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Lung metastasis is a fatal and late-stage event for many solid tumors. Multiple lines of evidence have demonstrated that diallyl trisulfide (DATS), an active ingredient of garlic, possesses striking antimetastatic effects. However, the lack of highly efficient organ-compatible carriers restricts its application. In the present study, we showed that extracellular microparticles encapsulated with DATS (DATS-MPs) were capable of interfering with the prometastatic inflammatory microenvironment in local tissues. DATS-MPs were successfully prepared and exhibited typical characteristics of B16BL6-derived extracellular vesicles. The DATS-MPs preferentially fused with cancer cells and endogenous cells (mouse lung epithelial MLE-12 cells) from the metastatic organs in vitro. More interestingly, the systemically administered MPs predominantly accumulated in the lung tissue that serves as their main metastatic organ. The drug-loaded MPs exerted higher antimetastatic effects than DATS alone in both the spontaneous and the experimental metastasis models in mice (*p < 0.05). Additionally, we found that DATS-MPs inhibited tumor cell migration and interfered with the prometastatic inflammatory microenvironment via decreasing the release of S100A8/A9, serum amyloid A (SAA), and interleukin-6 (IL-6) and inhibiting the expression of fibronectin, MRP8, myeloperoxidase (MPO), and the toll-like receptor 4 (TLR4)-Myd88 in the lung tissues. Collectively, DATS-MPs appeared to enhance the antimetastatic efficiency of DATS in animal models under study.

Hybrid bonded/bolted (HBB) joint has been widely used in engineering practice because it can overcome the potential weakness of pure bonded and pure bolted joints. However, studies on HBB joint are still at the initial stage. In this paper, tensile properties of a composite–metal single-lap HBB joint was investigated experimentally. And a detailed finite element model (FEM) was established to simulate the tensile behavior of the joint. The model was verified by the experimental results. Then the damage propagation and load transfer mechanism were explored based on the FEM. The results show that the HBB joint can provide multi-load transmission paths and resist damage propagation in the adhesive. The HBB joint has higher strength and energy absorption capacity than the pure bonded joint. And the HBB joint has greater initial damage load and tensile stiffness than pure bolted joint. Adhesive fillets can obviously improve the tensile performances of the HBB joint. Lateral stiffness of the joint boundary and testing machine show obvious effects on tensile performances of single-lap hybrid joints.

To evaluate the feasibility of cervical conization and laparoscopic pelvic lymphadenectomy as a fertility-sparing surgery to treat early-stage cervical cancer.We conducted a retrospective analysis from a prospectively maintained database of patients with stage IA1-IB1 grossly invisible cervical cancers undergoing conization plus laparoscopic lymphadenectomy between January 2014 and July 2019.Forty patients were identified. Five patients (12.5%) had stage IA1 with lymphovascular space invasion, 21 (52.5%) had stage IA2, and 14 (35.0%) had stage IB1. All of the patients had tumors2 cm. Histology included 35 (87.5%) squamous-cell carcinomas, three (7.5%) adenocarcinomas, and two (5.0%) adenosquamous carcinomas. Median duration of the procedure was 105 min (range, 31-219), and the median estimated blood loss was 50 ml (range, 30-200). One patient received abdominal radical trachelectomy due to the presence of positive margin after conization. Three patients developed postoperative cervical stenosis. After a median follow-up of 35 months (range, 8-74), only one patient (2.5%) developed a recurrence in the remaining cervix, and no patients died. Four of 17 patients attempting to conceive had a spontaneous pregnancy: three delivered at term and one was currently pregnant.Cervical conization and pelvic lymphadenectomy seems to be an acceptable treatment for well-selected patients with low-risk, early-stage cervical cancer who wish to preserve fertility. It offers excellent oncologic outcomes, low perioperative morbidities, and good reproductive results. Further large prospective studies are warranted to prove the effectiveness of this surgery.

Objective To evaluate the effect of ixekizumab on self-reported functioning and health in patients with active nonradiographic axial spondyloarthritis (SpA). Methods COAST-X was a randomized, controlled trial conducted in patients with nonradiographic axial SpA over 52 weeks. Participants were randomized at a ratio of 1:1:1 to receive 80 mg of ixekizumab subcutaneously every 4 weeks or 2 weeks or placebo for 52 weeks. Self-reported functioning and health end points included the Medical Outcomes Study Short Form 36 (SF-36) health survey, Assessment of Spondyloarthritis International Society (ASAS) health index, and European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) health-utility descriptive system. Results Compared to placebo, ixekizumab treatment resulted in improvement of SF-36 physical component summary scores from baseline, with a score of 4.7 improving to 8.9 with ixekizumab therapy every 4 weeks (P < 0.05) and a score of 9.3 with ixekizumab therapy every 2 weeks (P < 0.01); the greatest improvements were observed in the domains of physical functioning, role-physical, and bodily pain at weeks 16 and 52. A higher proportion of patients receiving ixekizumab therapy every 2 weeks reported >= 3 improvements based on the ASAS health index from baseline to weeks 16 and 52 (P < 0.05). Significantly more patients receiving ixekizumab every 4 weeks reported improvements in "good health status" on the ASAS health index (ASAS score of

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, metastasis accounts for most of the cases. Angiogenesis plays an important role in cancer metastasis, but how tumor cells affect the function of endothelial cells by dictating their microRNA (miRNA) expression remains largely unknown. Differentially expressed miRNAs (DEMs) were identified through dataset downloaded from the Gene Expression Omnibus (GEO) database and analyzed by GEO2R. We then used online tools to obtain potential targets of candidate miRNAs and functional enrichment analysis, as well as the protein-protein interaction (PPI). Finally, the function of miR-302c-3p was validated through in vitro assay. In the current study, we found that HCC cells altered miRNA expression profiles of human umbilical vein endothelial cells (HUVECs) and miR-302c-3p was the most down-regulated miRNA in HUVECs when they were co-cultured with HCC-LM3 cells. Functional enrichment analysis of the candidate targets revealed that these genes were involved in epigenetic regulation of gene expression, in particular, cytosine methylation. In addition, PPI network demonstrated distinct roles of genes targeted by miR-302c-3p. Importantly, inhibition of angiogenesis, migration and permeability by the most down-regulated miR-302c-3p in HUVECs was confirmed in vitro. These findings brought us novel insight into the regulation of angiogenesis by HCC cells and provided potential targets for the development of therapeutic strategies.

Objective To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi).

BackgroundRadical trachelectomy is considered a viable option for fertility preservation in patients with low-risk, early-stage cervical cancer. Standard approaches include laparotomy or minimally invasive surgery when performing radical trachelectomy.Primary ObjectiveTo compare disease-free survival between patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive (laparoscopic or robotic) radical trachelectomy.Study HypothesisWe hypothesize that minimally invasive radical trachelectomy has similar oncologic outcomes to those of the open approach.Study DesignThis is a collaborative, multi-institutional, international, retrospective study. Patients who underwent a radical trachelectomy and lymphadenectomy between January 1, 2005 and December 31, 2017 will be included. Institutional review board approval will be required. Each institution will be provided access to a study-specific REDCap (Research Electronic Data Capture) database maintained by MD Anderson Cancer Center and will be responsible for entering patient data.Inclusion CriteriaPatients with squamous, adenocarcinoma, or adenosquamous cervical cancer FIGO (2009) stages IA2 and IB1 (≤2 cm) will be included. Surgery performed by the open approach or minimally invasive approach (laparoscopy or robotics). Tumor size ≤2 cm, by physical examination, ultrasound, MRI, CT, or positron emission tomography (at least one should confirm a tumor size ≤2 cm). Centers must contribute at least 15 cases of radical trachelectomy (open, minimally invasive, or both).Exclusion CriteriaPrior neoadjuvant chemotherapy or radiotherapy to the pelvis for cervical cancer at any time, prior lymphadenectomy, or pelvic retroperitoneal surgery, pregnant patients, aborted trachelectomy (intra-operative conversion to radical hysterectomy), or vaginal approach.Primary EndpointThe primary endpoint is disease-free survival measured as the time from surgery until recurrence or death due to disease. To evaluate the primary objective, we will compare disease-free survival among patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive radical trachelectomy.Sample SizeAn estimated 535 patients will be included; 256 open and 279 minimally invasive radical trachelectomy. Previous studies have shown that recurrence rates in the open group range from 3.8% to 7.6%. Assuming that the 4.5-year disease-free survival rate for patients who underwent open surgery is 95.0%, we have 80% power to detect a 0.44 HR using α level 0.10. This corresponds to an 89.0% disease-free survival rate at 4.5 years in the minimally invasive group.

Thyroid hormone reference intervals are crucial for diagnosing and monitoring thyroid dysfunction during early pregnancy, and the dynamic change trend of thyroid hormones during pregnancy can assist clinicians to assess the thyroid function of pregnant women. This study aims to establish early pregnancy related thyroid hormones models and reference intervals for pregnant women. We established two derived databases: derived database* and derived database#. Reference individuals in database* were used to establish gestational age-specific reference intervals for thyroid hormones and early pregnancy related thyroid hormones models for pregnant women. Individuals in database# were apparently healthy non-pregnant women. The thyroid hormones levels of individuals in database# were compared with that of individuals in database* using nonparametric methods and the comparative confidence interval method. The differences in thyroid stimulating hormone and free thyroxine between early pregnant and non-pregnant women were statistically significant (p

Background: Recent studies suggest that gut microbiota was associated with the bidirectional gut-brain axis which could modulate neuropsychological functions of the central nervous system. Gut microbiota could produce gamma aminobutyric acid (GABA) that could modulate the gut–brain axis response. Jianpi Jieyu (JPJY) decoction, a traditional Chinese formula, is mainly composed of Astragalus membranaxeus and Radix Pseudostellariae. Although the JPJY decoction has been used to treat the depression in China, the potential action of its antidepressant has not been well understood. Thus this study was aim to investigate the role of JPJY improve gut microbiota homeostasis in the chronic stress induced depressive mice.Methods: The antidepressant effect of JPJY on chronic unpredictable mild stress (CUMS) mice was evaluated by using sucrose preference test, tail suspension test and forced swim test. Fatigue-like behaviors were evaluated using degree of redness, grip strength test, and exhaustive swimming test. The new object recognition test was used to evaluate cognition performance. Fecal samples were collected and taxonomical analysis of intestinal microbial distribution was conducted with 16S rDNA. Serum level of GABA was measured using high performance liquid chromatography (HPLC). The expression of GluR1 and p-Tau protein in the hippocampus was determined using Western blotting.Results: The dose of 9.2 g/kg JPJY produced antidepressant-like effects. JPJY and its major components also modulated gut microbiota diversity in the CUMS mice. Serum level of GABA and the expressions of hippocampal GluR1 and p-Tau were reversed after the administration of JPJY in CUMS mice.Conclusion: JPJY regulates gut microbiota to produce antidepressant-like effect and improve cognition deficit in depressive mice while its molecular mechanism possibly be enhanced NR1 and Tau expression in hippocampus and increased GABA in serum.

BackgroundEpithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows an aggressive phenotype and poor prognosis. Neuronal pentraxin II (NPTX2) is a member of the neuronal pentraxin family and plays a contradictory role in different tumors. However, there has been no report about the possible role and effect of NPTX2 in EOC.MethodsBioinformatics analysis, qPCR, western blotting and immunohistochemistry were used to detect the expression of NPTX2 in EOC. Lentivirus-based transfection for NPTX2 overexpression or knockdown was performed on the EOC cell lines A2780, HEY, SKOV3 and OVCAR-3. The effect of NPTX2 on the malignant phenotype of EOC was examined through methods of MTS assay, Edu assay, transwell assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment.ResultsEOC tissues showed higher NPTX2 expression than the normal tissues with poor prognosis. NPTX2 overexpression can promote the proliferation, invasion, migration and tumorigenesis of EOC via IL6-JAK2/STAT3 signaling pathway. Moreover, hypoxia-inducible factor-1(HIF-1) can promote the transcription and expression of NPTX2 under the hypoxic environment. NPTX2 knockdown abolished the hypoxia-induced malignant phenotypes in ECO.ConclusionsThe above results suggest that NPTX2 may play a novel role in ovarian cancer’s malignant phenotype and act as a promising treatment target for EOC molecular therapy.

Fowl adenovirus (FAdV), belonging to the Aviade-novirus genus of Adenoviridae family, poses an increasing threat to poultry industry across the globe. In particular, the occurrence of hepatitis hydroper-icardium syndrome (HHS) in flocks in China has caused severe economic losses to stakeholders since 2015. Some serotypes of the FAdVs, especially FAdV-4, -2, -7 and -11, are highly pathogenic to 3- to 6-week-old chickens and responsible for HHS and inclusion body hepatitis (IBH). On the contrary, lines of evidence indicate that adenovirus could serve as an optimal vector to deliver protective antigens of other pathogens in host. This review mainly focuses on the pathogenesis and control of HHS, and discusses over the possible role of FAdV as a vector in controlling other avian diseases.

PDGFRα signaling is critically important in ocular development. Previous data on PDGFRα lacks an expression map with high spatial and temporal resolution and lineage information. In this study, we aim to present a detailed PDGFRα expression and lineage map from early embryogenesis to adulthood. PDGFRα-CreER; mT/mG reporter mice were analyzed. mEGFP-positive cells contributed to multiple ocular lineages in a spatiotemporally regulated manner. A dynamic PDGFRα expression was identified in corneal stromal cells, lens epithelial cells, lens fiber cells, and retinal astrocytes during the entire period of eye development, while PDGFRα expression in retinal astrocytes from E17.5 onwards and in Müller glial cells was identified within two weeks after birth. By revealing detailed characterization of gene expression and function, we present a comprehensive map of PDGFRα-expressing cells in the eye for a better understanding of PDGFRα signaling’s role during eye development.

Supernumerary Robotic Limbs (SRL) are body augmentation robotic devices by adding extra limbs or fingers to the human body different from the traditional wearable robotic devices such as prosthesis and exoskeleton. We proposed a novel MI-based BCI paradigm based on the sixth-finger which imagines controlling the extra finger movements. The goal of this work was to investigate the EEG characteristics and the application potential of MI-based BCI systems based on the new imagination paradigm (sixth-finger MI). 14 subjects participated in the experiment involving the sixth-finger MI tasks and rest state. Event-related spectral perturbation (ERSP) was adopted to analyze EEG spatial and time-frequency features. Common spatial patterns (CSP) were used for feature extraction and classification was implemented by support vector machine (SVM). ERD (event-related desynchronization) was found in the supplementary motor area (SMA) and primary motor area (M1) with a faint contralateral dominance. Unlike traditional human hand MI, ERD was also found in frontal lobe. The highest accuracy of 80% and mean accuracy of 70%. This work provided a novel paradigm for MI-based MI system, widened the control bandwidth of the BCI system. In addition, we discussed the application potential of the sixth-finger MI.

Introduction Patients with ankylosing spondylitis (AS) are burdened with symptoms impacting work productivity measured by presenteeism, absenteeism, overall work impairment, and activity impairment. Ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been demonstrated to improve disease signs and symptoms in two phase 3 trials of AS. This study investigated for 52 weeks the effect of ixekizumab treatment on work productivity in patients with active AS. Methods COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, controlled trials investigating the efficacy of ixekizumab 80 mg every 4 weeks (Q4W) and every 2 weeks (Q2W) in patients with AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) or who were inadequate responders or intolerant to tumor necrosis factor inhibitors (TNFi; COAST-W). Work productivity was measured with the Work Productivity and Activity Impairment Questionnaire for Spondyloarthritis at weeks 16 and 52. Absenteeism, presenteeism, and overall work impairment were assessed for patients reporting paid work. Activity impairment was assessed regardless of work status. Results At baseline, 66.2% (434/656) of patients reported paid work. At week 16, bDMARD-naïve patients treated with both ixekizumab dose regimens and TNFi-experienced patients treated with ixekizumab Q2W reported significant improvements in activity impairment (p

Purpose N-methyl-N-nitrosourea (MNU) is an alkylating toxicant with potent mutagenic ability. This study was designed to induce apoptosis in lens epithelial cells (LECs) and corneal endothelial cells (CECs) via MNU administration. We sought to build ocular disease models of cataract and corneal endothelial decompensation. Methods MNU was delivered into the intraperitoneal cavities of neonatal rats and the anterior chambers of adult rabbits. The MNU-treated animals were then subjected to a series of functional and morphological analyses at various time points. Results MNU treatment induced pervasive apoptosis of LECs and CECs. These effects were dose and time dependent. Mature cataracts were found in neonatal rats 3 weeks after MNU treatment. Histological analysis revealed that MNU toxicity induced swelling, vacuolation, and liquefaction in lens fibers of MNU-treated rats. Pentacam examination showed that the average density of rat lens increased significantly after MNU administration. Terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) analysis showed pervasive apoptotic staining in the lenses of MNU-treated rats. In rabbit eyes, intracameral treatment with MNU induced corneal edema and significantly increased central corneal thickness, which peaked at P14. Morphological and immunohistochemical analysis showed that CECs were effectively ablated in the MNU-treated rabbits. The expression of 8-OHdG increased significantly in the cornea of MNU-treated rabbits, compared with vehicle-treated controls. Conclusions MNU is sufficient to induce ocular cell apoptosis in animal models. These models of MNU-induced cataract and corneal endothelial decompensation represent valuable tools for efforts to develop relevant therapies.

Epidemiological studies of malignant primary conjunctival tumors are rare. We extracted data pertaining to primary site-labeled conjunctival cancer patients present within the Surveillance, Epidemiology, and End Results (SEER) database from 1992 to 2001 and from 2002 to 2011. The Kaplan-Meier approach was used for comparisons of overall survival (OS) between patients, while OS-related risk factors were identified via a Cox proportional hazards regression approach. We then constructed a nomogram that could be used to predict the 3- and 5-year OS, with the accuracy of this predictive model based on receiver operating characteristic (ROC) curve. We observed a significant reduction in age-adjusted incidence of conjunctival cancer in the 50-69-year-old age group of the 2002-2011 cohort relative to the 1992-2001 cohort (APC, P<0.05). There were no significant differences in OS between the 1992-2001 and 2002-2011 conjunctival cancer patient cohorts. Being ≥30 years old (P<0.05), male (P<0.001), single (P<0.05), divorced (P<0.001), or widowed (P<0.001) were all associated with an increased OS-related risk of primary conjunctival cancer (1992-2011). Our nomogram was able to accurately predict 3- and 5-year OS in conjunctival cancer patients. In verification mode, the 3-year area under the curve (AUC) was 0.697 and the 5-year AUC was 0.752. We found that age, sex, and marital status were all associated with primary conjunctival cancer survival. Our results further suggest that conjunctival cancer incidence and survival rates have been relatively stable over the last two decades, and using these data, we were able to generate a satisfactory risk prediction model for this disease.

Background While many studies have established reference intervals (RIs) for thyroid hormones using patient data, this approach has not been validated. Therefore, in this study, we aimed to validate an approach for establishing RIs for thyroid hormones only using patient data from clinical laboratories. Methods We established two derived databases: derived database* and derived database#. Reference individuals in derived database* were selected using strict exclusion criteria, and the RIs established by the database were considered standard RIs (RIs*). Individuals in derived database# were the physical examination population, whose information was downloaded directly from the Laboratory Information System, and RIs established from this database were evaluated (RIs#). The comparative confidence interval (CI) method and consistency of the decision results based on external databases were used to compare RIs* and RIs#. Results RIs# and RIs* for the thyroid hormones tested were similar. The 90% CIs of the upper and lower limits of RIs for most thyroid hormones overlapped between RIs# and RIs*, and the limit of RIs# was within the 90% CI of RIs*. The consistency rates for the results of the RIs* and RIs# in the external database were greater than 98% for all thyroid hormones tested. Conclusion It was possible to establish RIs for thyroid hormones using only patient data from clinical laboratories after adopting appropriate statistical methods.

Hydropericardium-Hepatitis Syndrome (HHS) caused by Fowl Adenovirus Serotype 4 (FAdV4) infection is a severe threat to the poultry industry worldwide, especially in China since 2015. Recent studies show that FAdV4 induces liver injury through apoptosis. However, the underlying molecular mechanism is still unclear. We report here that FAdV4 infection caused apoptosis in Leghorn male hepatocellular (LMH) cells and that PX, a structural protein of FAdV4, acted as a major viral factor inducing apoptosis. Furthermore, the nuclear localization of PX is determined by the R/K regions of PX and required for PX-induced apoptosis. Moreover, alanines 11 and 129 of PX are crucial to PX-induced apoptosis. Inhibition of FAdV4-induced apoptosis by caspase inhibitors retarded viral replication, suggesting that PX serves as a virulence factor for FAdV4 infection, which may further our understandings of the pathogenesis of FAdV4 infection.

Background the ageing population has increased in many countries, including China. However, reference intervals (RIs) for older people are rarely established because of difficulties in selecting reference individuals. Here, we aimed to analyse the factors affecting biochemical analytes and establish RI and age-related RI models for biochemical analytes through mining real-world big data. Methods data for 97,220 individuals downloaded from electronic health records were included. Three derived databases were established. The first database included 97,220 individuals and was used to build age-related RI models after identifying outliers by the Tukey method. The second database consisted of older people and was used to establish variation source models and RIs for biochemical analytes. Differences between older and younger people were compared using the third database. Results sex was the main source of variation of biochemical analytes for older people in the variation source models. The distributions of creatinine and uric acid were significantly different in the RIs of biochemical analytes for older people established according to sex. Age-related RI models for biochemical analytes that were most affected by age were built and visualized, revealing various patterns of changes from the younger to older people. Conclusion the study analysed the factors affecting biochemical analytes in older people. Moreover, RI and age-related RI models of biochemical analytes for older people were established to provide important insight into biological processes and to assist clinical use of various biochemical analytes to monitor the status of various diseases for older people.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression posttranscriptionally by silencing or degrading their targets and play important roles in the host response to pathogenic infection. Although infectious bursal disease virus (IBDV)-induced apoptosis in host cells has been established, the underlying molecular mechanism is not completely unraveled. Here, we show that infection of DF-1 cells by IBDV induced gga-miR-16-5p (chicken miR-16-5p) expression via demethylation of the pre-miR-16-2 (gga-miR-16-5p precursor) promoter. We found that ectopic expression of gga-miR-16-5p in DF-1 cells enhanced IBDV-induced apoptosis by directly targeting the cellular antiapoptotic protein B-cell lymphoma 2 (Bcl-2), facilitating IBDV replication in DF-1 cells. In contrast, inhibition of endogenous miR-16-5p markedly suppressed apoptosis associated with enhanced Bcl-2 expression, arresting viral replication in DF-1 cells. Furthermore, infection of DF-1 cells with IBDV reduced Bcl-2 expression, and this reduction could be abolished by inhibition of gga-miR-16-5p expression. Moreover, transfection of DF-1 cells with gga-miR-16-5p mimics enhanced IBDV-induced apoptosis associated with increased cytochrome c release and caspase-9 and -3 activation, and inhibition of caspase-3 decreased IBDV growth in DF-1 cells. Thus, epigenetic upregulation of gga-miR-16-5p expression by IBDV infection enhances IBDV-induced apoptosis by targeting the cellular antiapoptotic protein Bcl-2, facilitating IBDV replication in host cells. IMPORTANCE Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive disease in young chickens, causing severe economic losses to stakeholders across the globe. Although IBD virus (IBDV)-induced apoptosis in the host has been established, the underlying mechanism is not very clear. Here, we show that infection of DF-1 cells by IBDV upregulated gga-miR-16-5p expression via demethylation of the pre-miR-16-2 promoter. Overexpression of gga-miR-16-5p enhanced IBDV-induced apoptosis associated with increased cytochrome c release and caspase-9 and -3 activation. Importantly, we found that IBDV infection induced expression of gga-miR-16-5p that triggered apoptosis by targeting Bcl-2, favoring IBDV replication, while inhibition of gga-miR-16-5p in IBDV-infected cells restored Bcl-2 expression, slowing down viral growth, indicating that IBDV induces apoptosis by epigenetic upregulation of gga-miR-16-5p expression. These findings uncover a novel mechanism employed by IBDV for its own benefit, which may be used as a potential target for intervening IBDV infection.

Summary Background Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. Methods COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0–10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov , number NCT02757352 . Findings Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. Interpretation Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Funding Eli Lilly and Company.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005–2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20–42) years for open surgery vs 31 (18–45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0–31) mm for open surgery and 12 (0.8–40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20–16.70) years for open surgery and 3.1 years (0.02–11.10) years for minimally invasive surgery (P

Extraintestinal pathogenic Escherichia coli (ExPEC) are important human pathogens responsible for urinary tract infection and meningitis. Therefore, infection of chickens by highly pathogenic E. coli with multi-drug resistance has become a major concern to food safety. In this study, we isolated a strain of E. coli (HB2016) from the oviduct of a diseased chicken with colibacillosis. Inoculation of chickens with 2 × 106 CFU of the isolate E. coli HB2016 by intraperitoneal injection successfully reproduced colibacillosis in chickens. We also found that E. coli HB2016 harbored four more virulence genes (tsh, trat, cvaC and cvaA/B) than E. coli reference strain CVCC1428. Importantly, E. coli HB2016 was resistant to cefuroxime, tobramycin, medemycin, cefazolin, cefoperazone, streptomycin and ampicillin, and carried multiple antibiotic resistance genes such as strA, strB, blaCMY-2, blaCTX-M-19, blaTEM-1B, fosA, mph(A), floR, sul2, tet(A) and tet(B). These findings suggest that the causative E. coli act as a potential zoonotic agent affecting human health.

Objective To report the reproductive and obstetric outcomes of patients undergoing abdominal radical trachelectomy (ART) for the treatment of early-stage cervical cancers in Fudan, China. Methods We retrospectively reviewed a prospectively collected database of 360 patients with stage IA1-IB1 cervical cancers who underwent ART between 2004 and 2018. Results Overall, 211 women (58.6%) did not plan to get pregnant immediately after ART, and 89.6% of them were due to childbearing before surgery or unmarried. Among 149 women who attempted to conceive, 26 (17.4%) of them achieved 30 pregnancies. Eighty-six patients (57.7%) had infertility problems, 44 attempted to conceive with assisted reproductive technologies, and 12 (27.3%) succeeded. Post-operative cervical stenosis (26, 27.4%) and fallopian tube obstruction (22, 23.2%) were the most common reasons for infertility after surgery. Among the patients who conceived, there were 3 first-trimester miscarriages, 6 second-trimester miscarriages, and 2 elective terminations. A total of 19 pregnancies reached the third trimester, and 84.2% of them ended after 36 weeks. Twelve of 20 cases in patients with cerclage placed had full-term birth, while 3 of 5 patients without cerclage placed suffered from second-trimester miscarriage or preterm birth. Conclusions Immediately after ART, many patients were reluctant to conceive, while others suffered from cervical stenosis or fallopian tube obstruction, which had led to low pregnancy rate. Pregnant patients might experience miscarriage or preterm labor which could be prevented by cervical cerclage. Assisted reproductive technology should be encouraged to improve obstetric outcomes.

MicroRNAs (miRNAs), as post-transcriptional regulators, play important roles in the process of viral infection through inhibiting virus replication or modulating host immune response. However, the role of miRNAs in host response against infectious bursal disease virus (IBDV) infection is still unclear. In this study, we found that gga-miR-454 of the host was decreased in response to IBDV infection and that transfection of DF-1 cells with miR-454 inhibited IBDV replication via directly targeting the specific sequence of IBDV genomic segment B, while blockage of endogenous miR-454 by inhibitors enhanced virus replication. Furthermore, gga-miR-454 increased the expression of IFN-β by targeting Suppressors of Cytokine Signaling 6 (SOCS6), enhancing the antiviral response of host cells. These findings highlight a crucial role of gga-miR-454 in host defense against IBDV infection.

Six new cyclopentenone derivatives (+)-nigrosporione A (+)-1, (-)-nigrosporione A (-)-1, nigrosporione B (2), nigrosporione C (3), (+)-nigrosporione D (+)-4, and (-)-nigrosporione D (-)-4 were isolated from an endophytic fungus Nigrospora sphaerica ZMT05, collected from the rice grasshopper ( Oxya chinensis Thunberg), which is an insect pest in rice and which is also used as a food for people in some countries. Their planar and spatial structures were determined by spectroscopic analyses and eletronic circular dichroism (ECD) calculations. Compounds (+)-1, (-)-1, and 2 inhibited the plant pathogens Fusarium oxysporum, Colletotrichum musae, Penicillium italicum, and Fusarium graminearum, compounds 3 and (-)-4 inhibited F. oxysporum, C. musae, and P. italicum, and compound (+)-4 inhibited F. oxysporum, C. musae, and F. graminearum, showing antifungal activities stronger than triadimefon. Additionally, compounds (+)-1, (-)-1, 2, and 3 displayed moderate antibacterial activities against Staphyloccocus aureus and Escherichia coli.

Viruses have developed a variety of methods to evade host immune response. Our previous study showed that infectious bursal disease virus (IBDV) inhibited type I interferon production via interaction of VP4 with cellular glucocorticoid-induced leucine zipper (GILZ) protein. However, the exact underlying molecular mechanism is still unclear. In this study, we found that IBDV VP4 suppressed GILZ degradation by inhibiting K48-linked ubiquitylation of GILZ. Furthermore, mutation of VP4 (R41G) abolished the inhibitory effect of VP4 on IFN-β expression and GILZ ubiquitylation, indicating that the amino acid 41R of VP4 was required for the suppression of IFN-β expression and GILZ ubiquitylation. Moreover, IBDV infection or VP4 expression markedly inhibited endogenous GILZ ubiquitylation. Thus, IBDV VP4 suppresses type I interferon expression by inhibiting K48-linked ubiquitylation of GILZ, revealing a new mechanism employed by IBDV to suppress host response.

Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive avian disease caused by IBD virus (IBDV). IBDV VP3 is a multifunctional protein playing a key role in virus assembly and pathogenesis. To investigate the role of VP3 in pathogenesis, we transfected DF-1 cells with pRK5-FLAG-vp3 and found that VP3 enhanced type I interferon expression and suppressed IBDV replication. Furthermore we found that VP3 interacted with chicken Ribosomal Protein L18 (chRPL18) in host cells and knockdown of chRPL18 by RNAi significantly promoted Type I interferon expression and inhibited IBDV replication. Moreover, our data show that chicken double-stranded RNA-activated protein kinase (chPKR) interacted with both VP3 and chRPL18. Thus chRPL18 in association with VP3 and chPKR affects viral replication.

Background:Radiographic-axial spondyloarthritis (r-axSpA) is a progressive chronic inflammatory disease primarily affecting the spine and sacroiliac joints. However, about 30-40% of patients (pts) with axSpA can have peripheral joint involvement, including joint tenderness and swelling, which can contribute significantly to burden of disease. Ixekizumab (IXE), a monoclonal antibody that neutralizes the pro-inflammatory cytokine interleukin-17A, has demonstrated a high level of efficacy in the treatment of r-axSpA.Objectives:The aim of this study is to evaluate the efficacy of IXE through 52 weeks (wks) in improving peripheral joint pain and swelling for pts with r-axSpA.Methods:Data was derived from two phase III randomised, double-blind, placebo (PBO)-controlled trials: one in pts with r-axSpA, who were biological disease-modifying anti-rheumatic drug (bDMARD)-naïve (COAST-V: NCT02696785), and the other in pts who were tumor necrosis factor inhibitor-experienced (COAST-W: NCT02696798). All pts had a confirmed diagnosis of r-axSpA and had to meet ASAS (Assessment of SpondyloArthritis international Society) criteria. IXE (80 mg) or PBO were administered subcutaneously every 2 (Q2W) or 4 (Q4W) wks during a 52-wk treatment period, after receiving a starting dose of 80 mg or 160 mg at wk 0. COAST-V/W pts originally randomised to PBO were re-randomised 1:1 to IXE Q4W or Q2W at wk 16. We present a post-hoc analysis of data from an integrated dataset from COAST-V and W (COAST-V/W); with intent to treat (ITT) pts categorized by baseline (BL) peripheral joint status. The presence of peripheral joint involvement was defined using a 46-joint tender joint count (TJC) >0 or 44-joint swollen joint count (SJC) >0. Treatment response through wk 52 was evaluated based on % improvement (20%, 50% or 70%) and resolution of tender or swollen joints of pts with BL TJC>0 or SJC>0, respectively. Missing data were imputed by non-responder imputation (NRI). Treatment comparison vs PBO at wk 16 was performed using Cochran-Mantel-Haenszel test.Results:This analysis includes 359 pts (63.4% of ITT) with baseline TJC>0 and 203 pts (35.9% ITT) with baseline SJC>0. The mean (SD) baseline TJC and SJC were 7.7 (8.3) and 4.3 (4.5), respectively. Mean BL TJC and SJC values by treatment group are presented in Table 1. A significant improvement of SJC by 20% and 50% was seen in pts treated with IXE Q4W compared to PBO at wk 16. Pts treated with IXE resulted in a numerically higher improvement in TJC and SJC symptoms up to wk 16 compared to PBO, and efficacy was sustained up to wk 52 (Table 1). A higher proportion of IXE-treated pts achieved high-hurdle efficacy endpoints (50% and 70% improvements) in comparison to PBO at wk 16 (Table 1). Over this time period, IXE treatment led to a high proportion of pts experiencing complete resolution of TJC or SJC vs PBO at wk 16, which was sustained up to wk 52 (Fig 1).Conclusion:In this post hoc analysis, pts with r-axSpA treated with IXE showed substantial improvement in peripheral joint pain and swelling.Table 1.Improvement of Tender or Swollen Joint Counts for pts with radiographic-axSpA with TJC>0 or SJC>0 at baseline (COAST-V/W)a - NRI Results% ImprovementRadiographic-AxSpAWk1652bPBOIXE Q4WIXE Q2WIXE Q4WIXE Q2WN (TJC>0)116129114129114BL TJC mean (SD)7.4 (8.8)8.4 (8.4)7.3 (7.5)%TJC improvement20%66.475.271.168.272.850%52.661.264.9*65.167.570%37.947.35055.854.4N (SJC>0)6772647264BL SJC mean (SD)3.8 (4.6)5.2 (5.2)3.8 (3.3)%SJC improvement20%64.283.3*76.677.878.150%56.777.8†70.37576.670%46.362.560.969.471.9Abbreviations: COAST-V/W= integrated COAST-V and COAST-W; PBO = placebo; IXE= ixekizumab; Q4W = 80 mg IXE every 4 wks; Q2W = 80 mg IXE every 2 wksaImprovement in the number of tender or swollen joints were summarized on ITT patients who had tender (TJC>0) or swollen (SJC>0) joints at baseline, respectivelybCOAST-V/W PBO data are not available at wk 52 as pts originally randomised to PBO were re-randomised 1:1 to IXE Q4W or IXE Q2W at wk 16p-value vs. PBO at wk 16: *PAcknowledgements:Writing support was provided by Sinéad O’ Loughlin, an employee of Eli Lilly and CompanyDisclosure of Interests:Marina Magrey Consultant of: Novartis, UCB, Pfizer, Eli Lilly, Abbvie, Janssen, Kurt de Vlam Speakers bureau: UCB, Novartis, Pfizer, Eli Lilly, Amgen, Celgene, Paid instructor for: UCB, Amgen, Celgene, Consultant of: UCB, Novartis, Pfizer, Eli Lilly, Amgen, Celgene, Grant/research support from: Pfizer, Amgen, Celgene, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Rebecca Bolce Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Denis Poddubnyy Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Biocad, Gilead, GlaxoSmithKline, Eli Lilly, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Eli Lilly, MSD, Novartis, and Pfizer

Purpose Previous work by our group has demonstrated the value of N-methyl-N-nitrosourea (MNU)-induced corneal endothelial decompensation in animal models. The aim of this study was to investigate the effect of molecular hydrogen (H2) on MNU-induced corneal endothelial cell (CEC) injury and the underlying mechanism. Methods MNU-induced animal models of CEC injury were washed with hydrogen-rich saline (HRS) for 14 days. Immunofluorescence staining, immunohistochemical staining, and corneal endothelial assessment were applied to determine architectural and cellular changes on the corneal endothelium following HRS treatment. MNU-induced cell models of CEC injury were co-cultured with H2. The effect of H2 was examined using morphological and functional assays. Results It was shown that MNU could inhibit the proliferation and specific physiological functions of CECs by increasing apoptosis and decreasing the expression of ZO-1 and Na+/K+-ATPase, whereas H2 improved the proliferation and physiological function of CECs by anti-apoptosis. Cell experiments further confirmed that H2 could reverse MNU damage to CECs by decreasing oxidative stress injury, interfering with the NF-κB/NLRP3 pathway and the FOXO3a/p53/p21 pathway. Conclusions This study suggests that topical application of H2 could protect CECs against corneal damage factors through anti-apoptotic effect, reduce the incidence and severity of corneal endothelial decompensation, and maintain corneal transparency.

As a novel separation mode of capillary electrophoresis (CE), liposome electrokinetic capillary chromatography (LEKC) has aroused considerable attention in recent years; however, the enantioseparation based on this new system has not been previously investigated. In this study, we proposed a brand-new LEKC chiral separation approach using liposomes comprised of phosphatidylcholine (PC) and cholesterol as pseudo-stationary phase and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as chiral selector. Compared with the single CD system and CD-SDS-MEKC system, this LEKC method presented an obviously preferable enantioseparation of four model drugs (naproxen, warfarin, ketoprofen and amlodipine). In this new established system, all the enantiomers represented baseline separations with the resolution and selectivity respectively achieving 1.584/1.067 (for naproxen), 2.226/1.045 (for warfarin), 1.537/1.038 (for ketoprofen) and 2.592/1.097 (for amlodipine), while other two comparative systems demonstrated no separation or a poor separation. Several important parameters affecting the enantioseparation, such as buffer pH, concentration of liposomes, phosphate buffer solution (PBS) and chiral selector (SBE-β-CD), and applied voltage were systematically investigated. Satisfactory repeatability was achieved through intra-day, inter-day and batch-to-batch investigations with relative standard deviations less than 3.40%. Furthermore, the established method was successfully applied to test the chiral impurity of naproxen sample.

Alzheimer’s disease is still incurable and neurodegenerative, and there is a lack of detection methods with high sensitivity and specificity. In this study, by taking different month old Alzheimer’s mice as models, we have explored the possibility of the target bioimaging of diseased sites through the initial injection of zinc gluconate solution into Alzheimer’s model mice post-tail vein and then the combination of another injection of ferrous chloride (FeCl2) solution into the same Alzheimer’s model mice post-stomach. Our observations indicate that both zinc gluconate solution and FeCl2 solution could cross the blood–brain barrier (BBB) to biosynthesize the fluorescent zinc oxide nanoclusters and magnetic iron oxide nanoclusters, respectively, in the lesion areas of the AD model mice, thus enabling high spatiotemporal dual-modality bioimaging (i.e., including fluorescence bioimaging (FL) and magnetic resonance imaging (MRI)) of Alzheimer’s disease for the first time. The result presents a novel promising...

Introduction The SAMe-TT 2 R 2 score has been proposed to predict whether patients with atrial fibrillation (AF) would be well anti-coagulated with warfarin or not. However, it might over-estimate the number of patients under suboptimal warfarin treatment in non-Caucasians. This study was designed to modify the SAMe-TT 2 R 2 score with genotypes and validate it in Chinese AF patients treated with warfarin. Material and methods Consented Chinese-Han patients (n=510) with AF under the treatment of warfarin for at least 3months were randomly divided into a derivation (n=310) and a validation cohort (n=200). For each patient, CYP2C9*3 and VKORC1 −1639 A/G genotyping was performed, and the time in therapeutic range (TTR) was calculated over this period. Results The modified SAMe-TT 2 R 2 score was established by adding "warfarin genotype bins" to replace "the non-white race" variable. In the validation cohort, the discrimination performance of the modified score for good anticoagulation control (TTR≥70%) was significantly improved (c- index increased from 0.60 to 0.67). Significantly increased risks of major bleedings (HR: 4.91; 95% CI: 1.03–23.37; adjusted p=0.04) and all bleedings (HR: 1.93; 95% CI: 1.14–3.25; adjusted p=0.01) were found in patients with modified scores ≥2, as compared with patients with modified scores of 0–1. Conclusions The modified SAMe-TT 2 R 2 score could improve the ability for the identification of good anticoagulation control, and the prediction of major bleeding events in Chinese patients with AF treated by warfarin.

Early diagnosis remains highly important for efficient cancer treatment, and hence, there is significant interest in the development of effective imaging strategies. This work reports a new multimodal bioimaging method for accurate and rapid diagnosis of cancer cells by introducing aqueous Fe2+ and Zn2+ ions into cancer cells (i.e., HeLa, U87, and HepG2 cancer cells). We found that the biocompatible metal ions Fe2+ and Zn2+ forced the cancer cells to spontaneously synthesize fluorescent ZnO nanoclusters and magnetic Fe3O4 nanoclusters. These clusters could then be used for multimodal cancer imaging by combining fluorescence imaging with magnetic resonance imaging and computed tomography imaging. Meanwhile, for normal cells (i.e., L02) and tissues, neither fluorescence nor any other obvious difference could be detected between preand post-injection. This multimodal bioimaging strategy based on the in situ biosynthesized Zn&Fe oxide nanoclusters might therefore be useful for early cancer diagnosis and therapy.

Background:Patients with ankylosing spondylitis (AS) are burdened with decreased work productivity.1Ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been shown to improve disease signs and symptoms in 2 phase 3 trials assessing patients with active AS.2, 3Objectives:This study investigated the effect of IXE treatment for 52 weeks on work productivity and activity impairment as measured by absenteeism, presenteeism, overall work impairment, and activity impairment in patients with active AS.Methods:COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, double-blind, placebo (PBO)-controlled (COAST-V active-controlled with adalimumab) trials investigating the efficacy of IXE every 4 weeks (Q4W) and every 2 weeks (Q2W) in 341 patients with active AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) and in 316 patients who were inadequate responders or intolerant to 1 or 2 tumor necrosis factor inhibitors (TNFi; COAST-W). Patients receiving PBO were switched to IXE Q4W or Q2W at Week 16; patients receiving adalimumab (ADA) were switched to IXE Q4W or Q2W at Week 20. Data for IXE Q4W and Q2W were combined for PBO/IXE and ADA/IXE groups. Changes from baseline in work productivity were measured for those reporting full- or part-time work at Weeks 16 and 52 with the Work Productivity and Activity Impairment (WPAI) Questionnaire for Spondyloarthritis.Results:Compared to bDMARD-naïve patients (COAST-V), TNFi-experienced patients (COAST-W) were slightly older, had longer disease duration, reported less paid employment, and had greater scores for impaired work productivity, signifying more severe baseline disease. At Week 16, bDMARD-naïve patients treated with IXE Q4W or Q2W had significant improvements in activity impairment compared to placebo (pConclusion:Both bDMARD-naïve and TNFi-experienced patients with AS receiving IXE had greater improvements in aspects of work productivity compared to placebo. Improvements were sustained through Week 52.References:[1]Boonen, van der Linden. (2006).J Rheumatol Suppl.78:4-11.[2]Van der Heijde, et al. (2018)Lancet. 392(10163):2441-51.[3]Deodhar, et al. (2019)Arthritis Rheumatol.71(4):599-611.Disclosure of Interests:Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB, Philip J Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer, Sun Pharma, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer, UCB Pharma, Proton Rahman Grant/research support from: Janssen and Novartis, Consultant of: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Speakers bureau: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer, Victoria Navarro-Compán Consultant of: Abbvie, Lilly, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Lilly, Novartis, Pfizer, UCB, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, James Cheng-Chung Wei Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB Pharma, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Theresa Hunter Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Baojin Zhu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCBFigure.Changes from baseline in Overall Work Impairment in A) bDMARD-naïve (COAST-V) and B) TNFi-experienced (COAST-W) patients and Activity Impairment in C) bDMARD-naïve and D) TNFi-experienced patients.

Objectives To compare disease-free survival (DFS) between patients who underwent open (ORT) versus minimally invasive (MIS) radical trachelectomy (RT) [laparoscopic (LRT) or robotic (RRT)]. Methods Eligibility criteria included 1) RT and pelvic lymphadenectomy with/without sentinel lymph node mapping, 2) 1/2005 to 12/2017 3) squamous, adenocarcinoma, or adenosquamous histology, 4) stage IA2-IB1, 5) tumors ≤2 cm, 6) 15 or more cases per center. Results A total of 698 patients [open (n=388) vs. MIS (310)] were included. The median follow-up time was 40.9 months (range, 1–179.1) [MIS 38.6 (range, Conclusions Surgical approach in radical trachelectomy for low-risk cervical cancer was not associated with differences in recurrence rates or survival. MIS had worse perioperative outcomes.

Progranulin (PGRN) is a growth factor with significant biological effects in different types of cancer. However, its role in melanoma progression has not been explored. In this study, we first analyze clinical datasets and show that high PGRN expression levels are correlated with poor prognosis of melanoma patients. Further, we demonstrate in a transplanted murine melanoma model in which the endogenous Grn gene encoding PGRN has been deleted that tumor-derived, not host-derived PGRN, promotes melanoma growth and metastasis. Immunological analyses reveal an enhanced infiltration of natural killer cells, but not T lymphocytes, into PGRN-deficient tumors compared to the wild type control. Antibody-mediated depletion confirms the critical role of NK cells in controlling B16 tumor growth. RNA-seq analysis reveals that several chemokines including CCL5 are strongly upregulated in PGRN-deficient tumor. Silencing CCL5 expression in PGRN-deficient tumor reduces NK cell recruitment and restores tumor growth to the control level. Lastly, we show that PGRN inhibits Ccl5 gene expression at the transcriptional level. This study highlights a novel and critical role of PGRN in melanoma growth and metastasis and suggests that it may represent a potential therapeutic target.

Penile squamous cell carcinoma (PSCC) is a malignancy that affects the skin and tissues of the penis, but the knowledge of pathogenesis and carcinogenesis is limited. Here, we characterize the PSCC genomic landscape using whole-exome sequencing. Of the 30 paired blood and tumor samples, we identified recurrent mutations in 11 genes; confirmed previous findings for FAT1 (4/30), HRAS (4/30), NOTCH1 (4/30), TP53 (3/30) and PIK3CA (3/30); and revealed novel candidate driver genes [CASP8 (4/30), SLITRK2 (3/30), FLG (3/30) and TRRAP (3/30)]. Our in vitro experiments suggested CASP8 was involved in mediating TRAIL-induced apoptosis of penile cancer cell lines. We also observed the frequently altered pathways for potential therapeutic implications: alterations in the Notch (30% of sample altered), RTK-RAS (26.7% altered) and Hippo (23.3% altered) pathways accounted for over 50% of tumors. The frequently altered genes (>10%) in these pathways were proved to be expressed in penile tumors by immunohistochemistry assay. These findings provide new insight into the mutational and pathway landscapes of PSCC and suggest potential novel therapeutic opportunities for this malignancy.

Background:It is important to understand the potential effect long-term therapy with biologics can have on structural changes in the spine among patients with active radiographic axial spondyloarthritis (r-axSpA, ankylosing spondylitis).Objectives:We examined radiographic progression in the spine among patients with active r-axSpA treated with ixekizumab, an IL-17A antagonist, for 2 years, and potential predictors of spinal radiographic progression.Methods:Patients with active r-axSpA, biologic-naive (COAST-V, NCT02696785) or with prior experience with a maximum of 2 TNF inhibitors (COAST-W, NCT02696798), received 80 mg ixekizumab every 2 or 4 weeks for 2 years (108 weeks, of which 56 weeks were the COAST-Y extension study, NCT03129100). Mean change from baseline of modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) (average score from 2 selected readers, blinded for time order) for patients treated with ixekizumab for 2 years with data at both baseline and year 2 is presented (N=230; 54% of total randomized patients). Non-progression is presented for all patients and subgroups based on TNFi-experience. Predictors were identified in multivariate logistic regression models with stepwise selection criteria of p-value Results:At baseline, patients (N=230) were predominately male (82%) with an average age of 43 years, mean symptom duration of 16 years, 52% were TNFi-experienced, mean (SD) ASDAS score was 4.0 (0.7), most were HLA-B27 positive (87%) and 40% had syndesmophytes (identified by both selected readers at the same location). Baseline mSASSS (SD) was 11.0 (16.3) and change from baseline at year 2 of treatment was 0.3 (1.8) (Table 1). The proportion of non-progressors (mSASSS change from baseline 0) were age, baseline syndesmophytes, HLA-B27 status and gender (Table 1). Week 52 inflammation in MRI SPARCC spine was also identified as a predictor for structural progression at year 2 in a separate model for patients from COAST-V where MRI measures were available at baseline and Week 52 (N=109).Conclusion:The majority of patients treated with ixekizumab for 2 years did not show radiographic progression, and the overall mean progression was low. Similar levels of non-progression were observed in biologic-naive patients and patients previously exposed to TNFis. Predictors were generally consistent with previous studies.Table 1.Spinal radiographic changes for patients with active r-axSpA treated with ixekizumab for 2 yearsChange in mSASSS at year 2All patientsaN=230Biologic-naiveN=110TNFi-experiencedN=120 Baseline mSASSS, mean (SD)11.0 (16.3)10.1 (15.5)11.7 (17.0) Change at year 2, mean (SD)0.3 (1.8)0.3 (2.0)0.4 (1.6) Change in total mSASSS 206 (89.6)100 (90.9)106 (88.3) Change in total mSASSS ≤0, n (%)174 (75.7)86 (78.2)88 (73.3)Multivariable logistic regression modelPrediction for change in total mSASSS >0, OR (95% CI), p-valueAll patientsa,bN=228 Age (≥40 years vs. 2.97 (1.41, 6.28)p=0.004c Baseline syndesmophytesb (yes vs. no)2.31 (1.18, 4.54)p=0.015c Baseline HLA-B27 (positive vs. negative)3.78 (1.04, 13.75)p=0.044c Gender (male vs. female)3.16 (1.01, 9.86)p=0.047c Baseline ASDAS state (>3.5 vs. [2.1, 3.5])2.26 (0.96, 5.34)p=0.063aCombined ixekizumab group of Q2W and Q4W patients with baseline and year-2 mSASSS databIdentified by both selected readers at the same location (2 patients were not evaluable by both readers)cpAbbreviations: ASDAS=Assessment of Disease Activity, CI=confidence interval, IXE=ixekizumab, mSASSS=modified Stoke Ankylosing Spondylitis Spinal Score, OR=odds ratio, Q2W=every 2 weeks, Q4W=every 4 weeks, SD=standard deviation, TNFi=tumor necrosis factor inhibitorDisclosure of Interests:Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma, Employee of: Director of Imaging Rheumatology bv., Mikkel Østergaard Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Eli Lilly and Company, Janssen, Merck, Pfizer, Roche, UCB, Celgene, Sanofi, Regeneron, Novartis, Grant/research support from: AbbVie, BMS, Merck, UCB, Celgene, Novartis, John D Reveille Paid instructor for: UCB, Eli Lilly and Company, Consultant of: UCB, Eli Lilly and Company, Pfizer, Novartis, Grant/research support from: Janssen, Eli Lilly and Company, Xenofon Baraliakos Speakers bureau: Abbvie, BMS, Lilly, Janssen, Novartis, MSD, Pfizer, Galapagos, Gilead, UCB, Paid instructor for: Abbvie, BMS, Lilly, Janssen, Novartis, MSD, Pfizer, Galapagos, Gilead, UCB, Consultant of: Abbvie, BMS, Lilly, Janssen, Novartis, MSD, Pfizer, Galapagos, Gilead, UCB, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Hilde Carlier Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Walter P Maksymowych Speakers bureau: Abbvie, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Boehringer, BMS, Eli Lilly and Company, Novartis, Pfizer, UCB, Grant/research support from: Abbvie, Novartis, Pfizer

Diethylstilbestrol (DES) is a synthetic estrogen with significant public health impact. Developing recognition elements of DES is of great significance for the establishment of DES detection methods. Aptamers are short and single-stranded (ss) oligonucleotides able to recognize target molecules with high affinity. Currently, a variety of estrogen specific aptamers were screened and used for the design of detection probes and the establishment of rapid detection methods. In order to obtain aptamer of DES, magnetic-bead SELEX was applied. In this work, DES was immobilized on the magnetic beads, and the nucleotide chains that bind to DES were obtained by magnetic separation. Negative and reverse screening processes were designed to enhance the specificity and affinity of the selected aptamers. After 11 rounds of screening, multiple nucleic acid chains were obtained by SELEX and the chains was sequenced. Two aptamers with better affinity were obtained and the value of the dissociation constant (Kd) were calculated to be 98.5 nM and 126.3 nM, respectively. The specificity of the aptamer candidate was initially determined by gold nanoparticle (Au-NP) colorimetric assay and the potential application of the aptamers was also investigated by this method.

To study the relation of loss of consciousness (LOC) to white matter integrity after mild traumatic brain injury (mTBI), we acquired diffusion tensor imaging (DTI) at 3 Tesla in 79 participants with mTBI and normal computed tomography (age 18 to 50 years) whom we imaged after a mean post-injury interval of 25.9 h (standard deviation = 12.3) and at 3 months. For comparison, 64 participants with orthopedic injury (OI) underwent DTI at similar intervals. Quantitative tractography was used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the left and right uncinate fasciculus (UF), left and right inferior frontal occipital fasciculus (IFOF), and the genu of the corpus callosum. Generalized estimating equation models assessed the association between LOC and both MD and FA across time after mTBI and compared their DTI metrics with the OI group. LOC was significantly related to MD in UF and IFOF (p values ranged from p 0.0001 to 0.0270) and to FA in left UF (p = 0.0104) and right UF (p = 0.0404). Between-group differences in MD were significant for left UF, left and right IFOF, and the genu of the corpus callosum on initial DTI, but not at 3 months post-injury, and these differences were specific to the mTBI subgroup with LOC. Groups did not differ in FA at either occasion. Early DTI may provide a biomarker for mTBI with LOC, even in patients whose consciousness recovers by arrival in the emergency department. MD better differentiates mTBI from OI than FA on early DTI, but this is specific to mTBI with LOC. DTI findings support a continuum of white matter injury in early mTBI.

Cancer treatment has a far greater chance of success if the neoplasm is diagnosed before the onset of metastasis to vital organs. Hence, cancer early diagnosis is extremely important and remains a major challenge in modern therapeutics. In this contribution, facile and new method for rapid multimodal tumor bioimaging is reported by using biosynthesized iron complexes and gold nanoclusters via simple introduction of AuCl4- and Fe2+ ions. The observations demonstrate that the biosynthesized Au nanoclusters may act as fluorescent and computed tomography probes for cancer bioimaging while the iron complexes behave as effective contrast agent for magnetic resonance imaging. The biosynthesized iron complexes and gold nanoclusters are found biocompatible in vitro (MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay) and in vivo for all the vital organs of circulatory and excretory system. These observations raise the possibility that the biosynthesized probes may find applications in future clinical diagnosis for deep seated early neoplasms by multimodal imaging.