Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).

High-throughput RNA-sequencing reveals novel targets of tofacitinib in the treatment of rheumatoid arthritis.

OBJECTIVES: Although tofacitinib has been confirmed to have good efficacy and safety in the treatment of rheumatoid arthritis (RA), the relevant mechanism at the whole transcriptome level has not yet been revealed. In this study, peripheral blood mononuclear cells (PBMCs) from patients with active RA before and after tofacitinib treatment were analysed using whole transcriptome sequencing technology. METHODS: Fourteen patients with active RA were selected to detect the alterations of mRNAs, lncRNAs, circRNAs, and miRNAs in PBMCs before and after tofacitinib treatment using whole transcriptome sequencing. Through bioinformatics analysis, differentially expressed RNAs and their functions were identified. Then the competitive endogenous RNA (ceRNA) network and the protein interaction network were constructed. And qRT-PCR validation was performed for RNAs in the ceRNA network. RESULTS: Based on 69 DEmRNAs, 1743 DElncRNAs, 41 DEcircRNAs, and 4 DEmiRNAs obtained from whole transcriptome sequencing, an RNA interaction network including mRNA DEPDC1, lncRNA ENSG00000272574, circRNA hsa_circ_0034415, miR-190a-5p, and miR-1298-5p was constructed according to ceRNA theory. The qRT-PCR validation results of DEPDC1, hsa_circ_0034415 and miR-1298-5p involved in the network were consistent with the sequencing results, which provided important research evidence for further study of these RNAs. CONCLUSIONS: The new discovered circRNA/lncRNA-miRNA-mRNA network in RA patients relevant to tofacitinib therapy will provide new enlightenment for the role of tofacitinib in the treatment of RA and shed light on a new direction for further exploring the deep-seated mechanism of this drug.

Effects of Cryopreservation on Sperm with Cryodiluent in Viviparous Black Rockfish (Sebastes schlegelii).

Black rockfish is an economically important fish in East Asia. Little mention has been paid to the sperm cryopreservation in black rockfish. In this study, the optimal cryodiluent was selected from 48 combinations by detecting various sperm parameters. Transcriptome and methylome analysis were further performed to explore the molecular mechanism of inevitable cryoinjuries. The results showed that cryopreservation had negative effects on the viability, DNA integrity, mitochondrial activity, total ATPase and LDH of sperm even with optimal cryodiluent (FBS + 15% Gly). Transcriptome and methylome analysis revealed that the expression of 179 genes and methylation of 1266 genes were affected by cryopreservation. These genes were enriched in GO terms of death, G-protein coupled receptor signaling pathway, response to external stimulus and KEGG pathways of phospholipase D signaling pathway and xenobiotic and carbohydrate metabolism pathways. The role of PIK3CA and CCNA2 were highlighted in the protein-protein interaction network, and the sperm quality-related imprinted gene mest was identified among the 7 overlapping genes between transcriptome and methylome. Overall, the cryodiluent for black rockfish sperm was optimized, providing a feasible method for cryopreservation. The transcriptome and methylome data further demonstrated the underlying molecular mechanisms of cryoinjuries, proving clues for improvement of cryopreservation method of black rockfish.

Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate-inadequate responder Chinese patients with active rheumatoid arthritis: 24-week results from a randomised, double-blind, placebo-controlled phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.

Altered Olfactory Function in Patients with Systemic Lupus Erythematosus.

BACKGROUND The objective of this study was to detect the level of olfactory function in patients with systemic lupus erythematosus (SLE) and to explore the relationship between impaired olfactory function and anti-ribosomal P protein antibody (ARPA), disease duration, and age. MATERIAL AND METHODS The level of olfactory function in 65 patients with SLE and 50 healthy participants was detected using the Connecticut Chemosensory Clinical Research Center (CCCRC) method; serum ARPA levels in SLE patients and the healthy control group were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS CCCRC scores in the active SLE group was lower than that in the inactive SLE and healthy control groups (P<0.01). In SLE patients, the CCCRC scores of ARPA-positive patients were lower than those of ARPA-negative patients (P<0.01). A negative correlation was discovered between CCCRC scores and ARPA serum levels in SLE patients. Multiple linear regression analyses showed a correlation among the CCCRC score, age, and ARPA. CONCLUSIONS Olfactory dysfunction was found in patients with active SLE; which correlated with SLE disease activity and ARPA levels.

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats.

Background Diabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study. Methods The mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively. Results The mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats. Conclusion The findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.

The Effects of IGF-1 on TNF-α-Treated DRG Neurons by Modulating ATF3 and GAP-43 Expression via PI3K/Akt/S6K Signaling Pathway.

Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-α and the biological effects, produced by interaction of IGF-1 and TNF-α, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-α challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-α (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-α (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-α (10 ng/mL) challenge. In contrast, lower concentration of TNF-α (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These data imply that IGF-1 counteracts the toxic effect of higher concentration of TNF-α, while potentiates the growth-promoting effect of lower concentration of TNF-α, with the node for TNF-α and IGF-1 interaction being the PI3K/Akt/S6K signaling pathway. This study is helpful for interpretation of the association of IGF-1 with TNF-α and the neurobiological effects elicited by interaction of IGF-1 and TNF-α in neurological disorders.

Insulin-like growth factor-1 attenuates apoptosis and protects neurochemical phenotypes of dorsal root ganglion neurons with paclitaxel-induced neurotoxicity in vitro.

Paclitaxel (PT)-induced neurotoxicity is a significant problem associated with successful treatment of cancers. Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Whether IGF-1 has protective effects on neurite growth, cell viability, neuronal apoptosis and neuronal phenotypes in DRG neurons with PT-induced neurotoxicity is still unclear. In this study, primary cultured rat DRG neurons were used to assess the effects of IGF-1 on DRG neurons with PT-induced neurotoxicity. The results showed that PT exposure caused neurite retraction in a dose-dependent manner. PT exposure caused a decrease of cell viability and an increase in the ratio of apoptotic cells which could be reversed by IGF-1. The percentage of calcitonin gene-related peptide immunoreactive (CGRP-IR) neurons and neurofilament (NF)-200-IR neurons, mRNA, and protein levels of CGRP and NF-200 decreased significantly after treatment with PT. IGF-1 administration had protective effects on CGRP-IR neurons, but not on NF-200-IR neurons. Either extracellular signal-regulated protein kinase (ERK1/2) inhibitor PD98059 or phosphatidylinositol 3-kinase (PI3 K) inhibitor LY294002 blocked the effect of IGF-1. The results imply that IGF-1 may attenuate apoptosis to improve neuronal cell viability and promote neurite growth of DRG neurons with PT-induced neurotoxicity. Moreover, these results support an important neuroprotective role of exogenous IGF-1 on distinct subpopulations of DRG neurons which is responsible for skin sensation. The effects of IGF-1 might be through ERK1/2 or PI3 K/Akt signaling pathways. These findings provide experimental evidence for IGF-1 administration to alleviate neurotoxicity of distinct subpopulations of DRG neurons induced by PT.

Erythropoietin attenuates advanced glycation endproducts-induced toxicity of Schwann cells in vitro.

Advanced glycation endproducts (AGEs)-induced cytotoxicity is regarded as one of the main mechanisms responsible for neurological disorders. Although erythropoietin (EPO) is demonstrated to have neuroprotective effects in neurodegenerative diseases, the effects of EPO on AGEs-induced toxicity of Schwann cells (SCs) remain open for investigation. Primary cultured SCs isolated from 4 day-old Wistar rats were exposed to AGEs with or without EPO treatment for 5 days. AGEs decreased cell viability, increased apoptotic rate, elevated intracellular reactive oxygen species levels, and reduced total glutathione levels of SCs. The AGEs-induced toxic effects on SCs were partially blocked by AGER siRNA or AGER inhibitor FPS-ZM1. SCs exposed to AGEs exhibited higher mRNA and protein levels of receptor for AGEs (AGER), EPO, and EPO receptor (EPOR). Exogenous EPO treatment attenuated AGEs-induced oxidative stress and apoptosis probably by reducing the mRNA and protein expression of AGER. The protective effect of EPO against AGEs-induced toxicity was blocked by EPOR siRNA. The data of the present study gives, for the first time, evidence of the protective effects of EPO on SCs with AGEs-induced oxidative stress and apoptosis. These results imply that EPO might be a novel valuable agent for treating AGEs-induced toxicity.

Insulin-like growth factor-1 prevents dorsal root ganglion neuronal tyrosine kinase receptor expression alterations induced by dideoxycytidine in vitro.

Dideoxycytidine (zalcitabine, ddC) produces neurotoxic effects. It is particularly important to understand the toxic effects of ddC on different subpopulations of dorsal root ganglion (DRG) neurons which express distinct tyrosine kinase receptor (Trk) and to find therapeutic factors for prevention and therapy for ddC-induced peripheral sensory neuropathy. Insulin-like growth factor-1 (IGF-1) has been shown to have neurotrophic effects on DRG sensory neurons. However, little is known about the effects of ddC on distinct Trk (TrkA, TrkB, and TrkC) expression in DRG neurons and the neuroprotective effects of IGF-1 on ddC-induced neurotoxicity. Here, we have tested the extent to which the expression of TrkA, TrkB, and TrkC receptors in primary cultured DRG neurons is affected by ddC in the presence or absence of IGF-1. In this experiment, we found that exposure of 5, 25, and 50 µmol/L ddC caused a dose-dependent decrease of the mRNA, protein, and the proportion of TrkA-, TrkB-, and TrkC-expressing neurons. IGF-1 (20 nmol/L) could partially reverse the decrease of TrkA and TrkB, but not TrkC, expression with ddC exposure. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 µmol/L) blocked the effects of IGF-1. These results suggested that the subpopulations of DRG neurons which express distinct TrkA, TrkB, and TrkC receptors were affected by ddC exposure. IGF-1 might relieve the ddC-induced toxicity of TrkA- and TrkB-, but not TrkC-expressing DRG neurons. These data offer new clues for a better understanding of the association of ddC with distinct Trk receptor expression and provide new evidence of the potential therapeutic role of IGF-1 on ddC-induced neurotoxicity.

Classification criteria of early rheumatoid arthritis and validation of its performance in a multi-centre cohort.

OBJECTIVES: To develop classification criteria for early rheumatoid arthritis (ERA) based on a large cohort of early inflammatory arthritis patients and to evaluate the performance of these criteria. METHODS: The study population comprised a cohort of early inflammatory arthritis patients with symptom duration less than one year. Classification criteria of ERA were developed by incorporating the most sensitive or specific variables. Performance of the ERA criteria, 1987 ACR and 2010 ACR/EULAR criteria were evaluated. RESULTS: A total of 803 patients were enrolled in this study. By the end of the one year follow-up, 514 patients were diagnosed with RA, 251 with other rheumatic diseases, and 38 patients with undifferentiated arthritis. The ERA criteria are as follows: 1) morning stiffness ≥30 minutes; 2) arthritis of 3 or more joint areas; 3) arthritis of hand joints; 4) positive RF; 5) positive anti-CCP antibody. Rheumatoid arthritis is defined by the presence of 3 or more of the criteria. The sensitivity (84.4%) of the ERA classification criteria was much higher than the 1987 ACR criteria (58.0%). In a validation cohort of early inflammatory arthritis patients, the area under the ROC curves (AUC) showed a better performance for the ERA criteria (0.906, 95%CI 0.866 to 0.945) than the 1987 ACR criteria (0.786, 95%CI 0.725 to 0.848) and the 2010 ACR/EULAR criteria (0.745, 95%CI 0.677 to 0.814). CONCLUSIONS: A set of ERA classification criteria has been developed with good performance for early RA. It is applicable in clinical practice and research.

Revealing the changes in signaling pathways caused by tofacitinib in patients with rheumatoid arthritis through RNA sequencing and the correlation with clinical parameters.

OBJECTIVES: The current study is to accelerate the understanding of how tofacitinib works in patients with rheumatoid arthritis (RA) due to the lack of relevant information. METHOD: We selected ten patients with active RA and obtained the expression profile for their peripheral blood mononuclear cells before and after the tofacitinib treatment by RNA sequencing. The gene set enrichment analysis was conducted, and the significantly enriched gene sets were identified. The hub gene highly correlated with clinical parameters in the gene set was selected. We constructed the weighted gene co-expression network, linked modules with clinical indicators, and screened hub genes. The expression of representative hub genes was validated by real-time quantitative PCR (qPCR). RESULTS: Gene set interferon (IFN) α and IFN ß signaling was the most significantly down-regulated after tofacitinib treatment. In this gene set, genes Oas2 and Oasl showed a significant positive correlation with morning stiffness. In co-expression network, gene Vgll3 from the violet module with the highest correlation coefficient, was positively correlated with morning stiffness. Among them, Oasl and Vgll3 have shown significant down-regulation in qPCR validation. CONCLUSIONS: Our results highlighted the role of type I IFN, mainly including IFN α and IFN ß, in the pathogenesis of RA and action for tofacitinib, and provided a new entry point for further elucidating the mechanism of morning stiffness. Key Points • Gene set IFN α and IFN ß signaling was the most significantly down-regulated after tofacitinib treatment in RA patients. • Gene Oasl and Vgll3 were correlated with morning stiffness and significantly down-regulated due to the action of tofacitinib. • Type I IFN system was highlighted in the action of tofacitinib.

S2DA-Net: Spatial and spectral-learning double-branch aggregation network for liver tumor segmentation in CT images.

Accurate liver tumor segmentation is crucial for aiding radiologists in hepatocellular carcinoma evaluation and surgical planning. While convolutional neural networks (CNNs) have been successful in medical image segmentation, they face challenges in capturing long-term dependencies among pixels. On the other hand, Transformer-based models demand a high number of parameters and involve significant computational costs. To address these issues, we propose the Spatial and Spectral-learning Double-branched Aggregation Network (S2DA-Net) for liver tumor segmentation. S2DA-Net consists of a double-branched encoder and a decoder with a Group Multi-Head Cross-Attention Aggregation (GMCA) module, Two branches in the encoder consist of a Fourier Spectral-learning Multi-scale Fusion (FSMF) branch and a Multi-axis Aggregation Hadamard Attention (MAHA) branch. The FSMF branch employs a Fourier-based network to learn amplitude and phase information, capturing richer features and detailed information without introducing an excessive number of parameters. The FSMF branch utilizes a Fourier-based network to capture amplitude and phase information, enriching features without introducing excessive parameters. The MAHA branch incorporates spatial information, enhancing discriminative features while minimizing computational costs. In the decoding path, a GMCA module extracts local information and establishes long-term dependencies, improving localization capabilities by amalgamating features from diverse branches. Experimental results on the public LiTS2017 liver tumor datasets show that the proposed segmentation model achieves significant improvements compared to the state-of-the-art methods, obtaining dice per case (DPC) 69.4 % and global dice (DG) 80.0 % for liver tumor segmentation on the LiTS2017 dataset. Meanwhile, the pre-trained model based on the LiTS2017 datasets obtain, DPC 73.4 % and an DG 82.2 % on the 3DIRCADb dataset.

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial.

BACKGROUND: Biosimilars provide an opportunity to address unmet medical need by expanding access to biological treatments. This study aimed to show equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles of a proposed tocilizumab biosimilar BAT1806/BIIB800, to reference tocilizumab, in participants with rheumatoid arthritis with an inadequate response to methotrexate. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled, equivalence study comprised a 24-week initial treatment period (results reported here) and a 24-week secondary treatment period. Participants were recruited at 54 centres across five countries (China, Ukraine, Poland, Georgia, and Bulgaria). Patients with active rheumatoid arthritis with an inadequate response to methotrexate were randomly assigned (1:1:2) to receive reference tocilizumab up to week 48, or reference tocilizumab up to week 24 followed by BAT1806/BIIB800 up to week 48 (the two reference tocilizumab groups were analysed as a single group in this analysis), or BAT1806/BIIB800 up to week 48 (the BAT1806/BIIB800 group), administered by intravenous infusion once every 4 weeks at a starting dose of 8 mg/kg. The primary endpoint was the proportion of participants who had a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 (for the European Medicines Agency [EMA]) or week 24 (for the US Food and Drug Administration [FDA] and China National Medical Products Administration [NMPA]) using prespecified equivalence margins (95% CI -14·5 to +14·5 [EMA], 90% CI -12·0 to +15·0 [FDA], and 95% CI -13·6 to +13·6 [NMPA]). The International Council for Harmonisation E9(R1) estimand framework, with strategies for addressing intercurrent events, was implemented for the efficacy evaluations with expected differences as per the predefined equivalence margins. This trial is registered at ClinicalTrials.gov (NCT03830203) and EudraCT (2018-002202-31), and is closed to new participants. FINDINGS: Between Dec 19, 2018, and Jan 5, 2021, we randomly assigned 621 participants: 309 to the reference tocilizumab group and 312 to the BAT1806/BIIB800 group. The mean age was 50·5 years (SD 12·0), 534 (86%) were women, 87 (14%) were men, and 368 (59%) were White. For the primary estimands, estimated ACR20 response rates were 64·8% in the reference tocilizumab group and 69·0% in the BAT1806/BIIB800 group (treatment difference 4·1% [95% CI -3·6 to 11·9]) at week 12, and 67·9% in the reference tocilizumab group and 69·9% in the BAT1806/BIIB800 group (treatment difference 1·9% [90% CI -4·0 to 7·9; 95% CI -5·2 to 9·1]) at week 24. All confidence intervals were contained within the predefined equivalence margins. Comparable pharmacokinetic and immunogenicity profiles were observed for the reference tocilizumab and BAT1806/BIIB800 groups. Adverse events were reported by 201 (65%) participants in the reference tocilizumab group and 206 (66%) in the BAT1806/BIIB800 group; 196 (63%) participants in the reference tocilizumab group and 201 (64%) participants in the BAT1806/BIIB800 group reported a treatment-emergent adverse event. Five participants had a fatal event (reference tocilizumab n=1; BAT1806/BIIB800 n=4). INTERPRETATION: BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab. FUNDING: Bio-Thera Solutions and Biogen.

Glucocorticoid regulates interleukin-37 in systemic lupus erythematosus.

The aim of this study was to research the expression of IL-37 in systemic lupus erythematosus (SLE) patients and the effect of glucocorticoid on IL-37. Thirty newly diagnosed severe SLE patients receiving prednisone 1 mg/kg/day for 14 consecutive days and 30 healthy subjects were enrolled into this study. The plasma levels of IL-37 and other cytokines were detected by ELISA and the relative mRNA amounts of IL-37 and other cytokines were detected by RT-PCR. The plasma levels of IL-37, IL-18, IL-18BP, IFN-γ, and IL-6 in SLE patients increased significantly compared with healthy controls (p<0.05). The relative amount of IL-37 mRNA increased by 2.45-fold in pre-treatment SLE patients compared with controls (p<0.05). Plasma concentrations of IL-37 correlated with IL-18, IL-18BP, IFN-γ, IL-6 and SLEDAI score in both pre-treatment and post-treatment SLE patients. The plasma levels of IL-37 decreased significantly after treatment of glucocorticoid. The relative amount of IL-37 mRNA decreased by 24.5 % in post-treatment SLE patients compared with pre-treatment ones (p<0.01). In conclusion, IL-37 is upregulated in active SLE patients. IL-37 is correlated with pro-inflammatory cytokines and SLEDAI. Glucocorticoid can downregulate the expression of IL-37 and other cytokines in SLE patients.

Effects of insulin-like growth factor-1 on neurochemical phenotypes of cultured dorsal root ganglion neurons with excitotoxicity induced by glutamate.

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. The neuropeptide- and neurofilament (NF)-immunoreactive (IR) neurons are two major phenotypical classes in DRG. Whether IGF-1 affects neurochemical phenotypes of DRG neurons remains unknown. In the present study, primary cultured DRG neurons were used to determine the effects of IGF-1 on neurochemical phenotypes of the neurons with excitotoxicity induced by glutamate (Glu). DRG neurons were dissociated and cultured for 48 hours and then exposed to IGF-1 (20 nmol/L), Glu (0.2 mmol/L), Glu (0.2 mmol/L) plus IGF-1 (20 nmol/L) for additional 24 hours. The DRG neurons were continuously exposed to culture media as control. After that, all above cultured DRG neurons were processed for detecting mRNA levels of calcitonin gene-related peptide (CGRP) and neurofilament-200 (NF-200) by real time-PCR analysis. CGRP and NF-200 expression in situ was determined by fluorescent labeling technique. The results showed that CGRP mRNA, but not NF-200 mRNA, increased after IGF-1 administration in the absence or presence of Glu. IGF-1 could increase the percentage of CGRP-expressing neurons, but not NF-200-expressing neurons, in the absence or presence of Glu. The ability of IGF-1 on CGRP expression may play a role in neurogenic inflammation or nociception.

GCHA-Net: Global context and hybrid attention network for automatic liver segmentation.

Liver segmentation is a critical step in liver cancer diagnosis and surgical planning. The U-Net's architecture is one of the most efficient deep networks for medical image segmentation. However, the continuous downsampling operators in U-Net causes the loss of spatial information. To solve these problems, we propose a global context and hybrid attention network, called GCHA-Net, to adaptive capture the structural and detailed features. To capture the global features, a global attention module (GAM) is designed to model the channel and positional dimensions of the interdependencies. To capture the local features, a feature aggregation module (FAM) is designed, where a local attention module (LAM) is proposed to capture the spatial information. LAM can make our model focus on the local liver regions and suppress irrelevant information. The experimental results on the dataset LiTS2017 show that the dice per case (DPC) value and dice global (DG) value of liver were 96.5% and 96.9%, respectively. Compared with the state-of-the-art models, our model has superior performance in liver segmentation. Meanwhile, we test the experiment results on the 3Dircadb dataset, and it shows our model can obtain the highest accuracy compared with the closely related models. From these results, it can been seen that the proposed model can effectively capture the global context information and build the correlation between different convolutional layers. The code is available at the website: https://github.com/HuaxiangLiu/GCAU-Net.

Transcriptome sequencing reveals ovarian immune response and development during female sperm storage in viviparous black rockfish (Sebastes schlegelii).

Black rockfish (Sebastes schlegelii) is a viviparous teleost fish whose spermatozoa were transferred into the female ovary cavity and stored for up to five months and then fertilized with the matured eggs. There is no clarity about the molecular characteristics of ovarian follicles during female sperm storage in Sebastes schlegelii. In this study, histological observation, transcriptomic analysis and hormone level detection were performed in ovaries at stages of pre-mating (PRM), post-mating (POM) and pre-fertilization (PRF). Histological observation displayed that oocytes developed from the primary growth (PG) stage to the mature stage during the three stages. Furthermore, somatic cells around the oocyte were proliferated and spermatozoa were found near the layer of epithelial cells. Transcriptomic analysis showed that there were 437 and 747 differentially expressed genes (DEGs) in ovarian comparison of PRM-vs-POM and POM-vs-PRF, respectively. GO enrichment and KEGG analysis revealed that lots of DEGs from PRM-vs-POM were linked to immune-related pathways, such as antigen processing and presentation, immune response, and complement and coagulation cascade. Meanwhile, seven DEGs associated with immune response were differentially expressed after spermatozoa treatment in ovarian tissue in vitro. While the DEGs from POM-vs-PRF were mostly enriched in the pathways related to homeostasis maintenance and cellular junction and metabolism. In addition, we found increased estrogen (E2) and 11-ketotestosterone (11-KT) level and decreased testosterone level in ovarian follicles during the sperm storage period by ELISA, suggesting that sex hormones are involved in the dynamic change of ovarian follicles. In total, this study could provide new hints for understanding the immune adaption and developmental signatures of ovarian follicles post copulation in black rockfish and other viviparous fish.

BAF-Net: Bidirectional attention fusion network via CNN and transformers for the pepper leaf segmentation.

The segmentation of pepper leaves from pepper images is of great significance for the accurate control of pepper leaf diseases. To address the issue, we propose a bidirectional attention fusion network combing the convolution neural network (CNN) and Swin Transformer, called BAF-Net, to segment the pepper leaf image. Specially, BAF-Net first uses a multi-scale fusion feature (MSFF) branch to extract the long-range dependencies by constructing the cascaded Swin Transformer-based and CNN-based block, which is based on the U-shape architecture. Then, it uses a full-scale feature fusion (FSFF) branch to enhance the boundary information and attain the detailed information. Finally, an adaptive bidirectional attention module is designed to bridge the relation of the MSFF and FSFF features. The results on four pepper leaf datasets demonstrated that our model obtains F1 scores of 96.75%, 91.10%, 97.34% and 94.42%, and IoU of 95.68%, 86.76%, 96.12% and 91.44%, respectively. Compared to the state-of-the-art models, the proposed model achieves better segmentation performance. The code will be available at the website: https://github.com/fangchj2002/BAF-Net.

Latent Tuberculosis Infection and Associated Factors in Patients with Systemic Lupus Erythematosus: a Multicenter, Cross-Sectional Study.

The objectives of this study were to screen for latent tuberculosis infection (LTBI) among patients with systemic lupus erythematosus (SLE) using the T-SPOT.TB assay and to identify factors affecting the assay results. SLE patients were enrolled from 13 tertiary hospitals in eastern, central, and western China from September 2014 to March 2016 and were screened using the T-SPOT.TB assay to detect LTBI. Basic information about the subjects was collected, including gender, age, body mass index (BMI), course of disease, evidence of previous tuberculosis, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, and the use of glucocorticoids and immunosuppressants. Univariate analysis and multivariable logistic regression were performed to identify factors affecting the results of the T-SPOT.TB assay. In all, 2,229 SLE patients were screened using the T-SPOT.TB assay, of whom 334 patients tested positive, yielding a positivity rate of 15% (95% confidence interval [CI], 13.5% to 16.5%). The positivity rate was higher in male than female patients and had an increasing trend with age. Multivariable logistic regression analysis showed that patients over 40 (odds ratio [OR], 1.65; 95% CI, 1.29 to 2.10) and with evidence of previous tuberculosis (OR, 4.43; 95% CI, 2.81 to 6.99) were more likely to have positive T-SPOT.TB results, while patients with a SLEDAI-2K score of ≥10 (OR, 0.61; 95% CI, 0.43 to 0.88), a glucocorticoid dose of ≥60 mg/d (OR, 0.62; 95% CI, 0.39 to 0.98), leflunomide (LEF) treatment (OR, 0.51; 95% CI, 0.29 to 0.88), or tacrolimus (FK506) treatment (OR, 0.40; 95% CI, 0.16 to 1.00) were more likely to have negative T-SPOT.TB results. The frequencies of CFP-10-specific gamma interferon (IFN-γ)-secreting T cells were significantly lower in SLE patients with severe disease activity or high-dose glucocorticoids (P < 0.05). The positivity rate of the T-SPOT.TB assay was 15% among SLE patients. Severe, active SLE disease and the use of high-dose glucocorticoids and some types of immunosuppressants are likely to result in negative T-SPOT.TB results. For SLE patients with the above conditions, diagnosing LTBI based on a positive T-SPOT.TB result may lead to underestimation of the prevalence. IMPORTANCE The burden of tuberculosis and systemic lupus erythematosus in China ranks among the top three in the world. Therefore, active screening for LTBI and preventive intervention in SLE patients are of great significance in China. In view of the lack of relevant data in a large sample, we conducted a multicenter, cross-sectional study using T-SPOT.TB as a screening method for LTBI, to investigate the prevalence of LTBI and analyze the factors affecting the results of the T-SPOT.TB assay in SLE patients. Our study showed that the overall positivity rate of the T-SPOT.TB assay in SLE patients was 15.0%, which was lower than the estimated LTBI prevalence in the general population in China (~20%). For SLE patients with severe, active disease, high-dose glucocorticoids, and some types of immunosuppressants, a diagnosis of LTBI based on only positive T-SPOT.TB results may lead to underestimation of the prevalence.