A suprapubic refractory skin ulcer following keloid radiotherapy: from hyper-proliferation to hypo-proliferation.

Radiation-induced skin ulcer following cancer and/or tumour is well-documented in the literature. However, radiation-induced skin ulcer following the excision of keloid is yet to be reported. Here, we report the case of a 33-year-old female patient with a suprapubic skin ulcer of five months' duration following keloid treatment with electron beam therapy at recommended dosage. Various examinations, including a skin biopsy, metagenomic sequencing, magnetic resonance imaging and immunochemistry, indicated that the skin ulcer was induced by radiotherapy. While postoperative radiotherapy has been recommended immediately following keloid excision to reduce the risk of recurrence, the present case highlights the risk of skin refractory ulcer following keloid radiotherapy.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies.

BACKGROUND: SHR-1707 is a novel humanized anti-Aß IgG1 monoclonal antibody that binds to Aß fibrils and monomers to block the formation of Aß plaques or to promote the microglial phagocytosis of Aß. Preclinical studies showed that SHR-1707 reduced brain Aß deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects. METHODS: Two randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18-45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55-80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg). RESULTS: Sixty-two (part 1/2, n = 50/12; age range, 18-42/55-63 years) and 30 subjects (age range, 18-42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2-60 mg/kg in young adults; there was a dose-dependent increase in plasma Aß42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed. CONCLUSIONS: A single intravenous dose of SHR-1707 at 2-60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development. TRIAL REGISTRATION: NCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Versatility of 14-3-3 proteins and their roles in bone and joint-related diseases.

Bone and joint-related diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), and bone tumors, pose significant health challenges due to their debilitating effects on the musculoskeletal system. 14-3-3 proteins, a family of conserved regulatory molecules, play a critical role in the pathology of these diseases. This review discusses the intricate structure and multifunctionality of 14-3-3 proteins, their regulation of signaling pathways, and their interactions with other proteins. We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts, osteoclasts, chondrocytes, and bone remodeling, all key factors in the maintenance and dysfunction of bone and joint systems. Specific focus is directed toward elucidating the contribution of 14-3-3 proteins in the pathology of OA, RA, and bone malignancies, where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes. This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders, including joint destruction and osteolytic activity. We highlight cutting-edge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets, offering new avenues for disease intervention and management.

A Randomized, Double-Blind, Parallel-Group Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of CMAB015, a Candidate Secukinumab Biosimilar, with Its Reference Product Cosentyx® in Healthy Chinese Male Subjects.

Purpose: Secukinumab, a monoclonal antibody targeting interleukin (IL)-17A, is approved for the treatment of psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, enthesitis-related arthritis, and hidradenitis suppurativa. This study compared the pharmacokinetics (PK), safety, and immunogenicity of CMAB015, a candidate secukinumab biosimilar, with the reference product secukinumab (Cosentyx®) in healthy Chinese male subjects. Patients and methods: This double-blind, parallel-group study randomized healthy Chinese male subjects (N=130) to receive either a single dose of 150 mg CMAB015 or secukinumab subcutaneously. Primary study endpoints were PK parameters such as the maximum concentration (Cmax) and area under the curve from zero to infinity (AUC0-inf), while safety and immunogenicity were secondary endpoints. Results: The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of Cmax and AUC0-inf for CMAB015 to secukinumab were all within the bioequivalence limits (80.00-125.00%). Other PK parameters were comparable between the groups. The safety profile of CMAB015 was similar to that of secukinumab, with no serious adverse events related to treatment. The incidence of TEAEs was slightly higher in the CMAB015 group, but these events were mild to moderate in severity and did not lead to any withdrawals from the study. Immunogenicity analysis revealed low rates of anti-drug antibody (ADA) positivity, with similar rates between CMAB015 and secukinumab. Conclusion: This study demonstrated equivalent PK, comparable safety, and immunogenicity of CMAB015 to secukinumab in healthy Chinese male subjects. These findings support further clinical evaluation of CMAB015 as a secukinumab biosimilar. Trial Registration: The trial was registered on Clinicaltrials.gov (Identifier No. NCT05734482) and Chinadrugtrials.org.cn (Identifier No. CTR20230105).

A Three-Step Approach (MUC) for Umbilicoplasty: Creating a Deep Umbilical Depression in Lipoabdominoplasty.

BACKGROUND: Various methods of umbilicoplasty have been proposed to create an aesthetically pleasing umbilicus. However, following conventional lipoabdominoplasty, some patients, particularly those with a thin layer of abdominal fat, may exhibit a shallow navel. METHODS: A modified umbilicoplasty with a three-step approach was performed between Jan 2019 and Mar 2023. The three-step procedure included multiple plications, umbilical stalk fixation, umbilical insertion and central gathering (MUC). Patients were followed up for at least 6 months. Umbilical depth and complications were recorded. RESULTS: A total of 36 patients were performed with MUC umbilicoplasty, with a mean age of 36.1 years. Patients were satisfied with umbilical appearance. The average depth of the navel after MUC procedure was 1.8±0.3 cm. A patient developed a hypertrophic scar in the umbilicus, which was treated with an intralesional injection of triamcinolone acetonide. No other complications were observed. CONCLUSION: The MUC approach to umbilicoplasty provides a deep umbilical depression with minimal scars. This three-step procedure is particularly beneficial for patients with a thin layer of abdominal fat. LEVEL OF EVIDENCE IV: 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 .

Macrophage membrane-camouflaged biomimetic nanoparticles for rheumatoid arthritis treatment via modulating macrophage polarization.

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic joint inflammation and cartilage damage. Current therapeutic strategies often result in side effects, necessitating the development of targeted and safer treatment options. This study introduces a novel nanotherapeutic system, 2-APB@DGP-MM, which utilizes macrophage membrane (MM)-encapsulated nanoparticles (NPs) for the targeted delivery of 2-Aminoethyl diphenylborinate (2-APB) to inflamed joints more effectively. The NPs are designed with a matrix metalloproteinase (MMP)-cleavable peptide, allowing for MMP-responsive drug release within RA microenvironment. Comprehensive in vitro and in vivo assays confirmed the successful synthesis and loading of 2-APB into the DSPE-GPLGVRGC-PEG (DGP) NPs, as well as their ability to repolarize macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. The NPs demonstrated high biocompatibility, low cytotoxicity, and enhanced cellular uptake. In a collagen-induced arthritis (CIA) mouse model, intra-articular injection of 2-APB@DGP-MM significantly reduced synovial inflammation and cartilage destruction. Histological analysis corroborated these findings, demonstrating marked improvements in joint structure and delayed disease progression. Above all, the 2-APB@DGP-MM nanotherapeutic system offers a promising and safe approach for RA treatment by modulating macrophage polarization and delivering effective agents to inflamed joints.

Ion channels in osteoarthritis: emerging roles and potential targets.

Osteoarthritis (OA) is a highly prevalent joint disease that causes substantial disability, yet effective approaches to disease prevention or to the delay of OA progression are lacking. Emerging evidence has pinpointed ion channels as pivotal mediators in OA pathogenesis and as promising targets for disease-modifying treatments. Preclinical studies have assessed the potential of a variety of ion channel modulators to modify disease pathways involved in cartilage degeneration, synovial inflammation, bone hyperplasia and pain, and to provide symptomatic relief in models of OA. Some of these modulators are currently being evaluated in clinical trials. This review explores the structures and functions of ion channels, including transient receptor potential channels, Piezo channels, voltage-gated sodium channels, voltage-dependent calcium channels, potassium channels, acid-sensing ion channels, chloride channels and the ATP-dependent P2XR channels in the osteoarthritic joint. The discussion spans channel-targeting drug discovery and potential clinical applications, emphasizing opportunities for further research, and underscoring the growing clinical impact of ion channel biology in OA.

Efferocytosis: Unveiling its potential in autoimmune disease and treatment strategies.

Efferocytosis is a crucial process whereby phagocytes engulf and eliminate apoptotic cells (ACs). This intricate process can be categorized into four steps: (1) ACs release "find me" signals to attract phagocytes, (2) phagocytosis is directed by "eat me" signals emitted by ACs, (3) phagocytes engulf and internalize ACs, and (4) degradation of ACs occurs. Maintaining immune homeostasis heavily relies on the efficient clearance of ACs, which eliminates self-antigens and facilitates the generation of anti-inflammatory and immunosuppressive signals that maintain immune tolerance. However, any disruptions occurring at any of the efferocytosis steps during apoptosis can lead to a diminished efficacy in removing apoptotic cells. Factors contributing to this inefficiency encompass dysregulation in the release and recognition of "find me" or "eat me" signals, defects in phagocyte surface receptors, bridging molecules, and other signaling pathways. The inadequate clearance of ACs can result in their rupture and subsequent release of self-antigens, thereby promoting immune responses and precipitating the onset of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. A comprehensive understanding of the efferocytosis process and its implications can provide valuable insights for developing novel therapeutic strategies that target this process to prevent or treat autoimmune diseases.

NS8593 inhibits chondrocyte ferroptosis and alleviates cartilage injury in rat adjuvant arthritis through TRPM7 / HO-1 pathway.

Ferroptosis is an emerging target in rheumatoid arthritis (RA). We previously reported that transient receptor potential melastatin 7 (TRPM7) expression is correlated with RA cartilage destruction and demonstrated that TRPM7 mediates ferroptosis in chondrocytes. Here, we further determined the role and mechanism of (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593), a TRPM7 inhibitor, in chondrocyte ferroptosis of RA. We established in vitro models of ferroptosis in human chondrocytes (C28/I2 cells) by using ferroptosis inducer Erastin. The results showed that NS8593 could protect C28/I2 cells from ferroptosis by inhibiting TRPM7 channel, which was manifested by restoring cell viability, reducing cytotoxicity, affecting the expression of ferroptosis marker protein, and restoring redox balance to alleviate Erastin-induced oxidative stress injury. Mechanistically, the Heme oxygenase-1 (HO-1) axis responded to Erastin stimulation, which resulted in TRPM7-mediated chondrocyte ferroptosis, NS8593 could reduce the expression of HO-1 by inhibiting TRPM7 channel. Moreover, NS8593 alleviated articular cartilage destruction and inhibited chondrocyte ferroptosis in AA rats. In conclusion, NS8593 mitigated articular cartilage damage and chondrocyte ferroptosis through the TRPM7/HO-1 pathway, suggesting that NS8593 may be a potential novel drug for the treatment of RA.

NS8593 inhibits sodium nitroprusside-induced chondrocyte apoptosis by mediating the STING signaling pathway.

Articular cartilage damage and chondrocyte apoptosis are among the distinguishing features of osteoarthritis. (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) is a transient receptor potential cation channel subfamily M member 7 (TRPM7) channel inhibitor and was initially considered a potent inhibitor of small-conductance Ca2+-activated K+ channels(SK1-3 or KCa2.1-2.3 channels). Since SK is one of the targets for atrial fibrillation therapy, several studies have been conducted using NS8593 and it has been shown to be effective in improving atrial fibrillation in rats, dogs and horses. Recently, inhibition of TRPM7 has been reported to alleviate articular cartilage destruction. However, the role and mechanism of NS8593 on articular chondrocyte damage is unknown. The purpose of this study was to investigate the effect and mechanism of NS8593 on sodium nitroprusside (SNP)-induced chondrocyte apoptosis in vitro. The results showed that SNP decreased cell viability and induced chondrocyte apoptosis. NS8593 dose-dependently inhibited the SNP-induced decrease in cell viability and reduced chondrocyte apoptosis. In addition, SNP stimulation significantly increased the phosphorylation level of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), and NS8593 treatment partially reversed the alteration of STING phosphorylation level. Treatment with the STING inhibitor H-151 inhibited SNP-induced chondrocyte apoptosis. These results suggest that NS8593 may inhibit SNP-induced chondrocyte apoptosis by suppressing the STING signaling pathway.

A 16-Year-Old Girl with Sinonasal Cutaneous Fistula Following Excision and Radiotherapy for Rhabdomyosarcoma Requiring Reconstructive Surgery Using an Expanded Forehead Flap.

BACKGROUND Sinonasal rhabdomyosarcoma (RMS) is a rare malignancy in children and adolescents. It is aggressive and locally invasive, and can require local postoperative radiotherapy. This report presents the case of a 16-year-old girl with a sinonasal-cutaneous fistula following excision and radiotherapy for rhabdomyosarcoma, which required reconstructive surgery using an expanded forehead flap. CASE REPORT We report the case of a16-year-old girl who was referred to our clinic with sinonasal-cutaneous fistula. Prior to presentation at our department, she presented with bilateral intermittent nasal congestion 3 years ago. At a local hospital, orbital computed tomography and nasal endoscopic biopsy revealed an embryonal rhabdomyosarcoma (ERMS). One month later, skull base tumor resection, nasal cavity and sinus tumor resection, and low-temperature plasma ablation were performed at a local hospital. Two weeks after the operation, the patient received intensity-modulated radiation therapy for a total of 50 Gy. Chemotherapy started 15 days after radiotherapy, using a vincristine, dactinomycin, and cyclophosphamide (VAC) regimen. Approximately 1 month later, an ulcer appeared at the nasal root and the lesion gradually expanded. The patient was referred to our hospital due to the defect. Firstly, a tissue expander was implanted at the forehead for 7 months. Then, the skin around the defect was trimmed and forehead flap was separated to repair the lining and external skin. The flap survived well 1-year after the operation. CONCLUSIONS This report highlights the challenges of post-radiation reconstructive surgery and describes how an expanded forehead flap can achieve an acceptable cosmetic outcome in a patient with a sinonasal-cutaneous fistula.

Safety, tolerability, and pharmacokinetics of the novel RdRp inhibitor SHEN26 against SARS-CoV-2: a randomized, placebo-controlled, double-blind Phase I study in healthy subjects.

BACKGROUND: SHEN26, an oral broad-spectrum antiviral drug, possesses potent preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has a favorable safety profile. METHODS: We report safety, tolerability, and pharmacokinetic data from a randomized, double-blind, placebo-controlled phase I study of SHEN26. Eighty-six healthy subjects were enrolled in the three studies: a single ascending-dose study (SAD), a multiple ascending-dose study (MAD), and a food-effect study (FE). RESULTS: In the SAD trial, the maximum observed plasma concentration (Cmax) and area under the curve (AUC) of the SHEN26 rapid metabolite SHEN26-69-0 increased approximately dose-proportionally in the 50-400 mg fasting dose range. In the 800 mg dose group, standard meals increased the Cmax and AUC of SHEN26-69-0. In the MAD trial, the accumulation ratios of Cmax and AUC indicated slight accumulation upon repeated SHEN26 dosing. In the FE trial, a high-fat meal prolonged the time to maximum plasma concentration (Tmax) and increased the Cmax and AUC of SHEN26-69-0 compared with fasting administration. Most treatment-related adverse events were mild and resolved without treatment. CONCLUSION: SHEN26 demonstrated satisfactory safety and tolerability in healthy subjects, which supports the continued study of SHEN26 against SARS-CoV-2. TRIAL REGISTRATION: The trial is registered in ClinicalTrials.gov (CT. gov identifier: NCT05504746).

ASH2L Mediates Epidermal Differentiation and Hair Follicle Morphogenesis through H3K4me3 Modification.

The processes of epidermal development in mammals are regulated by complex molecular mechanisms, such as histone modifications. Histone H3 lysine K4 methylation mediated by COMPASS (complex of proteins associated with Set1) methyltransferase is associated with gene activation, but its effect on epidermal lineage development remains unclear. Therefore, we constructed a mouse model of specific ASH2L (COMPASS methyltransferase core subunit) deletion in epidermal progenitor cells and investigated its effect on the development of mouse epidermal lineage. Furthermore, downstream target genes regulated by H3K4me3 were screened using RNA sequencing combined with Cleavage Under Targets and Tagmentation sequencing. Deletion of ASH2L in epidermal progenitor cells caused thinning of the suprabasal layer of the epidermis and delayed hair follicle morphogenesis in newborn mice. These phenotypes may be related to the reduced proliferative capacity of epidermal and hair follicle progenitor cells. ASH2L depletion may also lead to depletion of the epidermal stem cell pools in late mouse development. Finally, genes related to hair follicle development (Shh, Edar, and Fzd6), Notch signaling pathway (Notch2, Notch3, Hes5, and Nrarp), and ΔNp63 were identified as downstream target genes regulated by H3K4me3. Collectively, ASH2L-dependent H3K4me3 modification served as an upstream epigenetic regulator in epidermal differentiation and hair follicle morphogenesis in mice.

TRPM7 facilitates fibroblast-like synoviocyte proliferation, metastasis and inflammation through increasing IL-6 stability via the PKCα-HuR axis in rheumatoid arthritis.

Transient receptor potential melastatin 7 (TRPM7) is a cation channel that plays a role in the progression of rheumatoid arthritis (RA), yet its involvement in synovial hyperplasia and inflammation has not been determined. We previously reported that TRPM7 affects the destruction of articular cartilage in RA. Herein, we further confirmed the involvement of TRPM7 in fibroblast-like synoviocyte (FLS) proliferation, metastasis and inflammation. We observed increased TRPM7 expression in FLSs derived from human RA patients. Pharmacological inhibition of TRPM7 protected primary RA-FLSs from proliferation, metastasis and inflammation. Furthermore, we found that TRPM7 contributes to RA-FLS proliferation, metastasis and inflammation by increasing the intracellular Ca2+ concentration. Mechanistically, the PKCα-HuR axis was demonstrated to respond to Ca2+ influx, leading to TRPM7-mediated RA-FLS proliferation, metastasis and inflammation. Moreover, HuR was shown to bind to IL-6 mRNA after nuclear translocation, which could be weakened by TRPM7 channel inhibition. Additionally, adeno-associated virus 9-mediated TRPM7 silencing is highly effective at alleviating synovial hyperplasia and inflammation in adjuvant-induced arthritis rats. In conclusion, our findings unveil a novel regulatory mechanism involved in the pathogenesis of RA and suggest that targeting TRPM7 might be a potential strategy for the prevention and treatment of RA.

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Extracellular CIRP induces abnormal activation of fibroblast-like synoviocytes from patients with RA via the TLR4-mediated HDAC3 pathways.

The development of rheumatoid arthritis (RA) is closely related to the excessive activation of fibroblast-like synoviocytes (FLSs), which are regulated by a variety of endogenous proinflammatory molecules. Extracellular cold-inducible RNA-binding protein (CIRP), as a novel endogenous proinflammatory molecule, plays an important role in inflammatory diseases. More importantly, the synovial concentration of CIRP in patients with RA was significantly higher than that in patients with osteoarthritis (OA). Thus, this study aimed to investigate the role of extracellular CIRP in the abnormal activation of RA-FLSs and its related mechanisms. Our study showed that extracellular CIRP induced proliferation, migration and invasion of RA-FLSs, increased the expression of N-cadherin and MMP-3, and promoted the release of IL-1ß and IL-33. However, blocking of extracellular CIRP with C23 inhibited CIRP-induced abnormal activation of RA-FLSs and alleviated the arthritis severity in AA rats. Accumulating evidence suggests that the activity and proinflammatory effects of CIRP are mediated through Toll-like receptor 4 (TLR4). Further studies demonstrated that the TLR4 knockdown inhibited CIRP-induced abnormal activation, and histone deacetylase 3 (HDAC3) expression in RA-FLSs. In addition, we found that HDAC3 knockdown and the specific inhibitor RGFP966 significantly suppressed CIRP-induced abnormal activation of RA-FLSs. We further found that treatment with HDAC3 specific inhibitor effectively alleviated the severity of arthritis in AA rats. Taken together, these findings indicate that extracellular CIRP induces abnormal activation of RA-FLSs via the TLR4-mediated HDAC3 pathways.

KIF4A functions as a diagnostic and prognostic biomarker and regulates tumor immune microenvironment in skin cutaneous melanoma.

BACKGROUND: KIF4A is upregulated in various malignancies and serves as an independent risk factor. However, its function in skin cutaneous melanoma (SKCM) and the regulation of the immunological environment remains unknown. METHODS: We first explored the mRNA and protein levels of KIF4A in SKCM through public databases. Then, the co-expressed genes with KIF4A in SKCM and their functional enrichment analysis were performed. Moreover, the clinical value, relationship with immune infiltration and tumor microenvironment (TME), as well as the correlation between KIF4A and immunomodulators were evaluated. In addition, we validated the function of KIF4A by in vitro experiments such as CCK-8 assay, clone formation and wound healing assay. RESULTS: Our data reveal that the mRNA and protein levels of KIF4A are highly expressed in SKCM. Moreover, functional enrichment analysis of the top 50 co-expressed genes with KIF4A showed significant association with organelle fission, tubulin binding and immune processes. KIF4A can distinguish SKCM from normal tissue and predict a poorer prognosis. A negative association was observed between KIF4A and TME, and KIF4A exhibited a negative correlation with most immunomodulators. Additionally, the knockdown of KIF4A inhibited the proliferation and migration ability of A375 cells. CONCLUSIONS: Our findings suggest that KIF4A promotes the progression of SKCM and is negatively associated with immune infiltration and immunomodulators, which indicates a poor prognosis.

Safety and Pharmacokinetics of HRS-2261, a P2X3 Receptor Antagonist, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

BACKGROUND: P2X3 receptor antagonists hold promising potential as a therapeutic option for patients with refractory or unexplained chronic cough, a condition lacking approved therapies. This study assessed the safety, tolerability, and pharmacokinetics (PK) of HRS-2261, a novel selective P2X3 receptor antagonist, in healthy subjects. METHODS: This randomized, double-blinded, placebo-controlled phase 1 trial of HRS-2261 consisted of three phases: the single ascending dose (SAD) study phase, the food-effect study phase, and the multiple ascending dose (MAD) study phase. In the SAD phase, healthy subjects were randomly assigned to receive a single oral dose of HRS-2261 (25, 100, 200, 400, 800, and 1200 mg) or placebo. Subjects in the 200 mg group of the SAD phase progressed directly to the food-effect phase following safety evaluation. In the MAD phase, healthy subjects were randomized to receive HRS-2261 (50, 200, and 400 mg) or placebo twice daily for 14 consecutive days. The primary endpoints were safety and tolerability. RESULTS: A total of 62 and 30 subjects were enrolled in the SAD and MAD phases, respectively, with 12 subjects from the SAD phase transitioning to the food-effect phase. The incidence and severity of adverse events (AEs) were not dose dependent, and most AEs were mild except for one moderate AE (epididymitis, which was not related to treatment) in the 400 mg group. Dysgeusia was reported in nine subjects, including two from the SAD phase, one from the food-effect phase, and six from the MAD phase. The median Tmax and geometric mean t1/2 were 0.9-2.0 h and 4.1-8.5 h in the SAD, and 2.0-2.7 h and 4.6-5.0 h on day 14 in the MAD, respectively. Drug exposures in the SAD and MAD phases were both less than dose proportional. The accumulation of the drug was slight with repeated twice-daily dosing. Food-effect study results showed that food intake did not affect the plasma exposure of HRS-2261. CONCLUSIONS: HRS-2261 demonstrated good tolerability, with a low incidence of dysgeusia. The PK profile was favorable. This study supports further development of HRS-2261 as a potential P2X3 receptor antagonist for chronic cough. TRIAL REGISTRATION NUMBER: Clinical trials.gov, identifier: NCT05274516. Trial registration date: March 10, 2022.

IUPHAR ECR review: The cGAS-STING pathway: Novel functions beyond innate immune and emerging therapeutic opportunities.

Stimulator of interferon genes (STING) is a crucial innate immune sensor responsible for distinguishing pathogens and cytosolic DNA, mediating innate immune signaling pathways to defend the host. Recent studies have revealed additional regulatory functions of STING beyond its innate immune-related activities, including the regulation of cellular metabolism, DNA repair, cellular senescence, autophagy and various cell deaths. These findings highlight the broader implications of STING in cellular physiology beyond its role in innate immunity. Currently, approximately 10 STING agonists have entered the clinical stage. Unlike inhibitors, which have a maximum inhibition limit, agonists have the potential for infinite amplification. STING signaling is a complex process that requires precise regulation of STING to ensure balanced immune responses and prevent detrimental autoinflammation. Recent research on the structural mechanism of STING autoinhibition and its negative regulation by adaptor protein complex 1 (AP-1) provides valuable insights into its different effects under physiological and pathological conditions, offering a new perspective for developing immune regulatory drugs. Herein, we present a comprehensive overview of the regulatory functions and molecular mechanisms of STING beyond innate immune regulation, along with updated details of its structural mechanisms. We discuss the implications of these complex regulations in various diseases, emphasizing the importance and feasibility of targeting the immunity-dependent or immunity-independent functions of STING. Moreover, we highlight the current trend in drug development and key points for clinical research, basic research, and translational research related to STING.

Weighted gene co-expression network analysis and machine learning identified the lipid metabolism-related gene LGMN as a novel biomarker for keloid.

The aetiology of keloid formation remains unclear, and existing treatment modalities have not definitively established a successful approach. Therefore, it is necessary to identify reliable and novel keloid biomarkers as potential targets for therapeutic interventions. In this study, we performed differential expression analysis and functional enrichment analysis on the keloid related datasets, and found that multiple metabolism-related pathways were associated with keloid formation. Subsequently, the differentially expressed genes (DEGs) were intersected with the results of weighted gene co-expression network analysis (WGCNA) and the lipid metabolism-related genes (LMGs). Then, three learning machine algorithms (SVM-RFE, LASSO and Random Forest) together identified legumain (LGMN) as the most critical LMGs. LGMN was overexpressed in keloid and had a high diagnostic performance. The protein-protein interaction (PPI) network related to LGMN was constructed by GeneMANIA database. Functional analysis of indicated PPI network was involved in multiple immune response-related biological processes. Furthermore, immune infiltration analysis was conducted using the CIBERSORT method. M2-type macrophages were highly infiltrated in keloid tissues and were found to be significantly and positively correlated with LGMN expression. Gene set variation analysis (GSVA) indicated that LGMN may be related to promoting fibroblast proliferation and inhibiting their apoptosis. Moreover, eight potential drug candidates for keloid treatment were predicted by the DSigDB database. Western blot, qRT-PCR and immunohistochemistry staining results confirmed that LGMN was highly expressed in keloid. Collectively, our findings may identify a new biomarker and therapeutic target for keloid and contribute to the understanding of the potential pathogenesis of keloid.