5-aminolevulinic acid photodynamic therapy protects against UVB-induced skin photoaging: A DNA-repairing mechanism involving the BER signalling pathway.

Low-dose 5-aminolevulinic acid photodynamic therapy (ALA-PDT) has been used to cope with skin photoaging, and is thought to involve DNA damage repair responses. However, it is still unknown how low-dose ALA-PDT regulates DNA damage repair to curb skin photoaging. We established a photoaging model using human dermal fibroblasts (HDFs) and rat skin. RNA-sequencing (RNA-seq) analysis was conducted to identify differentially expressed genes (DEGs) in HDFs before and after low-dose ALA-PDT treatment, followed by bioinformatics analysis. Senescence-associated ß-galactosidase (SA-ß-gal) staining was employed to assess skin aging-related manifestations and Western blotting to evaluate the expression of associated proteins. A comet assay was used to detect cellular DNA damage, while immunofluorescence to examine the expression of 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) in cells and skin tissues. In both in vivo and in vitro models, low-dose ALA-PDT alleviated the manifestations of ultraviolet B (UVB)-induced skin photoaging. Low-dose ALA-PDT significantly reduced DNA damage in photoaged HDFs. Furthermore, low-dose ALA-PDT accelerated the clearance of the photoproduct 8-oxo-dG in photoaged HDFs and superficial dermis of photoaged rat skin. RNA-seq analysis suggested that low-dose ALA-PDT upregulated the expression of key genes in the base excision repair (BER) pathway. Further functional validation showed that inhibition on BER expression by using UPF1069 significantly suppressed SA-ß-gal activity, G2/M phase ratio, expression of aging-associated proteins P16, P21, P53, and MUTYH proteins, as well as clearance of the photoproduct 8-oxo-dG in photoaged HDFs. Low-dose ALA-PDT exerts anti-photoaging effects by activating the BER signalling pathway.

Novel needle-type electrocoagulation and combination pharmacotherapy: Basic and clinical studies on efficacy and safety in treating keloids.

BACKGROUND AND AIM: Keloids cannot be effectively treated using monotherapy regimens. This study aimed to evaluate the efficacy and safety of ablation (a novel needle-assisted electrocoagulation technique) combined with pharmacotherapy (corticosteroid and 5-fluorouracil [5-FU] injections) in removing keloids and to investigate the underlying biological mechanisms. METHODS: The effects of energy consumption and duration of needle-assisted electrocoagulation on the ablation zone were tested in porcine liver tissue, which simulates human skin. The regulatory effects of ablation combined with pharmacotherapy on collagen deposition, cell proliferation, and angiogenesis were analyzed in a keloid-bearing nude mouse model in vivo. In a clinical trial involving six patients with keloids, the Vancouver Scar Scale (VSS) and Patient and Observer Scar Assessment Scale (POSAS) scores were graded before treatment and 1 month after one cycle of ablation combined with corticosteroid and 5-FU therapy. RESULTS: Higher energy consumption and longer duration of electrocoagulation resulted in a larger ablation zone and higher surface temperature. Ablation combined with pharmacotherapy significantly reduced keloid volume in nude mice, upregulated MMP-1 and MMP-3, downregulated COL I and COL III, and inhibited angiogenesis and proliferation. This combination also significantly reduced the VSS and POSAS scores in patients with keloids after treatment without any obvious adverse events. CONCLUSION: Our findings show that electroablation combined with pharmacotherapy effectively reduces keloid volume by inhibiting collagen deposition, angiogenesis, and cell proliferation. Thus, this novel combination may serve as a safe therapeutic approach for keloid removal.

Longitudinal associations of social jetlag with obesity indicators among adolescents - Shanghai adolescent cohort.

OBJECTIVE: To explore the longitudinal association between social-jetlag (SJL) and obesity development among adolescents, sex-difference and related modifying factors in the association. METHODS: Based on Shanghai-Adolescent-Cohort during 2017-2021, a total of 609 students were investigated. In grade 6, 7 and 9, the information on SJL was collected using questionnaires, and anthropometric measures were conducted. The fingernail cortisol and progesterone levels in grade 6 (using LC-MS/MS) and body composition in grade 9 (using Inbody-S10) were measured. By the latent-class-mixture-modeling, two trajectories for SJL (high-level vs. low-level) throughout 4 years were developed. The prospective associations of SJL trajectories and weight/fat gains were analyzed by sex and under different (high/moderate/low) cortisol/progesterone stratifications. RESULTS: In grades 6-9, 39.00%-44.50 % of adolescents experienced at least 1 h of SJL. Compared with the low-level SJL trajectory, the high-level SJL trajectory was associated with greater differences in body-mass-index Z-scores and waist-to-height ratios across 4 years, higher levels of body-fat-percentage and fat-mass-index in grade 9 (P-values<0.05), and such associations were stronger among girls and under moderate-to-high (vs. low) baseline cortisol and progesterone levels. However, no significant associations among boys were observed. CONCLUSIONS: High-level SJL in adolescents may be associated with the development of obesity, especially among adolescent girls and under relatively high baseline cortisol and progesterone levels.

ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells.

Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-ß1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-ß1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

Myeloid PTEN loss affects the therapeutic response by promoting stress granule assembly and impairing phagocytosis by macrophages in breast cancer.

Breast cancer (BRCA) has become the most common type of cancer in women. Improving the therapeutic response remains a challenge. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a classic tumour suppressor with emerging new functions discovered in recent years, and myeloid PTEN loss has been reported to impair antitumour immunity. In this study, we revealed a novel mechanism by which myeloid PTEN potentially affects antitumour immunity in BRCA. We detected accelerated stress granule (SG) assembly under oxidative stress in PTEN-deficient bone marrow-derived macrophages (BMDMs) through the EGR1-promoted upregulation of TIAL1 transcription. PI3K/AKT/mTOR (PAM) pathway activation also promoted SG formation. ATP consumption during SG assembly in BMDMs impaired the phagocytic ability of 4T1 cells, potentially contributing to the disruption of antitumour immunity. In a BRCA neoadjuvant cohort, we observed a poorer response in myeloid PTENlow patients with G3BP1 aggregating as SGs in CD68+ cells, a finding that was consistent with the observation in our study that PTEN-deficient macrophages tended to more readily assemble SGs with impaired phagocytosis. Our results revealed the unconventional impact of SGs on BMDMs and might provide new perspectives on drug resistance and therapeutic strategies for the treatment of BRCA patients.

Identification and bioactivity evaluation of twelve previously undescribed depsidone derivatives from Garcinia oligantha.

Phytochemical studies on the leaves and twigs of Garcinia oligantha Merr. led to the isolation of twelve previously undescribed depsidone derivatives (oliganthdepsidones A-L, 1-12). Their structures were elucidated by extensive spectroscopic analysis including 1H and 13C NMR, HSQC, HMBC and NOESY along with HRESIMS. The structures of oliganthdepsidones G and J were finally determined using DFT-NMR chemical shift calculations and DP4+ methods. Cytotoxicity test in four human cancer cell lines indicated that oliganthdepsidone F had relatively strong cytotoxic effect against A375 (melanoma), A549 (lung cancer), HepG2 (liver cancer), and MCF-7 (breast cancer) cell lines with IC50 of 18.71, 15.44, 10.92, and 15.90 µM, respectively. The dose- and time-dependent antiproliferative effects of oliganthdepsidone F on these cell lines were also observed by CCK-8 test. As determined by fluorescent microscopy and flow cytometry in these cell lines, oliganthdepsidone F could promote cell apoptosis, leading to the inhibition of cell proliferation. The results of wound healing assay and transwell assay showed that oliganthdepsidone F could inhibit the migration and invasion of A549 and MCF-7 cell lines in a concentration-dependent manner.

Selective catalytic oxidation of DMF over Cu-Ce/H-MOR by modulating the surface active sites.

Selective catalytic oxidation of the hazardous DMF exhaust gas presents a significant challenge in balancing oxidation activity and products selectivity (CO, NOx, N2, etc.). It is found that Cu/H-MOR demonstrates superior performance for DMF oxidation compared to CuO on other supports (γ-Al2O3, HY, ZSM-5) in terms of product selectivity and stability. The geometric and electronic structures of CuO active sites in Cu/H-MOR have been regulated by CeO2 promoter, leading to an increase in the ratio of active CuO (highly dispersed CuO and Cu+ specie). As a result, the oxidation activity and stability of the Cu/H-MOR catalyst were enhanced for DMF selective catalytic oxidation. However, excessive CuO or CeO2 content led to decreased N2 selectivity due to over-high oxidation activity. It is also revealed that Ce3+ species, active CuO species, and surface acid sites play a critical role in internal selective catalytic reduction reaction during DMF oxidation. The 10Cu-Ce/H-MOR (1/4) catalyst exhibited both high oxidation activity and internal selective catalytic reduction activity due to its abundance of active CuO specie as well as Ce3+ species and surface acid sites. Consequently, the 10Cu-Ce/H-MOR (1/4) catalyst demonstrated the widest temperature window for DMF oxidation with high N2 selectivity. These findings emphasize the importance of surface active sites modification for DMF selective catalytic oxidation.

A nomogram to predict anal condyloma acuminatum recurrence in HIV-negative patients following photodynamic therapy: A decade-long retrospective clinical study at a single tertiary hospital.

BACKGROUND: Anal condyloma acuminatum (CA) is marked by its thorny treatment and high recurrence rate. Although 5-aminolevulinic acid photodynamic therapy (ALA-PDT) demonstrates significant efficacy and safety in treating anal CA, it does not completely prevent recurrence. This study aimed to develop and validate a nomogram model in predicting the risk of relapse in HIV-negative patients with anal CA following treatment with ALA-PDT. METHODS: A retrospective analysis was conducted on patients diagnosed with anal CA who received combined CO2 laser vaporization and ALA-PDT between January 2013 and May 2023. Patients were divided into recurrence and non-recurrence groups. A nomogram was developed based on factors showing statistical significance in multivariable logistic regression analysis. The discriminative ability and clinical utility of the nomogram were assessed via ROC curves and decision curve analysis, with internal validation performed through bootstrap resampling. RESULTS: Among the 176 patients included, 33 (18.75 %) experienced recurrence, while 143 did not. Independent predictors for recurrence included HPV types, history of anal intercourse, and the number of CO2 laser treatments received. Incorporating these predictors, the nomogram demonstrated a superior diagnostic performance (area under the curve = 0.881, 95 % CI: 0.818-0.935) and a significant net benefit in decision curve analysis. CONCLUSIONS: The nomogram accurately predicts the risk of recurrence in HIV-negative patients with anal CA following ALA-PDT. It offers a valuable tool for guiding preoperative clinical decision-making and establishing personalized treatment strategies to minimize the risk of relapse.

Photoresponsive Hydrogels for Tissue Engineering.

Hydrophilic and biocompatible hydrogels are widely applied as ideal scaffolds in tissue engineering. The "smart" gelation material can alter its structural, physiochemical, and functional features in answer to various endo/exogenous stimuli to better biomimic the endogenous extracellular matrix for the engineering of cells and tissues. Light irradiation owns a high spatial-temporal resolution, complete biorthogonal reactivity, and fine-tunability and can thus induce physiochemical reactions within the matrix of photoresponsive hydrogels with good precision, efficiency, and safety. Both gel structure (e.g., geometry, porosity, and dimension) and performance (like conductivity and thermogenic or mechanical properties) can hence be programmed on-demand to yield the biochemical and biophysical signals regulating the morphology, growth, motility, and phenotype of engineered cells and tissues. Here we summarize the strategies and mechanisms for encoding light-reactivity into a hydrogel and demonstrate how fantastically such responsive gels change their structure and properties with light irradiation as desired and thus improve their applications in tissue engineering including cargo delivery, dynamic three-dimensional cell culture, and tissue repair and regeneration, aiming to provide a basis for more and better translation of photoresponsive hydrogels in the clinic.

The engineered agonistic anti-CD40 antibody potentiates the antitumor effects of ß-glucan by resetting TAMs.

Anti-CD40 antibodies (Abs) have been shown to induce antitumor T-cell responses. We reported that the engineered agonistic anti-CD40 Ab (5C11, IgG4 isotype) recognized human CD40 antigen expressed on a human B lymphoblastoid cell line as well as on splenic cells isolated from humanized CD40 mice. Of note, a single high dosage of 5C11 was able to prohibit tumor growth in parallel with an increase in the population of infiltrated CD8+ T cells. Furthermore, the antitumor effects of 5C11 were enhanced in the presence of ß-glucan along with an increase in the population of infiltrated CD8+ T cells. In addition, the numbers of CD86+ TAMs and neutrophils were elevated in the combination of 5C11 and ß-glucan compared with either 5C11 or ß-glucan alone. Furthermore, the abundance of Faecalibaculum, one of the probiotics critical for tumor suppression, was obviously increased in the combination of 5C11 and ß-glucan-treated mice. These data reveal a novel mechanism of tumor suppression upon the combination treatment of 5C11 and ß-glucan and propose that the combination treatment of agonistic anti-human CD40 antibody 5C11 and ß-glucan could be a promising therapeutic strategy for cancer patients.

Near-Infrared Luminescent Materials Incorporating Rare Earth/Transition Metal Ions: From Materials to Applications.

The spotlight has shifted to near-infrared (NIR) luminescent materials emitting beyond 1000 nm, with growing interest due to their unique characteristics. The ability of NIR-II emission (1000-1700 nm) to penetrate deeply and transmit independently positions these NIR luminescent materials for applications in optical-communication devices, bioimaging, and photodetectors. The combination of rare earth metals/transition metals with a variety of matrix materials provides a new platform for creating new chemical and physical properties for materials science and device applications. In this review, the recent advancements in NIR emission activated by rare earth and transition metal ions are summarized and their role in applications spanning bioimaging, sensing, and optoelectronics is illustrated. It started with various synthesis techniques and explored how rare earths/transition metals can be skillfully incorporated into various matrixes, thereby endowing them with unique characteristics. The discussion to strategies of enhancing excitation absorption and emission efficiency, spotlighting innovations like dye sensitization and surface plasmon resonance effects is then extended. Subsequently, a significant focus is placed on functionalization strategies and their applications. Finally, a comprehensive analysis of the challenges and proposed strategies for rare earth/transition metal ion-doped near-infrared luminescent materials, summarizing the insights of each section is provided.

Synthesis of sinomenine derivatives with potential anti-leukemia activity.

In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Protective autophagy enhances antistress ability through AMPK/ULK1 signaling pathway in human immortalized keratinocytes.

Keratinocytes, located in the outermost layer of human skin, are pivotal cells to resist environmental damage. Cellular autophagy plays a critical role in eliminating damaged organelles and maintaining skin cell homeostasis. Low-dose 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) has been demonstrated to enhance skin's antistress ability; however, the regulatory mechanisms of autophagy in keratinocytes remain unclear. In this study, we treated immortalized human keratinocytes (HaCaT cells) with low-dose ALA-PDT (0.5 mmol/L, 3 J/cm2). Through RNA-sequencing analysis, we identified that low-dose ALA-PDT modulated autophagy-related pathways in keratinocytes and pinpointed Unc-51-like kinase 1 (ULK1) as a key gene involved. Western blot results revealed that low-dose ALA-PDT treatment upregulated the expression of autophagy-related proteins Beclin-1 and LC3-II/LC3-I ratio. Notably, low-dose ALA-PDT regulated autophagy by inducing an appropriate level of reactive oxygen species (ROS), transiently reducing mitochondrial membrane potential, and decreasing adenosine triphosphate production; all these processes functioned on the AMP-activated protein kinase (AMPK)/ULK1 pathway to activate autophagy. Finally, we simulated external environmental damage using ultraviolet B (UVB) at a dose of 60 mJ/cm2 and observed that low-dose ALA-PDT mitigated UVB-induced cell apoptosis; however, this protective effect was reversed when using the autophagy inhibitor 3-methyladenine. Overall, these findings highlight how low-dose ALA-PDT enhances antistress ability in HaCaT cells through controlling ROS generation and activating the AMPK/ULK1 pathway to arouse cellular autophagy.

Low-Toxicity and High-Efficiency Streptomyces Genome Editing Tool Based on the Miniature Type V-F CRISPR/Cas Nuclease AsCas12f1.

Genome editing tools based on SpCas9 and FnCpf1 have facilitated strain improvements for natural product production and novel drug discovery in Streptomyces. However, due to high toxicity, their editing requires high DNA transformation efficiency, which is unavailable in most streptomycetes. The transformation efficiency of an all-in-one editing tool based on miniature Cas nuclease AsCas12f1 was significantly higher than those of SpCas9 and FnCpf1 in tested streptomycetes, which is due to its small size and weak DNA cleavage activity. Using this tool, in Streptomyces coelicolor, we achieved 100% efficiency for single gene or gene cluster deletion and 46.7 and 40% efficiency for simultaneous deletion of two genes and two gene clusters, respectively. AsCas12f1 was successfully extended to Streptomyces hygroscopicus SIPI-054 for efficient genome editing, in which SpCas9/FnCpf1 does not work well. Collectively, this work offers a low-toxicity, high-efficiency genome editing tool for streptomycetes, particularly those with low DNA transformation efficiency.

ZX703: A Small-Molecule Degrader of GPX4 Inducing Ferroptosis in Human Cancer Cells.

Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction of ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, and biological evaluation of endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with the aim of inducing ferroptosis in cancer cells. Our efforts led to the discovery of compound 5i (ZX703), which significantly degraded GPX4 through the ubiquitin-proteasome and the autophagy-lysosome pathways in a dose- and time-dependent manner. Moreover, 5i was found to induce the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, thereby inducing ferroptosis. This study provides an attractive intervention strategy for ferroptosis-related diseases.

New aporphine alkaloids with antitumor activities from the roots of Thalictrum omeiense.

Two new aporphine alkaloids, 6aR-2'-(3-oxobutenyl)-thaliadin (1) and N-methylthalisopynine (2), along with ten known analogs (3-12), were isolated from the roots of Thalictrum omeiense W. T. Wang et S. H. Wang. Their structures were determined by extensive spectroscopic and X-ray crystallographic analyses. Compounds 1-7 and 9-12 were tested for their antiproliferative effects in vitro against two human cancer cell lines (A549 and MCF-7). Among them, compounds 1, 3, and 7 exhibited moderate inhibitory activity against the tested cell lines with IC50 values ranging from 23.73 to 34.97 µM.

Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model.

BACKGROUND: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options. Recombinant adeno-associated virus (rAAV) provides a promising platform for gene therapy on such kinds of diseases. A microRNA (miRNA) let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated. AIM: To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a xenobiotic-induced mouse model of sclerosing cholangitis. METHODS: A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding for 2 wk or 6 wk. A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding. Upon sacrifice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation and fibrosis were evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot. RESULTS: rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk. The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers, and prevent the proliferation of cholangiocytes and biliary fibrosis. Furthermore, inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1, which consequently inhibit of NF-κB-mediated hepatic inflammation. CONCLUSION: Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis, which provides a possible clinical translation of PSC of human.

Increased ACSL6 Expression Predicts a Favorable Prognosis in Triple-negative Breast Cancer.

BACKGROUND: Long-chain acyl-coenzyme A synthases (ACSLs) are responsible for the catalysis of fatty acids into their corresponding fatty acyl-CoAs. The dysregulation of ACSLs has been increasingly recognized in cancer patients. However, the function of ACSL6 in triple-negative breast cancer (TNBC) is still completely unknown. METHODS: In this study, immunohistochemistry was applied to detect ACSL6 protein expression using a TNBC tissue microarray. Additionally, the mRNA levels of ACSL6 in human normal tissues and pancancer tissues were analyzed using Genotype Tissue Expression (GTEx) datasets and The Cancer Genome Atlas (TCGA) database. The correlations between the levels of ACSL6 expression and clinical characteristics were analyzed. The survival analysis of ACSL6 in TNBC was carried out using the Kaplan‒Meier Plotter online tool. Associations of ACSL6 with immune infiltration analyses were conducted using the ESTIMATE, CIBERSORT, and TISIDB databases. The relationship between ACSL6 and sensitivity to drugs was analyzed from Genomics of Drug Sensitivity in Cancer (GDSC). RESULTS: The results indicated a significant increase in ACSL6 expression in TNBC tissues compared to adjacent normal tissues. However, high ACSL6 expression was significantly associated with favorable survival outcomes in TNBC patients. Enrichment analysis revealed that coexpressed genes of ACSL6 were significantly enriched in various immunity processes. ACSL6 was positively correlated with the infiltration of memory CD4 T cells, while a negative correlation was found between ACSL6 and M2 macrophages and resting dendritic cells. Further analysis revealed that high levels of ACSL6 correlated with increased survival outcomes in cancer patients who received immunotherapy. CONCLUSION: Altogether, the current findings highlight the potential value of ACSL6 as a diagnostic and prognostic marker in the treatment of TNBC.

Efficacy and safety of fractional microneedle radiofrequency for atrophic acne scars: A real-world clinical study of 126 patients.

OBJECTIVE: To analyze the clinical efficacy and safety of fractional microneedle radiofrequency (FMR) for facial atrophic acne scars in a real-world setting. METHODS: The clinical data of patients with atrophic acne scars who had received FMR therapy from February 2018 to August 2022 were retrospectively analyzed. The improvement of atrophic acne scars was assessed using the ECCA Grading Scale (échelle d'évaluation clinique des cicatrices d'acné), Global Aesthetic Improvement Scale (GAIS), and modified Manchester Scar Scale (mMSS). Adverse reactions during FMR treatment were also recorded. Univariate and multivariate logistic regression analyses were performed to evaluate the efficacy and safety of FMR for atrophic acne scars. RESULTS: A total of 126 patients with facial atrophic acne scars were included. A total of 590 FMR treatment sessions were accomplished, with each of 82 patients receiving 4 or more treatment sessions, and 1 receiving a maximum of 14 sessions. All patients showed improvement in symptoms after FMR treatment, with moderate to significant improvement (ECCA score reduction of 26%-100%) in 92 (73.0%) patients. As the number of treatment sessions increased, the ECCA score gradually decreased from an average of 85.6 before to 35.0 after FMR. The average scores for distortion, color, and visual analogue scale (VAS) of mMSS all showed certain reductions. The change in GAIS score indicated improvement after treatment, with minimal improvement in 16 patients (12.7%), good improvement in 57 patients (45.2%), significant improvement in 45 patients (35.7%), and optimal improvement in 8 patients (6.4%). The univariate and multivariate logistic regression analyses revealed that the long pulse width and the number of FMR treatment sessions were positively associated with clinical efficacy. Compared to the short pulse-width group (200 ms), the longer pulse-width group (300 ms) (odds ratio [OR] = 8.3, p = 0.003) and the even longer pulse-width group (400-500 ms) (OR = 52.6, p < 0.001) demonstrated stronger efficacies. Patients who received more than three treatment sessions had better outcomes compared to those who received three or fewer treatment sessions (OR = 4.0, p = 0.036). All patients experienced posttreatment transient erythema, but no crusting, infection, or blister. Six cases developed grid-like erythema around 1 month posttreatment and one case experienced hyperpigmentation, both of which resolved within 1-3 months after appropriate management. CONCLUSION: FMR is a safe and effective treatment modality for improving facial atrophic acne scars, and the number of FMR treatment sessions and pulse width are associated with clinical efficacy.

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.

Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.