Efficacy and safety of rademikibart (CBP-201), a next-generation mAb targeting IL-4Rα, in adults with moderate to severe atopic dermatitis: A phase 2 randomized trial (CBP-201-WW001).

BACKGROUND: Rademikibart (CBP-201) is a next-generation IL-4 receptor alpha-targeting antibody. OBJECTIVE: We sought to evaluate rademikibart in adults with moderate to severe atopic dermatitis. METHODS: A total of 226 patients were randomized, double-blind, to subcutaneous rademikibart (300 mg every 2 weeks [Q2W], 150 mg Q2W, 300 mg every 4 weeks [Q4W]; plus 600-mg loading dose) or placebo. Randomization began in July 2020. The trial was completed in October 2021. RESULTS: The WW001 phase 2 trial achieved its primary end point: significant percent reduction from baseline in least-squares mean Eczema Area Severity Index (EASI) to week 16 with rademikibart 300 mg Q2W (-63.0%; P = .0007), 150 mg Q2W (-57.6%; P = .0067), 300 mg Q4W (-63.5%; P = .0004) versus placebo (-39.7%). EASI scores decreased significantly with 300 mg Q2W and Q4W at the earliest assessment (week 2), with no evidence of plateauing by week 16. Significant improvements were also observed in secondary end points, including pruritus. Across the primary and secondary end points, efficacy tended to be comparable with 300 mg Q2W and Q4W dosing. Rademikibart and placebo had similar, low incidence of treatment-emergent adverse events (TEAEs) (48% vs 54%), serious TEAEs (1.8% vs 3.6%), TEAEs leading to treatment discontinuation (1.2% vs 1.8%), conjunctivitis of unspecified cause (2.9% vs 0%), herpes (0.6% vs 1.8%), and injection-site reactions (1.8% vs 1.8%). Although no discontinuations were attributed to coronavirus disease 2019, pandemic-related restrictions likely had an impact on trial conduct. CONCLUSIONS: Rademikibart was efficacious and well tolerated at Q2W and Q4W intervals. Q4W dosing is a more convenient frequency than approved for current therapies.

Trial of Spesolimab for Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares. METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity. RESULTS: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. CONCLUSIONS: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).

Enhanced quality of hESC-derived melanocytes through modified concentration of endothelin-1.

The study investigated the effectiveness of EDN1 and EDN3 cytokines in the differentiation of melanocytes from hESCs. The findings showed that 100 nM EDN1 was more effective in promoting hESC to CD117+/TYR+ melanoblasts compared to 100 nM EDN3. Additionally, maintaining melanoblasts is beneficial for preserving the ability to proliferate. The study found that 10 nM EDN1 helped maintain the proliferation of melanoblasts without over maturing them into melanocytes in the late stage of differentiation. Thus, using 100 nM EDN1 in the initial stage and 10 nM EDN1 in the late stage proved to be an efficient and cost-effective method for obtaining hESC-derived melanocytes. The preliminary results suggest that EDN1 promotes melanoblast formation during the initial differentiation stage through its binding to both the EDNRB receptor and EDNRA receptor. This study provides a valuable tool for studying the development of human melanocytes and modelling the biology of disease.

MMP2hi Fibroblasts Regulate CD8+ T Cell Residency and Inflammation via CD100 in Psoriasis.

BACKGROUND: Psoriasis, a T cell-mediated chronic inflammatory skin condition, is characterized by the interaction of T cells with various cell types, forming an inflammatory microenvironment that sustains psoriatic inflammation. The homeostasis of these tissue-resident T cells are supported by fibroblasts, the primary structural cells in the dermis. In psoriasis, there is an increased expression of matrix metalloproteinase 2 (MMP2), mediating the structural alterations of skin tissues and the modulation of inflammation. Additionally, the CD100-PLXNB2 axis is known to enhance psoriasis inflammation via keratinocytes, and CD103 levels are associated with the severity of psoriasis upon relapse. OBJECTIVE: To elucidate the role of fibroblasts and the MMP2/CD100 axis in modulating psoriasis inflammation. METHODS: CD100 expression and function in psoriasis were assessed using immunofluorescence, ELISA, single-cell transcriptome sequencing, cellular interaction analyses, and qRT-PCR. CD8+ T cells from psoriasis patients were isolated using magnetic beads to investigate the regulatory effect of MMP2 on CD100 expression on their membranes. Single-cell transcriptome sequencing, spatial transcriptome sequencing, mimetic timing analysis, immunofluorescence, and flow cytometry were utilized to determine the origin of MMP2 and its impact on CD103+CD8+ T cells. The hypotheses were further validated in vivo using MMP2 and CD100 inhibitors. RESULTS: Soluble CD100 (sCD100) was significantly upregulated in both psoriatic lesions and peripheral blood, amplifying psoriasis inflammation by promoting the production of inflammatory cytokines by keratinocytes, fibroblasts, and endothelial cells through the sCD100-PLXNB2 axis. Fibroblasts with high MMP2 expression (MMP2hi) exacerbate psoriasis symptoms by facilitating CD100 shedding from CD8+ T cell membranes. Additionally, it was demonstrated that fibroblasts enhance the upregulation of the CD8+ T cell residency factor CD103 in co-cultures with CD8+ T cells. Inhibitors targeting MMP2 and CD100 proved effective in reducing inflammation in a model of imiquimod-induced psoriasis. CONCLUSION: Our findings underscore the pivotal role of MMP2hi fibroblasts in the amplification and recurrence of inflammatory responses in psoriasis. These fibroblasts augment psoriasis inflammation through the CD100-PLXNB2 axis by facilitating CD100 shedding on CD8+ T cell membranes and by upregulating CD103, thereby enhancing CD8+ T cell residency.

Gallic acid attenuates LPS-induced inflammation in Caco-2 cells by suppressing the activation of the NF-κB/MAPK signaling pathway.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by intestinal barrier dysfunction, inflammatory synergistic effects and excessive tissue injury. Gallic acid (GA) is renowned for its remarkable biological activity, encompassing anti-inflammatory and antioxidant properties. However, the underlying mechanisms by which GA protects against intestinal inflammation have not been fully elucidated. The aim of this study is to investigate the effect of GA on the inflammation of a lipopolysaccharide (LPS)-stimulated human colon carcinoma cell line (Caco-2) and on the intestinal barrier dysfunction, and explore the underlying molecular mechanism involved. Our findings demonstrate that 5 µg/mL GA restores the downregulation of the mRNA and protein levels of Claudin-1, Occludin, and ZO-1 and decreases the expressions of inflammatory factors such as IL-6, IL-1ß and TNF-α induced by LPS. In addition, GA exhibits a protective effect by reducing the LPS-enhanced early and late apoptotic ratios, downregulating the mRNA levels of pro-apoptotic factors ( Bax, Bad, Caspase-3, Caspase-8, and Caspase-9), and upregulating the mRNA levels of anti-apoptotic factor Bcl-2 in Caco-2 cells. GA also reduces the levels of reactive oxygen species increased by LPS and restores the activity of antioxidant enzymes, namely, superoxide dismutase and catalase, as well as the level of glutathione. More importantly, GA exerts its anti-inflammatory effects by inhibiting the LPS-induced phosphorylation of key signaling molecules in the NF-κB/MAPK pathway, including p65, IκB-α, p38, JNK, and ERK, in Caco-2 cells. Overall, our findings show that GA increases the expressions of tight junction proteins, reduces cell apoptosis, relieves oxidative stress and suppresses the activation of the NF-κB/MAPK pathway to reduce LPS-induced intestinal inflammation in Caco-2 cells, indicating that GA has potential as a therapeutic agent for intestinal inflammation.

Chin Augmentation and Treatment of Chin Retrusion with a Flexible Hyaluronic Acid Filler in Asian Subjects: A Randomized, Controlled, Evaluator-Blinded Study.

BACKGROUND: Aesthetic improvement of the chin is increasingly requested by patients, including those of Chinese origin. METHODS: A randomized, evaluator-blinded, no-treatment controlled study evaluated the effectiveness and safety of a flexible hyaluronic acid (HA) filler, Restylane® DefyneTM (HADEF), in the correction of chin retrusion in a Chinese adult population over 12 months after treatment. On Day 1, subjects were randomized 3:1 into two groups, HADEF or delayed-treatment controls, and those in the HADEF group were administered treatment. An optional touch-up treatment was administered 1 month after treatment to obtain optimal chin augmentation. The initially untreated control group was offered delayed-treatment after 6 months (including 1-month touch-up). RESULTS: HADEF was superior to no-treatment in improving chin retrusion according to the blinded evaluator at 6 months [Galderma Chin Retrusion Scale (GCRS) responder rate (≥ 1-point improvement from baseline) of 81% vs. 5% for untreated controls; p < 0.001, meeting the primary effectiveness objective. A majority of subjects maintained improvement at 12 months (61% in the HADEF group). All subjects reported satisfaction with results at 6 months after treatment with HADEF and aesthetic improvement rates per the global aesthetic improvement scale (GAIS) were high for 12 months following treatment, with an acceptable safety profile. CONCLUSIONS: These results demonstrated HADEF to be effective and safe for the correction of mild-to-moderate chin retrusion in Chinese subjects, confirming findings previously observed in a western population. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The role of B-cell ferroptosis in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the dysregulation of B cell subpopulation and function. Recent studies have suggested a potential role of ferroptosis, an iron-dependent form of regulated cell death, in the pathogenesis of SLE. Here, we demonstrate that B-cell ferroptosis occurs both in lupus patients and MRL/lpr mice. Treatment with liproxstatin-1, a potent ferroptosis inhibitor, could reduce autoantibody production, improve renal damage, and alleviate lupus symptoms in vivo. Furthermore, our results suggest that ferroptosis may regulate B cell differentiation and plasma cell formation, indicating a potential mechanism for its involvement in SLE. Taken together, targeting ferroptosis in B cells may be a promising therapeutic strategy for SLE.

Measurement properties of the patient global assessment numerical rating scale in moderate-to-severe psoriasis.

BACKGROUND: Patient global assessment (PtGA) has been recommended as one of the core domains in psoriasis clinical trials. Among multiple versions of PtGA, the single-question, 11-point PtGA numeric rating scale (NRS) remains to be validated in patients with plaque psoriasis. OBJECTIVES: To evaluate the psychometric characteristics of an 11-point PtGA NRS for disease severity in patients with moderate-to-severe plaque psoriasis. METHODS: Data were analysed from 759 patients with moderate-to-severe psoriasis in the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), a prospective, multicentre and observational registry assessing the comparative effectiveness and safety of biologics (adalimumab, ustekinumab, secukinumab or ixekizumab), conventional systemic therapies (acitretin or methotrexate) and phototherapy. RESULTS: The test-retest reliability of the PtGA NRS showed good agreement (intraclass correlation coefficient range 0.79-0.83). No floor or ceiling effects of PtGA NRS were observed. The PtGA NRS was significantly correlated with the Psoriasis Area and Severity Index (PASI), static Physician Global Assessment (sPGA), body surface area, Dermatology Quality of Life Index (DLQI) and Hospital Anxiety and Depression Scale. Relatively large correlations of PtGA NRS with PASI and the DLQI 'symptoms and feelings' domain (all correlations ≥ 0.4 except at baseline) supported convergent validity. The presence of psoriatic arthritis or joint symptoms had no significant association with the PtGA NRS. In multivariate regression analyses, the PtGA NRS at baseline was predicted by age, lesion extent, lesion intensity, patients' symptoms and feelings, and impact on work or school. The PtGA NRS displayed known-groups validity with the PASI, sPGA and DLQI score bands. The PtGA NRS was responsive to change in PASI and DLQI after treatment. Anchor- and distribution-based approaches supported -3 as the minimal important difference for PtGA NRS. An absolute PtGA NRS ≤ 2 during follow-up was concordant with the state of minimal disease activity based on a 90% reduction in PASI (PASI 90) or PASI 90 plus a DLQI of 0/1. Sensitivity analysis using subgroup comparison and multiple imputation model yielded consistent conclusions. CONCLUSIONS: The PtGA NRS showed good reliability, validity and responsiveness in patients with psoriasis, and was feasible in clinical trials and daily practice.

Carboxylated mesoporous carbon hollow spheres for the efficient solid-phase microextraction of aromatic amines.

An efficient and stable fiber coating is of great importance for solid-phase microextraction (SPME). In this study, carboxylated mesoporous carbon hollow spheres (MCHS-COOH) were developed as an efficient SPME coating of polar aromatic amines (AAs) for the first time. The MCHS-COOH coating material with high specific surface area (1182.32 m2 g-1), large pore size (10.14 nm), and rich oxygen-containing groups was fabricated via a facile H2O2 post-treatment. The as-prepared MCHS-COOH-coated fiber exhibited fast adsorption rate and excellent extraction properties, mainly due to its π-π interactions, hollow structure, and abundant affinity sites (carboxyl groups). Subsequently, coupled with gas chromatography-tandem mass spectrometry (GC-MS/MS), a sensitive method with low limits of detection (0.08-2.0 ng L-1), a wide linear range (0.3-500.0 ng L-1), and good repeatability (2.0-8.8%, n = 6) was developed for the analysis of AAs. The developed method was validated against three river water samples, with satisfactory relative recoveries being obtained. The above results demonstrated that the prepared MCHS-COOH-coated fiber exhibited good adsorption capacity, suggesting a promising application to monitor trace polar compounds in real environment.

The origin of dielectric relaxation behavior in TiO2 based ceramics co-doped with Zn2+, W6+ ions under a N2/O2 sintering atmosphere.

Dense (Zn0.5W0.5)xTi1-xO2 (ZWTOx) ceramics were fabricated using a conventional solid state reaction method with sintering under a nitrogen atmosphere (ZWTOx-N2) and an oxygen atmosphere (ZWTOx-O2), respectively. Colossal permittivity (ε > 104) and low loss (tan δ < 0.1) were simultaneously achieved in ZWTOx-N2 ceramics, and two types of dielectric relaxation behaviors observed were interpreted to be due to interface polarization and disassociation between oxygen vacancies and trivalent titanium ions, respectively. The impedance plots suggested that the ZWTOx-N2 ceramics are electrical heterostructures composed of semiconductor and insulator grain boundaries, which proved that the CP performance of ZWTOx-N2 ceramics almost originates from the internal barrier layer capacitance (IBLC) effect. In addition, a series of anomalous dielectric behaviors such as low permittivity and low frequency dispersion were observed for ZWTOx-O2 ceramics; polarization (P)-electric field (E) hysteresis loop curves were obtained for ZWTOx-O2 ceramics, and that impedance plots have shown that the ZWTOx-O2 ceramics display higher insulation resistivity. Density functional theory (DFT) calculations illustrated that the Zn2+-W6+ ion pairs are easy to form in ZWTOx-O2 ceramics, which causes destruction of the local lattice and thus leads to abnormal dielectric behavior. This work will provide a new strategy for defect engineering in TiO2 and other CP materials.

Detection of skin thickness and density in healthy Chinese people by using high-frequency ultrasound.

OBJECTIVES: Due to a recent development of high-frequency ultrasound (HFUS) systems, it is easier to realize high-resolution in vivo imaging of the biological tissues. The object of this study was to map the thickness and echo density of skin layers in healthy Chinese people and assess the influence of gender, age, and region on it. METHODS: A total of 189 volunteers (85 male, 104 female) with age range of 22-75-year old (mean age of 41.2-year old) were enrolled. The thickness and density of the epidermis and dermis layer were detected by high-frequency (22 or 75 MHz) ultrasonography at 13 different anatomical sites, including the forehead, cheeks, flexor and extensor forearms, flexor and extensor upper arms, inner and outer legs, inner and outer thighs, back, and abdomen. RESULTS: The thickness and density of epidermis/dermis between different anatomical sites were statistically significant (p < 0.05). The epidermis thickness of the face and trunk were less than that of the limbs, whereas the thicknesses of the dermis were on the contrary. The density of the epidermis/dermis of the face and trunk were less than that of the limbs. The thickness of dermis in most of the sites were higher in male than in female, and the density of epidermis and dermis in most of the sites were less in men than in women. The thicknesses/densities of dermis were lower in older age group in almost all sites, whereas only several sites reached statistical. The difference between the north and south regions showed the environment also influenced the thickness and density of the skin. CONCLUSION: HFUS provides a simple noninvasive method for evaluating the skin thickness and echo-density, which, reflecting intradermal structure, exhibit systematic regional variation. With the establishment of Chinese phenotypic database of skin thickness and density, it will be helpful for the skin disease assessment, skin surgery, and cosmetology technology.

The copper (II) complex of salicylate phenanthroline inhibits proliferation and induces apoptosis of hepatocellular carcinoma cells.

In the present study, we investigated the antitumor effect and associated molecular mechanisms of the copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)] against hepatocellular carcinoma (HCC). Cu(sal)(phen) inhibited the proliferation of HCC cells (HepG2 and HCC-LM9) and induced apoptosis of HCC cells in a dose-dependent manner by upregulating mitochondrial reactive oxygen species (ROS) production. The expression of the antiapoptotic proteins survivin and Bcl-2 was decreased, while the expression of the DNA damage marker γ-H2 AX and the apoptotic marker cleaved PARP was upregulated with Cu(sal)(phen) treatment. In vivo, the growth of HepG2 subcutaneous xenograft tumors was greatly attenuated by Cu(sal)(phen) treatment. Immunohistochemistry staining showed that the expression of survivin, Bcl-2, and Ki67 in the tumor was downregulated by Cu(sal)(phen). Toxicity experiments with BALB/c mice revealed that Cu(sal)(phen) is a relatively safe drug. Our results indicate that Cu(sal)(phen) possesses great potential as a therapeutic drug for HCC.

First report of tomato leaf curl New Delhi virus infecting several cucurbit plants in China.

In autumn 2022, a novel and devastating viral disease affecting cucurbits emerged in Ningbo (Zhejiang province), Haimen (Jiangsu province), and Shanghai, China, causing an approximate 650-hectare infestation and resulting in nearly US$15 million in economic losses. The incidence rates of infection reached up to 72.5% on muskmelon (Cucumis melo L. ssp melo), oriental melon (Cucumis melo L. var. agrestis), pumpkin (Cucurbita moschata), luffa (Luffa acutangula), and squash (Cucurbita pepo), and were highly associated with the presence of whitefly (Bemisia tabaci). Infected plants exhibited symptoms such as dwarf stunting, reduced leaf size, leaf chlorotic patches, malformation, fruit deformation, leaf downward rolling, and yellowing (Figure 1). To identify the pathogen, forty cucurbit leaf samples were collected from Haimen (18), Ningbo (19), and Shanghai (3) and tested for cucurbits chlorotic yellows virus (CCYV), cucurbit yellow stunting disorder virus (CYSDV), and Begomovirus using RT-PCR or PCR. All samples tested negative for CCYV and CYSDV using species-specific primers; however, 29 out of 40 samples tested positive (see Supplementary Table 1) for Begomovirus using the degenerate primer pairs PA/PB (Deng et al. 1994). PCR products from seven samples, representing different regions and hosts, underwent Sanger sequencing. The nucleotide sequences of these products showed 98.2-99% identity to tomato leaf curl New Delhi virus (ToLCNDV) by BLASTn. Subsequently, the 29 positive cucurbit samples were confirmed using ToLCNDV-specific primer pairs NDVAF/NDVAR and NDVBF/NDVBR (Jyothsna et al. 2013) for DNA-A and DNA-B, respectively. The DNA-A and DNA-B genome sequences of ToLCNDV isolates from Haimen (Haimen4), Ningbo (Ningbo6), and Shanghai (Shanghai1) were obtained using the primer pairs NDVAF/NDVAR, A1961F/A2645R (covering complete DNA-A sequences), NDVBF/NDVBR, and B1613F/B2579R (covering complete DNA-B sequences，see Supplementary Table 2). No amplicon was produced with primer pairs UNA101/UNA102 and beta01/beta02 (Supplementary Table 2) for detecting Alphasatellite and Betasatellite DNAs, respectively. The complete DNA-A genome sequences (2739 bp) of Haimen 4 (accession no. OP585369), Ningbo 6 (accession no. OP585370), and Shanghai 1 (accession no. OP683993) isolates exhibited 99.5-99.6% nucleotide identity to each other, and their highest nucleotide sequence identity (99.3-99.4%) was shared with the DNA-A of ToLCNDV-Zhejiang isolate (accession no. OP356207) from tomato in Zhejiang Province, China. The complete nucleotide sequences (2693 nt) of DNA-B for Haimen 4 (accession no. OP683995), Ningbo 6 (accession no. OP683996), and Shanghai 1 (accession no. OP683994) isolates showed 99.0-99.1% identity to each other, and their highest nucleotide sequence identity (~99.1%) was shared with the DNA-B of ToLCNDV-Zhejiang isolate (accession no. OP356208).All ToLCNDV isolates from mainland China, including the Zhejiang isolate and the three isolates in this study, shared 98.3-98.7% nucleotide sequence identity and 98.2-98.4% with the DNA-A genome of the severe isolate (accession no. HM159454) from tomato in New Delhi, India, and the DNA-B genome of the India:Delhi:Cucumis:2012 isolate from cucumber in New Delhi, India, respectively. However, the genome sequence identities between mainland and Taiwan isolates (accession nos. GU180095 and GU180096) were below 93%, suggesting that mainland China isolates of ToLCNDV are more closely related to the India isolate than to the Taiwan isolate.To fulfill Koch's postulates, infectious clones of the Haimen 4 isolate were constructed and agroinfiltrated into muskmelon, oriental melon, pumpkin, luffa, and squash plants. In brief, two plasmids, containing 1.56-mer DNA-A and 1.4-mer DNA-B genome sequences, were constructed using enzyme digestion and ligation, transformed into Agrobacterium tumefaciens strain GV3101, respectively, and then co-agroinfiltrated into cucurbit plants. Initial symptoms appeared in the new leaves at 7 days post-inoculation (DPI), followed by severe leaf curling, dwarfing, stunting, reduced leaf size, and chlorotic leaf patches at 18 DPI. The presence of DNA-A and DNA-B of ToLCNDV in inoculated plants was confirmed by PCR using primer pairs A1961F/A2645R and B1613F/B2579R, respectively. Collectively, the pathogen of this emerging disease has been identified as ToLCNDV. ToLCNDV was first reported on tomato in India and is now the most predominant and economically significant disease affecting cucurbit and solanaceous crops in Southeast and East Asia, the Middle East, and the Mediterranean Basin (Moriones et al. 2017). In China, ToLCNDV was initially reported on oriental melon in Taiwan (Chang et al. 2010) and subsequently on tomato (Lycopersicon esculentum) in Zhejiang province (Li et al. 2022). To the best of our knowledge, this is the first report of ToLCNDV infecting muskmelon, pumpkin, luffa, and squash in China. Further investigations on the epidemiology of this viral disease in China are needed.

LncRNA AGXT2L1-2:2 facilitates keratinocytes proliferation and inhibits apoptosis by interacting with estrogen-related receptor alpha in psoriasis.

Our previous studies have revealed that long noncoding RNA (lncRNA) AGXT2L1-2:2 was highly expressed in keratinocytes of psoriasis. However, the functions of lnc-AGXT2L1-2:2 in keratinocytes remain unknown. Meanwhile, co-expression network analysis indicated lnc-AGXT2L1-2:2 could interact with estrogen-related receptor alpha (ERRα). In this study, interleukin (IL)-17A could stimulate the production of lnc-AGXT2L1-2:2 in keratinocytes, thus establishing an in vitro cellular model of psoriasis. Lnc-AGXT2L1-2:2 was overexpressed using lentiviral-vector and ERRα was downregulated with small interfering RNA. Then the effects of lnc-AGXT2L1-2:2 and ERRα on viability, apoptosis, and cell cycle in IL-17A-stimulated keratinocytes were assessed by CCK-8, EdU assay, and flow cytometry. We found that lnc-AGXT2L1-2:2 and ERRα both resulted in higher proliferation ability, lower apoptosis rates, and reduction of G0/G1 phase proportion. Furthermore, lnc-AGXT2L1-2:2 could promote the expression of ERRα and siERRα antagonized the effects of lnc-AGXT2L1-2:2 on the phenotypes above in IL-17A-induced keratinocytes. In conclusion, lnc-AGXT2L1-2:2 was found to promote keratinocytes proliferation, inhibit cell apoptosis and the effects of lnc-AGXT2L1-2:2 on keratinocytes are dependent on ERRα.

A multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study evaluating the efficacy and safety of vunakizumab in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Vunakizumab (SHR-1314) is a novel interleukin 17A monoclonal antibody that has shown preliminary efficacy and tolerability in phase I trials. OBJECTIVE: To evaluate the efficacy and safety of vunakizumab in moderate-to-severe plaque psoriasis. METHODS: In this 36-week, multicenter, double-blinded, phase II study (NCT03463187), 187 eligible patients with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive vunakizumab (40, 80, 160, or 240 mg) or placebo subcutaneously, every 4 weeks, until week 12 (2 more drug administrations for the vunakizumab groups on weeks 16 and 20). The primary end point was at least 75% improvement in the Psoriasis Area and Severity Index at week 12. RESULTS: At week 12, there were significantly greater proportions of responders with at least 75% improvement in the Psoriasis Area and Severity Index in all vunakizumab groups compared to placebo (40, 80, 160, and 240 mg: 56.8%, 65.8%, 81.6%, and 86.5%, respectively, vs 5.4%; P < .001 for all); the proportions of patients achieving Physician's Global Assessment responses of 0 or 1 were also higher with vunakizumab (45.9%, 47.4%, 60.5%, and 73.0%, respectively, vs 8.1%). No unexpected adverse effects were observed. LIMITATIONS: The study was relatively short in duration and included no active control. CONCLUSION: Vunakizumab showed promising efficacy for moderate-to-severe plaque psoriasis, with good tolerability, warranting further investigation in larger and longer-term studies.

Efficacy and safety of omalizumab in Chinese patients with anti-histamine refractory chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is characterized by the spontaneous development of wheals, itching, and/or angioedema, for ≥6 weeks. In China, non-sedating H1-antihistamines (H1AH) are the recommended first-line treatment, with escalation up to 4× the standard dose in symptomatic patients to achieve control. Treatment options for Chinese patients who remain symptomatic on H1AH treatment are limited. This 20-week randomized, double blind, placebo-controlled, parallel-group study investigated the efficacy and safety of omalizumab as an add-on therapy for the treatment of patients with CSU who remained symptomatic despite H1AH treatment in China. Adult patients (N = 418) diagnosed with refractory CSU for ≥6 months were randomized (2:2:1) to receive omalizumab 300 mg (OMA300), omalizumab 150 mg (OMA150) or placebo, subcutaneously, every 4 weeks. Primary outcome was change from baseline to week 12 in weekly itch severity score (ISS7). Safety was assessed by rates of adverse events (AEs). Demographic and disease characteristics at baseline were comparable across treatment groups. At week 12, statistically significant greater decreases from baseline were observed in ISS7 with OMA300 (least square mean difference [LSM]: -4.23; 95% confidence interval [CI]: -5.70, -2.77; p < 0.001) and OMA150 (LSM: -3.79; 95% CI: -5.24, -2.33; p < 0.001) versus placebo. Incidence of treatment-emergent AEs over 20 weeks was slightly higher with OMA300 (71.3%) compared to OMA150 and placebo groups (64.7% and 63.9%, respectively). The incidences of serious AEs were balanced between groups. This study demonstrated the efficacy and safety of omalizumab in Chinese adult patients with CSU who remained symptomatic despite H1AH therapy.

Circular RNA hsa_circ_0068252 Functions in Cisplatin Resistance and Immune Response via miR-1304-5p/PD-L1 Axis in Non-Small Cell Lung Cancer.

BACKGROUND: Research suggests that circRNAs play important roles in non-small cell lung cancer (NSCLC). The function of hsa_circ_0068252 in NSCLC, especially in cisplatin (DDP) resistance and the mechanisms, was explored in this study. METHODS: NSCLC patient samples and two NSCLC cell lines along with corresponding DDP-resistant cell lines were used. Expression levels of circ_0068252 were detected. SiRNA for circ_0068252 and inhibitor for miRNA were used in all functional analyses. A co-culture system of NSCLC cells with CD8+ T cells was used. The cellular location of circ_0068252 was detected and its target miRNA was predicted and verified. Finally, the mechanism responsible for circ_0068252 function on PD-L1 was analyzed using luciferase reporter assay in the two DDP-resistant cell lines, as well as in the co-culture system. The cytotoxicity of T cells was detected by lactate dehydrogenase assay. RESULTS: Our findings revealed that a high level of circ_0068252 was correlated with poor prognosis of NSCLC and DDP resistance. Knockdown of circ_0068252 could promote the sensitivity of DDP-resistant NSCLC cells to DDP. Moreover, knockdown of circ_0068252 could regulate the immune microenvironment which was mediated via CD8+ T cells. Finally, circ_0068252 could up-regulate PD-L1 expression by adsorbing miR-1304-5p. CONCLUSION: The circ_0068252/miR-1304-5p/PD-L1 signal axis participates in the regulation of DDP resistance and immune escape of NSCLC cells. Our results suggest that circ_0068252 may be a potential diagnostic marker and therapeutic target for DDP-resistant NSCLC.

Glycyrrhizin improves the pathogenesis of psoriasis partially through IL-17A and the SIRT1-STAT3 axis.

BACKGROUND: The anti-inflammatory effect of glycyrrhizin has been widely recognized, while the specific mechanism of glycyrrhizin in psoriasis remains poorly understood. RESULTS: In the imiquimod-induced mouse model of psoriasis (IMD), we found that glycyrrhizin can substantially improve the adverse symptoms in mice. The hematoxylin-eosin staining results showed that glycyrrhizin can also improve the pathological state of skin cells in IMD mice. Using enzyme-linked immunosorbent assay (ELISA), we found that glycyrrhizin substantially inhibited the expression of IL-17A and IFN-γ in the serum of IMD mice. In order to simulate the effect of IL-17A on keratinocytes in psoriasis, we treated HaCaT cells with 100 ng/mL IL-17A (IL-17A-HaCaT cells) for 48 h. Then, using cell-counting kit-8 (CCK-8) and ELISA assays, we found that glycyrrhizin inhibited the proliferation of IL-17A-HaCaT cells and reversed the promotion of IL-6, CCL20, and TNF-α induced by IL-17A. Further, western blotting (WB) results indicated that glycyrrhizin promoted the expression of SIRT1 and inhibited the expression of STAT3 and phosphorylated STAT3 (p-STAT3). By treating IL-17A-HaCaT cells with EX-527 (a potent and selective inhibitor of SIRT1), combined with CCK-8 and WB experiments, we initially found that EX-527 inhibited the proliferation of IL-17A-HaCaT cells and promoted the expression of STAT3, p-STAT3, and acetylated STAT3 (a-STAT3). However, when glycyrrhizin was added at the same time, the proliferation of IL-17A-HaCaT cells increased, and the expression of STAT3, p-STAT3, and a-STAT3 reduced. We then knocked down the expression of SIRT1 via small interfering RNA in IL-17A-HaCaT cells, and the results were consistent with those of EX-527. CONCLUSIONS: Together, these results indicated that glycyrrhizin improved psoriasis by inhibiting the expression of IL-17A and IFN-γ in vivo and suppressed the proliferation of IL-17A-HaCaT cells and the expression of STAT3, p-STAT3, and a-STAT3 by upregulating SIRT1 in vitro.

Human embryonic stem cell-derived melanocytes exhibit limited immunogenicity.

Although surgical interventions have become optional for refractory vitiligo, grafting related injuries is inevitable. Embryonic stem cell (ESC) derivatives can be used in transplantation to address this issue, but the immune rejection due to allogeneic transplantation is of great concern. To investigate the immunogenicity of ESC derived melanocytes (ES-MC), we established a co-culture system of ES-MC and allogeneic PBMC. The results showed that ES-MC were similar to human primary melanocytes, with low expression of immune related molecules, and limited capability of stimulating allogeneic lymphocytes in vitro. Taken together, our findings confirm that ES-MC are of limited immunogenicity, providing new insights into the application of ES-MC in the regenerative medicine such as treating vitiligo.

Bioinformatic analysis of key biomarkers and immune filtration of skin biopsy in discoid lupus erythematosus.

OBJECTIVE: Discoid lupus erythematosus (DLE) is the most common category of chronic cutaneous lupus erythematosus, where the pathological process is proved to be closely associated with immunity. This bioinformatic analysis sought to identify key biomarkers and to perform immune infiltration analysis in the skin biopsy samples of DLE. METHODS: GSE120809, GSE100093, GSE72535, GSE81071 were used as the data source of gene expression profiles, altogether containing 79 DLE samples and 47 normal controls (NC). Limma package was applied to identify differentially expressed genes (DEGs) and additional Gene Ontology (GO) together with The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were done. Protein-protein interaction network (PPI) was constructed using STRING and Cytoscape. Hub genes were selected by CytoHubba. Finally, immune filtration analysis was finished by the CIBERSORT algorithm, and comparisons between the two groups were accomplished. RESULTS: A total of 391 DEGs were identified, which were composed of 57 up-regulated genes and 334 down-regulated genes. GO and KEGG enrichment analyses revealed that DEGs were closely related with different steps in the immune response. Top 10 hub genes included GBP2, HLA-F, IFIT2, RSAD2, ISG15, IFIT1, IFIT3, MX1, XAF1 and IFI6. Immune filtration analysis from CIBERSORT had found that compared with NC, DLE samples had higher percentages of CD8+ T cells, T cells CD4 memory activated, T cells gamma delta, macrophages M1 and lower percentages of T cells regulatory, macrophages M2, dendritic cells resting, mast cells resting, mast cells activated. CONCLUSION: This bioinformatic study selected key biomarkers from the contrast between DLE and NC skin samples and is the first research to analyze immune cell filtration in DLE.