2% supramolecular salicylic acid hydrogel vs. adapaline gel in mild to moderate acne vulgaris treatment: A multicenter, randomized, evaluator-blind, parallel-controlled trial.

OBJECTIVE: Salicylic acid (SA) has been used for treatment of acne of different severity levels. However, there are few researches about the safety and efficacy for treatment of mild to moderate acne, and the improvement of the skin condition by using 2% supramolecular salicylic acid (SSA) compared to Davuwen Adapaline gel. METHODS: A multicenter, randomized, assessor-blind and parallel-controlled study was conducted. A total of 500 patients (trial group: 249, control group: 251) with mild to moderate (grade I-II) facial acne vulgaris were recruited in this study over a 16-week trial period. Patients in the trial group were treated with Broda 2% SSA hydrogel, while control group treated with Davuwen Adapaline gel once a day. The number of inflammatory papules, comedones, and pustules were counted and the rate of lesion reduction was calculated pre- and post-treatment. Then, the skin physiological indicators, including L*a*b*, TEWL, skin sebum and hydration were measured. Statistical analysis was conducted using SAS 9.4. Significance was set at p = 0.05. RESULTS: At the end of 12 weeks' therapy, the regression and markedly improvement rate of the trail group and the control group were 51.01% and 43.10% respectively, and there was no significant difference in the improvement rate between two groups (p = 0.0831). Although, there was no difference in adverse events rate between two groups, the adverse events rate of the trail group was 0.40%, a little lower than the control group (0.80%). Moreover, there was a significant difference in the numbers of pores at T1 between two groups. CONCLUSION: Both 2% SSA and Adapaline gel were equally effective in the treatment of mild to moderate acne vulgaris. 2% SSA is worth the clinical promotion and application in mild to moderate acne vulgaris.

The dose response of erythemal area and intensity on the unprotected skin fits well to a logistic 3P model in SPF tests of a Chinese population, which has the potential to improve the precision and consistency of minimal erythema dose determination.

BACKGROUND: The current ISO guidelines for minimal erythema dose (MED) determination require assessment of erythema area of UV-irradiated skin sites. However, this parameter has not been adequately quantified in daily practice. The aims of this study were to investigate the dose response on the unprotected skin sites by quantifying the erythema area and intensity and to show the potential for improving the precision and consistency of MEDu determination by developing predictive models. METHODS: Standard radiation tests were conducted on the back of 31 healthy Chinese volunteers and the MEDu site of each subject was clinically determined by dermatologists. Images of test sites were captured 24 h after radiation, and the erythema area (%EA) and intensity (∆a*) were measured by image analysis. The data were fitted to a logistic 3P function to obtain dose-response curves, and a set of logit (inverse-logistic) models were then derived. An erythema area threshold of %EA = 52% was established to predict MEDu based on the clinical endpoints defined by ISO 24444:2019. RESULTS: Analysis of the clinically determined MEDu sites revealed wide ranges of %EA (62.3 ± 15% SD) and ∆a* (2.96 ± 0.92 SD). The dose response fitted well to a logistic 3P model (mean R2 = 0.965 and 0.975 for %EA and ∆a*, respectively). Applying the area threshold, values of MEDu were determined by the logit model for the test population, which significantly improved the consistency of MEDu determination (52 ± 0% SD and 2.73 ± 0.61 SD for %EA and ∆a*, respectively). CONCLUSION: This study demonstrated that the dose response of UV-induced erythema can be quantified and modeled once the erythema area and intensity are measured. The results of this study show the potential to improve the precision and consistency of MEDu determination in an SPF test. The similar potential in photodermatological, therapeutic, and diagnostic applications was also implied.

FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance.

Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2, PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer.

Integrating plan complexity and dosiomics features with deep learning in patient-specific quality assurance for volumetric modulated arc therapy.

PURPOSE: To investigate the feasibility and performance of deep learning (DL) models combined with plan complexity (PC) and dosiomics features in the patient-specific quality assurance (PSQA) for patients underwent volumetric modulated arc therapy (VMAT). METHODS: Total of 201 VMAT plans with measured PSQA results were retrospectively enrolled and divided into training and testing sets randomly at 7:3. PC metrics were calculated using house-built algorithm based on Matlab. Dosiomics features were extracted and selected using Random Forest (RF) from planning target volume (PTV) and overlap regions with 3D dose distributions. The top 50 dosiomics and 5 PC features were selected based on feature importance screening. A DL DenseNet was adapted and trained for the PSQA prediction. RESULTS: The measured average gamma passing rate (GPR) of these VMAT plans was 97.94% ± 1.87%, 94.33% ± 3.22%, and 87.27% ± 4.81% at the criteria of 3%/3 mm, 3%/2 mm, and 2%/2 mm, respectively. Models with PC features alone demonstrated the lowest area under curve (AUC). The AUC and sensitivity of PC and dosiomics (D) combined model at 2%/2 mm were 0.915 and 0.833, respectively. The AUCs of DL models were improved from 0.943, 0.849, 0.841 to 0.948, 0.890, 0.942 in the combined models (PC + D + DL) at 3%/3 mm, 3%/2 mm and 2%/2 mm, respectively. A best AUC of 0.942 with a sensitivity, specificity and accuracy of 100%, 81.8%, and 83.6% was achieved with combined model (PC + D + DL) at 2%/2 mm. CONCLUSIONS: Integrating DL with dosiomics and PC metrics is promising in the prediction of GPRs in PSQA for patients underwent VMAT.

Evaluation the benefits of additional radiotherapy for gastric cancer patients after D2 resection using CT based radiomics.

OBJECTIVES: The value of adding radiotherapy (RT) is still unclear for patients with gastric cancer (GC) after D2 lymphadenectomy. The purpose of this study is to predict and compare the overall survival (OS) and disease-free survival (DFS) of GC patients treated by chemotherapy and chemoradiation based on contrast-enhanced CT (CECT) radiomics. METHODS: A total of 154 patients treated by chemotherapy and chemoradiation in authors' hospital were retrospectively reviewed and randomly divided into the training and testing cohorts (7:3). Radiomics features were extracted from contoured tumor volumes in CECT using the pyradiomics software. Radiomics score and nomogram with integrated clinical factors were developed to predict the OS and DFS and evaluated with Harrell's Consistency Index (C-index). RESULTS: Radiomics score achieved a C index of 0.721(95%CI: 0.681-0.761) and 0.774 (95%CI: 0.738-0.810) in the prediction of DFS and OS for GC patients treated by chemotherapy and chemoradiation, respectively. The benefits of additional RT only demonstrated in subgroup of GC patients with Lauren intestinal type and perineural invasion (PNI). Integrating clinical factors further improved the prediction ability of radiomics models with a C-index of 0.773 (95%CI: 0.736-0.810) and 0.802 (95%CI: 0.765-0.839) for DFS and OS, respectively. CONCLUSIONS: CECT based radiomics is feasible to predict the OS and DFS for GC patients underwent chemotherapy and chemoradiation after D2 resection. The benefits of additional RT only observed in GC patients with intestinal cancer and PNI.

Endometrial microstimulation effects on endometrial receptivity assessed by transvaginal color Doppler sonography.

OBJECTIVE: This study investigated the effect of endometrial microstimulation (EM) on endometrial receptivity using transvaginal color Doppler sonography (TVCDS). METHOD: Women of childbearing age who were preparing to conceive (n = 90) were randomly divided into the EM group (n = 30), who were examined by EM on days 3-5 of the menstrual cycle, and the control group (n = 60). TVCDS was conducted during the implantation window phase, and endometrial thickness, endometrial pattern, endometrial movement, blood flow type, and uterine and spiral arterial hemodynamic parameter measurements were made. The groups were compared to identify differences. RESULTS: Endometrial thickness (0.97 ± 0.18 cm and 0.95 ± 0.17 cm), endometrial movement (type 1: 46.7% and 51.7%; type 2: 30.0% and 28.3%; type 3: 6.7% and 5.0%; type 5: 16.7% and 15.0%), and hemodynamic parameters of the uterine (pulsatility index [PI]: 2.46 ± 0.50 and 2.41 ± 0.48; resistance index [RI]: 0.85 ± 0.05 and 0.84 ± 0.05) and spiral (PI: 1.11 ± 0.32 and 1.19 ± 0.33; RI: 0.48 ± 0.11 and 0.51 ± 0.08) arteries did not differ significantly between groups (P > 0.05). However, the endometrial pattern (a trilaminar pattern: 80.0% and 58.3%; P = 0.041) and blood flow type (type I: 16.7% and 43.3%; type II: 63.3% and 40.0%; type III 20.0% and 16.7%; P = 0.038) differed significantly between groups. CONCLUSION: Endometrial microstimulation did not alter endometrial pathological staging, endometrial thickness, or movement, nor did it affect uterine and spiral arterial blood flow parameters. However, it may be able to abrade abnormal endometrial tissue, optimizing the endometrial pattern. Endometrial microstimulation may support local spiral artery regeneration and increase endometrial blood supply in new cycles.

hMSC exosomes as a novel treatment for female sensitive skin: An in vivo study.

Background: Recent studies have reported that the incidence of sensitive skin is increasing. Skin sensitivity and skin barrier functions were related to many skin diseases including atopic dermatitis, psoriasis, rosacea, and so on. Mesenchymal stem cell (MSC)-derived exosomes (hMSC) might be considered as a new effective therapeutic scheme. Aims: This study aims to investigate the safety and efficacy of hMSC exosomes as a novel topical treatment for sensitive skin. Patients/Methods: Exosomes were extracted from primary hMSC via ultracentrifugation method. The morphology of hMSC exosomes was studied via transmission electron microscope. Expression of exosome specific surface marker was detected via Western blot. 22 subjects (female, aged 18-55) diagnosed with sensitive skin were enrolled. Follow-up was conducted before, 7-day, 14-day, and 28-day after hMSC exosomes use. Transepidermal water loss (TEWL), surface hydration, sebum secretion, and L*a*b* value were simultaneously tested at the same time point in an environment-controlled room. Results: Under transmission electron microscopy, the extracted hMSC exosomes were circular or elliptical with intact membrane structure, and their diameters ranged mainly from 40 to 80 nm. Western blot showed that the expression of markers CD63, CD9, and Tsg101 was positive. Brownian motion based nanoparticle trajectory analysis (NTA) showed that the main peak of particle size distribution occurred around 96 nm, the average particle size was 122 nm, and the main peak accounted for 96.7%. All this conformed to the biological characteristics of exosomes standardized by the International Society for Extracellular Vesicles. In the clinical trial, scores of objective symptoms including roughness, scales, erythema, and subjective symptoms including tension, burning, or itching, were improved after 7-, 14-, and 28- day using hMSC-exosomes. TEWL, hydration, sebum, pH, and a* values were tended to return to the level of healthy skin. Conclusion: The hMSC-exosomes, with the advantages of biocompatibility and biodegradability, could improve clinical symptoms and eruptions in sensitive skin patients, and might be as an MSC cell-free novel therapy in sensitive skin-related disease treatment.

Efficient dose-volume histogram-based pretreatment patient-specific quality assurance methodology with combined deep learning and machine learning models for volumetric modulated arc radiotherapy.

BACKGROUND: Weak correlation between gamma passing rates and dose differences in target volumes and organs at risk (OARs) has been reported in several studies. Evaluation on the differences between planned dose-volume histogram (DVH) and reconstructed DVH from measurement was adopted and incorporated into patient-specific quality assurance (PSQA). However, it is difficult to develop a methodology allowing the evaluation of errors on DVHs accurately and quickly. PURPOSE: To develop a DVH-based pretreatment PSQA for volumetric modulated arc therapy (VMAT) with combined deep learning (DL) and machine learning models to overcome the limitation of conventional gamma index (GI) and improve the efficiency of DVH-based PSQA. METHODS: A DL model with a three-dimensional squeeze-and-excitation residual blocks incorporated into a modified U-net was developed to predict the measured PSQA DVHs of 208 head-and-neck (H&N) cancer patients underwent VMAT between 2018 and 2021 from two hospitals, in which 162 cases was randomly selected for training, 18 for validation, and 28 for testing. After evaluating the differences between treatment planning system (TPS) and PSQA DVHs predicted by DL model with multiple metrics, a pass or fail (PoF) classification model was developed using XGBoost algorithm. Evaluation of domain experts on dose errors between TPS and reconstructed PSQA DVHs was taken as ground truth for PoF classification model training. RESULTS: The prediction model was able to achieve a good agreement between predicted, measured, and TPS doses. Quantitative evaluation demonstrated no significant difference between predicted PSQA dose and measured dose for target and OARs, except for Dmean of PTV6900 (p = 0.001), D50 of PTV6000 (p = 0.014), D2 of PTV5400 (p = 0.009), D50 of left parotid (p = 0.015), and Dmax of left inner ear (p = 0.007). The XGBoost model achieved an area under curves, accuracy, sensitivity, and specificity of 0.89 versus 0.88, 0.89 versus 0.86, 0. 71 versus 0.71, and 0.95 versus 0.91 with measured and predicted PSQA doses, respectively. The agreement between domain experts and the classification model was 86% for 28 test cases. CONCLUSIONS: The successful prediction of PSQA doses and classification of PoF for H&N VMAT PSQA indicating that this DVH-based PSQA method is promising to overcome the limitations of GI and to improve the efficiency and accuracy of VMAT delivery.

The Influence of Different Ultrasonic Machines on Radiomics Models in Prediction Lymph Node Metastasis for Patients with Cervical Cancer.

Objective To investigate the effects of different ultrasonic machines on the performance of radiomics models using ultrasound (US) images in the prediction of lymph node metastasis (LNM) for patients with cervical cancer (CC) preoperatively. Methods A total of 536 CC patients with confirmed histological characteristics and lymph node status after radical hysterectomy and pelvic lymphadenectomy were enrolled. Radiomics features were extracted and selected with US images acquired with ATL HDI5000, Voluson E8, MyLab classC, ACUSON S2000, and HI VISION Preirus to build radiomics models for LNM prediction using support vector machine (SVM) and logistic regression, respectively. Results There were 148 patients (training vs validation: 102:46) scanned in machine HDI5000, 75 patients (53:22) in machine Voluson E8, 100 patients (69:31) in machine MyLab classC, 110 patients (76:34) in machine ACUSON S2000, and 103 patients (73:30) in machine HI VISION Preirus, respectively. Few radiomics features were reproducible among different machines. The area under the curves (AUCs) ranged from 0.75 to 0.86, 0.73 to 0.86 in the training cohorts, and from 0.71 to 0.82, 0.70 to 0.80 in the validation cohorts for SVM and logistic regression models, respectively. The highest difference in AUCs for different machines reaches 17.8% and 15.5% in the training and validation cohorts, respectively. Conclusions The performance of radiomics model is dependent on the type of scanner. The problem of scanner dependency on radiomics features should be considered, and their effects should be minimized in future studies for US images.

Contrast-enhanced CT based radiomics in the preoperative prediction of perineural invasion for patients with gastric cancer.

PURPOSE: To investigate the feasibility and accuracy of radiomics models based on contrast-enhanced CT (CECT) in the prediction of perineural invasion (PNI), so as to stratify high-risk recurrence and improve the management of patients with gastric cancer (GC) preoperatively. METHODS: Total of 154 GC patients underwent D2 lymph node dissection with pathologically confirmed GC and preoperative CECT from an open-label, investigator-sponsored trial (NCT01711242) were enrolled. Radiomics features were extracted from contoured images and selected using Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) after inter-class correlation coefficient (ICC) analysis. Models based on radiomics features (R), clinical factors (C) and combined parameters (R + C) were built and evaluated using Support Vector Machine (SVM) and logistic regression to predict the PNI for patients with GC preoperatively. RESULTS: Total of 11 radiomics features were selected for final analysis, along with two clinical factors. The area under curve (AUC) of models based on R, C, and R + C with logistic regression and SVM were 0.77 vs. 0.83, 0.71 vs.0.70, 0.86 vs. 0.90, and 0.73 vs.0.80, 0.62 vs. 0.64, 0.77 vs. 0.82 in the training and testing cohorts, respectively. SVM(R + C) achieved a best AUC of 0.82(0.69-0.94) in the test cohorts with a sensitivity, specificity and accuracy of 0.63, 0.91, and 0.77, respectively. CONCLUSIONS: The performance of these models indicates that radiomics features alone or combined with clinical factors provide a feasible way to classify patients preoperatively and improve the management of patients with GC.

Effect of Hysteroscopic Polypectomy Combined with Mirena Placement on Postoperative Adverse Reactions and Recurrence Rate of Endometrial Polyps: Based on a Large-Sample, Single-Center, Retrospective Cohort Study.

Objective: To investigate the effect of hysteroscopy surgery combined with Mirena on postoperative adverse reactions and recurrence rate of endometrial polyps (EP). Methods: A total of 312 patients who underwent hysteroscopic polypectomy of EP in our hospital from June 2017 to November 2020 were enrolled retrospectively. Among them, 42 patients did not take any treatment after the operation (control group), 156 patients were treated with levonorgestrel intrauterine birth control system (Mirena group), and 114 patients were treated with oral spironolone ethinylestradiol tablets (oral group). The clinical data of 312 patients were recorded and followed up regularly. All patients were followed up through an outpatient clinic or telephone to 12 months after the operation. The patients' age, disease course, number of pregnancies, clinical manifestations, endometrial thickness before the operation, duration of operation, amount of bleeding during the operation, and number and size of polyps were analyzed. The recurrence and postoperative side effects of EP in the three groups were followed up within 12 months after the operation. Results: There was no significant difference in endometrial thickness among the three groups before treatment (P > 0.05). After 3 months, 6 months, and 12 months of treatment, the endometrial thickness of the three groups decreased, while the decrease in the Mirena group and the oral group was better compared to the control (P < 0.05). The decrease in the Mirena group was better than that in the oral group (P < 0.05). There was no significant difference in hemoglobin levels among the three groups before treatment (P > 0.05). After 3, 6, and 12 months of treatment, the hemoglobin levels of the three groups increased to varying degrees, while the levels of the Mirena group and oral group were better compared to the control (P < 0.05). Three months after the operation, the improvement of clinical symptoms was similar in the three groups, and there was no significant difference among the three groups (P > 0.05). At 6 and 12 months after the operation, the improvement of clinical symptoms in the oral group and Mirena group was better compared to the control group (P < 0.05), but there was no significant difference between the oral group and Mirena group (P > 0.05). After the operation, some patients had complications such as lower abdominal pain, breast distension pain, irregular vaginal bleeding, and abnormal liver function. There was no significant difference in the number of complications among the three groups (P > 0.05). During the follow-up to 12 months after the operation, the recurrence rate in the oral group and Mirena group was lower compared to the control (P < 0.05), and the recurrence rate in the Mirena group was lower than that in the oral group (P < 0.05). Conclusion: Placing Mirena immediately after hysteroscopic polypectomy of EP can reduce the recurrence rate of endometrial polyps, increase the level of hemoglobin, and reduce the thickness of the endometrium, which can be employed and popularized according to the condition of patients in clinical work.

RefineNet-based 2D and 3D automatic segmentations for clinical target volume and organs at risks for patients with cervical cancer in postoperative radiotherapy.

PURPOSE: An accurate and reliable target volume delineation is critical for the safe and successful radiotherapy. The purpose of this study is to develop new 2D and 3D automatic segmentation models based on RefineNet for clinical target volume (CTV) and organs at risk (OARs) for postoperative cervical cancer based on computed tomography (CT) images. METHODS: A 2D RefineNet and 3D RefineNetPlus3D were adapted and built to automatically segment CTVs and OARs on a total of 44 222 CT slices of 313 patients with stage I-III cervical cancer. Fully convolutional networks (FCNs), U-Net, context encoder network (CE-Net), UNet3D, and ResUNet3D were also trained and tested with randomly divided training and validation sets, respectively. The performances of these automatic segmentation models were evaluated by Dice similarity coefficient (DSC), Jaccard similarity coefficient, and average symmetric surface distance when comparing them with manual segmentations with the test data. RESULTS: The DSC for RefineNet, FCN, U-Net, CE-Net, UNet3D, ResUNet3D, and RefineNet3D were 0.82, 0.80, 0.82, 0.81, 0.80, 0.81, and 0.82 with a mean contouring time of 3.2, 3.4, 8.2, 3.9, 9.8, 11.4, and 6.4 s, respectively. The generated RefineNetPlus3D demonstrated a good performance in the automatic segmentation of bladder, small intestine, rectum, right and left femoral heads with a DSC of 0.97, 0.95, 091, 0.98, and 0.98, respectively, with a mean computation time of 6.6 s. CONCLUSIONS: The newly adapted RefineNet and developed RefineNetPlus3D were promising automatic segmentation models with accurate and clinically acceptable CTV and OARs for cervical cancer patients in postoperative radiotherapy.

A new product of multi-plant extracts improved skin photoaging: An oral intake in vivo study.

BACKGROUND: Besides the topical application of cosmetics, nutraceuticals represent a promising strategy for preventing skin photoaging and skin cancers. METHODS: To determine the effect of a new multi-plant extracts product containing Cucumis melo extract, acerola extract, olive fruit, aloe vera gel, grape seed extract, and lycopene, a randomized, placebo-controlled, double-blind clinical trial and an ultraviolet (UV)-induced murine photoaging model were deployed. 55 healthy subjects aged 45-60 were enrolled and randomized to take the product or placebo orally for 12 weeks. Skin aging and whitening indexes were measured with non-invasive techniques. 90 Balb/c mice aged 7-8 weeks were randomly divided into six groups: normal, UV, UV+vehicle, UV+different doses of the product (0.500 g/kg.BW, 0.250 g/kg.BW, 0.125 g/kg.BW, respectively). Except the normal group, mid-dorsal regions were irradiated with UVA+UVB for 8 weeks. Factors of oxidative stress, tyrosinase, and histological analysis of the mid-dorsal skin were determined. RESULTS: In the clinical trial, the TEWL, hydration, sebum, elasticity, and the L*, a*, melanin index change from baseline, ITA° were significantly improved in the experiment group. In the animal experiment, compared to the UV+vehicle group, UV+high dose group showed significantly lower malondialdehyde (MDA) and tyrosinase, but higher superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px). The UV+moderate dose group showed significant improvement of MDA and GSH-Px, and the UV+low dose group only showed improvement of GSH-Px. Histological photoaging manifestations were attenuated in the UV+high and moderate dose groups. CONCLUSIONS: The multi-plant extracts product improved skin photoaging possibly via antioxidant and anti-tyrosinase ways.

Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion.

Background: Unexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis. Objective: To investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA. Methods: We profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated in vitro. Results: RP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients (P = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and in vitro overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes (HSPA1A and HSPA1B) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis (HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B (P = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and HNRNPH3 knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1ß, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA. Conclusion: Our results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70 via binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.

Level of Foxp3, DNMTs, methylation of Foxp3 promoter region, and CD4 + CD25 + CD127low regulatory T cells in vulvar lichen sclerosus.

This study is to investigate the pathogenesis of vulvar lichen sclerosus (VLS) by analyzing the level of Foxp3, DNMTs, methylation of Foxp3 promoter region, and CD4 + CD25 + CD127low Regulatory T cells (Tregs). This study enrolled 15 VLS patients and 25 controls. Lesional and extralesional vulvar skin tissues, normal vulvar skin tissues and peripheral blood were collected. Compared with the control group, Foxp3 protein in the lesional and extralesional skin of VLS group was significantly reduced. The levels of DNMT1 and DNMT3b proteins in lesional skin of VLS group were significantly increased. There was no difference in the total methylation rates of the promoter region of the Foxp3 gene. The methylation rates of CpG1, CpG4, CpG9, and CpG10 were significantly higher in lesional skin of VLS group than in control group. There was no correlation between the total methylation rates of 10 CpG sites and the level of Foxp3 and DNMT1 proteins; there was a positive correlation between Foxp3 and DNMT1 protein in lesional skin of VLS group (r = 0.675, p < 0.05), and a negative correlation (r = -0.665, p < 0.05) in extralesional skin of VLS group. However, there was no correlation of Foxp3 with DNMT3b. The number of CD4 + CD25 + CD127low Tregs VLS decreased significantly. The expression of Foxp3 protein and the quantity of CD4 + CD25 + CD127low Tregs in patients with VLS decreased, which may cause local or systemic abnormal immunosuppression of Tregs, leading to the occurrence of VLS. This may be related with methylation or DNMT1, which needs further verification.

Skin barrier damaging and repairing process: A new application field of dermoscopy.

BACKGROUND: Although more and more noninvasive detection technologies have been used in assessing skin barrier integrity and functions, more accurate, intuitive, and convenient detective methods still needed to be explored and developed. AIMS: To investigate the characteristic image changes under the dermoscopy and to explore the relationship with skin physiological indexes in skin barrier damaging and repairing process. PATIENTS/METHODS: 25 healthy subjects with normal skin in forearm were included and divided into different groups according to the operated strips numbers (30, 35, and 40 times). Before tape stripping, and immediately, 3, 7, 14, and 21 days after tape stripping, dermoscopic examination and skin transepidermal water loss (TEWL), surface hydration, and L*a*b* value were simultaneously tested in the same region. RESULTS: Immediately after different times tape stripping, the amount of cuticle cells residues and the microvascular images were different. In skin barrier repairing process, the scab forming time observed under dermoscopy was day 14, day 7, and day 3 on 30 times, 35 times, and 40 times stripped skin, respectively. A small amount of cuticle cells and blurry vessels could be identified in hydration value <40 group, while there was no cuticle cell residue, and the branching vessels were obvious in hydration value >40 group. CONCLUSIONS: Unique manifestations could be observed under dermoscopy in different time points of skin barrier with various degree of injury and in skin barrier repairing process. By combining dermoscopy and skin indexes assessing technologies, the skin barrier integrity and function could be observed and evaluated more accurately and precisely.

Impact of setup errors on multi-isocenter volumetric modulated arc therapy for craniospinal irradiation.

Multi-isocenter volumetric modulated arc therapy (VMAT) is recommended for craniospinal irradiation (CSI) to smooth the dose distribution in the junction regions relying solely on inverse optimization. However, few studies have measured the dosimetric impact of setup errors on this multi-isocenter VMAT in the junction areas. The purpose of this study is to evaluate the impact of positional errors during VMAT CSI with two-dimension (2D) and three-dimension (3D) dosimetric measurements. A total of 20 patients treated by three-isocenter VMAT CSI were retrospectively reviewed and analyzed. A 3D diode array ArcCHECK and radiochromic film EBT3 were applied to measure the percentage gamma passing rates (%GPs) and dose distributions in the junction areas between the cranial/upper-spinal and the upper/lower-spinal fields with intentionally introduced setup errors of ± 1 mm, ±2 mm, ±3 mm, ±5 mm, and ± 8 mm, respectively. The length and volume of planning target volume (PTV) for these CSI patients ranged from 50.14 to 80.8 cm, and 1572.3 to 2114.5 cm3 , respectively. The %GPs for ±3 mm, ±5 mm, and ±8 mm positional errors were around 95%, 90%, and 85%, respectively, in the junction areas. The dosimetric verification results with EBT3 films indicated that cold and hot areas were observed with the increase of introduced setup errors. In conclusion, the dosimetric verification with intentionally introduced setup errors demonstrated that positional errors within 3 mm have a little impact for VMAT CSI, although setup errors should be minimized. Relying on the inverse optimization of VMAT to smooth the dose distribution in the junction areas is feasible for CSI.

Cross verification of independent dose recalculation, log files based, and phantom measurement-based pretreatment quality assurance for volumetric modulated arc therapy.

Independent treatment planning system (TPS) check with Mobius3D software, log files based quality assurance (QA) with MobiusFX, and phantom measurement-based QA with ArcCHECK were performed and cross verified for head-and-neck (17 patients), chest (16 patients), and abdominal (19 patients) cancer patients who underwent volumetric modulated arc therapy (VMAT). Dosimetric differences and percentage gamma passing rates (%GPs) were evaluated and compared for this cross verification. For the dosimetric differences in planning target volume (PTV) coverage, there was no significant difference among TPS vs. Mobius3D, TPS vs. MobiusFX, and TPS vs. ArcCHECK. For the dosimetric differences in organs at risks (OARs), the number of metrics with an average dosimetric differences higher than ±3% for TPS vs Mobius3D, TPS vs MobiusFX, and TPS vs ArcCHECK were 1, 1, 7; 2, 1, 4; 1, 1, 5 for the patients with head-and-neck, abdomen, and chest cancer, respectively. The %GPs of global gamma indices for Mobius3D and MobiousFX were above 97%, while it ranged from 92% to 96% for ArcCHECK. The %GPs of individual volume-based gamma indices were around 98% for Mobius3D and MobiousFX, except for γPTV for chest and abdominal cancer (88.9% to 92%); while it ranged from 86% to 99% for ArcCHECK. In conclusion, some differences in dosimetric metrics and gamma passing rates were observed with ArcCHECK measurement-based QA in comparison with independent dosecheck and log files based QA. Care must be taken when considering replacing phantom measurement-based IMRT/VMAT QA.

Simultaneous determination and determination of sildenafil and its active metabolite in human plasma using LC-MS/MS method.

A sensitive and selective high-performance liquid chromatography-tandam mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma. Sildenafil-d8 was used as an internal standard. The analytes were extracted by precipitation extraction and chromatographed on a C18 column using mobile phase A of water (containing 0.1% formic acid) and mobile phase B of acetonitrile (containing 0.1% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 → m/z 283.3 for sildenafil, m/z 461.4 → m/z 283.2 for N-desmethyl sildenafil and m/z 483.3 → m/z 108.1 for IS in positive ionization mode. The calibration curve was established over the range of 2.00-1,000 ng/ml and the correlation coefficient was >0.99. The intra-day and inter-day relative standard deviations were <6.5% for sildenafil and 6.3% for N-desmethyl sildenafil respectively. Accuracy determinaed at four concentrations was 86.50-105.67% for sildenafil and 96.83-114.40% for N-desmethyl sildenafil. This method was successfully applied to a pharmacokinetic description of sildenafil and the effect of food intake on the pharmacokinetics of sildenafil was also demonstrated in healthy Chinese volunteers.

Skin sensitivity evaluation: What could impact the assessment results?

BACKGROUND: For the evaluation results of skin sensitivity, such as clinical parameters, stinging test records and biophysical assessments dates might be impacted by many factors, the influence factors need to be further explored, and the skin sensitivity evaluation process and methodology needed distinction and normalization. In this study, we investigated the changes of sensitive skin indexes and lactic acid stinging test results in different seasons, facial regions, skin photo-type, and living habits. METHODS: Twenty-four healthy subjects had completed this study. Lactic acid stinging test was performed in different seasons. Transepidermal water loss (TEWL), skin hydration, sebum secretion, and pH were measured in an environment-controlled room. Correlations between stinging responses, skin biophysical parameters, and sensitive skin inducements in different seasons were statistically analyzed. RESULTS: Skin TEWL, hydration, sebum secretion, and pH values on different facial parts were various. Two-way correlation analysis between the results of lactic acid stinging test in different seasons and the sensitivity factors showed differences between summer, autumn, and winter. The mean scores of lactic acid stinging test increased in autumn. Linear regression analysis of skin sensitivity factors in type III and type IV photobiology skin found that the frequency of sleeping time and eating spicy food in the past of week could infect the sensitive skin evaluation dates statistically (P < .05). DISCUSSION/CONCLUSIONS: Skin sensitivity assessment results were impacted by seasonal transformation, living habits and customs, and facial regions. These indicted that we should consider above interfering factors when evaluated the skin sensitivity for getting more precise dates.