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Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by γ-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the γ-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active γ-secretase complex on the cell surface, and inhibited the γ-secretase activity by competing with the substrate binding in vitro . Moreover, A5226A abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of γ-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant γ-secretase activity and Notch signaling.

Suction-embedded plate anchors (SEPLAs) have been developed to answer the growing need for anchors to withstand significant vertical loading. The concept combines the advantage of suction caissons (known penetration depth and location) and ‘drag-embedded' plate anchors (efficiency and low cost). The main issue associated with SEPLAs relates to the keying process, as the anchor is first loaded, and the associated loss of embedment and reduction in capacity. The paper presents a plasticity model developed to predict the trajectory and load development during anchor keying, and up to peak load. Rigid plasticity is assumed, allowing the kinematics of the anchor to be determined from a yield surface and associated plastic potential. The trajectory and performance of a typical SEPLA are predicted using the model, and are compared with results from centrifuge tests and large-deformation finite-element analysis. The anchor loss of embedment ranged from ∼0·2 to 1·5 times the anchor height for loading inclinations between 40° and 90° from the horizontal. The model was used further to calculate the anchor loss of embedment and capacity for varying padeye offsets. Results indicated that the loss of embedment could be reduced significantly by increasing the offset, but at the detriment of the ultimate anchor capacity.

β-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-β precursor protein (APP) leading to the generation of amyloid-β peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1⁺/⁻ mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1⁻/⁻ mice with impaired processing of NRG1. We demonstrate that BACE1⁻/⁻ mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1⁻/⁻ mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1⁻/⁻ mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

Pulmory nocardiosis is a rare respiratory infection which commonly affects immunocompromised patients but also in immunocompetent hosts. The clinical manifestation is variable and endobronchial nocardiosis is a very rare condition. We report a case of endobronchial nocardiosis associated with the presence of a broncholith. The pathogenesis and the treatment of this condition are discussed below.

Background:While carotid ultrasound (US) has been advocated for cardiovascular (CV) risk screening in patients with rheumatoid arthritis as various traditional scores underestimate CV risk, whether subclinical carotid atherosclerosis (SCA) is associated with coronary atherosclerosis on coronary computed tomography angiography (CCTA) in patients with psoriatic arthritis (PsA) remains uncertain.Objectives:This study aimed to identify carotid US parameters which can discriminate PsA patients with coronary artery disease (CAD) and obstructive CAD (O-CAD), and determine the utility in combination with Framingham Risk Score (FRS).Methods:Ninety-one PsA patients (56 males; age: 50±11years, disease duration: 9.4±9.2years) without overt CV diseases were recruited. Carotid intima-media thickness (cIMT), presence of plaque and total plaque area (TPA) were determined by high-resolution US. CAD was defined as the presence of any coronary plaque on CCTA. O-CAD was defined as >50% stenosis of the lumen. FRS <10% indicates low CV risk, 10-19% indicates intermediate risk while ≥20% indicates high risk (1).Results:Thirty-five (38%) patient had carotid plaque. Fifty-five (60%) patients had CAD and 9 (10%) patients had O-CAD. 53 (58%), 25 (17%) and 13 (14%) were classified as low, moderate and high CV risk according to the FRS respectively. FRS underestimated the CV risk as only 11/55 (20%) of subjects with CAD were correctly identified as having high CV risk by FRS (Figure 1). Fifteen patients out of 53 (28%) with low CV risk based on FRS were reclassified as high CV risk by the presence of carotid plaque. Nine out of these 15 (60%) had CAD and 1/15 (6.7%) had O-CAD. Concerning the carotid ultrasound parameters, cIMT (mean and maximum) and TPA were increased in both the CAD+ and O-CAD+ group compared to those without CAD or O-CAD (Table 1). Multivariate logistic regression analysis revealed that mean cIMT (OR=1.06, 95% CI:1.01-1.11, p=0.013) was an independent explanatory variables associated with CAD. Meanwhile, mean cIMT (OR=1.06, 95%CI: 1.01-1.11, p=0.013) maximum cIMT (OR=1.06, 95%CI: 1.00-1.13, p=0.043), and TPA (OR=1.55, 95%CI: 1.01-2.36, p=0.043) were independent explanatory variables associated with O-CAD after adjusting for covariates. Based on Receiver Operating Curve (ROC) analysis, an optimal cut off for FRS at 5% and mean cIMT at 0.62mm yield 63% sensitivity and 73% specificity for the presence of CAD (AUC: 0.71, p=0.001).Table 1.Relationship between carotid ultrasound parameters and the presence and extent of coronary artery disease on coronary computed tomography angiography.Coronary artery diseaseNo (n=37)Yes (n=54)pMean carotid IMT, mm0.63±0.120.69±0.10.017Maximum carotid IMT, mm0.77±0.170.84±0.140.040Carotid Plaque, n, %Absence2646.4%3053.6%0.156Presence1131.4%2468.6%Total plaque area, mm20.0[0,6]0.0[0, 10.8]0.059Obstructive coronary artery diseaseNo (n=82)Yes (n=9)pMean carotid IMT, mm0.65±0.120.76±0.070.011Maximum carotid IMT, mm0.80±0.160.93±0.140.020Carotid Plaque, n, %Absence5393.0%47.0%0.235Presence2985.3%514.7%Total plaque area, mm20.0[0, 7.0]6.0[0, 15.3]0.103IMT-intima media thickness; coronary computed tomography angiography.Conclusion:Increased cIMT and TPA were associated with CAD and O-CAD in PsA patients while the presence of carotid plaque alone was insufficient to discriminate patient with or without CAD. A combination of US parameters should be considered for CV risk stratification in patients with PsA.References:[1]Ford ES et al., J Am Coll Cardiol. 2004;43(10):1791-6.Disclosure of Interests:Isaac T. Cheng: None declared, Ka Tat Wong: None declared, Edmund Li: None declared, Priscilla C Wong: None declared, Billy Tin Lok Lai: None declared, Cheuk Wan Yim: None declared, Shirley King Yee Ying: None declared, Kitty Yan Kwok: None declared, Martin Li: None declared, Tena K. Li: None declared, Jack Jock Wai Lee: None declared, Alex Pui Wai Lee: None declared, Lai-Shan Tam Grant/research support from: Janssen, Pfizer, Novartis, Speakers bureau: Abbvie, Lilly, Sanofi

Background:Psoriatic arthritis (PsA) is associated with accelerated atherosclerosis due to underlying inflammation. Whether inflammatory burden and drugs used to suppress inflammation over time are associated with cardiovascular (CV) events remains unclear.Objectives:This study aims to examine the time-varying effect of C-reactive protein (CRP) levels and the use of drugs including non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of CV events independent of traditional CV risk factors in PsA patients.Methods:A retrospective cohort analysis was performed in patients with PsA who were recruited from 2008 to 2015 and followed till the end of 2019. The outcome was occurrence of a first CV event. Framingham risk score (FRS) was used to quantify the traditional CV risk. Cox proportional hazard models with time-varying CRP levels and drugs used were analyzed to identify the risk factors for CV events in PsA patients.Results:200 patients with PsA (median age: 47.5[40.0 – 56.0]; male: 119 [59.5%]) were recruited (Table 1. next page). After a mean follow-up of 8.8±3.8 years, 30 (15%) patients developed a first CV event. The Kaplan-Meier survival analysis indicated a significant difference in the CV event-free survival between patients with and without CRP level >3 mg/L (Figure 1A) and an inverse relationship between time-varying NSAIDs exposure and CV event-free survival (Figure 1B). The multivariable Cox regression model showed that time-varying CRP level (HR 1.02, 95% CI 1.00 to 1.04) and NSAIDs exposure (HR 0.30, 95% CI 0.15 to 0.95) were significantly associated with CV events after adjusting for baseline FRS (HR 5.04, 95% CI 1.83 to 13.85).Table 1.Baseline demographic and clinical characteristics, cardiovascular risk factors and treatments received.VariablesAll patients n=200 median (IQR) or n (%)CVD -ve, n=170 median (IQR) or n (%)CVD +ve, n=30 median (IQR) or n (%)p-valueNSAID -ve, n=61 median (IQR) or n (%)NSAID +ve, n=139 median (IQR) or n (%)p-valueMale, n (%)119 (59.5%)100 (58.6%)19 (63.3%)0.22839 (63.9%)80 (57.6%)0.397Age, years47.5 (40.0 – 56.0)46.5 (37.7 – 54.0)57.0 (45.3 – 65.8)<0.001*49.0 (44.0 – 56.5)46.0 (38.0 – 54.8)0.176Disease duration, years4.3 (1.8 – 7.9)4.1 (1.7 – 7.0)6.0 (2.1 – 8.6)0.0664.6 (1.5 – 8.7)4.3 (1.9 – 7.3)0.393Diabetes, n (%)45 (22.5%)30 (17.6%)15 (50.0%)<0.001*10 (16.4%)35 (25.2%)0.171Hypertension, n (%)68 (34.0%)46 (27.1%)22 (73.3%)<0.001*21 (34.4%)47 (33.9%)0.933CRP, mg/L4.9 (1.7 – 12.6)4.2 (1.5 – 12.0)11.3 (2.4 – 19.6)0.035*5.5 (1.7 – 15.1)7.2 (1.4 – 15.8)0.770ESR, mm/hr21 (10.0 – 38.0)20 (9 – 35)31 (14 – 60)0.038*21 (7 – 33)21 (11 – 43)0.291Systolic blood pressure, mmHg125 (115 – 140)124 (115 – 137)144 (129 – 160)<0.001*123 (118 – 137)125 (115 – 141)0.889Diastolic blood pressure, mmHg78 (70 – 85)78 (70 – 84)82 (72 – 90)0.19978 (72 – 86)78 (70 – 85)0.697FRS8.4 (4.0 – 17.0)7.5 (3.3 – 14.0)19.6 (13.4 – 43.0)<0.001*7.9 (3.5 – 15.5)8.7 (4.2 – 17.1)0.885Lipid-lowering drugs, n (%)30 (15.0%)25 (14.7%)5 (16.7%)0.7829 (14.8%)21 (15.1%)0.949MTX, n (%)99 (49.5%)81 (47.6%)18 (60.0%)0.21225 (41.0%)74 (53.2%)0.111bDMARDs, n (%)17 (8.5%)13 (7.6%)4 (13.3%)0.3036 (9.8%)11 (7.9%)0.654NSAIDs, n (%)139 (69.2%)119 (70.0%)20 (66.7%)0.715N/AN/AN/ASteroid, n (%)2 (1.0%)2 (1.2%)0 (0%)1.0001 (1.6%)1 (0.7%)0.518*statistically significant at p≤ 0.05CVD+ve, patients who developed cardiovascular events during subsequent follow-up;CVD-ve, patients who did not developed cardiovascular events during subsequent follow-up;NSAIDs, nonsteroidal anti-inflammatory drugs; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FRS, Framingham Risk Score; MTX, methotrexate; bDMARDs, biological disease-modifying antirheumatic drugs.Conclusion:Increased inflammatory burden as reflected by elevated CRP level was associated with increased risk of CV events, while the risk was significantly reduced with NSAIDs use in PsA patients.Disclosure of Interests:None declared.

In mammals, the sperm deliver mRNA of unknown function into the oocytes during fertilization. The role of sperm microRNAs (miRNAs) in preimplantation development is unknown. miRNA profiling identified six miRNAs expressed in the sperm and the zygotes but not in the oocytes or preimplantation embryos. Sperm contained both the precursor and the mature form of one of these miRNAs, miR-34c. The absence of an increased level of miR-34c in zygotes derived from α-amanitin—treated oocytes and in parthenogenetic oocytes supported a sperm origin of zygotic miR-34c. Injection of miR-34c inhibitor into zygotes inhibited DNA synthesis and significantly suppressed first cleavage division. A 3′ UTR luciferase assay and Western blotting demonstrated that miR-34c regulates B-cell leukemia/lymphoma 2 (Bcl-2) expression in the zygotes. Coinjection of anti—Bcl-2 antibody in zygotes partially reversed but injection of Bcl-2 protein mimicked the effect of miR-34c inhibition. Oocyte activation is essential for the miR-34c action in zygotes, as demonstrated by a decrease in 3′ UTR luciferase reporter activity and Bcl-2 expression after injection of precursor miR-34c into parthenogenetic oocytes. Our findings provide evidence that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression.

BackgroundPeriarticular and systemic osteoporosis is a major feature in patients with rheumatoid arthritis (RA). Bone loss in RA is considered to be a result of chronic inflammation, particularly at the early stage of the disease. High Resolution peripheral Quantitative Computed Tomography (HR-pQCT) is an in vivo 3D imaging modality dedicated to peripheral skeleton imaging. Whether a better controlling of the disease inflammation could lead to a preservation of vBMD and microarchitecture is to be determined.ObjectivesThis one-year cohort study in RA patients with early disease (onset <2 years) aimed to compare changes of vBMD and bone microarchitecture indices at the distal radius and tibia between patients who achieved and those who did not achieve disease remission.MethodsForty-seven RA patients (age: 54.5±11.8 years) with disease onset <2 years and with active disease (Disease Activity Score in 28 joints [DAS28] ≥3.2) were recruited for this one-year study. Disease remission at 12 months was assessed as Simplified Disease Activity Score ≤3.3. HR-pQCT imaging of the distal radius and tibia was performed at baseline and 12 months.ResultsAt 12 months, 20 patients achieved disease remission and 27 patients remained with activity disease. There was no significant difference in baseline DAS28 score (4.93 vs. 4.92, p>0.05) and age between the two groups. In patients who did not achieve disease remission, particularly at the distal radius, there were decreases in cortical and trabecular vBMD, cortical thickness and trabecular number, and increase in trabecular separation (Table 1). Increase in cortical porosity presented as the most prominent deterioration of bone microarchitecture (20%). Only changes in trabecular separation (2.87%) and cortical vBMD (-1.12%) achieve statistical significance. In patients who achieve disease remission, decrease in vBMD and deterioration in bone microarchitecture were in general to a lesser extent than their counterparts. In particular, there appeared to be a decrease in cortical porosity in these patients (-6.62%). However, there was no significant group-wise difference in changes of vBMD and microarchitectural indices (all p>0.05).Table 1.Percentage changes of all HR-pQCT indices between two groupsVariablesNo remission (n=27)Remission (n=20)p-valueRadius Cortical vBMD−0.19±1.760.63±3.190.269 Trabecular vBMD−2.41±7.30−3.06±7.220.765 Cortical thickness−1.12±4.51−0.11±3.430.407 Cortical pore volume20.1±105−6.22±25.80.282 Cortical porosity19.7±95.0−6.62±25.90.236 Trabecular number−2.21±8.34−0.55±7.310.483 Trabecular thickness0.21±2.28−0.51±1.500.227 Trabecular separation2.87±8.421.21±6.900.475Tibia Cortical vBMD−1.12±3.07−0.90±1.580.773 Trabecular vBMD−0.13±2.690.11±1.570.718 Cortical thickness−0.34±3.490.39±2.510.432 Cortical pore volume6.27±17.285.05±11.60.785 Cortical porosity7.89±18.54.95±12.40.542 Trabecular number2.20±7.711.72±8.850.843 Trabecular thickness−0.58±1.80−0.24±1.470.494 Trabecular separation−1.37±7.29−0.92±8.890.847RA, rheumatoid arthritis; CCP, cyclic citrullinated peptide; MMP-3, matrix metalloproteinase-3; DAS28-CRP, disease activity score 28 with C-reactive protein; mHAQ, modified Health Assessment Questionnaire; GC, glucocorticoid.ConclusionsThere was a trend towards a preservation of vBMD and bone microarchitecture in RA patients who achieve disease remission. An early and better control of disease activity might reduce the future risk of osteoporosis in RA patients.Disclosure of InterestNone declared

Background:Bone erosion is a key feature of RA reflecting both disease severity and progression. HR-pQCT is an in-vivo clinical imaging system allowing detailed analysis of bone structure, including bone erosion. Several circulating microRNAs have already been suggested as potential biomarkers in RA.Objectives:To determine whether plasma cell-free circulating miRNAs are 1) associated with bone erosion at presentation and 2) predictive of erosion progression at 12 months as determined by HR-pQCT in patients with early rheumatoid arthritis (ERA).Methods:In this prospective study, 124 ERA patients were treated with a tight control protocol aiming at remission by using conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). The second metacarpophalangeal joint (MCP2) was assessed for erosions by HR-pQCT at baseline and after 12 months. Plasma cell-free circulating miRNAs at baseline were identified by microRNA array in 10 treatment-naïve ERA patients with maximal erosion volume at MCP2; in 10 treatment-naïve ERA patients without erosion; and in 6 age- and sex-matched healthy controls. The 4 most dysregulated miRNAs were identified by TaqMan® qRT-PCR in these same 20 ERA patients. Thereafter, the expression of these 4 selected miRNAs was validated in all 124 ERA patients at baseline.ResultsOf the 377 screened miRNAs, 155 miRNAs were detectable. 94 (60.6%) of these detectable miRNAs were upregulated in ERA patient with erosions, with 13 (8.4%) upregulated more than twofold. 61 (39.4%) miRNAs were downregulated in ERA patients with erosions, with 6 (3.9%) downregulated more than twofold. A total of 16 miRNAs were differentially expressed (P<0.05) and 4 were possibly differentially expressed (P ≤0.1) between ERA patients with and without erosions. At baseline, expressions of miR-143–3p, miR-145–5p and miR-99b-5p were significantly higher in ERA patients with erosions than those without erosions (P<0.05 for all). After 12 months of csDMARDs treatment, 31.7%, 47.7%, and 20.6% of the ERA patients had erosion progression, stable erosion and partial erosion repair respectively. Logistic regression analysis revealed baseline expression of miR-99b-5p to be an independent predictor of erosion progression at 12 months (Exp [B]= 4.203, 95% CI 1.166–15.147, P=0.028) (table 1).UnivariateMultivariate P valueExp (B)95% CIP valueExp (B)95% CI Depth0.0680.4790.217–1.0560.0850.1770.025–1.269Width0.1080.7460.522–1.0670.8711.0690.481–2.373RF+0.1023.8330.764–19.2240.0875.4070.784–37.317ACPA>250U0.0623.2810.941–11.4390.0844.2380.822–21.843miR99b-5p0.0752.5120.913–6.9050.0284.2031.166–15.147Conclusions:Increased level of cell-free circulating miR-99b-5p was associated with erosions at presentation in ERA patients and could predict erosion progression as assessed by HR-pQCT over a period of 12 months, indicating that it may well serve as a biomarker of poor response to csDMARDs. Whether early biologic DMARDs use in these miR-99b-5p positive patients could reduce or prevent progression of erosion will need to be addressed in future studies.Acknowledgements:This study was partly supported by the Health and Medical Research Fund (project no 10110071).Disclosure of Interest:None declared