Background: Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective: To further explore the relationship between FXI and venous thrombosis, we ...evaluated FXI‐deficient and wild‐type mice in a ferric chloride (FeCl3)‐induced vena cava thrombosis model. Methods and Results: Thrombosis was induced by 3‐min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild‐type mice, FXI‐deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg−1, i.v.), clopidogrel (30 mg kg−1, p.o.) or argatroban (30 mg kg−1, i.p.). These antithrombotic agents resulted in off‐scale bleeding in a tail bleeding time assay, whereas the bleeding time of FXI‐deficient mice was unchanged compared to wild‐type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI‐deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion: Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis.
Human protein arginine N-methyltransferase 2 (PRMT2, HRMT1L1) is a protein that belongs to the arginine methyltransferase family, and it has diverse roles in transcriptional regulation through ...different mechanisms depending on its binding partners. In this study, we provide evidences for the negative effect of PRMT2 on breast cancer cell proliferation in vitro and in vivo. Morever, cyclin D1, one of the key modulators of cell cycle, was found to be downregulated by PRMT2, and PRMT2 was further shown to suppress the estrogen receptor α-binding affinity to the activator protein-1 (AP-1) site in cyclin D1 promoter through indirect binding with AP-1 site, resulting in the inhibition of cyclin D1 promoter activity in MCF-7 cells. Furthermore, a positive correlation between the expression of PRMT2 and cyclin D1 was confirmed in the breast cancer tissues by using tissue microarray assay. In addition, PRMT2 was found to show a high absent percentage in breast caner cell nuclei and the nuclear loss ratio of PRMT2 was demonstrated to positively correlate with cyclin D1 expression and the increasing tumor grade of invasive ductal carcinoma. Those results offer an essential insight into the effect of PRMT2 on breast carcinogenesis, and PRMT2 nuclear loss might be an important biological marker for the diagnosis of breast cancer.
Endoscopy and histopathology are pivotal for evaluating disease activity in ulcerative colitis UC; correlation between validated endoscopic and histological indices has not been examined. We aim to ...correlate the Ulcerative Colitis Endoscopic Index of Severity UCEIS with two new validated histological indices in patients with established UC.
This was a single-centre cohort of patients with established UC, who underwent flexible sigmoidoscopy or colonoscopy by a single endoscopist. The UCEIS was scored at the worst affected area in the distal colon, which was biopsied; histological disease activity using Nancy NI and Robarts' Histological RHI indices was scored by a pathologist blinded to the endoscopy. Spearman correlation between the UCEIS, NI, and RHI, and between NI and RHI, was performed.
A total of 125 patients, median age 37 years range 16-81 years, with UCEIS scores scale 0-8: 0, n = 21; 1-3, n = 48; 4-6, n = 51; and 7-8, n = 5, were included. Correlation coefficients between UCEIS and NI scale 0-4 were r = 0.84 (95% confidence interval CI 0.76-0.89, p < 0.001) and between UCEIS and RHI scale 0-33 r = 0.86 95% CI 0.80-0.90, p < 0.001. The difference in correlation was not significant p = 0.57. There was excellent correlation between the two histological indices r = 0.92, 95% CI 0.87-0.95, p < 0.001. Quiescent disease activity defined as the absence of neutrophils Nancy 0-1, Robarts 0-3 was most closely correlated with UCEIS = 0.
The UCEIS strongly correlates with both NI and RHI. Complete mucosal healing is best defined as a UCEIS = 0/8, since this correlates with the absence of microscopic disease activity.
During mammalian embryogenesis, spatial regulation of gene expression and cell signaling are functionally coupled with lineage specification, patterning of tissue progenitors, and germ layer ...morphogenesis. While the mouse model has been instrumental for understanding mammalian development, comparatively little is known about human and non-human primate gastrulation due to the restriction of both technical and ethical issues. Here, we present a spatial and temporal survey of the molecular dynamics of cell types populating the non-human primate embryos during gastrulation. We reconstructed three-dimensional digital models from serial sections of cynomolgus monkey (Macaca fascicularis) gastrulating embryos at 1-day temporal resolution from E17 to E21. Spatial transcriptomics identifies gene expression profiles unique to the germ layers. Cross-species comparison reveals a developmental coordinate of germ layer segregation between mouse and primates, and species-specific transcription programs during gastrulation. These findings offer insights into evolutionarily conserved and divergent processes during mammalian gastrulation.
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•A high-resolution anatomical atlas of cynomolgus gastrulation embryos•A three-dimensional digital embryo template spanning five time points•A two-dimensional spatial transcriptome of the germ layers of gastrulating embryos•Cross-species comparison infers conservation of functional attributes of regulome
Cui et al. perform a morphological and molecular survey of spatiotemporal dynamics of cell types populating the cynomolgus monkey embryo during gastrulation. The three-dimensional digital models and spatial transcriptome provide a resource and additional insights into mammalian embryogenesis.
Summary
Premature ejaculation (PE) is one of the most prevalent male sexual dysfunctions. Selective resection of the dorsal nerve (SRDN) of penis has recently been used for the treatment of PE and ...has shown some efficacy. To further clarify the efficacy and safety of SRDN on PE, we performed a preliminary, randomized, placebo‐controlled clinical observational study. Persons with the complaints of rapid ejaculation, asking for circumcision because of redundant foreskin, intravaginal ejaculation latency time (IELT) within 2 min, not responding to antidepressant medication or disliking oral medication were randomly enrolled in two groups. From April 2007 to August 2010, a total of 101 eligible persons were enrolled, 40 of them received SRDN which dorsal nerves of the penis were selectively resected, and those (n = 61) enrolled in the control group were circumcised only. IELT and the Brief Male Sexual Function Inventory (BMSFI) questionnaire were implemented pre‐ and post‐operatively for the evaluation of the effect and safety of the surgery. There are no statistically significant differences in the baseline data including mean ages, mean IELTs, perceived control abilities and the BMSFI mean scores between the two groups. With regard to the post‐operative data of the surgery, both IELTs and perceived control abilities were significantly increased after SRDN (1.1 ± 0.9 min vs. 3.8 ± 3.1 min for pre‐ and post‐operative IELT, respectively, p < 0.01),whereas the post‐operative results were not significantly improved for the control group (1.2 ± 0.7 min vs. 1.5 ± 1.1 min, p > 0.05). Also, there were no statistically significant differences both in BMSFI composite and subscale scores between the two groups after surgery. Hence, we conclude that SRDN is effective in delaying ejaculation and improving ejaculatory control, whereas erectile function is not affected. The results imply that SRDN may be an alternative method for the treatment of PE for some patients.
Vascular endothelial growth factor receptor (VEGFR) is an important receptor tyrosine kinase (RTK) in the induction of angiogenesis. Abnormal activation of VEGFR leads to several disorders including ...cancer. Nowadays, inhibition of VEGFR kinase has been one of the most powerful clinical strategies in cancer treatment and great efforts to design and synthesize small molecular VEGFR inhibitors for cancer research have been made in recent years. This review highlights the major progress and development of them, including their structure and pharmacophore features, biological activities and structure-activity relationships (SAR). Special attentions are paid to the compounds available in market or in advanced clinical stages.
Highlights • A phase II trial of dasatinib-cetuximab in cetuximab-resistant patients was conducted. • Low serum IL6 was associated with clinical benefit and prolonged survival. • Preclinical studies ...also support IL6 as a modulator of dasatinib-cetuximab effects.
In vitro plants of sand pear (Pyrus pyrifolia cv. Jinshui no. 2), which were infected by Apple chlorotic leaf spot virus (ACLSV) and Apple stem grooving virus (ASGV), were treated by chemotherapy ...with ribavirin, thermotherapy at 35±0.5°C and the combined application of both methods. Results showed that chemotherapy with ribavirin at 15–25μg/ml for 5–30 days could enhance the growth and proliferation of in vitro pear plants. Chemotherapy combined with thermotherapy could greatly improve the efficiency of virus eradication as it was compared with the separated application of both methods. A high virus eradication efficiency of 100% was achieved by chemotherapy of ribavirin at 25μg/ml combined with thermotherapy at 35°C for 40 days, followed by culturing of 0.5–1mm long meristem-tips. The efficacy of ribavirin for the elimination of both ASGV and ACLSV had no significant difference.
► In vitro pears were treated by thermotherapy, chemotherapy, and their combination. ► Increased ribavirin and prolonged treatment duration could improve the eradication efficacy. ► High virus eradication efficacy was achieved by ribavirin at 25μg/ml combined with 35°C for 40 days.
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