Efficacy and safety of topical minocycline foam (FMX101 4%) in treatment of Chinese subjects with moderate-to-severe facial acne vulgaris: A phase 3, multi-centre, randomized, double-blind, vehicle-controlled study.

BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.

[Corrigendum] All­trans retinoic acid alters the expression of the tight junction proteins Claudin­1 and ­4 and epidermal barrier function­associated genes in the epidermis.

Following the publication of the above article, the authors contacted the Editorial Office to explain that they had identified a pair of duplicate images in the control (Vehicle) group of mouse images in Fig. 1A on p. 1792. Specifically, the same image (corresponding correctly to the 'Day 5' experiment) was inadvertently chosen to represent the cutaneous manifestations of mice in the Vehicle group on 'Day 3' and 'Day 5' in Fig. 1A. This error arose as a consequence of repetitive application and duplication procedures within the image set, resulting in the inadvertent reuse of the same photo. Additionally, due to minimal alterations observed in the skin condition of mice from the control group following treatment, each mouse exhibited a similar appearance; this similarity further contributed to the delayed identification of this error during the paper revision stage. Consequently, this duplication of the same image was made as a result of insufficient scrutiny. The revised version of Fig. 1, showing the correct image for the 'Day 3' experiment in Fig. 1A, is shown on the next page. The authors can confirm that the error associated with the assembly of this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 1789­1805, 2019; DOI: 10.3892/ijmm.2019.4098].

New clinical classification of stiff skin syndrome.

BACKGROUND: Stiff skin syndrome (SSS) is a rare disease characterized by thickened, indurated skin and limited joint movement. Multiple diverse phenotypes have been reported, and the correlation of severity with the clinical heterogeneity and histopathological findings of SSS needs to be refined. OBJECTIVE: To define subtypes based on clinical features and predict the prognosis of a new SSS classification. METHODS: Eighty-three patients with SSS were retrospectively reviewed for clinicopathological manifestations and routine laboratory workup, including 59 cases obtained from a PubMed search between 1971 and 2022 and 24 cases diagnosed in our department between 2003 and 2022. RESULTS: Among the 83 patients, 27.7, 41, and 31.3% had classic widespread, generalized segmental, and localized SSS, respectively. Joint immobility was present in 100, 71, and 20% of classic, generalized, and localized cases, respectively. Histopathologic findings were common among the 3 groups, and based on that, we further found a difference in the distribution of proliferative collagen. 54.5% of classic and 50% of generalized cases occurred throughout the dermis or the subcutis, whereas 76% of localized cases were mainly involved in the reticular dermis or subcutis. In patients with incipient localized SSS, 42% (21/50) developed generalized SSS, and only 6% (3/50) progressed to classic SSS, whereas more than half of the incipient generalized SSS cases (60.6%, 20/33) developed classic SSS. LIMITATIONS: This retrospective study was limited to previously published cases with limited data. CONCLUSIONS: We propose a distinct clinical classification characterized by lesion distribution, including classic widespread, generalized segmental, and localized SSS, associated with disease severity and prognosis.

The impact of smoking and alcohol consumption on rosacea: a multivariable Mendelian randomization study.

Backgrounds: Observational studies have shown that cigarette smoking is inversely associated with risk of rosacea, However, it remains uncertain whether this association is causal or it is a result of reverse causation, and whether this association is affected by drinking behaviors. Methods: This study utilized the summary-level data from the largest genome-wide association study (GWAS) for smoking, alcohol consumption, and rosacea. The objective was to investigate the effect of genetically predicted exposures to smoking and alcohol consumption on the risk of developing rosacea. Two-sample bidirectional Mendelian randomization (MR) was applied, accompanied by sensitive analyses to validate the robustness of findings. Furthermore, multivariable MR was conducted to evaluate the direct impact of smoking on rosacea. Results: A decreased risk of rosacea was observed in individuals with genetically predicted lifetime smoking [odds ratio (OR)MR - IVW = 0.53; 95% confidence interval (CI), 0.318-0.897; P = 0.017], and number of cigarettes per day (ORMR - IVW = 0.55; 95% CI, 0.358-0.845; P = 0.006). However, no significant associations were found between initiation of regular smoking, smoking cessation, smoking initiation, alcohol consumption and rosacea. Reverse MR analysis did not show any associations between genetic liability toward rosacea and smoking or alcohol drinking. Importantly, the effect of lifetime smoking and the number of cigarettes per day on rosacea remained significant even after adjusting for alcohol consumption in multivariable MR analysis. Conclusion: Smoking was causally related to a lower risk of rosacea, while alcohol consumption does not appear to be associated with risk of rosacea.

Hematoporphyrin monomethyl ether-mediated photodynamic therapy for acquired port-wine stain at lower extremity: Two case reports.

Two cases of acquired port-wine stain (APWS) at lower extremity were treated with hematoporphyrin monomethyl ether (HMME) and 532 nm LED green light-mediated photodynamic therapy (HMME-PDT). No serious adverse reactions were observed during or post-treatment period. Five-month follow-up showed significant reduction of red patches after a single HMME-PDT treatment in both cases.

Decreased TET2/5-hmC reduces the integrity of the epidermal barrier via epigenetic dysregulation of filaggrin in psoriatic lesions.

BACKGROUND: TET2 participates in tumor progression and intrinsic immune homeostasis via epigenetic regulation. TET2 has been reported to be involved in maintaining epithelial barrier homeostasis and inflammation. Abnormal epidermal barrier function and TET2 expression have been detected in psoriatic lesions. However, the mechanisms underlying the role of TET2 in psoriasis have not yet been elucidated. OBJECTIVE: To define the role of TET2 in maintaining epithelial barrier homeostasis and the exact epigenetic mechanism in the dysfunction of the epidermal barrier in psoriasis. METHODS: We analyzed human psoriatic skin lesions and datasets from the GEO database, and detected the expression of TET2/5-hmC together with barrier molecules by immunohistochemistry. We constructed epidermal-specific TET2 knockout mice to observe the effect of TET2 deficiency on epidermal barrier function via toluidine blue penetration assay. Further, we analyzed changes in the expression of epidermal barrier molecules by immunofluorescence in TET2-specific knockout mice and psoriatic model mice. RESULTS: We found that decreased expression of TET2/5-hmC correlated with dysregulated barrier molecules in human psoriatic lesions. Epidermal-specific TET2 knockout mice showed elevated transdermal water loss associated with abnormal epidermal barrier molecules. Furthermore, we observed that TET2 knockdown in keratinocytes reduced filaggrin expression via filaggrin promoter methylation. CONCLUSION: Aberrant epidermal TET2 affects the integrity of the epidermal barrier through the epigenetic dysregulation of epidermal barrier molecules, particularly filaggrin. Reduced TET2 expression is a critical factor contributing to an abnormal epidermal barrier in psoriasis.

Influence of Curvature on Cell Motility and Morphology during Cancer Migration in Confined Microchannels.

Microchannels often serve as highways for cancer migration, and their topology largely determines the migration efficiency. Curvature, a topological parameter in biological systems, has recently been reported to be efficient in guiding cell polarization and migration. Curvature varies widely along curved microchannels, while its influence on cell migration remains elusive. Here, we recapitulated the curved microchannels, as observed in clinical tumor tissues with hydrogels, and studied how cancer cells respond to curvature. We found that cells bend more significantly in a larger curvature and exhibit less spreading as well as lower motility. The underlying mechanism is probably based on the hindrance of the movement of cytoskeletal molecules at the curved microchannel walls. Collectively, our results demonstrated that the accelerated actin retrograde flow rate under local curvature has an effective negative regulation on cell motility and morphology, leading to shortened and bent cell morphologies as well as hampered cell migration efficiency.

Enhanced gene transfection and induction of apoptosis in melanoma cells by branched poly(ß-amino ester)s with uniformly distributed branching units.

Melanoma, one of the most devastating forms of skin cancer, currently lacks effective clinical treatments. Delivery of functional genes to modulate specific protein expression to induce melanoma cell apoptosis could be a promising therapeutic approach. However, transfecting melanoma cells using non-viral methods, particularly with cationic polymers, presents significant challenges. In this study, we synthesized three branched poly(ß-amino ester)s (HPAEs) with evenly distributed branching units but varying space lengths through a two-step "oligomer combination" strategy. The unique topological structure enables HPAEs to condense DNA to form nano-sized polyplexes with favorable physiochemical properties. Notably, HPAEs, especially HPAE-2 with intermediate branching unit space length, demonstrated significantly higher gene transfection efficiency than the leading commercial gene transfection reagent, jetPRIME, in human melanoma cells. Furthermore, HPAE-2 efficiently delivered the Bax-encoding plasmid into melanoma cells, leading to a pronounced pro-apoptotic effect without causing noticeable cytotoxicity. This study establishes a potent non-viral platform for gene transfection of melanoma cells by harnessing the distribution of branching units, paving the way for potential clinical applications of gene therapy in melanoma treatment.

Tildrakizumab for moderate-to-severe plaque psoriasis in Chinese patients: A 12-week randomized placebo-controlled phase III trial with long-term extension.

BACKGROUND: There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. METHODS: In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. RESULTS: At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician's Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs . 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs . 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. CONCLUSION: Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05108766.

Decrease of 5-hydroxymethylcytosine in primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoproliferative disorder

Abstract Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-Cell lymphoproliferative disorder (PC-SMTLD) has been considered as a controversial dermatological disease that has been included in cutaneous T-cell lymphoma group, presenting most commonly as a solitary nodule and/or plaque with a specific and characteristic head and neck predilection. Due to the considerable overlap between PC-SMTLD and pseudolymphoma (PL), the differential diagnosis is often challenging. Methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, it has rarely been studied in cutaneous lymphomas. Objectives: The authors aimed to explore the role of differential 5-hmC immunostaining as a useful marker to distinguish PC-SMTLD from PL. Methods: Retrospective case series study with immunohistochemical and immunofluorescence analysis of 5-hmC was performed in PL and PC-SMTLD. Results: Significant decrease of 5-hmC nuclear staining was observed in PC-SMTLD when compared with PL (p<0.0001). By semi-quantitative grade integration, there were statistical differences in the final 5-hmC scores in the two study groups. The IF co-staining of 5-hmC with CD4 revealed a decrease of 5-hmC in CD4+ lymphocytes of PC-SMTLD. Study limitations: The small clinical sample size of the study. Conclusions: The immunorreactivity of 5-hmC in CD4+ lymphocytes was highly suggestive of a benign process as PL. Furthermore, the decrease of 5-hmC nuclear staining in PC-SMTLD indicated its lymphoproliferative status and helped to make the differential diagnosis with PL. © 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Mast Cells Initiate Type 2 Inflammation through Tryptase Released by MRGPRX2/MRGPRB2 Activation in Atopic Dermatitis.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by T helper 2 inflammation as the core pathogenic mechanism. MRGPRX2 plays a key role in nonhistamine allergies and neuroimmune mechanisms in chronic inflammatory dermatitis. However, the role of MRGPRX2 in AD and the development of type 2 inflammation is not yet clear. This study aimed to define the role of MRGPRX2 in type 2 inflammation development and cytokine release in AD by determining its levels in patients with AD and healthy controls. Furthermore, MrgprB2-conditional knockout (MrgprB2-/-) and wild-type mice were used to construct an MC903-induced AD mouse model to observe skin inflammation and cytokine release. Tryptase and its antagonist were applied separately to MrgprB2-/- mice with AD and wild-type mice with AD to confirm the role of the MRGPRB2-tryptase axis in the development of type 2 inflammation in AD. We found that AD severity and type 2 cytokine levels were not associated with IgE levels but were associated with MRGPRX2/MRGPRB2 expression. MrgprB2-/- mice with AD showed milder phenotypes and inflammatory infiltration in the skin than wild-type mice with AD. Tryptase released by MRGPRX2/MRGPRB2 activation is involved in the release of type 2 cytokines, which contributes to inflammatory development in AD.

Decrease of 5-hydroxymethylcytosine in primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoproliferative disorder.

BACKGROUND: Primary cutaneous CD4+ small/medium-sized pleomorphic T-Cell lymphoproliferative disorder (PC-SMTLD) has been considered as a controversial dermatological disease that has been included in cutaneous T-cell lymphoma group, presenting most commonly as a solitary nodule and/or plaque with a specific and characteristic head and neck predilection. Due to the considerable overlap between PC-SMTLD and pseudolymphoma (PL), the differential diagnosis is often challenging. Methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, it has rarely been studied in cutaneous lymphomas. OBJECTIVES: The authors aimed to explore the role of differential 5-hmC immunostaining as a useful marker to distinguish PC-SMTLD from PL. METHODS: Retrospective case series study with immunohistochemical and immunofluorescence analysis of 5-hmC was performed in PL and PC-SMTLD. RESULTS: Significant decrease of 5-hmC nuclear staining was observed in PC-SMTLD when compared with PL (p < 0.0001). By semi-quantitative grade integration, there were statistical differences in the final 5-hmC scores in the two study groups. The IF co-staining of 5-hmC with CD4 revealed a decrease of 5-hmC in CD4+ lymphocytes of PC-SMTLD. STUDY LIMITATIONS: The small clinical sample size of the study. CONCLUSIONS: The immunorreactivity of 5-hmC in CD4+ lymphocytes was highly suggestive of a benign process as PL. Furthermore, the decrease of 5-hmC nuclear staining in PC-SMTLD indicated its lymphoproliferative status and helped to make the differential diagnosis with PL.

Hemoporfin-mediated photodynamic therapy for angiokeratoma corporis diffusum: A case report.

SIGNIFICANCE: Angiokeratoma corporis diffusum (ACD) is one type of angiokeratomas which are characterized on histology by superficial dilated capillaries with epidermal proliferation. ACD seriously influences patients' appearance and quality of life. Many therapies have been used to solved this problem. However, all the treatments have not been proved very effective. Hemoporfin-mediated photodynamic therapy (Hemoporfin-PDT) was considered recently as a promising treatment for PWS according to the principle of targeted photodynamic destruction of the vascular wall of the lesion. APPROACH: APPROACH: A 27-year-old male patient diagnosed with angiokeratoma corporis diffusum (ACD) by skin tissue biopsy has undergone pulsed dye laser for times, but the result was unsatisfying. After evaluating and obtaining the patient's agreement, we utilized Hemoporfin-PDT with 530 nm LED green light to treat ACD. When followed up in the 1 year after 2 treatments, the patient was pleased with the efficacy that most red papules on his face disappeared. RESULTS: The patient achieved great improvement after two treatments. CONCLUSIONS: Hemoporfin-PDT could be used to treat ACD.

Cold atmospheric plasma sensitizes melanoma cells to targeted therapy agents in vitro.

Cold atmospheric plasma (CAP) has been reported to kill melanoma cells in vitro and in vivo. BRAF and MEK inhibitors are targeted therapy agents for advanced melanoma patients with BRAF mutations. However, low overall survival and relapse-free survival are still tough challenges due to drug resistance. In this study, we confirmed that CAP alleviated innate drug resistance and promoted the anti-tumor effect of targeted therapy in A875 and WM115 melanoma cells in vitro. Further, we revealed that CAP altered the expression of various molecules concerning MAPK and PI3K-AKT pathways in A875 cells. This study demonstrates that CAP promises to work as adjuvant treatment with targeted therapy to overcome drug resistance for malignant tumors in future.

Exosomes from hypoxic pretreated ADSCs attenuate ultraviolet light-induced skin injury via GLRX5 delivery and ferroptosis inhibition.

Accumulation studies have found that adipose-derived stem cell (ADSC) exosomes have anti-oxidant and anti-inflammatory characteristics. The current study verified their therapeutic potential to elucidate mechanisms of ADSC exosome actions in ultraviolet B (UVB) light-induced skin injury. Exosomes were isolated from ADSCs and hypoxic pretreated ADSCs. Next-generation sequencing (NGS) was applied to characterize differential mRNA expression. A UV-induced mice skin injury model was generated to investigate therapeutic effects regarding the exosomes via immunofluorescence and ELISA analysis. Regulatory mechanisms were illustrated using luciferase report analysis and in vitro experiments. The results demonstrated that exosomes from hypoxic pretreated ADSCs (HExos) inhibited UVB light-induced vascular injury by reversing reactive oxygen species, inflammatory factor expression and excessive collagen degradation. NGS showed that HExos inhibits UV-induced skin damage via GLRX5 delivery, while GLRX5 downregulation inhibited the therapeutic effect of HExos on UV-induced skin damage. GLRX5 upregulation increased the protective Exo effect on UV-induced skin and EPC damage by inhibiting ferroptosis, inflammatory cytokine expression and excessive collagen degradation. Therefore, the data indicate that HExos attenuate UV light-induced skin injury via GLRX5 delivery and ferroptosis inhibition.

Dual effect of tacrolimus on mast cell-mediated allergy and inflammation through Mas-related G protein-coupled receptor X2.

BACKGROUND: Topical tacrolimus, although widely used in the treatment of dermatoses, presents with an immediate irritation on initial application resembling a pseudo-allergic reaction. Mas-related G protein-coupled receptor X2 (MRGPRX2) in mast cells (MCs) mediates drug-induced pseudo-allergic reaction and immunoglobulin E (IgE)-independent pruritis in chronic skin diseases. However, the immunosuppression mechanism of tacrolimus on MCs via MRGPRX2 has not been reported. OBJECTIVE: To investigate the role of MRGPRX2 and the mechanism of action of tacrolimus on its short-term and long-term applications. METHODS: Wild-type mice, KitW-sh/W-sh mice, and MrgprB2-deficient (MUT) mice were used to study the effect of tacrolimus on in vivo anaphylaxis model. LAD2 cells and MRGPRX2-knockdown LAD2 cells were specifically used to derive the associated mechanism of the tacrolimus effect. RESULTS: Short-term application of tacrolimus triggers IgE-independent activation of MCs via MRGPRX2/B2 in both in vivo and in vitro experiments. Tacrolimus binds to MRGPRX2, which was verified by fluorescently labeled tacrolimus in cells. On long-term treatment with tacrolimus, the initial allergic reaction fades away corresponding with the downregulation of MRGPRX2, which leads to decreased release of inflammatory cytokines (P < 0.05 to P < 0.001). CONCLUSION: Short-term treatment with tacrolimus induces pseudo-allergic reaction via MRGPRX2/B2 in MCs, whereas long-term treatment downregulates expression of MRGPRX2/B2, which may contribute to its potent immunosuppressive effect in the treatment of various skin diseases.