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Background: Breast cancer is the leading cause of cancer death in women. The current methods of chemotherapy for breast cancer generally have strong adverse reactions and drug resistance. Therefore, the discovery of novel anti-breast cancer lead compounds is urgently needed. Objective: This study aimed to design and synthesize a series of 2-alkyl substituted fluorinated genistein analogues and evaluate their anti-breast cancer activity. Methods: Target compounds were obtained in a multistep reaction synthesis. The anti-tumor activity of compounds I-1~I-35 was evaluated with MCF-7, MDA-MB-231, MDA-MB-435, and MCF-10A cell lines in vitro, with tamoxifen as the positive control. Molecular docking was used to study the interaction between the synthesized compounds and PI3K-gamma. Results: A series of 2-alkyl substituted fluorinated genistein analogues was designed, synthesized, and screened for their bioactivity. Most of the compounds displayed better selectivity toward breast cancer cell lines as compared to tamoxifen. Among these analogues, I-2, I-3, I-4, I-9, I-15, and I-17 have the strongest selective inhibition of breast cancer cells. Compounds I-10, I-13, I-15, I-17, and I- 33 were found to have significant inhibitory effects on breast cancer cells. Molecular docking studies have shown that these compounds may act as PI3Kγ inhibitors and may further exhibit anti-breast cancer effects. Conclusion: Most of the newly synthesized compounds could highly, selectively inhibit breast cancer cell lines. The experimental results indicate that the synthesized analogs may also have obvious selective inhibitory effects on other malignant proliferation cancer cells.

Background Epicutaneous sensitization is an important route for the production of IgE, and skin inflammation-induced IgE has recently been reported having features of natural antibody. Atopic dermatitis (AD) and psoriasis have differentially increased level of serum IgE; however, the production mechanism of IgE in these inflammatory skin diseases remains unknown. Objective To explore the origin of IgE in AD and psoriasis by analyzing the B cell receptor repertoire. Methods mRNA was prepared from peripheral blood mononuclear cells of AD and psoriasis patients that had elevated serum levels of IgE, and immunoglobulin heavy chain (IGH) repertoires were sequenced after reverse transcription. Clonal lineages of B cells containing members expressing IgE were identified, and somatic hypermutations in IGH inherited from common ancestors within the clonal lineage were used to infer the relationships between B cells. Results The proportions of IGHE from AD and psoriasis were higher than that of normal control, which were positively correlated with the levels of serum total IgE. The somatic hypermutation value of IGHE variable region was lower than that of IGHG and IGHA, but higher than IGHM and IGHD, indicating a mixed natural and adaptive origins of IgE; and psoriasis demonstrated lower level of hypermutation than AD. The Shannon indexes of CDR3 in IGHE of AD and psoriasis were higher than that of normal control, also supporting the natural origin. The VH usage of IgE was weakly biased in AD and psoriasis patients with high level of house dust mite-specific IgE. Comparison of the number of shared mutations in multi-isotype lineages containing IgE showed that isotype-switching from IgG-expressing B cells might be the major source of IgE in AD and psoriasis. Conclusion IgE has heterogeneous origin in AD and psoriasis, and skin inflammation may contribute to the increased production of natural IgE.

Behcet's syndrome (BS) is a chronic systemic inflammatory vasculitis with a wide range of clinical manifestations including recurrent oral and genital ulcers; cutaneous lesions; and ophthalmic, neurologic, and gastrointestinal involvement. BS has a global distribution but is particularly prevalent in so-called Silk Road populations. Disease onset is usually around the third or fourth decade of life, and the sex ratio is roughly 1:1. Both environmental and genetic factors contribute to the etiology of BS, although the detailed mechanisms remain unclear. At present, there is no laboratory examination with diagnostic value for BS; therefore, a diagnosis is made based on clinical manifestations. The International Study Group diagnostic criteria published in 1990 is the most widely used and recognized, but in order to improve sensitivity, the International Criteria for Behcet's Disease is developed in 2014. Evaluating disease activity in BS is an important basis for treatment selection and monitoring, the simplified Behcet's Disease Current Activity Form (2006 version) is a well-established scoring method. Given that multiple organs are affected in BS, it must be differentiated from other diseases with similar manifestations or that may be induced by drug treatment. The goal of BS treatment is to eradicate triggers and/or aggravating factors, alleviate and control clinical symptoms, prevent and treat any damage to organs, slow disease progression, and improve the patient's quality of life. The clinical management of BS depends on the affected organs and disease severity. In this review, we summarize the current state of knowledge of BS pathogenesis and therapeutic options.

Atopic dermatitis (AD) is a common disease clinically characterized by chronic recurrent eczematous lesions, dry skin, and pruritus. AD can negatively impact patients’ quality of life. The prevalence of AD in China has been increasing during the past few decades. Based on the most recent advances in the treatment of AD, we updated the 2014 version of the Guidelines for Diagnosis and Treatment of Atopic Dermatitis in China regarding the definition, epidemiology, pathogenesis, clinical classification, diagnosis, prevention, and treatment of AD.

Introduction: Although oxidative stress has been demonstrated to mediate acute ethanol-induced changes in autophagy in the heart, the precise mechanism behind redox regulation in acute ethanol heart disease remains largely unknown. Methods: Wild-type C57BL/6 mice were intraperitoneally injected with ethanol (3 g/kg/day) for 3 consecutive days. The effects of ethanol on cultured primary cardiomyocytes and H9c2 myoblasts were also studied in vitro. Levels of autophagic flux, cardiac apoptosis and function, reactive oxygen species (ROS) accumulation, NOX4, and NOX2 were examined. The NOX4 gene was knocked down with NOX4 siRNA. Results: In this study, we demonstrated that schisandrin B inhibited acute ethanol-induced autophagy and sequent apoptosis. In addition, schisandrin B treatment improved cardiac function in ethanol-treated mice. Furthermore, NOX4 protein expression was increased during acute ethanol exposure, and the upregulation of NOX4 was significantly inhibited by schisandrin B treatment. The knockdown of NOX4 prevented ROS accumulation, cell autophagy, and apoptosis. Conclusion: These results highlight that NOX4 is a critical mediator of ROS and elaborate the role of the NOX4/ROS axis in the effect of schisandrin B on autophagy and autophagy-mediated apoptosis in acute ethanol exposure, which suggests a therapeutic strategy for acute alcoholic cardiomyopathy.

Background: The efficacy of allergen-specific immunotherapy (AIT) is mainly depended on the tolerogenic immune responses elicited. Properly conjugated nano-vaccine has the advantages of both specific targeting and continuous and on-demand release of allergen. Objectives: The aim of this study is to investigate the effects of a dendritic cells (DCs)-targeting nano-vaccine for AIT. Methods: The nano-vaccine was produced by coupling polylactic-co-glycolic acid (PLGA)-encapsulated ovalbumin (OVA) with mannan. Allergen capture, human monocytes-derived DCs (hMoDCs) activation, and T cells responses were assessed by flow cytometry, confocal microscopy, quantitative real-time PCR, ELISA, and Cytometric Bead Array. Balb/c mice were immunized with the nano-vaccines, and the immune responses were analyzed. Results: OVA-PLGA nanoparticle (NP) displayed favorable safety profile. OVA-mannan-PLGA NP was captured more efficiently by hMoDCs than OVA-PLGA NP, which was mediated mainly through DC-specific intercellular adhesion molecule 3-grabbing nonintegrin. A tolerogenic phenotype of hMoDCs was induced by OVA-mannan-PLGA NP, but not OVA-PLGA NP, and increased number of regulatory T (Treg) cells was generated subsequently in in vitro coculture. Immunization of Balb/c mice with OVA-mannan-PLGA NP resulted in lower serum level of OVA-specific immunoglobulins and less production of pro-inflammatory cytokines in splenocytes culture than the mice immunized with OVA-PLAG NP, PLGA NP, or OVA, while the number of splenic Treg cells was higher in OVA-mannan-PLGA group than in other groups. Moreover, preimmunization with OVA-mannan-PLGA NP significantly inhibited the Th2 immune response induced by OVA sensitization. Conclusions: The biocompatible PLGA-encapsulated OVA coupling with mannan has augmented ability for tolerance induction and could be developed as a novel vaccine for AIT.

As a disease closely related to the metabolic syndrome, diabetes has become a public health issue that severely affects many people’s quality of life. The search for novel anti-diabetic agents remains the cornerstone to control this challenging disease. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin and leptin signaling pathways, has turned out to be a potential target of type II diabetes mellitus (T2DM) and obesity. In recent years, the development of novel anti-diabetic drugs based on PTP1B inhibitors has captured the attention of many researchers. Thiazole, a five-membered heterocycle containing sulfur and nitrogen atoms, has been considered as an essential core skeleton for various active compounds. Furthermore, thiazolidines, representing a series of compounds with saturated thiazole rings, widely exist in natural products and synthetic compounds with a variety of pharmacological activities. Here, we focus on the emphasis of PTP1B in diabetes and the development of PTP1B inhibitors based on thiazole and thiazolidine derivatives in the past decade. Many PTP1B inhibitors and their chemical structures, selectivity, potency, and structure-activity relationship have been elaborated. The great majority of PTP1B inhibitors containing thiazole and thiazolidine moieties described in this review exhibit preferable activities, which would be of importance for the rational design and efficient application of PTP1B inhibitors with anti-diabetes activity.

Background:. Psoriasis is a chronic inflammatory skin disease, affecting about 0.6% of the Chinese population. Many patients are not well controlled by conventional treatments, thus there is need for new treatment regimens. In this study, we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis. Methods:. This study was a 52-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 trial. A sub-population of study participants (≥18 years) of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab, or placebo. The co-primary endpoints were psoriasis area severity index (PASI) 75 and Investigator's Global Assessment (IGA) 0/1 at Week 12. Results:. A total of 441 Chinese patients were enrolled in this study. Co-primary outcomes were achieved; 300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75 (97.7% and 87.2% vs. 3.7%, respectively; P

Electroacupuncture (EA) can effectively alleviate anxiety disorders and memory impairments caused by various neurodegenerative diseases; however, the molecular mechanisms underlying its neuroprotective effects are unclear. Previous studies have shown that the renin-angiotensin system (RAS) comprises of two axes with mutual antagonism: the classical angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis and the protective angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/MasR) axis. In this study, we observed that chronic cerebral hypoperfusion (CCH) mediated anxiety-like behavior and memory impairments in spontaneously hypertensive rats (SHR) via upregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and the partial hippocampal protective axis (ACE2/Ang-(1-7)). However, Ang II levels were much higher than those of Ang-(1–7), indicating that the ACE/Ang II/AT1R axis plays a dominant role in the comorbidity of CCH and hypertension. Moreover, candesartan cilexetil (Canc) and perindopril (Peril) were used as positive control drugs. We found that EA, Canc, and Peril attenuated CCH-induced anxiety-like behavior and memory impairments in SHR, potentially via downregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and upregulation of the whole hippocampal protective axis (ACE2/Ang-(1-7)/MasR). These results suggest that EA therapy for CCH with hypertension may be mediated by two hippocampal RAS axes.

Introduction Previous studies found that vitamin D receptor (VDR) TaqI, BsmI, FokI and ApaI gene polymorphisms are associated with several inflammatory diseases. However, the relationship between VDR gene polymorphisms and chronic spontaneous urticaria (CSU) is not clear. Aim The purpose of our study was to explore the relationship between the polymorphism of VDR and the incidence of chronic spontaneous urticaria in the Chinese Han population. Meanwhile, the vitamin D levels in patients with chronic spontaneous urticaria were also detected and the effects of VDR gene polymorphism on vitamin D levels were detected. Material and methods The genotypes of four VDR polymorphisms (TaqI, BsmI, ApaI, and FokI) were studied using allele-specific PCR analysis in 90 CSU patients and 90 healthy controls. Results Compared to the control group, the mutant allele (C) of FokI were more common in patients with CSU (57.2% vs. 45%, p = 0.020, odds ratio (OR) = 0.612, 95% confidence interval (CI): 0.403-0.928). We found that serum vitamin D levels were significantly lower in CSU patients than in healthy controls (p = 0.023). However, the effect of VDR gene polymorphism on vitamin D levels was not found in patients of CSU. Conclusions We first reported the effect of VDR gene FokI (rs2228570) polymorphism on the incidence of chronic spontaneous urticaria in the Chinese Han population.

Supplemental material, sj-docx-1-wso-10.1177_17474930221138707 for Poor collateral flow with severe hypoperfusion explains worse outcome in acute stroke patients with atrial fibrillation by Jianhong Yang, Yuefei Wu, Xiang Gao, Qing Shang, Yao Xu, Qing Han, Jichuan Li, Chushuang Chen, Andrew Bivard, Mark W Parsons and Longting Lin in International Journal of Stroke

Supplemental material, sj-docx-1-wso-10.1177_17474930221138707 for Poor collateral flow with severe hypoperfusion explains worse outcome in acute stroke patients with atrial fibrillation by Jianhong Yang, Yuefei Wu, Xiang Gao, Qing Shang, Yao Xu, Qing Han, Jichuan Li, Chushuang Chen, Andrew Bivard, Mark W Parsons and Longting Lin in International Journal of Stroke

The papillary thyroid carcinoma (PTC) usually shows an excellent prognosis. But some patients suffer recurrence after treatment. Recent progress in RNA sequencing (RNA-Seq) allows us to explore whole-transcriptomic gene expression profiles to develop RNA-seq based predictive model for stratifying the risk of recurrence of PTC. RNA-seq and clinical data from The Cancer Genome Atlas thyroid carcinoma cohort were divided chronologically into a training cohort (before 2011, n = 240) and a validation cohort (after 2011, n = 239). A risk score model was developed in training cohort using univariate Cox analysis followed by stepwise multivariate Cox analysis, and assessed in the validation cohort. Univariate and multivariate analyses identified five independent predictive genes (TOP2A, RP11-180M15.7, RP11-635N19.1, PROSER3, and TMEM139) significantly (p

Objective To evaluate the clinical effect differences between conducting qi and regulating the spirit needling method and regular needling method. Methods Sixty-nine patients of insomnia were randomly divided into an observation group (35 cases) and a control group (34 cases). Baihui (百会 GV20), Sishencōng (四神聪 EX-HN1), Hegŭ (合谷 LI4), Taichōng (太冲 LR3), Zusānlĭ (足三里 ST36) and Sānyīnjiāo (三阴交 SP6) were selected in the two groups. The patients in the observation group were treated with needling method for conducting qi and regulating the spirit. The patients in the control group were treated with the regular needling method. The treatment was given once every other day, both groups were treated for 12 times. Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were observed before and after the treatment and the clinical effect was evaluated. Results After treatment, the total score and the score of each item of PSQI as well as the result of ESS were all improved after the treatment in the two groups (all P Conclusion The conducting qi and regulating the spirit needling method achieves a better effect on insomnia as compared with the regular needling method. This method achieves a remarkable improvement in sleep latency, sleep quality and daytime sleepiness.

Atopic dermatitis (AD) is a recurrent chronic inflammatory skin disease affecting up to 30% of the children population, and immuno-regulatory therapy that could modify the course of disease is urgently needed. Probiotics have demonstrated therapeutic effects on AD and could potentially regulate the disease process. However, the efficacy of probiotics for AD is inconsistent among different studies, which is mainly due to the elusive mechanism and different species and (or) strains used. In this study, we designed a mixture of five strains of probiotics (named IW5) and analyzed the effect and mechanism of IW5 on calcipotriol (MC903)-induced AD-like dermatitis. We found that IW5 significantly alleviated skin inflammation of the MC903-induced AD in mice. Administration with IW5 induced increased production of regulatory T cells and regulatory dendritic cells (DCregs) in the mesenteric lymph nodes. We also found that the diversity of the gut microbiota in the mice with MC903-induced dermatitis was increased after IW5 administration, and the level of butyrate in the gut was elevated. In cell culture, butyrate induced the production of DCregs. Our study revealed the therapeutic effects of a newly designed probiotics mixture and uncovered a possible mechanism, providing a foundation for future clinical studies.

Background: Patients undergoing carotid endarterectomy (CEA) for severe carotid stenosis are vulnerable to postoperative delirium, a complication frequently associated with poor outcome. This study investigated the impact of processed electroencephalogram (EEG)-guided anesthesia management on the incidence of postoperative delirium in patients undergoing CEA.Methods: This single-center, prospective, randomized clinical trial on 255 patients receiving CEA under general anesthesia compared the outcomes of patient state index (PSI) monitoring [SEDLine Brain Function Monitor (Masimo, Inc, Irvine, CA)] (standard group, n = 128) with PSI combined with density spectral array(DSA) -guided monitoring (intervention group, n = 127) to reduce the risk of intraoperative EEG burst suppression. All patients were monitored by continuous transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to avoid perioperative cerebral hypoperfusion or hyperperfusion. According to the surgical process, EEG suppression time was calculated separately for three stages: S1 (from anesthesia induction to carotid artery clamping), S2 (from clamping to declamping), and S3 (from declamping to the end of surgery). The primary outcome was incidence of postoperative delirium according to the Confusion Assessment Method algorithm during the first 3 days post-surgery, and secondary outcomes were other neurologic complications and length of hospital stay.Results: There were no episodes of cerebral hypoperfusion or hyperperfusion according to TCD and NIRS monitoring in either group during surgery. The incidence of postoperative delirium within 3 days post-surgery was significantly lower in the intervention group than the standard group (7.87 vs. 28.91%, P < 0.01). In the intervention group, the total EEG suppression time and the EEG suppression time during S2 and S3 were shorter (Total, 0 “0” vs. 0 “1.17” min, P = 0.04; S2, 0 “0” vs. 0 “0.1” min, P < 0.01; S3, 0 “0” vs. 0 “0” min, P = 0.02). There were no group differences in incidence of neurologic complications and length of postoperative hospital stay.Conclusion: Processed electroencephalogram-guided general anesthesia management, consisting of PSI combined with DSA monitoring, can significantly reduce the risk of postoperative delirium in patients undergoing CEA. Patients, especially those exhibiting hemodynamic fluctuations or receiving surgical procedures that disrupt cerebral perfusion, may benefit from the monitoring of multiple EEG parameters during surgery.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03622515.

Borderline personality disorder (BPD) is a severe psychological disorder that can cause a great deal of distress if left untreated. This paper describes the symptom and cause of the BPD and then identifies barriers to access to critical resources for BPD support and treatment services from the perspective of individuals seeking care. There is a growing number of effective forms of lower-intensity treatment for BPD, offering hope for improving the standard of care in general for these complex patients.

To determine the therapeutic efficacy and safety of risk‐adapted stereotactic body radiation therapy (SBRT) schedules for patients with early‐stage central and ultra‐central inoperable non‐small cell lung cancer. From 2006 to 2015, 80 inoperable T1‐2N0M0 NSCLC patients were treated with two median dose levels: 60 Gy in six fractions (range, 48‐60 Gy in 4‐8 fractions) prescribed to the 74% isodose line (range, 58%‐79%) for central lesions (ie within 2 cm of, but not abutting, the proximal bronchial tree; n = 43), and 56 Gy in seven fractions (range, 48‐60 Gy in 5‐10 fractions) prescribed to the 74% isodose line (range, 60%‐80%) for ultra‐central lesions (ie abutting the proximal bronchial tree; n = 37) on consecutive days. Primary endpoint was overall survival (OS); secondary endpoints included progression‐free survival (PFS), tumor local control rate (LC), and toxicity. Median OS and PFS were 64.47 and 32.10 months (respectively) for ultra‐central patients, and not reached for central patients. Median time to local failure, regional failure, and any distant failures for central versus ultra‐central lesions were: 27.37 versus 26.07 months, 20.90 versus 12.53 months, and 20.85 versus 15.53 months, respectively, all P

Objective: Serum total IgE (tIgE) levels are elevated in patients with chronic urticaria (CU); however, the nature of the elevated serum tIgE level in CU patients remains unclear. The aim of this study was to investigate the relationship between elevated serum levels of tIgE in patients with CU and the sensitivity of these patients to antihistamine treatments. Methods: Blood samples of 302 patients with CU were collected, and their levels of serum tIgE were measured. The patients were divided into two groups according to their serum tIgE level: High serum tIgE level group (≥150 U/mL) and Low serum tIgE level group (

Background Epicutaneous sensitization is an important route of immunization for allergens in atopic diseases; however, studies have also shown that application with protein on the intact skin induces antigen-specific tolerance. Langerhans cells (LCs) play an immunosuppressive role in several inflammatory skin diseases and mouse models, and the role of LCs in the skin-induced tolerance is not fully understood. Methods Langerin-DTA mice that were deficient in LCs were utilized to produce the model of skin-induced tolerance to ovalbumin (OVA). Binding of Langerin to OVA was analyzed by enzyme-linked immunosorbent assay, flow cytometry, and immunofluorescence. Homozygous Langerin-DTR mice that were deficient in Langerin were introduced to assess the role of Langerin in the skin-induced tolerance. Results Application with OVA onto the intact, but not tape-stripped, skin attenuated the production of OVA-specific IgE, IgG1, and IgG2a induced by subsequent subcutaneous immunization with OVA, and the inhibitory effects were abolished in Langerin-DTA mice. In contrast to the tape-stripped skin, the intact skin induced the production of IL-10 by LCs in draining lymph node after application with OVA. Langerin could bind OVA, and homozygous Langerin-DTR mice demonstrated similar humoral and cellular immune responses in the model of skin-induced tolerance compared to wide-type mice. Conclusion Our data suggested that LCs were critical in the intact skin-induced tolerance to protein antigen via Langerin, and LCs might be targeted via Langerin to regulate the immune responses in systemic and (or) skin inflammatory diseases.

Background: Environmental exposure to toxic metals is an important risk factor to human health. Traditional methods have examined associations between a health endpoint and exposure to heavy metals by either univariate or multiple regression. In the setting of ubiquitous heterogeneous environmental exposures, statistical methods that incorporate mixed exposures are increasingly relevant and may provide new insight into the association between metal exposure and important cardiovascular, renal and respiratory outcomes. Objective: The objective of this study was to classify the population of National Health and Nutrition Examination Survey (NHANES) into different exposure subgroups using modern unsupervised clustering methods based on lead, cadmium, mercury, and arsenic measured in urine or whole blood, and to assess the association between the identified exposure groups and twelve important health endpoints. Methods: We analyzed a sub-cohort of 9662 subjects participating in the 6 cycles (2003–2004 to 2013–2014) of NHANES study. The urine levels of 3 heavy metals (total arsenic, lead, cadmium) and blood levels of 3 heavy metals (lead, cadmium and mercury) were analyzed using a two-step approach. In the first step, we stratified the population into subgroups using unsupervised clustering (k-medoids) based on levels of metals either in urine or in blood. Then, we examine the association between 12 health endpoints and identified exposure subgroups while controlling for age, sex, race/ethnicity, education, smoking status, BMI, and urinary creatinine. Results: The k-medoids algorithm clustered NHANES population into 2 groups based on either blood or urinary levels of heavy metals. The concentrations of all the three heavy metals were significantly different between the identified groups in blood (p

Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state (LC1 and LC2) and two activated LC subsets in the epidermis of human skin and in LCs derived from CD34+ hemopoietic stem cells (HSC-LCs) by utilizing single-cell RNA sequencing and mass cytometry. Analysis of HSC-LCs at multiple time-points during differentiation revealed that EGR1 and Notch signaling were among the top pathways regulating the bifurcation of LC1 and LC2. LC1 were characterized as classical LCs, mainly related to innate immunity and antigen processing. LC2 were similar to monocytes or myeloid dendritic cells, involving in immune responses and leukocyte activation. LC1 remained stable under inflammatory microenvironment, whereas LC2 were prone to being activated and demonstrated elevated expression of immuno-suppressive molecules. We revealed distinct human LC subsets that require different developmental regulation and orchestrate reciprocal functions.

Although the original purpose of the systemic lupus erythematosus (SLE) classification criteria was to distinguish SLE from other mimic diseases, and to facilitate sample selection in scientific research, they have become widely used as diagnostic criteria in clinical situations. It is not known yet if regarding classification criteria as diagnostic criteria, what problems might be encountered? This is the first study comparing the three sets of classification criteria for SLE, the 1997 American College of Rheumatology (ACR’97), 2012 Systemic Lupus International Collaborating Clinics (SLICC’12) and 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR’19), for their ability to distinguish patients with SLE from patients with pure mucocutaneous manifestations (isolated cutaneous lupus erythematosus without internal disease, i-CLE) in the lupus disease spectrum. 1,865 patients with SLE and 232 patients with i-CLE were recruited from a multicenter study. We found that, due to low specificity, none of the three criteria are adept at distinguishing patients with SLE from patients with i-CLE. SLICC’12 performed best among the original three criteria, but if a positive ANA was removed as an entry criterion, EULAR/ACR’19 would performed better. A review of previous studies that compared the three sets of criteria was presented in this work.

To evaluate the efficacy of acellular collagen scaffold (ACS) in combination with basic fibroblast growth factor (bFGF) for the repair of traumatic tympanic membrane (TM) perforation in a rat model.A prospective controlled animal study in a rat model of traumatic TM perforation.Tertiary medical center.Sprague-Dawley rats (N = 84) with unilateral traumatic perforation of the right TMs were randomized to receive ACS, bFGF, ACS in combination with bFGF (ACS/bFGF), or nothing (spontaneous healing without any interventions as a control group). The healing outcomes were evaluated by otoscopy, optical coherence tomography, histology, and transmission electron microscopy at 1, 2, and 4 weeks postoperatively. The hearing outcomes were assessed with auditory brainstem response testing.ACS/bFGF resulted in higher perforation closure rates at an earlier stage than spontaneous healing, ACS, and bFGF. Based on histology, optical coherence tomography, and transmission electron microscopy, a trilaminar structure and uniform thickness with mature, densely packed collagen fibers were seen in the ACS/bFGF group. Auditory brainstem response evaluation also showed that ACS/bFGF treatment promoted faster functional hearing recovery as compared with the control group.ACS is an effective TM scaffold and a carrier for bFGF. ACS/bFGF improves the TM closure rate, results in better-reconstructed TMs, and improves hearing. ACS/bFGF serves as a potential substitute for TM perforations in clinical settings.

Background Skin commensal bacteria play important roles in skin homeostasis. Langerhans cells (LCs) are epidermis-resident dendritic cells that sense environmental stimuli and are critical in the induction of immune tolerance to allergen and bacterial skin flora. However, response of LCs to the metabolites of the skin microbiota is not clear. Objective To explore the effects of the skin microbial metabolites on LCs activation. Methods LCs derived from CD34+ hematopoietic stem cells in the cord blood were treated with a microbial metabolite of tryptophan, indole-3-aldehyde (IAId). Activation aryl hydrocarbon receptor (AhR) signaling, production of IL-10, and expression of receptor activator of NF-κB (RANK) / receptor activator of NF-κB ligand (RANKL) in LCs or keratinocytes were analyzed using quantitative PCR, western blotting and flow cytometry. LCs maturation induced by IAId and CD4+ T cell response induced by IAId-conditioned LCs were also investigated. Results IAId induced the production of indoleamine 2,3-dioxygenase (IDO) and IL-10 in LCs through the activation of AhR. IAId promoted the expression of RANK and RANKL on LCs and keratinocytes in an AhR-dependent manner respectively, which might result in activation of NF-κB signaling and production of IL-10. Moreover, a mature phenotype of LCs was induced by IAId, and IAId-activated LCs inhibited CD4+ T cell proliferation and induced IL-10 secretion. Conclusions Our study revealed a negatively regulatory function of a tryptophan metabolite on LCs through the activation of AhR, and the microbial metabolites could be utilized in future treatment for inflammatory skin diseases.

Sorafenib is currently the standard chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC). But its efficacy requires improvement, it is imperative to seek therapeutic strategies that combine sorafenib with other anticancer agents. In this study we investigated the synergistic anticancer effect of combining sorafenib and artesunate, an anti-malaria drug derivative, against HCC in vitro and in vivo. We first showed that artesunate (1–100 μM) alone dose-dependently inhibited the proliferation of five HCC cell lines tested with IC(50) values of around 100 μM. Artesunate treatment dose-dependently increased the ROS level in both HuH7 and Hep3B cells; addition of NAC significantly ameliorated the antiproliferation effect of artesunate against HuH7 and Hep3B cells. Then we demonstrated that combination of sorafenib and artesunate exerted synergistic antiproliferation effect and induced synergistic apoptosis in HCC cell lines. In nude mice bearing Hep3B xenografts, combined administration of sorafenib and artesunate significantly enhanced the suppression on tumor growth. We further revealed that sorafenib dose-dependently decreased the levels of p-ERK and p-STAT3, whereas artesunate markedly increased the levels of p-ERK and p-STAT3 in HuH7 and Hep3B cells. When used in combination, sorafenib abolished artesunate-elevated levels of p-STAT3 and p-ERK. Moreover, pharmacological inhibition of ERK by inhibitor PD0325901 or STAT3 by inhibitor Stattic markedly enhanced the anticancer activity of artesunate, suggesting that suppression of ERK and STAT3 signaling by sorafenib contributes to the synergistic anticancer activity against HCC caused by combination of sorafenib and artesunate. Taken together, our results provide an evidence for possible use of sorafenib plus artesunate or artemisinin analogs for treatment of HCC in the future.

Resveratrol is a natural phytoestrogen produced by plants to protect themselves from injury, UV irradiation, and fungal attack. The main active structure is E-resveratrol, which has many pharmacological activities. As the structure of resveratrol is similar to the natural estrogen 17β-estradiol and the synthetic estrogen E-diethylstilbestrol, resveratrol is used in reducing the incidence of breast cancer. However, the therapeutic application of resveratrol is limited due to its low bioavailability. To improve its bioavailability and pharmacological activity, some resveratrol derivatives have been designed and synthesized by substitutions of methoxy, hydroxyl, and other functional groups or heterocyclic esterification either on the "A" or "B" ring, and double bonds were replaced by imine bonds and isometric heterocycles such as naphthyl and imidazole, or synthetic resveratrol oligomers. The structures, synthetic routes, and evaluation of the biological activities of these compounds are discussed. These are aimed at providing some references for the study of resveratrol derivatives in anti-breast cancer treatment.

In this study, bamboo flour (BF) was chemically modified using alkyl ketene dimer (AKD) or alkali treatment for the preparation of high-density polyethylene/bamboo flour (HDPE/BF) composites with or without compatibilizer maleic anhydride grafted high-density polyethylene (HDPE-g-MAH). The modified BF was characterized by Fourier transformation infrared (FTIR) spectroscopy and contact angle measurement, and the mechanical properties, morphology and water resistance of the HDPE/BF composites were investigated and compared. The results show that highly hydrophobic BF can be obtained by a simple procedure using a common paper sizing agent AKD. AKD can react with the hydroxyl groups in cellulose to form β-keto ester. The combination of AKD treatment and addition of HDPE-g-MAH is more effective in improving the mechanical properties of HDPE/BF composites than using them alone. The impact strength, flexural strength and modulus of HDPE/A-BF/MAH composite are increased by 100.0%, 197.1% and 61.8% compared with that of HDPE/U-BF composites, and the water absorption and thickness swelling are decreased by 87.7% and 87.4% after immersion in water for one week, respectively. These results indicate that HDPE/BF composites with good mechanical properties and high water resistance can be obtained by AKD treatment.

Background In clinical practice, the laryngeal mask airway is an easy-to-use supraglottic airway device. However, the cis-atracurium dosage for laryngeal mask insertion has not been standardised. We aimed to determine the optimal dose of cis-atracurium using a sequential method for successful laryngeal mask insertion. Methods The cohort study protocol is registered at clinicaltrial.gov (NCT-03668262). Twenty-three patients undergoing elective urinary surgery were sequentially administered cis-atracurium doses as follows: 150, 100, 70, 50, 30, and 20 μg·kg− 1. The main outcome involved the determination of the response to laryngeal mask airway insertion: ≥16 points and cis-atracurium for laryngeal mask airway insertion. Results The median effective dose of cis-atracurium was 26.5 μg·kg− 1 (95% CI 23.6–29.8) using the sequential method. Heart rate was decreased in the 50 μg·kg− 1 group compared to that in the 30 μg·kg− 1 group at timepoints T7, T8, and T10 (P = 0.0482, P = 0.0460, and P = 0.0236, respectively), but no difference was observed in the 20 μg·kg− 1 group. Systolic blood pressure was decreased in the 50 μg·kg− 1 group compared to that in the 20 μg·kg− 1 group at timepoints T2, T3, and T4 (P = 0.0159, P = 0.0233, and P = 0.0428, respectively). The train-of-four value was significantly lower in the 50 μg·kg− 1 group than in the 30 μg·kg− 1 group at timepoint T3 (P = 0.0326). Conclusions The ED50 of cis-atracurium was 26.5 μg·kg− 1 for laryngeal mask airway insertion. Trial registration Clinicaltrial.gov Registry, NCT03668262, Registered on 11 September 2018.

Firstly discovered in 1980s, human immunodeficiency virus (HIV) continues to affect more and more people. However, there is no effective drug available for the therapy of HIV infection. Betulinic acid existing in various medicinal herbs and fruits exhibits multiple biological effects, especially its outstanding anti-HIV activity, which has drawn the attentions of many pharmacists. Among the derivatives of betulinic acid, some compounds exhibited inhibitory activities at the nanomolar concentration, and have entered phase II clinical trials. This paper summarizes the current investigations on the anti-HIV activity of betulinic acid analogues, and provides valuable data for subsequent researches.

The aim of the present study was to explore the clinical and histopathological characteristics and treatment of patients with bullous pemphigoid (BP) that initially manifested as non-bullous lesions and provide information for early diagnosis and improved treatment. Medical records of 491 cases of BP were collected. The clinical and histopathological characteristics, treatment and outcomes of patients who initially presented with non-bullous lesions (prodromal BP, PBP) were analyzed and compared with those from patients who initially presented with bullous lesions (classical BP, cBP). Of the BP patients studied, 36.8% had PBP and presented with diversified initial lesions before the appearance of typical bullae, with erythema as the most frequent (31.67%), followed by concurrent erythema and papules (30.4%). The mean duration before bullae appearance was 15.91 ± 0.65 months. The degree of itch in PBP patients was higher than that in cBP patients. There was no difference in the hospital stay and time to disease control between the PBP and cBP patients. However, the mean glucocorticoid dose for control of the lesions in PBP patients was significantly higher than that in cBP patients. In addition, the PBP patients experienced side-effects more frequently than did the cBP patients (87.85% vs 17.41%). In conclusion, intensive treatment is required for PBP patients due to delayed diagnosis and advanced development of the disease. Itching, concurrent erythema and papules occurring in the elderly may be clues for the early diagnosis of PBP.

// Yongjia Yang 1,2,* , Jianying Yuan 1,3,* , Xu Yao 1 , Rong Zhang 1,4 , Hui Yang 1,4 , Rui Zhao 1 , Jihong Guo 1,5 , Ke Jin 1 , Haibo Mei 1 , Yongqi Luo 1 , Liu Zhao 1 , Ming Tu 1 and Yimin Zhu 1,2 1 The Laboratory of Genetics and Metabolism, Hunan Children’s Research Institute , Hunan Children’s Hospital, University of South China, Changsha, China 2 Institute of Emergency Medicine, People’s Hospital of Hunan Province, Changsha, China 3 BGI-Shenzhen, Shenzhen, China 4 Division of Neonatology, Hunan Children’s Hospital, University of South China, Changsha, China 5 State Key Laboratory of Medical Genetics, Central South University, Changsha, China * These authors have contributed equally to this work Correspondence to: Yimin Zhu, email: // Keywords : BMPR1B, Pierre Robin sequence, gene fusion, BMP signalling, cleft palate, Chromosome Section Received : January 05, 2017 Accepted : February 27, 2017 Published : March 23, 2017 Abstract Background: We investigated a large family with Pierre Robin sequence (PRS). Aim of the study: This study aims to determine the genetic cause of PRS. Results: The reciprocal translocation t(4;6)(q22;p21) was identified to be segregated with PRS in a three-generation family. Whole-genome sequencing and Sanger sequencing successfully detected breakpoints in the intragenic regions of BMRP1B and GRM4 . We hypothesized that PRS in this family was caused by (i) haploinsufficiency for BMPR1B or (ii) a gain of function mechanism mediated by the BMPR1B - GRM4 fusion gene. In an unrelated family, we identified another BMPR1B -splicing mutation that co-segregated with PRS. Conclusion: We detected two BMPR1B mutations in two unrelated PRS families, suggesting that BMPR1B disruption is probably a cause of human PRS. Methods: GTG banding, comparative genomic hybridization, whole-genome sequencing, and Sanger sequencing were performed to identify the gene causing PRS.

Background Langerhans cells (LCs) are epidermis-resident dendritic cells that sense and mediate stimuli from skin and outside world, and participate in various skin diseases, playing either pro-inflammatory or regulatory roles. However, the exact function of LCs in the pathogenesis of psoriasis remains unclear, and the conclusions of previous studies are controversial. Objectives To explore the role of LCs in mouse model of imiquimod (IMQ)-induced psoriasis-like dermatitis using langerin-diphtheria toxin A (DTA) mice that are constitutively deficient in LCs. Methods IMQ (Aldara) was painted on the skin of mice to produce psoriasis-like dermatitis, and inflammation was evaluated by gross ear thickness, histopathology, flow cytometry and cytokine production. Bone marrow transplantation and fluorescein isothiocyanate tracing were applied to access the migration of LCs. Results The severity of IMQ-induced dermatitis in langerin-DTA mice was significantly lower than that of wild-type mice, as evidenced by decreased level of ear thickness, inflammatory cell infiltration (γδ T cells and neutrophils) and inflammatory cytokine expression (IL-17, IL-22, IL-23 and tumor necrosis factor-α). After application with IMQ, LCs expanded in epidermis and showed increased expression of CD80 and CD86, and migrated to draining lymph node within 48 h. LCs in the lymph node 48 h after application with IMQ expressed increased level of CD80, CD86, CD40 and CC chemokine receptor 7. Conclusion LCs were activated upon application with IMQ, and promoted the inflammatory responses in psoriasis-like dermatitis.

Introduction Cockroach allergen exposure elicits cockroach sensitization and poses an increased risk for asthma. However, the major components in cockroach allergen and the mechanisms underlying the induction of cockroach allergen-induced allergy and asthma remain largely elusive. We sought to examine the role of cockroach-associated glycan in regulating human basophil function. Methods N-linked glycans from naturally purified cockroach allergen Bla g 2 were characterized by MALDI-TOF mass spectrometry. Binding of cockroach allergen to serum IgE from cockroach allergic subjects was determined by solid-phase binding immunoassays. Role of cockroach associated glycan in histamine release and IL-4 production from human basophils was examined. Expression of C-type lectin receptors (CLRs) and their role in mediating glycan-uptake in the basophils was also investigated. Results MALDI-TOF mass spectrometric analysis of N-glycan from Bla g 2 showed complex hybrid-types of glycans that terminated with mannose, galactose, and/or N-acetyl glucosamine (GlcNAc). Deglycosylated Bla g 2 showed reduced binding to IgE and was less capable of inducing histamine release from human basophils. In contrast, N-glycan derived from Bla g 2 significantly inhibited histamine release and IL-4 production from basophils passively sensitized with serum from cockroach allergic subjects. An analysis of CLRs revealed the expression of DC-SIGN and DCIR, but not MRC1 and dectin-1, in human basophils. Neutralizing antibody to DCIR, but not DC-SIGN, significantly inhibited Bla g 2 uptake by human basophils. A dose-dependent bindings of cockroach allergen to DCIR was also observed. Conclusions These observations indicate a previously unrecognized role for cockroach allergen-associated glycans in allergen-induced immune reactions, and DCIR may play a role in mediating the regulation of glycan on basophil function.

Objective To evaluate the effect of atmospheric fine particulate matter (PM2.5) on the expression of skin barrier-associated proteins and proinflammatory cytokines in human keratinocytes. Methods Atmospheric PM2.5 samples were given by Professor Yufeng Zhou in Children′s Hospital of Fudan University. Human primary keratinocytes were isolated from circumcised foreskins of 5 males, and subjected to culture. These human primary keratinocytes were divided into several groups to be stimulated with PM2.5 at different concentrations of 0 (control group) , 10, 50, 100, 200 mg/L for 24 hours, and cell counting kit (CCK) -8 assay was performed to determine the survival rates of keratinocytes. Fluorescence-based quantitative PCR and Western blot analysis were conducted to determine the mRNA and protein expression of filaggrin, keratin-14 and claudin-1 in these keratinocytes respectively, and enzyme-linked immunosorbent assay (ELISA) was performed to detect levels of interleukin (IL) -1α, thymic stromal lymphopoietin (TSLP) and IL-33 in the culture supernatant of these keratinocytes. Statistical analysis was carried out with SPSS13.0 software by using one-way analysis of variance, least significant difference (LSD) -t test and Pearson correlation analysis. Results After 24-hour treatment with different concentrations of PM2.5, there was no significant difference in the survival rate of keratinocytes between the 10-mg/L PM2.5 group and control group (P > 0.05) , while the survival rates of keratinocytes were significantly lower in the 50-, 100-, 200-mg/L PM2.5 groups than in the control group (all P 0.05) . The 10-, 50-, 100- and 200-mg/L PM2.5 groups showed significantly increased keratin-14 expression compared with the control group (all P < 0.05) . The claudin-1 expression did not differ between the 10-mg/L PM2.5 group and control group (P = 0.87) , but significantly higher in the 50-, 100- and 200-mg/L PM2.5 groups than in the control group (all P < 0.05) . The stimulation with PM2.5 at 10, 50, 100 and 200 mg/L could induce an increase in the supernatant levels of TSLP, IL-1α and IL-33 (all P < 0.01) . Pearson correlation analysis showed that the supernatant levels of the proinflammatory cytokines TSLP, IL-1α and IL-33 were positively correlated with the concentration of PM2.5 (r = 0.57, 0.67, 0.91 respectively, all P < 0.05) . Conclusion The exposure to PM2.5 can induce decreased survival rate of keratinocytes, aberrant expression of filaggrin, keratin-14 and claudin-1, and elevated secretion of the proinflammatory cytokines TSLP, IL-1α and IL-33, which may lead to impaired skin barrier function. Key words: Keratinocytes; Particulate matter; Cell survival; Keratin-14; Claudins; Interleukin-1alpha; PM2.5; Barrier-associated proteins; Filaggrin; Interleukin-33; Thymic stromal lymphopoietin

Acquired cholesteatoma leads to significant morbidities while current surgical options remain a challenge. The principles of surgery include complete removal of disease, prevention of recurrence, and restoration of hearing function when possible. Traditionally, this has been performed using microscopes; however, a novel technique using endoscopes offers a new perspective on our understanding of anatomy, pathogenesis and surgical approaches. In recent years, various studies have demonstrated good outcomes with transcanal endoscopic ear surgery (EES) in cholesteatoma surgery. Nevertheless, the use of EES is not universal and remains controversial due to the efficacy of microscopes, specific limitations of endoscopes and the need to learn new skills. This review focuses on recent advances in EES for the treatment of acquired cholesteatoma, benefits, current challenges, and a discussion on the indications and contraindications of EES.

Cancer is a major public health issue in China, and effective anticancer drugs remain a huge unmet need. Generic drugs have long been the main products of pharmaceutical companies in China. In this decade, research on and development of innovative drugs has greatly advanced thanks to policy reforms and economic growth. Five innovative anticancer drugs - anlotinib, pyrotinib, fruquintinib, sintilimab, and toripalimab - that were developed by Chinese domestic pharmaceutical companies were approved by the National Medical Products Administration (NMPA) of China in 2018. Several novel anticancer drugs such as avitinib, flumatinib, zanubrutinib, and ensartinib may also receive approval for marketing in China in the near future. There are unprecedented opportunities for development of innovative drugs in China. In the future, innovative drug development in China is poised to shift from "me too" or "me better" drugs to "first-in-class" or "best-in-class" drugs.

Psoriasis is a chronic inflammatory skin disease in which dendritic cells (DCs) play a pivotal role by inducing Th1/Th17 immune responses; however, the regulation of DC activation in psoriasis remains largely unknown. Previously we found that the level of soluble CD100 was increased in sera of psoriasis patients, and CD100 promoted the activation of inflammasome in keratinocytes. In the present study, CD100 knockout mice were utilized for generation of imiquimod (IMQ)-induced psoriatic dermatitis, with the result that skin inflammation in the early, but not late, phase of the psoriatic dermatitis was significantly exacerbated compared to that in wild-type controls. This was attributed mainly to the deficiency of CD100 in hematopoietic cells. Bone marrow-derived DCs, but not T cells or keratinocytes, from CD100 knockout mice produced significantly increased levels of IL-1β, IL-36, and IL-23 upon stimulation with IMQ in a plexin-B2-dependent manner. Moreover, the surface level of plexin-B2 on DCs of psoriasis patients was lower than that of healthy individuals, and CD100 attenuated IMQ-induced production of IL-1β and IL-36 from monocyte-derived DCs of psoriasis patients. Our results uncovered a negative regulatory mechanism for DCs activation in psoriasis, which was mediated via CD100-plexin-B2 in a cell type- and receptor-specific manner. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hepatocellular carcinoma (HCC) is a prevalent and refractory cancer in the world and very few drugs are available for the disease treatment currently. Programmed cell death protein-1 (PD-1) monoclonal antibodies including nivolumab and pembrolizumab has received accelerated approval for treatment of advanced HCC based on phase 1/2 clinical trials. However, the recently disclosed results of phase 3 clinical trials showed that both nivolumab and pembrolizumab as monotherapy failed to meet the primary objectives, which might overshadow the prospect of PD-1 inhibitors as monotherapy in treatment of advanced and unresectable HCC. The feasibility of PD-1 inhibitors in combination with other therapies or in other HCC settings requires further verification in the future.

Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulatory arrest are unclear. After piglet models underwent 60 minutes of deep hypothermic circulatory arrest at 14°C, expression of microRNAs (miRNAs) was analyzed in the hippocampus by microarray. Subsequently, TargetScan 6.2, RNA22 v2.0, miRWalk 2.0, and miRanda were used to predict potential targets, and gene ontology enrichment analysis was carried out to identify functional pathways involved. Quantitative reverse transcription-polymerase chain reaction was conducted to verify miRNA changes. Deep hypothermic circulatory arrest altered the expression of 35 miRNAs. Twenty-two miRNAs were significantly downregulated and thirteen miRNAs were significantly upregulated in the hippocampus after deep hypothermic circulatory arrest. Six out of eight targets among the differentially expressed miRNAs were enriched for neuronal projection (cyclin dependent kinase, CDK16 and SLC1A2), central nervous system development (FOXO3, TYRO3, and SLC1A2), ion transmembrane transporter activity (ATP2B2 and SLC1A2), and interleukin-6 receptor binding (IL6R) - these are the key functional pathways involved in cerebral protection during deep hypothermic circulatory arrest. Quantitative reverse transcription-polymerase chain reaction confirmed the results of microarray analysis. Our experimental results illustrate a new role for transcriptional regulation in deep hypothermic circulatory arrest, and provide significant insight for the development of miRNAs to treat brain injuries. All procedures were approved by the Animal Care Committee of Xuanwu Hospital, Capital Medical University, China on March 1, 2017 (approval No. XW-INI-AD2017-0112).

The development and fecundity of the predator Chrysoperla carnea Stephens (Neuroptera: Chrysopidae) were assessed by feeding Aphis gossypii Glover (Hemiptera: Aphididae) that had been reared on transgenic Bacillus thuringiensis (Bt) cotton SGK321 and a non-Bt cotton control (SY321) for two successive generations. We found no significant differences in the developmental stage duration, stage survival, or egg hatch rate between C. carnea fed A. gossypii reared on the Bt and non-Bt cotton. The fecundity per female over a 25-day observation period was very similar between treatments; for C. carnea fed A. gossypii reared on SGK321 vs. SY321, the amount of eggs laid was not significantly different in both generations. Furthermore, a population dynamics of A. gossypii and lacewing (mainly C. carnea) were highly similar in the SGK321 and SY321 treatments during 2016–2017. These results suggest that Bt cotton does not have a significantly negative or positive effect on C. carnea in terms of development, survival, fecundity, or population dynamics.

Contains fulltext : 167701.pdf (Publisher’s version ) (Open Access) The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

There are no published studies that describe the DNA methylation of human leukocyte antigen class I molecules in psoriasis despite the fact that their association to disease has been known for several decades.we investigated the methylation status of HLA-A, -B and -C loci in psoriatic epidermis.The DNA and RNA specimens were obtained from the involved and uninvoled epidermis of 56 patients with plaque psoriasis and 28 healthy persons as the control group. Methylation of HLA was examined by MSP and Bisulfite sequencing. HLA-C mRNA expression was examined by Q-PCR. The severity of disease was evaluated by psoriasis area and severity index (PASI).In psoriatic lesions and psoriatic non-lesions, the percentage of promoter methylation for HLA-B was 3.57% (2/56) and 3.57% (2/56), while it was 14.28% (8/56) and 23.21% (13/56) for HLA-C, respectively. Methylation of HLA-A was not be detected in both psoriatic lesions and non-lesions. Methylation of HLA-A, -B and -C loci was not found in healthy controls. The frequency of promoter methylation for HLA-C in the psoriatic epidermis was significantly increased compared with healthy controls (p0.05). Interestingly, there was no significant difference in HLA-C methylation between psoriatic lesions and non-lesions (χ(2)=1.465, p=0.167), which was further confirmed by using bisulfite sequencing (t=1.958, p=0.055). HLA-C methylation was not found in healthy controls. The mean methylation rate of HLA-C in psoriatic lesions is relative to PASI score (r=0.316, p=0.018). The mean methylation rate of HLA-C in psoriatic lesions and non-lesions of the patients (onset age ≤18 years) are higher than the other patients, respectively (t=6.884, p0.001; t=6.551, p0.001). The mean HLA-C mRNA expression was significantly higher in psoriatic non-lesions than normal skin (t=2.895, p=0.005), while there is no significant difference between psoriatic lesions and non-lesions (t=1.966, p=0.054). The mean value of HLA-C mRNA expression is not relative to the promoter methylation of HLA-C in psoriatic lesions and non-lesions, respectively.We first demonstrate hypermethylation of HLA-C gene in psoriatic epidermis, suggesting that HLA-C hypermethylation may be an epigenetic marker in psoriasis.

Background: Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic recurrent dermatitis with profound itching. Most patients have personal and/or family history of atopic diseases. Several criteria have been proposed for the diagnosis of AD. Although the clinical features of childhood AD have been widely studied, there has been less large-scale study on adult/adolescent AD. The aim of this study was to investigate the clinical features of adult/adolescent patients with chronic symmetrical eczema/AD and to propose Chinese diagnostic criteria for adult/adolescent AD. Methods: A hospital-based study was performed. Forty-two dermatological centers participated in this study. Adult and adolescent patients (12 years and over) with chronic symmetrical eczema or AD were included in this study. Questionnaires were completed by both patients and investigators. The valid questionnaires were analyzed using EpiData 3.1 and SPSS 17.0 software. Results: A total of 2662 valid questionnaires were collected (1369 male and 1293 female). Of all 2662 patients, 2062 (77.5%) patients had the disease after 12 years old, while only 600 (22.5%) patients had the disease before 12 years old, suggesting late-onset eczema/AD is common. Two thousand one hundred and thirty-nine (80.4%) patients had the disease for more than 6 months. One thousand one hundred and forty-four (43.0%) patients had a personal and/or family history of atopic diseases. One thousand five hundred and forty-eight (58.2%) patients had an elevated total serum IgE and/or eosinophilia and/or positive allergen-specific IgE. Based on these clinical and laboratory features, we proposed Chinese criteria for adult/adolescent AD. Of all 2662 patients, 60.3% were satisfied with our criteria, while only 48.2% satisfied with Hanifin Rajka criteria and 32.7% satisfied with Williams criteria, suggesting a good sensitivity of our criteria in adult/adolescent AD patients. Conclusion: Late-onset of eczema or AD is common. The clinical manifestations of AD are heterogeneous. We have proposed Chinese diagnostic criteria for adolescent and adult AD, which are simple and sensitive for diagnosis of adult/adolescent AD.

A novel series of resveratrol derivatives were synthesized according to Wittig-Horner reaction with 3,5-dihydroxybenzyl alcohol or 3,5-dimethoxybenzyl alcohol or 4-hydroxybenzyl alcohol as raw material and the inhibitory activities on breast carcinoma (MDA-MB-231) and gastric carcinoma cell lines (SGC-7901) in vitro were evaluated by the standard methyl thiazole tetrazolium (MTT) method. The result of biological test shows that some of resveratrol derivatives possess stronger anti-cancer activities than 5-FU. Compound 5c shows the strongest activity against breast carcinoma (MDA-MB-231) and gastric carcinoma cell lines (SGC-7901) with IC50 value of 50.19 ± 1.02 μM, 122.68.27 ± 2.04 μM, compared to that IC50 value of 5-FU is 98.59±3.61 μM,156.74±6.16 μM, respectively.

Antibody therapy based on PD-1/PD-L1 blocking or ADCC effector has produced significant clinical benefit for cancer patients. We generated a novel anti-B7-H3 antibody (07B) and engineered the Fc fragment to enhance ADCC. To improve efficacy and tumor selectivity, we developed anti-B7-H3/PD-1 bispecific fusion proteins that simultaneously engaged tumor associate marker B7-H3 and immune suppressing ligand PD-L1 as well as enhanced ADCC to promote potent and highly selective tumor killing. Fusion proteins were designed by fusing human PD-1 extra domain to 07B in four different formats and showed good binding capacity to both targets. Indeed, the affinity of fusion proteins to B7-H3 is over 10,000 fold higher compared to that of the analogous PD-L1 and the blocking of fusion proteins to PD-L1 was worse but it greatly enhanced when bound to B7-H3, thus achieving directly PD-L1-blockade to B7-H3-expressing tumor cells. Importantly, IL-2 production was enhanced by fusion proteins from staphylococcal enterotoxin B (SEB) stimulated PBMC. Similarly, cytokines induced by fusion proteins was enhanced when co-cultured with stimulated CD8+ T cells and B7-H3/PD-L1 transfected raji cells. Additionally, fusion proteins improved activation to CD16a by Fc modification and delivered selective cytotoxicity to B7-H3 expressing tumor cells. In conclusion, fusion proteins blocked the PD-1/PD-L1 signal pathway and significantly increased potency of ADCC in a B7-H3-directed manner, thereby selectively activating CD8+ T cells and enhancing natural killing towards tumor. This novel fusion protein with its unique targeting preference may be useful to enhance efficacy and safety of immunotherapy for B7-H3-overexpressing malignancies.

Atopic dermatitis (AD) is often concomitant with increased levels of IgE against not only foreign allergens but also autoallergens. AD patients with autoallergy are likely to be more severe and difficult to treat, and self-reactive IgE might be a contributing factor in the pathogenesis of AD. However, how autoallergens are recognized by the immune system and what immune responses are induced subsequently remain largely unknown. We found that the serum level of IgE against transglutaminase 3 (TGase3) was significantly higher in AD patients than in healthy individuals and was positively correlated with disease severity. The expression of TGase3 in the lesional skin of AD patients was markedly increased compared with that of the controls, and Th2 cytokines and/or allergen promoted the expression of TGase3 in keratinocytes. TGase3 bond monocytes-derived dendritic cells (MoDCs) via dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), which resulted in the production of IL-6 and activation of the NF-κB signaling pathway in MoDCs; and TGase3-treated MoDCs facilitated Th1 polarization. Moreover, skin inflammation in the mouse model of MC903-induced AD was attenuated when TGase3 was inhibited. In conclusion, TGase3 was revealed as an autoallergen in AD and actively involved in skin inflammation; TGase3-targeting might be a therapeutic strategy for the treatment of AD.

Background Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. Objective We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD. Methods A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography–tandem mass spectrometry. A mouse model of calcipotriol (MC903)–induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)–null mice and keratinocyte cultures were used to investigate the mechanism. Results Major microbial metabolites of Trp were detected on the skin surfaces of healthy subjects, and the level of indole-3-aldehyde (IAId), an indole derivative of Trp catabolism, was significantly lower in lesional and nonlesional skin of patients with AD than that of healthy subjects. IAId significantly attenuated skin inflammation in mice with MC903-induced AD-like dermatitis, and this effect was blocked by an AhR antagonist and abolished in AhR-null mice. Furthermore, IAId was found to inhibit the MC903-induced expression of thymic stromal lymphopoietin in keratinocytes in vivo and in vitro, which was mediated by binding of AhR to the thymic stromal lymphopoietin promoter. Conclusion IAId, a skin microbiota–derived Trp metabolite, negatively regulated skin inflammation in patients with AD, revealing that skin microbiota play a significant functional role in the pathogenesis of AD.