critical driver to the onset and progression of colorectal cancer (CRC). But the relationship between antibiotics use and CRC was still disputed. Hence, we conducted this systematic review and meta-analysis to appraise and synthesize the present available evidence to clarify the association. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for relevant observational studies from inception to June 5, 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to explore the association between antibiotics use and CRC using random-effects model. Subgroup analyses, sensitive analyses, and publication bias were conducted to assess the robust reliability of pooled results. RESULTS: A total of 15 observational studies containing 5,164,138 patients were included in this meta-analysis. The pooled analysis indicated that the total antibiotic use was correlated with increased risk of CRC (OR, 1.11; 95% CI, 1.05-1.18). The subgroup analyses suggested that antibiotic use significantly elevated risk of colon cancer, but not rectal cancer. Furthermore, we found that penicillin, cephalosporin, anti-anaerobic, and anti-aerobic antibiotics increased the risk of CRC, in particular metronidazole but no significant associations were identified in macrolide, tetracycline, sulfonamides, nitrofurans, and quinolone use. The results of sensitive analyses and publication bias indicated the conclusions were robust. CONCLUSION: The findings showed that antibiotics use may be associated with the onset of CRC. Policy-makers and clinicians should adequately assess possible benefits and harms of antibiotics use, especially in some high-risk populations. Also, for high-risk patients with previous antibiotics use, it was suggested to perform early colonoscopy screening to find or even eliminate early-stage CRC.

TiSe2-mediated sonodynamic and checkpoint blockade combined immunotherapy in hypoxic pancreatic cancer.

BACKGROUND: Pancreatic cancer remains among the most prevalent and aggressive forms of cancer. While immunotherapeutic treatment strategies have shown some promise in affected patients, the benefits of these interventions have been limited by insufficient tumor infiltration by activated T cells. RESULTS: Here, Titanium diselenide (TiSe2) nanosheets were synthesized with good stability. When exposed to ultrasound (US), the TiSe2 nanosheets served as a reliable nano-sensitizer capable of inducing large amounts of reactive oxygen species (ROS) mediating sonodynamic therapy (SDT) under hypoxic and normoxic conditions. The tumor-released TAAs induced by TiSe2 nanosheet-mediated SDT promoted immunogenic cell death (ICD) conducive to the maturation of dendritic cells (DCs), and cytokine secretion and the subsequent activation and infiltration of T cells into the tumor. Combining TiSe2-mediated SDT with anti-PD-1 immune checkpoint blockade treatment led to the efficient suppression of the growth of both primary tumor and distant tumor, while simultaneously preventing lung metastasis. These improved immunotherapeutic and anti-metastatic outcomes were associated with activated systematic antitumor immune responses, including the higher levels of DC maturation and cytokine secretion, the increased levels of CD8+ T cells and the decreased levels of Treg cells infiltrated in tumors. CONCLUSION: TiSe2 can be used as a sonosensitizer with good efficacy and high safety to mediate efficient SDT. The combination treatment strategy comprised of TiSe2-mediated SDT and PD-1 blockade activate anti-tumor immune responses effectively thorough inducing ICD, resulting in the inhibition the growth and metastasis of tumor. The combination therapy holds promise as a novel immunotherapy-based intervention strategy for pancreatic cancer patients.

MSIFinder: a python package for detecting MSI status using random forest classifier.

BACKGROUND: Microsatellite instability (MSI) is a common genomic alteration in colorectal cancer, endometrial carcinoma, and other solid tumors. MSI is characterized by a high degree of polymorphism in microsatellite lengths owing to the deficiency in the mismatch repair system. Based on the degree, MSI can be classified as microsatellite instability-high (MSI-H) and microsatellite stable (MSS). MSI is a predictive biomarker for immunotherapy efficacy in advanced/metastatic solid tumors, especially in colorectal cancer patients. Several computational approaches based on target panel sequencing data have been used to detect MSI; however, they are considerably affected by the sequencing depth and panel size. RESULTS: We developed MSIFinder, a python package for automatic MSI classification, using random forest classifier (RFC)-based genome sequencing, which is a machine learning technology. We included 19 MSI-H and 25 MSS samples as training sets. First, we selected 54 feature markers from the training sets, built an RFC model, and validated the classifier using a test set comprising 21 MSI-H and 379 MSS samples. With this test set, MSIFinder achieved a sensitivity (recall) of 1.0, a specificity of 0.997, an accuracy of 0.998, a positive predictive value of 0.954, an F1 score of 0.977, and an area under the curve of 0.999. To further verify the robustness and effectiveness of the model, we used a prospective cohort consisting of 18 MSI-H samples and 122 MSS samples. MSIFinder achieved a sensitivity (recall) of 1.0 and a specificity of 1.0. We discovered that MSIFinder is less affected by a low sequencing depth and can achieve a concordance of 0.993 while exhibiting a sequencing depth of 100×. Furthermore, we realized that MSIFinder is less affected by the panel size and can achieve a concordance of 0.99 when the panel size is 0.5 M (million bases). CONCLUSION: These results indicate that MSIFinder is a robust and effective MSI classification tool that can provide reliable MSI detection for scientific and clinical purposes.

Phylogenetic analysis of infectious bronchitis virus circulating in southern China in 2016-2017 and evaluation of an attenuated strain as a vaccine candidate.

Avian infectious bronchitis (IB) is a highly contagious viral respiratory disease, caused by infectious bronchitis virus (IBV), that poses an important economic threat to the poultry industry. In recent years, genotypes GI-7, GI-13, and GI-19 have been the most prevalent IBV strains in China. However, in this study, we found that most IBV strains from southern China in 2016-2017 belonged to genotype GVI-1. This genotype, for which there is no vaccine, has been reported sporadically in the region. The GDTS13 strain, which caused severe IB outbreaks on the farms where it was isolated, was evaluated as a candidate vaccine strain. GDTS13 was serially passaged in specific-pathogen-free embryonated chicken eggs for 100 generations to produce GDTS13-F100. Safety testing indicated that GDTS13-F100 had no pathogenic effect on chickens. Additionally, GDTS13-F100 showed an excellent protective effect against GDTS13, with no clinical signs or virus shedding observed in immunized chickens challenged with the parent strain. These findings indicate that GVI-1 has become the most prevalent IBV genotype in southern China and that GDTS13-F100 may serve as an attenuated vaccine to protect against infection with this genotype.

A lipid transfer protein variant with a mutant eight-cysteine motif causes photoperiod- and thermo-sensitive dwarfism in rice.

Plant height is an important trait for architecture patterning and crop yield improvement. Although the pathways involving gibberellins and brassinosteroids have been well studied, there are still many gaps in our knowledge of the networks that control plant height. In this study, we determined that a dominant photoperiod- and thermo-sensitive dwarf mutant is caused by the active role of a mutated gene Photoperiod-thermo-sensitive dwarfism 1 (Ptd1), the wild-type of which encodes a non-specific lipid transfer protein (nsLTP). Ptd1 plants showed severe dwarfism under long-day and low-temperature conditions, but grew almost normal under short-day and high-temperature conditions. These phenotypic variations were associated with Ptd1 mRNA levels and accumulation of the corresponding protein. Furthermore, we found that the growth inhibition in Ptd1 may result from the particular protein conformation of Ptd1 due to loss of two disulfide bonds in the eight-cysteine motif (8-CM) that is conserved among nsLTPs. These results contribute to our understanding of the novel function of disulfide bonds in the 8-CM, and provide a potential new strategy for regulation of cell development and plant height by modifying the amino acid residues involved in protein conformation patterning.

Newcastle disease virus RNA-induced IL-1ß expression via the NLRP3/caspase-1 inflammasome.

Newcastle disease virus (NDV) infection causes severe inflammation and is a highly contagious disease in poultry. Virulent NDV strains (GM) induce large quantities of interleukin-1ß (IL-1ß), which is the central mediator of the inflammatory reaction. Excessive expression of IL-1ß exacerbates inflammatory damage. Therefore, exploring the mechanisms underlying NDV-induced IL-1ß expression can aid in further understanding the pathogenesis of Newcastle disease. Here, we showed that anti-IL-1ß neutralizing antibody treatment decreased body temperature and mortality following infection with virulent NDV. We further explored the primary molecules involved in NDV-induced IL-1ß expression from the perspective of both the host and virus. This study showed that overexpression of NLRP3 resulted in increased IL-1ß expression, whereas inhibition of NLRP3 or caspase-1 caused a significant reduction in IL-1ß expression, indicating that the NLRP3/caspase-1 axis is involved in NDV-induced IL-1ß expression. Moreover, ultraviolet-inactivated GM (chicken/Guangdong/GM/2014) NDV failed to induce the expression of IL-1ß. We then collected virus from GM-infected cell culture supernatant using ultracentrifugation, extracted the viral RNA, and stimulated the cells further with GM RNA. The results revealed that RNA alone was capable of inducing IL-1ß expression. Moreover, NLRP3/caspase-1 was involved in GM RNA-induced IL-1ß expression. Thus, our study elucidated the critical role of IL-1ß in the pathogenesis of Newcastle disease while also demonstrating that inhibition of IL-1ß via anti-IL-1ß neutralizing antibodies decreased the damage associated with NDV infection; furthermore, GM RNA induced IL-1ß expression via NLRP3/caspase-1.

Critical limitations of prognostic signatures based on risk scores summarized from gene expression levels: a case study for resected stage I non-small-cell lung cancer.

Most of current gene expression signatures for cancer prognosis are based on risk scores, usually calculated as some summaries of expression levels of the signature genes, whose applications require presetting risk score thresholds and data normalization. In this study, we demonstrate the critical limitations of such type of signatures that the risk scores of samples will change greatly when they are normalized together with different samples, which would induce spurious risk classification and difficulty in clinical settings, and the risk scores of independent samples are incomparable if data normalization is not adopted. To overcome these limitations, we propose a rank-based method to extract a prognostic gene pair signature for overall survival of stage I non-small-cell lung cancer. The prognostic gene pair signature is verified in three integrated data sets detected by different laboratories with different microarray platforms. We conclude that, different from the type of signatures based on risk scores summarized from gene expression levels, the rank-based signatures could be robustly applied at the individualized level to independent clinical samples assessed in different laboratories.

Multiprotein-bridging factor 1 regulates vegetative growth, osmotic stress, and virulence in Magnaporthe oryzae.

Multiprotein bridging factor 1 (MBF1) is a transcriptional co-activator that mediates transcriptional activation by bridging sequence-specific activator like proteins and the TATA-box binding protein (TBP). MBF1 has been well-studied in Arabidopsis thaliana, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens, but it is not well understood in filamentous fungi. In this study, we report the identification and characterization of a MBF1 ortholog (MoMBF1) in the rice blast fungus Magnaporthe oryzae), which causes the devastating rice blast disease and is an ideal model for studying the growth, development and pathogenic mechanisms of filamentous fungi. MoMBF1 encodes a 161 amino acid protein with a typical MBF1 domain and HTH domain. Bioinformatics were used to analyze the structural domains in MoMBF1 and its phylogenetic relationship to other homologs from different organisms. We have generated MoMBF1 deletion mutants (ΔMoMBF1) and functional complementation transformants, and found that the deletion mutants showed significant defects in vegetative growth and tolerance to exogenous stresses, such as 1 M sorbitol, 0.5 M NaCl, and 5 mM H2O2. Moreover, ΔMoMBF1 showed reduced pathogenicity with smaller infection lesions than wild type and the complementation strain, and decreased response to the accumulation of ROS (reactive oxygen species) in planta at the initial infection stage. Taken together, our data indicate that MoMBF1 is required for vegetative growth, pathogenicity and stress response in M. oryzae.

Correlation Between Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphisms and Pemetrexed Chemotherapy Efficacy/Toxicity in Non-Squamous Non-Small Cell Lung Cancer.

BACKGROUND In the present study, we aimed to retrospectively analyze the correlation between toxicity of pemetrexed (PEM) chemotherapy and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC). MATERIAL AND METHODS We used polymerase chain reaction, gene scanning, and restriction fragment length polymorphism to analyze MTHFR C677T in 51 patients with advanced non-sq NSCLC. The patients received chemotherapies with single-agent PEM (monotherapy group) or with PEM combined with cisplatin (joint group). The correlation between MTHFR C677T polymorphisms and chemotherapy efficacy/toxicity was also assessed. RESULTS There were 40 patients in the monotherapy group and 11 patients in the joint group. Among the 40 patients received single-agent PEM chemotherapy, those with the CT/TT genotype had higher incidence of leukopenia, neutropenia, nausea, and fatigue compared to patients with the with wild-type genotype CC (all P<0.05). However, polymorphisms of MTHFR C677T were not significantly associated with other adverse events and clinical outcomes. CONCLUSIONS Compared with genotype CC (the wild type), patients with the CT/TT genotype had higher incidence of leukopenia, neutropenia, nausea, and fatigue. Therefore, the MTHFR C677T polymorphism could be a predictive factor for leukopenia, neutropenia, nausea, and fatigue toxicities in non-sq NSCLC patients treated with single-agent PEM.

Effects of high-intensity focused ultrasound on cisplatin-resistant human lung adenocarcinoma in vitro and in vivo.

It is widely accepted that high-intensity focused ultrasound (HIFU) is a minimally invasive treatment option for different tumors, but its roles and the corresponding mechanism in cisplatin (DDP) chemoresistance in lung adenocarcinoma (LA) remain unclear. In this study, we investigated the response of DDP-resistant LA cells to HIFU and its underlying molecular mechanisms using molecular biology techniques. It was found that HIFU exposure inhibited the proliferation of DDP-resistant A549 (A549/DDP) cells through arresting cell cycle at the G1/G0 phase via the Cyclin-dependent pathway and promoting apoptosis in a Bcl-2-dependent manner. Furthermore, the results also showed that HIFU exposure could down-regulate the expressions of MDR1, MRP1, and LRP mRNAs, as well as P-gp, MRP1, and LRP proteins related to drug resistance in A549/DDP cells. In vivo experiments also demonstrated that HIFU could reduce the size and mass of subcutaneously transplanted tumors produced by A549/DDP cells through mediating Cyclin-dependent and Bcl-2-dependent pathways. These results suggested that HIFU treatment could inhibit the proliferation of DDP-resistant lung cancer cells and might be a novel therapeutic method for patients with DDP resistance.

An individualised signature for predicting response with concordant survival benefit for lung adenocarcinoma patients receiving platinum-based chemotherapy.

BACKGROUND: For lung adenocarcinoma (LUAD) patients receiving platinum-based adjuvant chemotherapy (ACT), predictive signatures extracted from survival data solely are not directly associated with platinum response. Another limitation of reported signatures, commonly based on risk scores summarised from gene expressions, is that they could not be applied directly to samples measured by different laboratories due to experimental batch effects. METHODS: Using 60 samples of LUAD patients receiving platinum-based ACT in TCGA, we pre-selected gene pairs whose within-samples relative expression orderings (REOs) were significantly associated with both pathological response and 5-year survival, from which we selected an optimal signature whose within-samples REOs could identify responders with improved 5-year survival rate. RESULTS: A predictive signature consisting of three gene pairs was developed. In an independent data set integrated from five small data sets, the predicted responders had a significantly higher 5-year survival rate than the predicted non-responders if and only if they received platinum-based ACT (log-rank P=0.0006). The predicted responders showed a 22% absolute benefit of platinum-based ACT in 5-year survival rate compared with untreated patients (log-rank P=0.0019). CONCLUSIONS: The REO-based signature can individually predict response to platinum-based ACT with concordant survival benefit directly for LUAD samples measured by different laboratories.

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.

Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss.

BACKGROUND: The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and recurrent pregnancy loss (RPL) risk is still contradictory. We thus performed a meta-analysis. MATERIAL AND METHODS: Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. An odds ratio (OR) with a 95% confidence interval (CI) was used to assess the association between PAI-1 4G/5G polymorphism and RPL risk. RESULTS: A total of 22 studies with 4306 cases and 3076 controls were included in this meta-analysis. We found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34-2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44-3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84-2.59; P=0.18). CONCLUSIONS: In conclusion, this meta-analysis suggests that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians.