[Effect of SHP-1 knockout in airway epithelial cells on emphysema phenotype in chronic obstructive pulmonary disease in mice].

Objective: To construct and characterize conditional Src homology region 2 protein tyrosine phosphatase 1 (SHP-1) knockout mice in airway epithelial cells and to observe the effect of defective SHP-1 expression in airway epithelial cells on the emphysema phenotype in chronic obstructive pulmonary disease (COPD). Methods: To detect the expression of SHP-1 in the airway epithelium of COPD patients. CRISPR/Cas9 technology was used to construct SHP-1flox/flox transgenic mice, which were mated with airway epithelial Clara protein 10-cyclase recombinase and estrogen receptor fusion transgenic mice (CC10-CreER+/+), and after intraperitoneal injection of tamoxifen, airway epithelial SHP-1 knockout mice were obtained (SHP-1flox/floxCC10-CreER+/-, SHP-1Δ/Δ). Mouse tail and lung tissue DNA was extracted and PCR amplified to discriminate the genotype of the mice; the knockout effect of SHP-1 gene in airway epithelial cells was verified by qRT-PCR, Western blotting, and immunofluorescence. In addition, an emphysema mouse model was constructed using elastase to assess the severity of emphysema in each group of mice. Results: Airway epithelial SHP-1 was significantly downregulated in COPD patients. Genotyping confirmed that SHP-1Δ/Δ mice expressed CC10-CreER and SHP-1-flox. After tamoxifen induction, we demonstrated the absence of SHP-1 protein expression in airway epithelial cells of SHP-1Δ/Δ mice at the DNA, RNA, and protein levels, indicating that airway epithelial cell-specific SHP-1 knockout mice had been successfully constructed. In the emphysema animal model, SHP-1Δ/Δ mice had a more severe emphysema phenotype compared with the control group, which was manifested by disorganization of alveolar structure in lung tissue and rupture and fusion of alveolar walls to form pulmonary alveoli. Conclusions: The present study successfully established and characterized the SHP-1 knockout mouse model of airway epithelial cells, which provides a new experimental tool for the in-depth elucidation of the role of SHP-1 in the emphysema process of COPD and its mechanism.

[The prospect and challenge of liquid biopsy in the diagnosis and treatment of chest malignancy].

In recent years, the incidence of chest malignant tumors in China has increased year by year, which has seriously threatened the health problems of people. Among them, early screening and intervention of patients with chest malignancies is the key to cancer prevention. Early detection, early diagnosis, and early treatment as the "three early prevention" of clinical practice are conducive to improve the survival rate of tumor patients. As a non-invasive and real-time reflection of tumor status, liquid biopsy has gradually received attention in clinical diagnosis and treatment. Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and exosomes as liquid biopsy "Three carriages" are not only widely used in the diagnosis, monitoring and prognostic evaluation of chest malignancies, but also face many unknown challenges. In this article, the application of liquid biopsy in chest malignancies in recent years is elaborated in detail, which provides a reference for the formulation of clinical tumor prevention and diagnosis and treatment strategies.

[Branchio-oto-renal syndrome or branchio-oto syndrome: the clinical and genetic analysis in five Chinese families].

Objective: To screen the causative genes of five families with branchio-oto-renal syndrome (BORS) or branchio-oto syndrome(BOS) and to analyze the phenotypic characteristics and clinical management strategies of patients. Methods: Five families with BORS/BOR from December 2018 to September 2021 were recruited, information of patients, including family history and medical history, was collected, and genealogies were drawn. The examinations concerning audiology, nephrology, and radiology were performed on the affected individuals. Peripheral blood was obtained for DNA extraction, then next-generation sequencing technology was used to screen candidate variants associated with BORS/BOS. Based on patient's clinical results, the appropriate interventions were recommended and implemented. Results: Eight individuals were diagnosed with BOS or BORS. Of the eight patients, all had hearing loss, preauricular pits and ear malformations, and only four presented with branchial cleft fistulae or cysts. Except for two patients(5-I-2, 5-II-2) who did not undergo renal examination, the remaining six lacked renal abnormalities. Genetic analysis identified four likely pathogenic or pathogenic EYA1 variants (c.1715G>T, c.1140+1G>A, c.639G>C, c.1475+1G>C; NM_000503.6), and c.1715G>T was first reported in this study. Middle ear ossicular reconstruction was performed in 1-II-2,2-I-2 and 3-II-2, but did not yield the expected results; then hearing aids and cochlear implantation were recommended and achieved satisfactory results. Conclusions: Next-generation sequencing technology facilitates the diagnosis and genetic counseling of BORS/BOS. Hearing loss, preauricular pits, ear malformations and branchial cleft fistulae or cysts are the most common manifestations of patients in this study. Middle ear surgeries for improving hearing loss may have some limitations in BORS/BOS patients, and hearing aids and cochlear implantation can contribute to hearing gains.

Prevalence of positivity to antibodies to hepatitis C virus among volunteer blood donors in China: a meta-analysis.

OBJECTIVES: Safe blood transfusion plays an important role in the prevention of transfusion-transmissible infections, and hepatitis C virus (HCV) infection is one of the major problems associated with this procedure. This meta-analysis aimed to determine the prevalence of HCV infection in Chinese blood donors. STUDY DESIGN: The study design of this study is a meta-analysis. METHODS: Eligible studies were retrieved from PubMed, Embase, China National Knowledge Infrastructure, China Science and Technology Journal Database and Wanfang literature databases from 2010 to 2020. The effect measure was presented as HCV prevalence with a 95% confidence interval (CI). Q test was used to assess the heterogeneity, and the I2 statistics was determined to decide whether a random effects model or a fixed effects model should be used as the pooling method. Subgroup analyses were also conducted. RESULTS: A total of 62 eligible studies, including 9,007,220 HCV blood donors, were analysed. Of the total blood donors, 35,017 were infected with HCV. The pooled HCV prevalence was 0.415% (95% CI: 0.371-0.458). The subgroup analysis revealed that the prevalence of positivity to anti-HCV antibodies was significantly different in each year (P < 0.05). However, no significant difference was observed in HCV prevalence in terms of sex. Moreover, the prevalence of positivity to anti-HCV was remarkably higher in first-time blood donors than in repeat blood donors (P < 0.05), and the rate of HCV infection among university students was significantly lower than that among soldiers (P < 0.05). CONCLUSIONS: The rate of HCV infection showed a downward trend from 2010 to 2014, increased in 2015-2016, and finally decreased in 2017-2018. Thus, the prevalence of HCV infection has decreased in Chinese blood donors after comprehensive prevention and treatment.

[Inhibitory effect of Xinhui citrus fermentation liquor on liver fibrosis in mice].

OBJECTIVE: To investigate the inhibitory effect of Xinhui citrus fermentation liquor on liver fibrosis in mice. OBJECTIVE: Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 in 105 male C57BL/6 mice, followed by gavage of 0.1 mL 40% CCl4 olive oil 3 times a week (model group, n=49) or daily gavage of citrus liquor at the dose of 0.26 mL (citrus liquor group, n=56) for 8 weeks. Seven mice receiving only olive oil treatment (0.1 mL, 3 times a week) and another 7 treated with citrus liquor served as the control group. Liver tissues and serum samples were collected from 7 mice in the citrus liquor group and model group each week and from the mice in the two control groups at the 8th week for pathological examination of the liver tissues using HE staining and Sirius red staining and for determination of the biochemical indexes of liver function. OBJECTIVE: The mice in the model group showed progressively worsened liver fibrosis with obvious hepatic steatosis, necrosis and inflammatory cell infiltration. These liver pathologies were much ameliorated in citrus liquor group, which showed significantly reduced vacuolation, inflammatory cell infiltration, collagen deposition and the Ishak score of the liver tissue (P < 0.05). Serum levels of cholyglycine, alanine aminotransferase, transglutaminase and alanine aminotransferase were all significantly lower in citrus liquor group than in the model group (P < 0.05). OBJECTIVE: Xinhui citrus fermentation liquor has protective effect on the liver and can significantly ameliorate liver fibrosis in mice.

[Study on the expression of p62 protein in patients with lung adenocarcinoma].

To explore the expression of p62 protein in lung adenocarcinoma (LUAD). In this study, a cross-sectional study was adopted. From December 2011 to May 2013, 60 patients with lung adenocarcinoma who were diagnosed and treated in Tongji Hospital of Tongji University, Shanghai were selected for paraffin embedding and tissue chip preparation, and immunohistochemistry (IHC) technology was used to detect the expression of p62 in lung adenocarcinoma patients' cancer tissues and adjacent tissues, and analyze the relationship between p62 expression and the clinicopathological characteristics and survival prognosis of patients with lung adenocarcinoma; at the same time, 6 cases of lung adenocarcinoma were selected by random sampling cancer tissues and adjacent tissues were detected by Western Blot (WB) to detect p62 protein and analyzed by gray value. Preoperative examination specimens of inpatients with lung adenocarcinoma diagnosed from April 2018 to early October 2019, and plasma specimens of healthy subjects were collected, and enzyme linked immunosorbent assay (ELISA) was used to detect lung adenocarcinoma patients and healthy patients. The expression of p62 in the plasma of the subjects was statistically analyzed using SPSS 22.0 software. The results of IHC showed that the positive expression rate of p62 in cancer tissues was significantly higher than that in adjacent tissues, and the difference was statistically significant (t=5.593, P<0.001). Similarly, WB results showed that the expression of p62 protein in cancer tissues was significantly higher than that in adjacent tissues. It is statistically relevant (t=2.238, P=0.049). The expression of p62 was statistically correlated with tumor size, clinicopathological stage and lymph node metastasis in patients with lung adenocarcinoma (all P<0.05). The overall survival of patients with lung adenocarcinoma with high p62 expression was worse than that of patients with low p62 expression (95%CI was 0.238-0.870, P=0.028), suggesting that the high expression of p62 is related to the poor prognosis of patients with lung adenocarcinoma. The level of p62 protein in the plasma of patients with lung adenocarcinoma was significantly higher than that in the healthy control group. The difference was statistically significant (t=8.533, P<0.001). The area under the receiver operating characteristic curve was 0.835 (95%CI was 0.779-0.891, P<0.001), which is significantly higher than CEA, CA125, CA153 and other single traditional indicators, and the combined detection of four indicators has the highest diagnostic efficiency. p62 was strongly expressed in cancer tissues and serum, which is related to the poor prognosis and overall survival rate of LUAD patients.

CTNNBIP1 modulates keratinocyte proliferation through promoting the transcription of ß-catenin/TCF complex downstream genes.

BACKGROUND: During psoriasis initiation and development, deregulations in signalling pathways and gene expression are observed. METHODS: Herein, we downloaded seven sets of microarray mRNA expression profiles showing differentially expressed genes in psoriasis lesion skin and non-lesion skin tissues and three sets of RNA-seq data and analysed these online data attempting to screen for crucial genes related to keratinocyte proliferation and psoriasis development. The expression of CTNNBIP1 in psoriasis patients and IMQ mouse model skin tissues were examined by RT-PCR, immunoblotting and IHC. The functions of CTNNBIP1 on HaCaT cell proliferation, apoptosis and ß-catenin/TCF complex were measured by MTT, EdU, flow cytometry, IF, luciferase assays and immunoblotting. RESULTS: The expression of catenin beta interacting protein 1 (CTNNBIP1) was remarkably downregulated within psoriasis lesion skin tissue samples compared to that within non-lesion skin tissues based on both online data and experimental results. In response to a period of different therapies, respectively, CTNNBIP1 expression could be rescued in lesion skin tissues. Within IMQ-induced psoriasis-like dermatitis in mice, CTNNBIP1 silence further aggravated psoriatic phenotypes. In human immortalized keratinocytes, HaCaT cells, CTNNBIP1 silence significantly inhibited cell apoptosis and promoted cell proliferation. Regarding the molecular mechanism, CTNNBIP1 silence in HaCaT cells promoted ß-catenin nucleus translocation, enhanced the transcriptional activity of TCF4 and increased ß-catenin/TCF complex downstream c-Myc and cyclin D1 proteins, and also increased the expression of cell proliferation marker ki-67. In contrast to CTNNBIP1, the expression of c-Myc and cyclin D1 showed to be dramatically upregulated within psoriasis lesion tissue samples than that within non-lesion tissue samples. Within tissues, c-Myc and cyclin D1 showed to be negatively correlated with CTNNBIP1, respectively. CONCLUSIONS: We identify CTNNBIP1 as an abnormally downregulated gene in psoriasis. CTNNBIP1 silence significantly disturbs the proliferation of keratinocytes through promoting the transcription of ß-catenin/TCF complex downstream genes.

[Cytogenetic abnormalities and morphological changes of bone marrow in multiple myeloma: a pathological analysis of 151 cases].

Objective: To investigate the relationship between six common cytogenetic abnormalities and bone marrow pathomorphology in multiple myeloma (MM). Methods: Bone marrow biopsy was performed on 151 newly-diagnosed MM patients. Meanwhile, myeloma cells were enriched by CD138 immunomagnetic beads, and then lq+, 13q-, 17p-, t(4;14), t (11;14), t (14;16) and other common genetic abnormalities were detected using interphase fluorescence in situ hybridization (FISH). The relationship between different genetic abnormalities and biopsy morphology was compared. Results: Of the 151 patients, 15 had extramedullary infiltration (9.9%). The rate of cytogenetic abnormalities was 76.2% (115/151), of which 1q+ accounted for 49.7% (75/151), 13q-39.1% (59/151), 17p-8.6% (13/151), t(4;14) 21.2% (32/151), t(11;14) 19.2% (29/151), and t(14;16) 2.0% (3/151). The proliferation patterns of MM plasma cells were nodular (48.3%, 73/151), interstitial (33.8%, 51/151) and diffuse (17.9%, 27/151). The morphology of plasma cells was mainly mature type (58.3%, 88/151), followed by juvenile type (20.5%, 31/151), intermediate type (15.9%, 24/151) and plasmacyte type (5.3%, 8/151). According to the mSMART risk stratification system, the proliferation pattern of myeloma cells in the high-risk group was mainly diffuse type, and the morphology was mainly immature and plasmacyte type. In the middle-risk group, mature type myeloma cells were mainly nodular proliferating. In the low-risk and negative group, mature type myeloma cells were mainly interstitial proliferating. There was no difference in the probability of different proliferation modes of intermediate type plasma cells in each group. Conclusions: The proliferation pattern and morphology of plasma cells in bone marrow biopsy combined with cytogenetic markers can more accurately predict the severity and prognosis of MM.

Association of genetic and environmental factors with dental caries among adolescents in south China: A cross-sectional study.

AIM: The objective of this study was to investigative genetic and environmental factors that contribute to caries susceptibility among adolescents in south China. MATERIALS AND METHODS: A cross-sectional study was conducted among 1055 adolescents aged 13-14 years old in south China. The International Caries Detection and Assessment System (ICDAS) was used to identify caries. Environmental variables were analysed by regression models. Twenty-three single nucleotide polymorphisms (SNPs) in 14 genes were identified from saliva samples. Regression analysis was used for the evaluation of effects of SNP markers using the minor allele as the effect allele. RESULTS: Our results suggest that gender, Cariostat score and Plaque Index were associated with dental caries. After the adjustment by age and gender, the G allele in AMBN (rs13115627) nominally was a protective factor for caries under additive model (P=0.028; OR=0.782; 95% CI, 0.627-0.974). However, the association did not meet the Bonferroni correction significance cut-off for multiple testing. CONCLUSION: Gender, Cariostat score and Plaque Index were associated with dental caries in this population. No selected SNPs showed a significant association with dental caries under either additive model or dominance model.

[Safety of biological valves for aortic valve replacement: A systematic review and meta-analysis].

OBJECTIVE: To provide a comprehensive and contemporary overview of the long-term safety outcomes after aortic valve replacements (AVR) with conventional biological heart valve (stented or stentless). METHODS: English databases (Medline, Embase, Web of Science, CENTRAL, and ClinicalTrial.gov) and Chinese databases (CNKI, VIP, WanFang, and SinoMed) were searched systemically from January 1, 2000 to January 26, 2019. Eligible randomized controlled trials, non-randomized clinical trials, cohort studies (retrospective or prospective), and unselected case series were included. Strict screening of the obtained literature was conducted to extract relevant data by two reviewers. Other inclusion criteria were studied reporting on outcomes of AVR with biological valves (stented or stentless), with or without coronary artery bypass grafting (CABG) or valve repair procedure, with mean follow-up length equal to or longer than 5 years. We excluded studies that reported only a specific patient group (e.g., patients with renal failure, or pregnancy), without the report of biological valve type, or with study population size less than 100. The meta-analysis was performed using Stata 14.0 software. RESULTS: In this study, 53 papers (in total 57 study groups) involving 47 803 patients were included. (1) The all-cause mortality was 6.33/100 patient-years (95%CI: 5.85-6.84). Subgroup analysis showed that the mortality rates of porcine and bovine valve prostheses were 5.69/100 patient-years (95%CI: 5.05-6.41) and 7.29/100 patient-years (95%CI: 6.53-8.13), respectively. The all-cause mortality rates for stented and stentless valve were 6.69/100 patient-years (95%CI: 6.12-7.30) and 5.21/100 patient-years (95%CI: 4.43-6.14), respectively. (2) The incidence rate of thromboembolism was 1.16/100 patient-years (95%CI: 0.96-1.40), the incidence rate of permanent pacemaker (PPM) implantation was 1.08/100 patient-years (95%CI: 0.75-1.54), the incidence rate of stroke was 0.74/100 patient-years (95%CI: 0.51-1.06), the incidence rate of structural valve dysfunction (SVD) was 0.73/100 patient-years (95%CI: 0.59-0.91), the incidence rate of major bleeding was 0.52/100 patient-years (95%CI: 0.41-0.65), the incidence rate of endocarditis was 0.38/100 patient-years (95%CI: 0.33-0.44), and the incidence rate of non-structural valve dysfunction (NSVD) was 0.20/100 patient-years (95%CI: 0.13-0.31). The total reoperation rate for biological aortic valve was 0.77/100 patient-years (95%CI: 0.65-0.91), and the SVD related reoperation rate was 0.46/100 patient-years (95%CI: 0.36-0.58). CONCLUSION: The all-cause mortality for conventional biological AVR was 6.33/100 patient-years. Thromboembolism, PPM implantation, reoperation, stroke, and SVD were major long term complications.

Diagnostic value of intraoperative bone marrow assessment for bone margins in patients with head and neck squamous cell carcinoma: a systematic review and meta-analysis.

A clear bone margin is essential for complete resection of the bone-involved tumour, but the evaluation of hard tissue takes time and is impractical intraoperatively. Bone marrow assessment remains controversial. The aim of this study was to investigate the diagnostic value of intraoperative bone marrow assessment for bone margins. PubMed and Web of Science were searched for studies published between 1990 and 2017. A systematic review was conducted. After quality assessment, 10 articles with 11 cohorts and 404 patients were identified. Sensitivity, specificity, and other measures were pooled for meta-analysis; the estimates for intraoperative bone marrow assessment were as follows: sensitivity 0.82 (95% confidence interval (CI) 0.62-0.93), specificity 0.99 (95% CI 0.96-1.00), positive likelihood ratio 109.79 (95% CI 22.99-524.34), negative likelihood ratio 0.18 (95% CI 0.08-0.42), and diagnostic odds ratio 241.82 (95% CI 90.33-647.38). Furthermore, sensitivity and specificity at the summary operating point of the summary receiver operating characteristic curve were 0.82 and 0.99, respectively, and the area under the curve was 0.99. Intraoperative bone marrow assessment was investigated by meta-analysis and shown to have a high level of overall accuracy for the diagnosis of bone margins.

The Differential Effect of Treadmill Exercise Intensity on Hippocampal Soluble Aß and Lipid Metabolism in APP/PS1 Mice.

Alzheimer's disease (AD) is characterized clinically by progressive impairments in learning and memory. Accumulating evidence suggests that regular exercise plays a neuroprotective role in aging-associated memory loss. Our previous study has confirmed that long-term treadmill exercise initiated either before or during the onset of ß-amyloid (Aß) pathology, was beneficial for reducing the levels of soluble Aß and further improved cognition. In this study, in APP/PS1 mice, we assessed changes in soluble Aß, and various blood biochemistry and molecular biological indices to assess whether exercise modulated lipid metabolism and thereby decelerated AD progression. Our results show that long-term treadmill exercise reduced the total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, and increased the level of high-density lipoprotein cholesterol. Exercise also decreased the levels of soluble Aß1-40 and Aß1-42, down-regulated retinoid X receptor expression, and up-regulated liver X receptor, Apolipoprotein E, Low density lipoprotein receptor, Low density lipoprotein receptor-related protein 1, and ATP-binding cassette transporter A1 expression. This indicates that long-term treadmill exercise alters the lipoprotein content, increases lipid metabolism and cholesterol transportation, reduces the soluble Aß, and therein plays an important neuroprotective role and delays AD progression. We further show that medium exercise intensity (60%-70% of maximal oxygen uptake) was more efficacious in increasing lipid metabolism and reducing blood lipid levels and soluble Aß levels, than low-intensity exercise (45-55% of maximal oxygen uptake). This research has broad prospects and implications, and offers a theoretical basis for the prevention of AD.

Prevention of Postdental Procedure Bacteremia: A Network Meta-analysis.

Postdental procedure bacteremia is common and troublesome. The comparative efficacy of multiple prophylactic interventions is unclear. We compared the efficacy of interventions for the prevention of postdental procedure bacteremia. We conducted a review of ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov from inception to December 4, 2018. Randomized controlled trials that evaluated prophylactic interventions for the prevention of postdental procedure bacteremia were eligible. The primary outcome was the incidence of postdental procedure bacteremia. A total of 24 trials were included with 2,147 participants. Our network meta-analysis demonstrated that intravenous administration of 1,000/200 mg of amoxicillin/clavulanate provided the least incidence of postdental procedure bacteremia among all the prophylactic interventions (odds ratio = 0.03, 95% CI = 0.00 to 0.63) as compared with the placebo/controls. Oral 3 g of amoxicillin had the least incidence of postdental procedure bacteremia among all oral or topical forms of prophylactic interventions (odds ratio = 0.10, 95% CI = 0.02 to 0.44) as compared with the placebo/controls. No serious adverse events, such as anaphylactic shock, mortality, and the development of antibiotic-resistant bacteria, were reported. None of the included subjects were of high risk of infectious endocarditis. Our network meta-analysis demonstrates that intravenous amoxicillin/clavulanate and oral amoxicillin might be the best prophylactic interventions in preventing postdental procedure bacteremia among all the oral/topical forms of interventions for the overall populations.

Response Mechanism of Oviposition and Relevant Protein Expression of Bactrocera cucurbitae (Coquillet) to Short-Term High-Temperature Conditions.

Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae) is an important pest of vegetables in Asia, the Middle East, Africa, and Hawaii. High temperature can significantly influence B. cucurbitae reproduction. The effect of short-term high-temperature exposure on proteins that affect oviposition was analyzed by proteomics. Among six key target genes for oviposition, the expression of Vitellogenin-1, Vitellogenin-2, and Vitellogenin receptor was similar in B. cucurbitae exposed to higher temperature compared to controls. However, levels of Vitellogenin-3 were reduced. Juvenile hormone (Jh)-inducible protein was downregulated and then upregulated, while the expression of Jh-epoxide hydrolase-2 showed the opposite Jh-inducible protein trend. Therefore, short-term high-temperature stress can cause differential expression of proteins related to oviposition in B. cucurbitae, which in turn further triggers the hormesis of oviposition. High-temperature conditions have become more frequent because of climate warming and are predicted to continue. The data indicate that climate effects on insect reproduction pose a significant threat to agriculture in a world of increasing population.

Seven Novel and Three Known Mutations in FOXL2 in 10 Chinese Families with Blepharophimosis Syndrome.

BACKGROUND: Blepharophimosis syndrome (BPES) is characterized by eyelid malformation with occasional premature ovarian failure. Mutations in FOXL2 underlie a fraction of BPES cases. OBJECTIVE: We aimed to investigate the genetic basis of BPES in 26 Chinese families that included 78 patients. METHODS: We performed ophthalmological examinations on each family member. We used Sanger sequencing to screen FOXL2 exons and their flanking sequences. We also performed bioinformatics studies, structural modeling and pathogenicity evaluations on all identified variations. Literature was reviewed and genotype-phenotype correlation analysis was performed. RESULTS: The patients had typical manifestations of BPES. Ten mutations were identified in ten of the twenty-six families. Among these, seven were novel mutations. These included the six truncating mutations, p.Glu69*, p.Gly256Glyfs*14, p.Ala14Serfs*135, p.Pro333Profs*200, p.Pro290Leufs*70, and p.Pro157Profs*91, and one missense mutation, p.Tyr59Cys. The mutations were scattered within the gene, and no mutational hotspots were found. Genotype-phenotype correlation analysis showed that frameshift or nonsense mutations were correlated with type I BPES, while in-frame or missense mutations were associated with type II BPES. CONCLUSION: We report the largest BPES cohort in China thus far as well as seven novel mutations in FOXL2. The identification of novel mutations has not only expanded the mutational spectrum of the gene (which is valuable for mutation detection-based screening) but also suggests that most mutations within the Chinese population may not have been characterized yet.

Identification of potential small-molecule protein-protein inhibitors of cancer metastasis by 3D epitope-based computational screening.

In cancer cells exposed to extracellular pressure or shear stress, AKT1-FAK interaction drives focal adhesion kinase (FAK) phosphorylation, leading to force-activated cancer cell adhesion and metastasis. Blocking the AKT1-FAK interaction is therefore an attractive target for cancer therapy, avoiding the side effects of global FAK inhibition. Starting with our previous identification of a short FAK peptide that binds AKT1, we identified a series of small-molecule inhibitor candidates using a novel approach for inhibiting protein-protein interactions. Using a 3D structural fragment of the FAK peptide as the query, millions of drug-like, commercially available molecules were screened to identify a subset mimicking the volume and chemistry of the FAK fragment to test for their ability to block pressure-sensitive FAK phosphorylation by AKT1. Two compounds reduced the stimulation of FAK phosphorylation in response to extracellular pressure in human SW620 colon cancer cells without affecting basal FAK phosphorylation. Thus, using a 3D protein interaction epitope as a novel query for ligand-based virtual screening can successfully identify small-molecules that show promise in modulating cancer cell adhesion and metastasis.

[Effect of the vacuum-formed retainer on preventing the proximal contact loss between implant supported crown and adjacent natural teeth].

OBJECTIVE: To evaluate the effect of the vacuum-formed retainer on preventing the proximal contact loss between the implant supported crown and its adjacent natural teeth. METHODS: Forty-six posterior implant crowns in the mandible including 92 interproximal contacts in 46 patients (19 men, 27 women) aged from 25 to 66 years were included. The participants in experimental group (22 cases) were vacuum-formed retainers at night, while participants in control group (24 cases) only received routine examination. The two groups were not different in age, gender, the time interval of the tooth loss and tooth position at baseline. Mesial and distal proximal contact tightness was measured using the orthodontic dynamometer and metallic articulating film immediately after crown delivery, and 1-month, 3-month, 6-month, and 1-year follow-up respectively. The articulating film was inserted interdentally from the occlusal direction, and then it was slowly removed in the buccallingual direction by the dynamometer. Increasing the number of films (N) piece by piece until the frictional force (F) was great than 0, and the number of films (N) was recorded. At each follow-up, proximal contact between implant crown and its adjacent teeth was considered to be loss if the number of films (N) used at immediate crown delivery passed without frictional force (F=0). Besides, the periodontal conditions [scored according to the probing depth (PD), bleeding index (BI), mobility (M)] and complaint of food impaction were recorded. The mesial and distal proximal contact loss rates were compared between the two groups at different times. Chi-square test or Fisher's exact test was used for statistical analysis. RESULTS: The proximal contact loss rate on the mesial surface of the implant supported crown continuously increased over the follow-up periods. At the end of the 1-, 3-, and 6-month follow ups, 18.2%, 22.7% and 27.3% were identified for the contact loss rates on the mesial surface of the implant supported crown in the experimental group, respectively. Meanwhile in control group, the rates were 20.8%, 37.5% and 45.8%. No significant differences were observed at the end of the 1-, 3-, and 6-month follow ups(1-month: χ2=0.000, P=1.000; 3-month: χ2=1.183, P=0.277; 6-month: χ2=1.697, P=0.193). The proximal contact loss rate on the mesial surface in control group (62.5%) was significantly higher than that in the experimental group (31.8%, χ2=4.330, P=0.037) at the end of the 1-year follow-up. However, no statistical difference was found on the distal surfaces between the two groups during the whole follow-up periods. The first open contact was noted 1 month after crown insertion. CONCLUSION: By wearing vacuum-formed retainer for one year, the incidence of open contacts between the posterior implant prostheses and mesial adjacent teeth in the mandible has been reduced.