Search

Mounting findings have revealed the increasingly appreciated functional importance of Retinoblastoma binding protein (RBBP) family members in tumorigenesis. However, the biological function of RBBP4 in breast cancer, especially in the most malignant and aggressive subtype, i.e., triple-negative breast cancer (TNBC), remains to be elucidated.The present study was aimed at elucidating the role of RBBP4 in TNBC pathogenesis.The expression of RBBP4 in TNBC tissues and cell lines was examined and its oncogenic-related functions were verified by performing a series of in vitro and in vivo experiments.At the cellular and tissue level, a marked increase in the RBBP4 expression was observed. Functionally, RBBP4 knockdown dramatically inhibited the proliferation, invasion, and migration of TNBC cells in vitro. Further, mechanistically, RBBP4 downregulation regulated the inactivation of epithelial-mesenchymal transition (EMT) of TNBC cells. In vivo xenograft model in nude mice also validated these results.Collectively, our results showed that the inhibition of RBBP4 suppresses the malignant progression of TNBC cells by regulating EMT. Thus, RBBP4 could serve as a novel biomarker and target for TNBC diagnosis and treatment.

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.

Secondary hyperparathyroidism (SHPT) and tertiary hyperparathyroidism (THPT) are common and complicated clinical endocrine diseases. The parathyroid glands maintain endocrine homeostasis by secreting parathyroid hormone to regulate blood calcium levels. However, structural alterations to multiple organs and systems occur throughout the body due to hyperactivity disorder in SHPT and THPT. This not only decreases the patients’ quality of life, but also affects mortality. Since current treatments for these diseases remains unclear, we aimed to develop a comprehensive review of advances in the treatment of SHPT and THPT according to the latest relevant researches.

Curcumin is a potential plant-derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti-breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non-heterocyclic modifications to systematically summarize curcumin derivatives with better anti-breast cancer activity.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) causes environmental contamination via respiratory droplets and persists on contaminants and environmental surfaces for anywhere from a few hours to 6 days. Therefore, it is particularly important to understand the transmission and containment of SARS-CoV-2 on the surface of objects within isolated environments. In this study, 356 environmental surface samples were collected and 79 tested positive, with the highest contamination rate (56.96%) in the wood category (bedside tables, wood floors, and walls). This study revealed differences in the detection rates of environmental surfaces in hospitalized and discharged rooms of patients with confirmed COVID-19 in 2 isolated settings (A: p = 0.001; B: p = 0.505) and suggested that environmental contamination may be an important route of virus transmission, providing a reference to guide the enhancement of ventilation, the use of hotel isolation model, the advocacy of cotton masks, and the effective suppression of virus transmission.

Immunotherapy has become the breakthrough strategies for treatment of cancer in recent years. The application of messenger RNA in cancer immunotherapy is gaining tremendous popularity as mRNA can function as an effective vector for the delivery of therapeutic antibodies on immune targets. The high efficacy, decreased toxicity, rapid manufacturing and safe administration of mRNA vaccines have great advantages over conventional vaccines. The unprecedent success of mRNA vaccines against infection has proved its effectiveness. However, the instability and inefficient delivery of mRNA has cast a shadow on the wide application of this approach. In the past decades, modifications on mRNA structure and delivery methods have been made to solve these questions. This review summarizes recent advancements of mRNA vaccines in cancer immunotherapy and the existing challenges for its clinical application, providing insights on the future optimization of mRNA vaccines for the successful treatment of cancer.

Although chronic spontaneous urticaria (CSU) is a common disease, GWASs of CSU are lacking. We aimed to identify susceptibility SNPs by performing a GWAS in Chinese Han adults with CSU. The discovery cohort included 430 CSU cases and 482 healthy controls. The GWAS findings were validated in 800 CSU cases and 900 healthy controls. Genetic, functional enrichment, and bioinformatic analyses of genome-wide significant SNPs were performed to assess the association between CSU and autoimmunity or atopy. Five genome-wide significant SNPs were identified: rs434124/LILRA3, rs61986182/IGHG1/2, rs73075571/TDGF1, rs9378141/HLA-G, and rs3789612/PTPN22. The first four SNPs were in linkage disequilibrium with autoimmune-related diseases‒associated SNPs and were cis-expression quantitative trait loci in immune cells. The five SNPs-annotated genes were significantly enriched in immune processes. Higher polygenic risk scores and allele frequencies of rs3789612∗T, rs9378141∗C, and rs73075571∗G were significantly associated with autoimmune-related CSU phenotypes, including positive antithyroglobulin IgG, positive anti-FcεRIα IgG, total IgE40 IU/ml, and positive antithyroid peroxidase IgG but not with atopic or allergic sensitized CSU phenotypes. This GWAS of CSU identifies five risk loci and reveals that CSU shares genetic overlap with autoimmune diseases and that genetic factors predisposing to CSU mainly manifest through associations with autoimmune traits.

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

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

As the Diagnostic and Statistical Manual of Mental Disorders fifth version (DSM-5) was published, the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version (K-SADS-PL) was modified to adapt the new version (K-SADS-PL DSM-5). We translated it to Chinese (K-SADS-PL-C DSM-5) and described its reliability and validity.A total of 154 groups of 6 to 18-year-old children and their guardians were included. Trained interviewers interviewed subjects using the K-SADS-PL-C DSM-5. Interrater reliability was assessed by audio recording. Parent-reported scales, like child behavior checklist (CBCL), the Chinese version of Swan-son Nolan and Pelham, version IV scale-parent form (SNAP-IV), social responsiveness scale (SRS-1), and children-reported scales like depression self-rating scale for children (DSRSC) and the screen for child anxiety related emotional disorders (SCARED) were used to examine the validity of depressive disorder, ADHD, ASD, and ODD.The K-SADS-PL-C DSM-5 had fair to excellent interrater (0.537-1.000) and test-retest (0.468-0.885) reliability of affective disorder and neurodevelopment disorder. The convergent validity of affective disorder and neurodevelopment disorder was good, and their divergent validity was acceptable.i) Clinical questionnaires were insensitive in classifying disorders and had limitations in derived diagnoses. ii) Samples only came from clinical environment, iii) covered limited disease species, and iv) were small.The K-SADS-PL-C DSM-5 can support reliable and valid diagnoses for children with affect, neurodevelopmental, and behavioral disorders in China.

Background and Objective To present 6 new cases with Homer-3 antibodies that expand their clinical spectra and to evaluate the effect of immunotherapy. Methods Patients with suspected autoimmune cerebellar disorder were tested for rare autoimmune cerebellar ataxia (ACA) antibodies (anti-Tr(DNER)/Zic4/ITPR1/Homer-3/NCDN/PKCγ/PCA-2/AP3B2/mGluR1/ATP1A3 antibodies) using both cell-based and tissue-based assays. Patients with positive serum or CSF results who were diagnosed with ACA were registered and followed up. This study reports and analyzes cases with Homer-3 antibodies. Results Of the serum and CSF samples of 750 patients tested, 6 were positive for Homer-3 antibodies. All manifested subacute or insidious-onset cerebellar ataxia. Furthermore, 2 patients each exhibited encephalopathy, myeloradiculopathy, REM sleep behavior disorder, and autonomic dysfunction. Brain magnetic resonance images were normal (n = 1) or revealed cerebellar atrophy (n = 1), cerebellum and pons atrophy with the hot cross bun sign (n = 2), and bilateral cerebral abnormalities (n = 2). Definite leukocytosis was identified in the CSF of 2 patients, protein concentration elevation was observed in the CSF of 1 patient, and oligoclonal bands were present in 2 patients. All patients received immunotherapy, including corticosteroid, IV immunoglobulin, plasma exchange, and mycophenolate mofetil, after which the residual disability was still severe (modified Rankin Scale score ≥3 at the last follow-up in 4 patients and final Scale for the Assessment and Rating of Ataxia scores of 12–29), although 4 patients partially improved and 1 patient stabilized. The remaining 1 patient continued to deteriorate after repeated immunotherapy. Two patients relapsed. Discussion Disorders associated with Homer-3 antibody can mimic multiple system atrophy with cerebellar features in both clinical and radiologic aspects. Accurate identification of autoimmune-mediated cases is critical. Timely, comprehensive immunotherapy is warranted, given the possibility of long-term clinical benefit.

This retrospective study aimed to explore the effect of enteral nutrition (EN) on immune and inflammatory factors after liver cancer surgery (LCS). It was retrospectively conducted on enrolled LCS patients between January 2017 and May 2020. The medical records of 528 patient case records were collected and reviewed. After selection, a total of 80 eligible patient case records were finally included. All those patients received routine diet, and they were allocated to a treatment group (n = 40) and a control group (n = 40). In addition, patients in the treatment group also received EN. The primary outcomes were immune factors (CD4+, CD8+, CD4+/CD8+) and inflammatory factors (interleukin-1, interleukin-6, and tumor necrosis factor-α). The secondary outcomes were postoperative hospital stay (day), time to first bowel sounds (hour), time to first flatus (day), time to first defecation (day), and complications. There were not significant differences in CD4+/CD8+ (P = .34), postoperative hospital stay (P = .39), and time to first bowel sounds (P = .17) between 2 groups. However, there were significant differences in CD4+ (P .05). The results of this study found that EN may benefit for patients after LCS during the recovery period. Future high quality prospective studies are needed to warrant the present conclusion.

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.

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

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

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.

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.

Purpose: The aim of this study was to evaluate the home-based physical activity (PA) environmental characteristics, and different types of physical behavior level of adolescents in different genders, and explore the impact of different domains of home-based PA environmental factors on different physical behaviors of adolescents in different genders. Methods: Five hundred forty-four adolescents aged from 12 to 18 years old (males: n = 358, females: n = 186) and their parents were analyzed in this cross-sectional survey. The volume of various physical behaviors of all adolescent subjects were measured by the ActiGraph wGT3X-BT accelerometer, and the level in different domains of home-based environmental characteristics were assessed by the Gattshall&rsquo, s home-based PA environment questionnaire, which was answered by adolescents&rsquo, parents. The difference in the volume of different physical behaviors was examined using Kruskal&ndash, Wallis analysis. The difference in home physical environment and home social environment for adolescents was examined using one-way analysis of variance (ANOVA). Multiple linear regression analysis in the adjusted model was used to evaluate the influence of different home-based PA environmental domains (PA availability, PA accessibility, Parental role-modeling of PA, and Parental policies around PA) on different physical behaviors (sedentary behavior, SB, light-intensity physical activity, LPA, and moderate-vigorous physical activity, MVPA) of adolescents (boys and girls). Results: The volume of LPA and MVPA, the score of PA accessibility in the home physical environment, and the score of home social environment of boys are significantly higher than those of girls, while the SB volume of boys is significantly lower than that of girls. The PA availability, the parents&rsquo, role-modeling of PA in same-sex parent&ndash, child dyads, and the parents&rsquo, policies around PA in opposite-sex parent&ndash, child dyads are significantly associated with adolescents&rsquo, decreased SB and increased LPA and MVPA. Conclusion: There is significant gender difference in adolescents&rsquo, physical behaviors and home-based environmental characteristics, as well as in the association between adolescents&rsquo, physical behaviors and their home-based environment. The PA availability, the parents&rsquo, child dyads can significantly promote adolescents&rsquo, healthy physical behaviors.

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.

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.

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.

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.

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.

A simple imine based receptor NA-1 has been synthesized for detection of Zinc ions. Probe NA-1 showed the selective colorimetric changes with Zinc (II) ions whereas other metal ions didn't showed any observable colorimetric changes. The probe showed the very selective turn-on fluorescence response with Zn(II) ions among other rival metal ions like Cd(II) and Hg(II). The mode of binding was studied by 1H-nmr titrations and fluorescence spectroscopy. Jobs plot analysis confirming that the probe NA-1 forms 1:1 complex with Zn(II). The observed fluorescence and absorption change further supported by theoretical calculations. The turn-on fluorescence of the probe NA-1 is probably attributable to the interruption of intramolecular charge transfer as well as ESIPT. The limit of detection of the probe for Zn(II) sensing is in the range of 14 nano molar. Cytotoxicity (MTT) assay of the probe in live HeLa cells is showing that the probe is least toxic to cells. The probe NA-1 is effectively applied to detect Zn(II) ions in HeLa cells and suggesting the probe is NA-l permeable to cell wall and viable for Zinc(II) ions imaging in live cells.

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.

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.

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.

Despite the success of convolutional neural network (CNN) in conventional closed-set recognition (CSR), it still lacks robustness for dealing with unknowns (those out of known classes) in open environment. To improve the robustness of CNN in open-set recognition (OSR) and meanwhile maintain its high accuracy in CSR, we propose an alternative deep framework called convolutional prototype network (CPN), which keeps CNN for representation learning but replaces the closed-world assumed softmax with an open-world oriented and human-like prototype model. To equip CPN with discriminative ability for classifying known samples, we design several discriminative losses for training. Moreover, to increase the robustness of CPN for unknowns, we interpret CPN from the perspective of generative model and further propose a generative loss, which is essentially maximizing the log-likelihood of known samples and serves as a latent regularization for discriminative learning. The combination of discriminative and generative losses makes CPN a hybrid model with advantages for both CSR and OSR. Under the designed losses, the CPN is trained end-to-end for learning the convolutional network and prototypes jointly. For application of CPN in OSR, we propose two rejection rules for detecting different types of unknowns. Experiments on several datasets demonstrate the efficiency and effectiveness of CPN for both CSR and OSR tasks.

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.

OBJECTIVE To identify potential mutations in two Chinese families affected with primary localized cutaneous amyloidosis. METHODS Peripheral blood samples of the family were collected with informed consent. Genomic DNA was extracted with a phenol chloroform method. All of the 17 exons and their flanking splicing sites of the OSMR gene were amplified with PCR and subjected to Sanger sequencing. Suspected mutations were verified with PCR - restriction fragment length polymorphism and high-resolution melting assays. RESULTS A missense mutation (c.1538GA) was found in exon 10 of the OSMR gene in all of the six patients from family 1. A missense mutation (c.2081CT) was found in exon 14 of the OSMR gene in all of the four patients from family 2. The same mutations were not found among the healthy controls. CONCLUSION Two missense mutations (c.1538GA and c.2081CT) were detected in the OSMR gene in two Chinese families affected with primary localized cutaneous amyloidosis. Our findings have further confirmed the pathogenicity of such mutations.

A rapidly increasing number of HIV-1 infections have been identified among men who have sex with men (MSM) in Fujian province of China since 2010. We aimed to investigate the causative factors underlying this surging epidemic. Using immunoassays for HIV-1 diagnosis and phylogenetic analysis for viral genotyping, we found that the number of MSM infections doubled from 171 in 2011 to 340 in 2013 with a significantly increased prevalent rate from 4.1% to 5.2%. Majority of these increased infections took place in Fuzhou, Xiamen, and Quanzhou, three large cities in Fujian, mainly among youth, unemployed, business, and well-educated MSMs. Phylogenetic analysis revealed three major HIV-1 genotypes including CRF01_AE, CRF07_BC, and B/B' yet the surging MSM infections were primarily associated with the rapid sexual spread of CRF07_BC in addition to CRF01_AE. In particular, there was a significant proportional expansion of CRF07_BC infections among recently infected MSMs from 19% in 2012 to 41.9% in 2013. This increase was accompanied by emergence of complex patterns of viral recombination including multiple hybrid variants derived from CRF01_AE and CRF07_BC. Full-genome analysis indicated that CRF07_BC in Fujian was likely originated from similar strains previously found among IDUs in Yunnan province but with unique recombination break points. Our findings indicated that HIV-1 CRF07_BC has adapted for rapid sexual transmission, resulting in the surging HIV-1 epidemic and the emergence of new recombinant strains among MSMs in Fujian. Our findings have implications to vaccine and passive immunization trials in Fujian with emphasis on the induction of cross-subtype protective immunity.

To observe the routes of acupuncture needle-insertion of the "nape four acupoints"(BL 10,GB 20,GB 12, SJ 16)in the human cadavers and to explore the possible trigger-point location of cervical headache, so as to provide anatomic evidence for their clinical application.Five human cadavers (male 3, female 2) were used in the present study. The needle inserting routes of the four acupoints Tianzhu (BL 10),Fengchi (GB 20),Wangu (GB 12) and Tianyou (SJ 16) at the nape were labeled with gentian violet first. The occipital tuberosity was taken as the original point, the horizontal projection of superior nuchal line as the abscissa, and the posterior median line as the ordinate, then, a two-dimension rectangular coordinate system was established to measure the horizontal projection of the "nape four points" and to estimate the trigger-point location, followed by making an analysis on their spatial relationship, and determining the reasonable routes of needle-insertion of the 4 acupoints.For the "nape four points", six needling-inserting routes or spots could be taken:(1) Tianzhu (BL 10) Ⅰ(perpendicular insertion), i.e., about 0.5According to anatomical analysis, it is recommended to insert the acupuncture needles into the nape four acupoints along the Tianzhu (BL 10) Ⅰ, Ⅱ, Ⅲ, Fengchi(GB 20)Ⅰ, Wangu (GB 12) Ⅰ and Tianyou(SJ 16)Ⅰ routes mentioned above for achieving a better therapeutic effect. Cervical headache may have a close relation with the trigger-points at the occipital nape.

The presence of mcr-1 among Enterobacteriaceae isolates collected from retail vegetables in China between 2015 and 2016 was investigated. Two Raoultella ornithinolytica and seven Escherichia coli strains recovered from lettuce and tomato samples were identified as MCR-1-producers. Similar to isolates from animals and humans, the mcr-1 gene was located on the IncHI2/ST3, IncI2, or IncX4 plasmids. The presence of MCR-1-producing organisms in ready-to-eat food samples represents a serious risk for human health.

The 5q14.3 deletion syndrome is a heterogeneous disorder with remarkable phenotypic diversity ranging from severe to mild manifestation. In this paper, we report on a patient with 5q14.3 q21.3 deletion who exhibited the severe phenotype and died at 5.5 months. This patient can be classified as having sudden unexplained death in epilepsy (SUDEP) [Tomson et al., 2008]. The deleted region (21.02 Mb, Chr.5: 88, 047, 621-109,072,596 × 1 dn), which included MEF2C and EFNA5, was a 16.5 Mb sequence that overlapped with previously reported deletions in a patient with the mild phenotype. This study further demonstrated the complexity of clinical cytogenetic correlation of the 5q14.3 deletion.

Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07-2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.

Previous studies have shown independently that the skin and gut microbiota are closely associated with atopic dermatitis (AD); however, the microbiota across different habitats of AD patients as an integrated community has not been characterized. In the present study, we comparatively analyzed the structure and function of the microbial communities in the skin, oral cavity, and gut of 172 AD patients and 120 healthy controls through 16S ribosomal RNA gene amplicon sequencing. The skin and oral cavity, but not the gut, of AD patients demonstrated differential reduction in the microbial diversity, and these were distinctly correlated with disease severity. Different degrees of shifts in the community structure were found among different habitats, and the lineage distance between the skin and oral microbiota of AD patients was closer than that observed in the controls. The different habitats of AD patients exhibited site-specific alterations at the genus level, and many oral-specific microbes of AD showed opposing directions of enrichment in the skin and oral cavity. Most interestingly, an inverse association in the functional pathways was found between the skin and oral microbiota of AD patients. Additionally, the alterations of the microbiota in different body sites of AD patients were differentially affected by age.

The effects of the antiepileptic drugs sodium valproate (VPA) and levetiracetam (LEV) on reproductive endocrine function, sexual function, and spermatozoa were explored, together with their possible etiological mechanisms, in Chinese Han men with epilepsy. Following VPA treatment (n = 32), luteinizing hormone and follicle-stimulating hormone levels were significantly lower than in controls (n = 30). The bioactive testosterone/luteinizing hormone ratio and the prolactin level were significantly elevated in the VPA treatment group. There were no significant differences in these hormones between the LEV treatment (n = 20) and control groups. The rates of sperm morphologic abnormality (head, body, and tail) were significantly higher in the VPA treatment group than the control group but did not differ significantly between the LEV treatment and control groups. The sperm motility rate was significantly lower in the VPA treatment group (grade A sperm motility rate