Q-switched 1064 nm Nd: YAG laser restores skin photoageing by activating autophagy by TGFß1 and ITGB1.

Excessive ultraviolet B ray (UVB) exposure to sunlight results in skin photoageing. Our previous research showed that a Q-switched 1064 nm Nd: YAG laser can alleviate skin barrier damage through miR-24-3p. However, the role of autophagy in the laser treatment of skin photoageing is still unclear. This study aims to investigate whether autophagy is involved in the mechanism of Q-switched 1064 nm Nd: YAG in the treatment of skin ageing. In vitro, primary human dermal fibroblast (HDF) cells were irradiated with different doses of UVB to establish a cell model of skin photoageing. In vivo, SKH-1 hairless mice were irradiated with UVB to establish a skin photoageing mouse model and irradiated with laser. The oxidative stress and autophagy levels were detected by western blot, immunofluorescence and flow cytometer. String was used to predict the interaction protein of TGF-ß1, and CO-IP and GST-pull down were used to detect the binding relationship between TGFß1 and ITGB1. In vitro, UVB irradiation reduced HDF cell viability, arrested cell cycle, induced cell senescence and oxidative stress compared with the control group. Laser treatment reversed cell viability, senescence and oxidative stress induced by UVB irradiation and activated autophagy. Autophagy agonists or inhibitors can enhance or attenuate the changes induced by laser treatment, respectively. In vivo, UVB irradiation caused hyperkeratosis, dermis destruction, collagen fibres reduction, increased cellular senescence and activation of oxidative stress in hairless mice. Laser treatment thinned the stratum corneum of skin tissue, increased collagen synthesis and autophagy in the dermis, and decreased the level of oxidative stress. Autophagy agonist rapamycin and autophagy inhibitor 3-methyladenine (3-MA) can enhance or attenuate the effects of laser treatment on the skin, respectively. Also, we identified a direct interaction between TGFB1 and ITGB1 and participated in laser irradiation-activated autophagy, thereby inhibiting UVB-mediated oxidative stress further reducing skin ageing. Q-switched 1064 nm Nd: YAG laser treatment inhibited UVB-induced oxidative stress and restored skin photoageing by activating autophagy, and TGFß1 and ITGB1 directly incorporated and participated in this process.

Rosacea and seborrheic dermatitis differentially respond to lactic acid sting and capsaicin tests in Chinese women.

BACKGROUND: Although rosacea and seborrheic dermatitis share some symptoms of sensitive skin, whether they respond differently to lactic acid sting and capsaicin tests, common tests for diagnosis of sensitive skin, is unknown. OBJECTIVES: To reveal the cutaneous responses to lactic acid sting (LAST) and capsaicin test (CAT) in females with either rosacea vs. seborrheic dermatitis. METHODS: A total of 60 patients with rosacea, 20 patients with seborrheic dermatitis and 40 normal controls were enrolled in the study. Their skin sensitivity to stimuli were evaluated following topical application of either 10% lactic acid solution or 0.001% capsaicin solution. Transepidermal water loss (TEWL) rates and erythema indexes were also measured on the face. RESULTS: In comparison to normal controls, the positive rate to either LAST or CAT was significantly higher in subjects with rosacea (p < 0.001), but not in that with seborrheic dermatitis. Similarly, individuals with rosacea displayed a higher positive rate to both LAST and CAT than those with seborrheic dermatitis and normal controls (p < 0.001). In parallel, the LAST scores and CAT scores in individuals with rosacea were significantly higher than in that with either seborrheic dermatitis or normal controls (p < 0.001). The baseline TEWL rates and erythema indexes were higher in individual with rosacea than in normal controls (p < 0.001). But the baseline TEWL rates and erythema indexes did not differ significantly between subjects with rosacea and that with seborrheic dermatitis. Moreover, LAST scores and CAT scores correlated positively with TEWL (p < 0.0001). TEWL rates were higher in CAT positive than in CAT negative subjects (p < 0.0001). Finally, erythema index correlated positively with CAT scores (p < 0.0001), but not with LAST scores (p = 0.0842). CONCLUSIONS: Skin responses to LAST and CAT differ between individuals with rosacea and those with seborrheic dermatitis, possibly due to the differences in epidermal permeability barrier and the neurovascular hyperreactivity. The higher LAST and CAT scores, as well as positive rates of both LAST and CAT can be attributable to inferior permeability barrier and the neurovascular hyperreactivity in subjects with rosacea.

Copy Number Analyses Identified a Novel Gene: APOBEC3A Related to Lipid Metabolism in the Pathogenesis of Preeclampsia.

Background: Preeclampsia is a heterogeneous and complex disease with its pathogenesis mechanism not fully elucidated. A certain subset of patients with preeclampsia exhibit disturbances in lipid metabolism before clinical symptoms. Moreover, there is a tendency for preeclampsia to run in families. Whether genetic factors play a role in abnormal lipid metabolism during the incidence of preeclampsia has not been well investigated. Methods: Preeclampsia patients (n = 110) and healthy age- and gravidity-matched pregnant women (n = 110) were enrolled in this study. Peripheral blood specimens were used for genomic analysis (n = 10/group) or laboratory validation (n = 100/group). We retrospectively obtained the baseline clinical characteristics of 68 preeclampsia patients and 107 controls in early pregnancy (12-14 gestational weeks). Correlation analyses between differential genes and baseline lipid profiles were performed to identify candidate genes. In vitro and in vivo gain-of-function models were constructed with lentivirus and adeno-associated virus systems, respectively, to investigate the role of candidate genes in regulating lipid metabolism and the development of preeclampsia. Results: We observed that preeclampsia patients exhibited significantly elevated plasma TC (P = 0.037) and TG (P < 0.001) levels and increased body mass index (P = 0.006) before the disease onset. Within the region of 27 differential copy number variations, six genes potentially connected with lipid metabolism were identified. The aberrant copies of APOBEC3A, APOBEC3A_B, BTNL3, and LMF1 between preeclampsia patients and controls were verified by quantitative polymerase chain reaction. Especially, APOBEC3A showed a significant positive correlation with TC (P < 0.001) and LDL (P = 0.048) in early pregnancy. Then, our in vitro data revealed that overexpression of APOBEC3A disrupted lipid metabolism in HepG2 cells and affected both cholesterol and fatty acid metabolisms. Finally, in vivo study in a hepatic-specific overexpressed APOBEC3A mouse model revealed abnormal parameters related to lipid metabolism. Pregnant mice of the same model at the end of pregnancy showed changes related to preeclampsia-like symptoms, such as increases in sFlt-1 levels and sFlt-1/PLGF ratios in the placenta and decreases in fetal weight. Conclusion: Our findings established a new link between genetics and lipid metabolism in the pathogenesis of preeclampsia and could contribute to a better understanding of the molecular mechanisms of preeclampsia.

Cost-effectiveness evaluation of different control strategies for Clonorchis sinensis infection in a high endemic area of China: A modelling study.

Clonorchiasis is an important food-borne parasitic disease caused by Clonorchis sinensis infection. The evaluation of long-term cost-effectiveness of control strategies is important for disease control and prevention. The present study aimed to assess the cost-effectiveness of the three recommended strategies (i.e., WHO, Chinese and Guangdong strategies) and different combinations of commonly used measures (i.e., preventive chemotherapy, information, education, and communication (IEC) and environmental improvement) on clonorchiasis. The study area, Fusha town in Guangdong Province, was a typical high endemic area in China. The analysis was based on a multi-group transmission model of C. sinensis infection. We set the intervention duration for 10 years and post-intervention period for 50 years. The corresponding costs and DALYs were estimated. Strategies with incremental cost-effectiveness ratios (ICERs) less than 1/5 of the willingness-to-pay threshold were identified as highly cost-effective strategies. The optimal control strategy was obtained using the next best comparator method. The ICERs of Guangdong strategy were $172 (95% CI: $143-$230) US for praziquantel and $106 (95% CI: $85-$143) US for albendazole, suggesting the highest cost-effectiveness among the three recommended strategies. For praziquantel, 470 sets of control strategies were identified as highly cost-effective strategies for achieving infection control (prevalence<5%). The optimal strategy consisted of chemotherapy targeted on at-risk population, IEC and environmental improvement, with coverages all being 100%, and with the ICER of $202 (95% CI: $168-$271) US. The results for transmission control (prevalence<1%) and albendazole were obtained with the same procedures. The findings may help to develop control policies for C. sinensis infection in high endemic areas. Moreover, the method adopted is applicable for assessment of optimal strategies in other endemic areas.

New laboratory evidence for the association between endothelial dysfunction and COVID-19 disease progression.

There is growing evidence that angiotensin-converting enzyme 2 is highly expressed on endothelial cells, endothelial dysfunction plays a critical role in coronavirus disease 2019 (COVID-19) progression, but laboratory evidence is still lacking. This study established a multicenter retrospective cohort of 966 COVID-19 patients from three hospitals in Wuhan, China. We found that male (62.8% vs. 46.5%), old age [72 (17) vs. 60.5 (21)], and coexisting chronic diseases (88.5% vs. 60.0%) were associated with poor clinical prognosis in COVID-19. Furthermore, the deteriorated patients exhibited more severe multiorgan damage, coagulation dysfunction, and extensive inflammation. Additionally, a cross-sectional study including 41 non-COVID-19 controls and 39 COVID-19 patients assayed endothelial function parameters in plasma and showed that COVID-19 patients exhibited elevated vascular cell adhesion molecule-1 (VCAM-1) (median [IQR]: 0.32 [0.27] vs. 0.17 [0.11] µg/ml, p < 0.001), E-selectin (21.06 [12.60] vs. 11.01 [4.63] ng/ml, p < 0.001), tissue-type plasminogen activator (tPA) (0.22 [0.12] vs. 0.09 [0.04] ng/ml, p < 0.001), and decreased plasminogen activator inhibitor-1 (0.75 [1.31] vs 6.20 [5.34] ng/ml, p < 0.001), as compared to normal controls. Moreover, VCAM-1 was positively correlated with d-dimer (R = 0.544, p < 0.001); tPA was positively correlated with d-dimer (R = 0.800, p < 0.001) and blood urea nitrogen (R = 0.638, p < 0.001). Our findings further confirm the strong association between endothelial dysfunction and poor prognosis of COVID-19, which offers a rationale for targeting endothelial dysfunction as a therapeutic strategy for COVID-19.

Single-cell transcriptome analysis revealed a suppressive tumor immune microenvironment in EGFR mutant lung adenocarcinoma.

BACKGROUNDS: Immunotherapy is less effective in patients with epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). Lower programmed cell death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB) are reported to be the underlying mechanism. Being another important factor to affect the efficacy of immunotherapy, tumor microenvironment (TME) characteristics of this subgroup of NSCLC are not comprehensively understood up to date. Hence, we initiated this study to describe the specific TME of EGFR-mutant lung adenocarcinoma (LUAD) from cellular compositional and functional perspectives to better understand the immune landscape of this most common subtype of NSCLC. METHODS: We used single-cell transcriptome sequencing and multiplex immunohistochemistry to investigate the immune microenvironment of EGFR-mutant and EGFR wild-type LUADs and determined the efficacy of immunotherapy. We analyzed single cells from nine treatment-naïve samples and compared them to three post-immunotherapy samples previously reported from single cell perspective using bioinformatics methods. RESULTS: We found that EGFR-mutant malignant epithelial cells had similar characteristics to the epithelial cells in non-responders. EGFR-mutant LUAD lacked CD8+ tissue-resident memory (TRM) cells, which could promote tertiary lymphoid structure generation by secreting CXCL13. In addition, other cell types, including tumor-associated macrophages and cancer-associated fibroblasts, which are capable of recruiting, retaining, and expanding CD8+ TRM cells in the TME, were also deficient in EGFR-mutant LUAD. Furthermore, EGFR-mutant LUAD had significantly less crosstalk between T cells and other cell types via programmed cell death-1 (PD-1) and PD-L1 or other immune checkpoints compared with EGFR wild-type LUAD. CONCLUSIONS: Our findings provide a comprehensive understanding of the immune landscape of EGFR-mutant LUAD at the single-cell level. Based on the results, many cellular components might have negative impact on the specific TME of EGFR-mutant LUAD through influencing CD8+ TRM. Lack of CD8+ TRM might be a key factor responsible for the suppressive TME of EGFR-mutant LUAD.

Clinical features and intervention timing in patients with pregnancy-associated non-small-cell lung cancer.

BACKGROUND: There is no standard procedure available to diagnose and treat with pregnancy-associated non-small cell lung cancer (NSCLC). The present study was to investigate the clinical and molecular features, and the proper intervention timing for this population. METHODS: This is a retrospective, pooled analysis. Cases from Guangdong Lung Cancer Institute and other published cases were collected and reviewed. The overall survival (OS) was analyzed according to the diagnosis timing, the treatment timing and the molecular character. The safety profile during pregnancy was also evaluated. RESULTS: Seventy-seven cases were collected including 11 patients from our center. The anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) mutation rates were 47% and 32%, respectively. The OS of patients treated during pregnancy, after delivery, and those not treated differed significantly [12 months vs. not reached (NR) vs. 1 month; P<0.001]. However, the OS between patients treated during pregnancy and after delivery was similar (P=0.173). Patients with ALK or EGFR exhibited a significantly better OS than those with wild-type [NR vs. 22 months vs. 8 months; P<0.001; hazard ratio (HR) =0.02, 95% confidence interval (CI): 0.00-0.22; HR =0.08, 95% CI: 0.01-0.76]. Fetal complications were observed in babies whose mothers were treated during pregnancy. CONCLUSIONS: The pregnancy-associated NSCLC population exhibited a high prevalence of driver genes and a promising effect of targeted therapy. No significant difference in the OS was observed between patients treated during pregnancy and patients treated after delivery.

Moving Average Based Index for Judging the Peak of the COVID-19 Epidemic.

A pneumonia outbreak caused by a novel coronavirus (COVID-19) has spread around the world. A total of 2,314,621 laboratory-confirmed cases, including 157,847 deaths (6.8%) were reported globally by 20 April 2020. Common symptoms of COVID-19 pneumonia include fever, fatigue, and dry cough. Faced with such a sudden outbreak of emerging infectious disease, traditional models for predicting the peak of the epidemic often show inconsistent results. With the aim to timely judge the epidemic peak and provide support for decisions for resuming production and returning to normal life based on publicly reported data, we used a seven-day moving average of log-transformed daily new cases (LMA) to establish a new index named the "epidemic evaluation index" (EEI). We used SARS epidemic data from Hong Kong to verify the practicability of the new index, and then applied it to the COVID-19 epidemic analysis. The results showed that the epidemic peaked, respectively, on 9 February and 5 February 2020, in Hubei Province and other provinces in China. The proposed index can be applied for judging the epidemic peak. While the global COVID-19 epidemic reached its peak in the middle of April, the epidemic peaks in some countries have not yet appeared. Global and united efforts are still needed to eventually eliminate the epidemic.

Q-switched 1064-nm dymium-doped yttrium aluminum garnet laser irradiation induces skin collagen synthesis by stimulating MAPKs pathway.

The 1064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is widely used in clinical practice. However, the effects of 1064-nm Q-switched Nd:YAG laser on skin collagen generation have not been fully elucidated. The objectives of the present study were to investigate whether the 1064-nm Q-switched Nd:YAG laser can be used for non-ablative rejuvenation and to explore the possible mechanism underlying the effects. Six-week-old SKH-1 hairless mice were irradiated by the 1064-nm Nd:YAG laser at fluences of 0, 0.5, 1, 1.5, and 2 J/cm2, respectively. The contents of hydroxyproline and hydration were detected after laser irradiation. Moreover, hematoxylin-eosin (HE) staining was preformed to evaluate the dermal thickness. Immunofluorescence was used to detect the expressions of MMP-2 and TIMP-1 in the skin after laser irradiation. Furthermore, qRT-PCR was performed to determine the expressions of TGF-ß1 and Smad3. In addition, the expressions of ERK1/2, p-ERK1/2, p38, p-p38, JNK, ERK5, and collagen were evaluated by Western blotting. The results indicated that the levels of hydroxyproline, hydration, and collagen were markedly increased; both the thickness of dermal was enhanced after low dose of laser treatment. Moreover, the expression of TIMP-1 was significantly increased, whereas the expression of MMP-2 was remarkably decreased after laser irradiation. Meanwhile, TGF-ß1, Smad3, p-ERK1/2, p-P38, and JNK productions were significantly enhanced in irradiated group compared with the ones non-irradiated. Nevertheless, no significant changes were observed in the expression of ERK5 after irradiation. In summary, our study demonstrated that Q-switched 1064-nm Nd:YAG laser can induce collagen generation, at least in part, through activating TGF-ß1/Smad3/MAPK signaling pathway.