AMPK signaling pathway regulated the expression of the ApoA1 gene via the transcription factor Egr1 during G. parasuis stimulation.

Glaesserella parasuis (G. parasuis) is the causative agent of porcine Glässer's disease, resulting in high mortality rates in pigs due to excessive inflammation-induced tissue damage. Previous studies investigating the protective effects of G. parasuis vaccination indicated a possible role of ApoA1 in reflecting disease progression following G. parasuis infection. However, the mechanisms of ApoA1 expression and its role in these infections are not well understood. In this investigation, newborn porcine tracheal (NPTr) epithelial cells infected with G. parasuis were used to elucidate the molecular mechanism and role of ApoA1. The study revealed that the AMPK pathway activation inhibited ApoA1 expression in NPTr cells infected with G. parasuis for the first time. Furthermore, Egr1 was identified as a core transcription factor regulating ApoA1 expression using a CRISPR/Cas9-based system. Importantly, it was discovered that APOA1 protein significantly reduced apoptosis, pyroptosis, necroptosis, and inflammatory factors induced by G. parasuis in vivo. These findings not only enhance our understanding of ApoA1 in response to bacterial infections but also highlight its potential in mitigating tissue damage caused by G. parasuis infection.

Ciliogenesis-associated Kinase 1 Promotes Breast Cancer Cell Proliferation and Chemoresistance via Phosphorylating ERK1.

Ciliogenesis-associated kinase 1 (CILK1) plays a key role in the ciliogenesis and ciliopathies. It remains totally unclear whether CILK1 is involved in tumor progression and therapy resistance. Here, we report that the aberrant high-expression of CILK1 in breast cancer is required for tumor cell proliferation and chemoresistance. Two compounds, CILK1-C30 and CILK1-C28, were identified with selective inhibitory effects towards the Tyr-159/Thr-157 dual-phosphorylation of CILK1, pharmacological inhibition of CILK1 significantly suppressed tumor cell proliferation and overcame chemoresistance in multiple experimental models. Large-scale screen of CILK1 substrates confirmed that the kinase directly phosphorylates ERK1, which is responsible for CILK1-mediated oncogenic function. CILK1 is also indicated to be responsible for the chemoresistance of small-cell lung cancer cells. Our data highlight the importance of CILK1 in cancer, implicating that targeting CILK1/ERK1 might offer therapeutic benefit to cancer patients.

Molecular design, construction and analgesic mechanism insights into the novel transdermal fusion peptide ANTP-BgNPB.

Toad venom, a traditional Chinese medicine, exhibits remarkable medicinal properties of significant therapeutic value. The peptides present within toad venom possess a wide range of biological functions, yet the neuropeptide B (NPB) and it modification requires further exploration to comprehensively understand its mechanisms of action and potential applications. In this study, a fusion peptide, ANTP-BgNPB, was designed to possess better analgesic properties through the transdermal modification of BgNPB. After optimizing the conditions, the expression of ANTP-BgNPB was successfully induced. The molecular dynamics simulations suggested that the modified protein exhibited improved stability and receptor binding affinity compared to its unmodified form. The analysis of the active site of ANTP-BgNPB and the verification of mutants revealed that GLN3, SER38, and ARG42 were crucial for the protein's recognition and binding with G protein-coupled receptor 7 (GPR7). Moreover, experiments conducted on mice using the hot plate and acetic acid twist body models demonstrated that ANTP-BgNPB was effective in transdermal analgesia. These findings represent significant progress in the development of transdermal delivery medications and could have a significant impact on pain management.

Risk factors and early detection of joint damage in patients with psoriasis: a case-control study.

BACKGROUND: Our aim was to target the unsatisfied need for early detection of the at-risk population and determine the subgroup of patients whose psoriasis (PsO) could transform into psoriatic arthritis (PsA). METHODS: A retrospective and longitudinal case-control study was conducted at Beijing Chao-yang Hospital. It included 75 patients who were clinically diagnosed with PsA in the case group and 345 who solely suffered from PsO without PsA in the control group. A variety of baseline covariates were gathered from every patient with PsO. Univariate and multivariate analyses and receiver operating characteristic (ROC) curves were used to identify underlying risk factors and determine whether it was necessary to examine the imaging of PsO patients. RESULTS: In multivariate logistic regression analysis, age ≥40 (odds ratio (OR): 1.04, 95% confidence interval (CI): 1.02-1.06, P < 0.01), nail involvement (OR: 1.17, 95% CI: 1.09-1.32, P < 0.01), erythrocyte sedimentation rate (ESR) (OR: 1.03, 95% CI: 1.01-1.06, P < 0.05) and elevated high-sensitivity C-reactive protein (hs-CRP) (OR: 1.31, 95% CI: 1.13-1.53, P < 0.01) were perceived to be risk factors for the transformation from PsO into clinical PsA. By combining magnetic resonance imaging (MRI)-detected enthesitis with tenosynovitis, combined predictors demonstrated better diagnostic efficacy, with an improvement in specificity (94.3% vs. 69%) and similarities in sensitivity (89% vs. 84.6%). The areas under the ROC curve (AUCs) amounted to 0.925 (95% CI: 0.882-0.967, P < 0.01) and 0.858 (95% CI: 0.814-0.903, P < 0.01). CONCLUSIONS: It was identified that age ≥40, nail involvement, as well as an elevated ESR, and hs-CRP served as independent risk factors for PsO transforming into PsA. Additionally, MRI provides additional value for the early recognition of PsA.

Ginkgo biloba L. exocarp petroleum ether extract inhibits methicillin-resistant Staphylococcus aureus by modulating ion transport, virulence, and biofilm formation in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: As reported in the Ancient Chinese Medicinal Books, Ginkgo biloba L. fruit has been used as a traditional Chinese medicine for the treatment asthma and cough or as a disinfectant. Our previous study demonstrated that G. biloba exocarp extract (GBEE), an extract of a traditional Chinese herb, inhibits the formation of methicillin-resistant Staphylococcus aureus (MRSA) biofilms. However, GBEE is a crude extract that contains many components, and the underlying mechanisms of purified GBEE fractions extracted with solvents of different polarities are unknown. AIM OF THE STUDY: This study aimed to investigate the different components in GBEE fractions extracted with solvents of different polarities and their antibacterial effects and mechanisms against MRSA and Staphylococcus haemolyticus biofilms both in vitro and in vivo. METHODS: The components in different fractions were detected by high-performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS). Microbroth dilution assays and time growth curves were used to determine the antibacterial effects of the fractions on 15 clinical bacterial isolates. Crystal violet staining, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to identify the fractions that affected bacterial biofilm formation. The potential MRSA targets of the GBEE fraction obtained with petroleum ether (PE), denoted GBEE-PE, were screened by transcriptome sequencing, and the gene expression profile was verified by quantitative polymerase chain reaction (qPCR). RESULTS: HPLC-HRMS analysis revealed that the four GBEE fractions (extracted with petroleum ether, ethyl acetate, n-butanol, and water) contained different ginkgo components, and the antibacterial effects decreased as the polarity of the extraction solvent increased. The antibacterial activity of GBEE-PE was greater than that of the GBEE fraction extracted with ethyl acetate (EA). GBEE-PE improved H. illucens survival and reduced MRSA colonization in model mouse organs. Crystal violet staining and SEM and TEM analyses revealed that GBEE-PE inhibited MRSA and S. haemolyticus biofilm formation. Transcriptional analysis revealed that GBEE-PE inhibits MRSA biofilms by altering ion transport, cell wall metabolism and virulence-related gene expression. In addition, the LO2 cell viability and H. illucens toxicity assay data showed that GBEE-PE at 20 mg/kg was nontoxic. CONCLUSION: The GBEE fractions contained different components, and their antibacterial effects decreased with increases in the polarity of the extraction solvent. GBEE-PE limited MRSA growth and biofilm formation by affecting ion transport, cell wall synthesis, and virulence-related pathways. This research provides a more detailed overview of the mechanism by which GBEE-PE inhibits MRSA both in vitro and in vivo and suggests that GBEE-PE is a new prospective antimicrobial with the potential to be used in MRSA therapeutics in the future.

Photocatalytic degradation of different types of microplastics by TiOx/ZnO tetrapod photocatalysts.

We investigated the use of titania coated ZnO tetrapods for photocatalytic degradation of two common types of microplastics, namely polyethylene (PE) microparticles and polyester (PES) microfibers. We found that the plastics morphology affects the rate of degradation, and that the use of electron scavengers is needed to maintain the reactivity of the photocatalysts over a prolonged period of time. Complete mass loss of PE and PES is achieved under UV illumination for 480 h and 624 h, respectively. In addition to pristine microplastics, the degradation of environmental microplastics sample (consisting primarily of polypropylene) was also demonstrated, though in this case longer degradation time (∼816 h) was needed to achieve complete mass loss of the samples.

Iron-Based Oxygen Scavengers on Mesoporous Silica Nanospheres.

Iron-based materials are among the most commonly used oxygen scavengers. Here, we investigated the mesoporous silica nanosphere (MSN)-supported iron-based scavengers, such as FeOx nanoparticles and different atomic layer deposition (ALD) coatings (FeOx and Fe). We found that the scavenger performance is a result of a complex interplay between available Brunauer-Emmett-Teller surface area and the scavenger composition, with the combination of infiltrated nanoparticles and Fe-ALD coating resulting in the best performance. When the glucose-based treatment of MSN is used to further enhance oxygen scavenging capacity, Fe-ALD coating yields the best performance, with a high oxygen adsorption capacity of 126.8 mL/g. ALD deposition of Fe represents a versatile method to introduce Fe-based oxygen scavengers onto different supports, and it can facilitate the integration of scavengers with different types of packaging, as the deposition can be performed at a low temperature of 150 °C.

Nerve growth factor mediates activation of transient receptor potential vanilloid 1 in neurogenic pruritus of psoriasis.

Pruritus is a common and painful symptom in psoriasis with profoundly negative impacts on quality of life. The underlying mechanisms of pruritus are complex and multifactorial, and accumulating evidence suggests that pruritus induced by neurogenic inflammation predominates in psoriasis. Nerve growth factor (NGF) -mediated transient receptor potential vanilloid receptor 1(TRPV1) pathway has emerged as a crucial node in the regulation of neurogenic pruritus. TRPV1 appears coupled to most pruritus-specific molecules via the neuro-immune axis. While the modes of regulation differ for each axis, TRPV1 is involved in substantial biochemical crosstalk-causing feedback loops with significant effects on neurogenic pruritus. Therefore, TRPV1 has emerged as a target molecular in drug development for pruritus in psoriasis. However, no significant clinical progress occurred in the development of systemic TRPV1 antagonists due to elevated core temperature. Thus, topical application of TRPV1 antagonists and interference with mediators linked to the TRPV1 activation pathway may be promising therapeutic options to ameliorate pruritus. This Review focuses on recent advances in complicated regulation of NGF-mediated TRPV1 pathway in psoriatic neurogenic pruritus, as well as the therapeutic options that arise from the dissection of the pathway.

Growth differentiation factor 15 is required for triple-negative breast cancer cell growth and chemoresistance.

Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine, which is involved in the cellular stress response following acute damage. However, the functional role of GDF15 in triple-negative breast cancer (TNBC) has not been fully elucidated. ELISA, Western blot, and PCR assays as well as bioinformatics analyses were conducted to observe the expression of GDF15. Cell Counting Kit-8, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet staining assays were conducted to evaluate paclitaxel resistance and cell viability. Cell apoptosis was analyzed by Western blotting. Murine xenograft model assay was employed to evaluate tumor growth in vivo . Our data indicate that GDF15 is markedly elevated in paclitaxel-resistant TNBC cells, which is significantly associated with unfavorable prognosis. Silencing of GDF15 robustly inhibits the proliferation of tumor cells and increases their sensitivity to paclitaxel in vitro and in vivo , whereas the treatment of purified GDF15 protein confers breast cancer cells with chemoresistance ability. Moreover, GDF15 activates protein kinase B (AKT) /mammalian target of rapamycin (mTOR) signaling, inhibition of AKT or mTOR reverses the prosurvival effect of GDF15 and enhances the antitumor efficacy of paclitaxel in TNBC cells. Altogether, our study uncovers the role of GDF15 in tumor growth and paclitaxel resistance, implicating a potential therapeutic target for TNBC.

Resistin secreted by porcine alveolar macrophages leads to endothelial cell dysfunction during Haemophilus parasuis infection.

Haemophilus parasuis (H. parasuis) causes exudative inflammation, implying endothelial dysfunction during pathogen infection. However, so far, the molecular mechanism of endothelial dysfunction caused by H. parasuis has not been clarified. By using the transwell-based cell co-culture system, we demonstrate that knocking out resistin in porcine alveolar macrophages (PAMs) dramatically attenuated endothelial monolayer damage caused by H. parasuis. The resistin secreted by PAMs inhibited the expression of the tight junction proteins claudin-5 and occludin rather than the adherens junction protein VE-cadherin in co-cultured porcine aortic endothelial cells (PAECs). Furthermore, we demonstrate that resistin regulated claudin-5 and occludin expression and monolayer PAEC permeability in an LKB1/AMPK/mTOR pathway-dependent manner. Additionally, we reveal that the outer membrane lipoprotein gene lppA in H. parasuis induced resistin expression in PAMs, as deleting lppA reduced resistin expression in H. parasuis-infected PAMs, causing a significant change in LKB1/AMPK/mTOR pathway activity in co-cultured PAECs, thereby restoring tight junction protein levels and endothelial monolayer permeability. Thus, we postulate that the H. parasuis lppA gene enhances resistin production in PAMs, disrupting tight junctions in PAECs and causing endothelial barrier dysfunction. These findings elucidate the pathogenic mechanism of exudative inflammation caused by H. parasuis for the first time and provide a more profound angle of acute exudative inflammation caused by bacteria.

Doublecortin-like kinase 2 promotes breast cancer cell invasion and metastasis.

BACKGROUND: Doublecortin-like kinase 2 (DCLK2) is a microtubule-associated protein kinase that participates in neural development and maturation; however, whether it is involved in tumour progression remains unclear. METHODS: DCLK2 overexpression and knockdown clones were established by lentivirus transfection. Western blot, PCR assays and bioinformatics analyses were conducted to observe the expression of DCLK2. CCK8, colony formation, scratch migration and Transwell assays were used to detect cell proliferation, migration and invasion, respectively. Tumour metastasis was evaluated in vivo using a tail vein metastasis model. Bioinformatics analyses were performed to analyse the expression correlation between DCLK2 and TCF4, or EMT markers in breast cancer. RESULTS: Our data indicate that DCLK2 is highly expressed in breast cancer cells and is associated with poor prognosis. Silencing DCLK2 does not affect the proliferation rate of tumour cells, but significantly suppresses migration and invasion as well as lung metastasis processes. Overexpression of DCLK2 can enhance the migratory and invasive abilities of normal breast epithelial cells. Moreover, TCF4/ß-catenin inhibitor LF3 downregulates the expression of DCLK2 and inhibits the migration and invasion of breast cancer cells. Furthermore, we found that the downregulation of DCLK2 blocks the epithelial-mesenchymal transition (EMT) process. CONCLUSION: Our study indicates that DCLK2 plays an important role in EMT, cell invasion and metastasis, suggesting that DCLK2 is a potential target for the treatment of metastatic breast cancer.

Rational design of highly efficient MXene-based catalysts for the water-gas-shift reaction.

Water molecules linked by hydrogen bonds are responsible for the high efficiency of bi-functional catalysts for the water-gas-shift (WGS) reaction because water can act as a proton transfer medium. Herein, we propose an associative pathway for the WGS reaction assisted by water to realize hydrogen production. Based on this pathway, we show by first-principles calculations that a large family of oxygen-terminated two-dimensional transition metal carbides and nitrides (MXenes) deposited on Au clusters are promising catalysts for the WGS reaction. Remarkably, the rate-determining barriers for *CO → *COOH on Au/Mn+1XnO2 are in the range from 0.15 eV to 0.39 eV, indicating that WGS can occur at much lower temperatures. Furthermore, a comprehensive microkinetic model is constructed to describe the turnover frequencies (TOF) for the product under the steady-state conditions. More importantly, there is a perfect linear scaling relationship between the rate-determining barriers of the WGS and the free energy of the adsorbed hydrogen. Besides, the potential energy diagrams for CO reforming reveal that the F terminations introduced in experiments have only a slight influence on the catalytic performance of the oxygen-terminated MXenes. Our work not only opens a new avenue towards the WGS reaction but also provides many ideal catalysts for hydrogen production.

Psoriasis to Psoriatic Arthritis: The Application of Proteomics Technologies.

Psoriatic disease (PsD) is a spectrum of diseases that affect both skin [cutaneous psoriasis (PsC)] and musculoskeletal features [psoriatic arthritis (PsA)]. A considerable number of patients with PsC have asymptomatic synovio-entheseal inflammations, and approximately one-third of those eventually progress to PsA with an enigmatic mechanism. Published studies have shown that early interventions to the very early-stage PsA would effectively prevent substantial bone destructions or deformities, suggesting an unmet goal for exploring early PsA biomarkers. The emergence of proteomics technologies brings a complete view of all involved proteins in PsA transitions, offers a unique chance to map all potential peptides, and allows a direct head-to-head comparison of interaction pathways in PsC and PsA. This review summarized the latest development of proteomics technologies, highlighted its application in PsA biomarker discovery, and discussed the possible clinical detectable PsA risk factors in patients with PsC.

Interleukin-31 Receptor α Is Required for Basal-Like Breast Cancer Progression.

Purpose: Interleukin-31 receptor α (IL31RA) usually mediates IL-31 induced inflammation and allergic diseases. However, the functional roles of IL-31/IL31RA signaling in basal-like breast cancer (BLBC) progression remain totally unclear. Methods: Tumorsphere formation, transwell, and wound healing assays were used to measure the BLBC progression. We implanted tumor cells in mammary fat pad and tail vein of nude mice to detect the growth and metastasis of BLBC cells. Luciferase and ChIP assays were employed to measure the transcriptional regulation. Western blot and real-time PCR assays as well as bio-informatics analyses were conducted to observe the expression of IL31RA. Results: We found that silencing of IL31RA suppresses the cancer stem cell-like properties, migration and invasion of BLBC cells in vitro as well as tumor growth and metastasis in vivo. Knockdown of IL31RA ameliorates IL-31-mediated pro-oncogenic functions. Overexpression of IL31RA in luminal breast cancer cells enhances the cancer stem cell-like properties and cell motility. Our data further identified IL31RA as a target gene of Twist/BRD4 transcription complex. Conclusion: Overall, these data indicate that IL31RA promotes basal-like breast cancer progression and metastasis, suggesting that targeting of IL-31/IL31RA axis might be beneficial to treatment of BLBC.

The flavonoid-enriched extract from the root of Smilax china L. inhibits inflammatory responses via the TLR-4-mediated signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Smilax china L. has been used clinically to treat various inflammatory disorders with a long history. AIM OF THE STUDY: To investigate the mechanisms underlying anti-inflammatory action of the extract from the herb. MATERIALS AND METHODS: The extract was identified and quantified using the Ultra Performance Liquid Chromatography-Photo Diode Array-Mass Spectrometer method. The anti-inflammatory activities were examined in xylene-induced mouse ear edema and cotton ball-induced rat granuloma. The inflammatory mediators, pro-inflammatory cytokines and TLR-4-mediated signals in LPS-stimulated RAW264.7 macrophages were determined using ELISA, real-time PCR, Western blot and/or immunofluorescence, respectively. RESULTS: The extract was found to enrich flavonoids (44.3%, mainly astilbin, engeletin, isoastilbin, cinchonain Ia, quercetin-3-O-a-L-rhamnopyranoside and chlorogenic acid). The flavonoid-enriched extract (FEE) inhibited xylene-induced mouse ear edema and cotton ball-induced rat granuloma, and suppressed LPS-induced over-release and/or overexpression of tumor necrosis factor-α, cyclooxygenase-2, inducible nitric oxide synthase, interleukin-1ß and interleukin-6 in RAW264.7 macrophages. Mechanistically, FEE suppressed protein overexpression of TLR-4 and its downstream signals, MyD88 protein, phosphorylated inhibitory κB-α, NF-κB-P65 and MAPK p38, as well as phosphorylation of phosphoinositide 3-kinase (PI3K) p85α at Tyr607 and Akt at Ser473 in LPS-stimulated macrophages. The mode of the anti-inflammatory action of FEE was similar to that of TAK-242 (a selective TLR-4 inhibitor). CONCLUSIONS: The present results demonstrate that FEE inhibit inflammatory responses via the TLR-4-mediated signaling pathway. Our findings go a new insight into the mechanisms underlying anti-inflammatory action of the herb, and provide a better understanding of its use for inflammatory diseases.

Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance.

BET bromodomain inhibitors (BETi), such as JQ1, have been demonstrated to effectively kill multiple types of cancer cells. However, the underlying mechanisms for BETi resistance remain largely unknown. Our evidences show that JQ1 treatment evicts BRD4 from the FOXD3-localized MIR548D1 gene promoter, leading to repression of miR-548d-3p. The loss of miRNA restores JunD expression and subsequent JunD-dependent transcription of RPS6KA2 gene. ERK1/2/5 kinases phosphorylate RSK3 (RPS6KA2), resulting in the enrichment of activated RSK3 and blockade of JQ1 killing effect. Dual inhibition of MEKs/ERKs or single EGFR inhibition are able to mimic the effect of JunD/RSK3-knockdown to reverse BETi resistance. Collectively, our study indicates that loss of BRD4/FOXD3/miR-548d-3p axis enhances JunD/RSK3 signalling and determines BET inhibition resistance, which can be reversed by targeting EGFR-MEK1/2/5-ERK1/2/5 signalling.

Efficacy and safety of imiquimod 5% cream for basal cell carcinoma: a meta-analysis of randomized controlled trial.

Background: We conducted this meta-analysis to compare the efficacy and safety of imiquimod with other treatments in patients with basal cell carcinoma (BCC).Methods: A comprehensive literature search was performed in the database of PubMed, Embase, and Web of Science, focusing on studies that evaluated the efficacy and safety profile of BCC patients who were treated with imiquimod. The main outcome measures included histological/composite clearance rate, success rate, complete response rate, tumor free survival, and adverse events. Results were expressed as risk ratio (RR) with 95% confidence intervals (CIs). Pooled estimates were calculated using a fixed-effects or random-effects model according to the heterogeneity among studies.Results: A total of 13 studies involving 4256 patients were included in this meta-analysis. Imiquimod was associated with significantly higher histological clearance rate and composite clearance rate. Moreover, imiquimod also significantly increased complete response rate but had no effect in the success rate and probability of tumor free survival, as compared with other treatments. There were more patients with imiquimod developed adverse events than those with other treatments.Conclusion: The present meta-analysis indicated the effects of imiquimod in improving the histological/composite clearance rates as compared with other treatments.

A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves Hyperthyroidism-A Proof-of-Concept Trial.

CONTEXT: The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. OBJECTIVE: Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. DESIGN: Open-label, phase II proof-of-concept study. SETTING: Multicenter. PATIENTS: Fifteen with GD. INTERVENTION: Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. MAIN OUTCOME MEASURES: Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. RESULTS: The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. CONCLUSION: Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Biocompatible and Biodegradable Magnesium Oxide Nanoparticles with In Vitro Photostable Near-Infrared Emission: Short-Term Fluorescent Markers.

Imaging of biological matter by using fluorescent nanoparticles (NPs) is becoming a widespread method for in vitro imaging. However, currently there is no fluorescent NP that satisfies all necessary criteria for short-term in vivo imaging: biocompatibility, biodegradability, photostability, suitable wavelengths of absorbance and fluorescence that differ from tissue auto-fluorescence, and near infrared (NIR) emission. In this paper, we report on the photoluminescent properties of magnesium oxide (MgO) NPs that meet all these criteria. The optical defects, attributed to vanadium and chromium ion substitutional defects, emitting in the NIR, are observed at room temperature in NPs of commercial and in-house ball-milled MgO nanoparticles, respectively. As such, the NPs have been successfully integrated into cultured cells and photostable bright in vitro emission from NPs was recorded and analyzed. We expect that numerous biotechnological and medical applications will emerge as this nanomaterial satisfies all criteria for short-term in vivo imaging.