Biomechanical characterization of normal and pathological human ascending aortic tissues via biaxial testing Experiment, constitutive modeling and finite element analysis.

BACKGROUND: Aortic dissection and atherosclerosis are two common pathological conditions affecting the aorta. Aortic biomechanics are believed to be closely associated with the pathological development of these diseases. However, the biomechanical environment that predisposes the aortic wall to these pathological conditions remains unclear. METHODS: Sixteen ascending aortic specimens were harvested from 16 human subjects and further categorized into three groups according to their disease states: aortic dissection group, aortic dissection with accompanied atherosclerosis group and healthy group. Experimental stress-strain data from biaxial tensile testing were used to fit the anisotropic Mooney-Rivlin model to determine material parameters. Computed tomography images or transesophageal echocardiography images were collected to construct computational models to simulate the stress/strain distributions in aortas at the pre-dissection state. Statistical analyses were performed to identify the biomechanical factors to distinguish three groups of aortic tissues. RESULTS: Material parameters of anisotropic Mooney-Rivlin model were fitted with average R2 value 0.9749. The aortic diameter showed no significant difference among three groups. Changes of maximum and average stress values from minimum pressure to maximum pressure (△MaxStress and △AveStress) had significantly difference between dissection group and dissection with accompanied atherosclerosis group (p = 0.0201 and 0.0102). Changes of maximum and average strain values from minimum pressure to maximum pressure (△MaxStrain and △AveStrain) from dissection group were significant different from healthy group (p = 0.0171 and 0.0281). CONCLUSION: Changes of stress and strain values during the cardiac cycle are good biomechanical factors for predicting potential aortic dissection and aortic dissection accompanied with atherosclerosis.

A putative role for ALDH inhibitors and chemoprevention of BRCA-mutation-driven tumors.

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers.

Peli1 deletion in macrophages attenuates myocardial ischemia/reperfusion injury by suppressing M1 polarization.

The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammatory response following myocardial ischemia/reperfusion injury. Peli1, an E3 ubiquitin ligase, is closely associated with inflammation and autoimmunity as an important regulatory protein in the Toll-like receptor signaling pathway. We aimed to explore the function of Peli1 in macrophage polarization under myocardial ischemia/reperfusion injury and elucidate the possible mechanisms. We show here that Peli1 is upregulated in peripheral blood mononuclear cells from patients with myocardial ischemia/reperfusion, which is correlated with myocardial injury and cardiac dysfunction. We also found that the proportion of M1 macrophages was reduced and myocardial infarct size was decreased, paralleling improvement of cardiac function in mice with Peli1 deletion in hematopoietic cells or macrophages. Macrophage Peli1 deletion lessened M1 polarization and reduced the migratory ability in vitro. Mechanistically, Peli1 contributed to M1 polarization by promoting K63-linked ubiquitination and nuclear translocation of IRF5. Moreover, Peli1 deficiency in macrophages reduced the apoptosis of cardiomyocytes in vivo and in vitro. Together, our study demonstrates that Peli1 deficiency in macrophages suppresses macrophage M1 polarization and alleviates myocardial ischemia/reperfusion injury by inhibiting the nuclear translocation of IRF5, which may serve as a potential intervention target for myocardial ischemia/reperfusion injury.

ZIF-67-derived nanoframes as efficient bifunctional catalysts for overall water splitting in alkaline medium.

In order to lower energy consumption it is critical to develop highly efficient and stable non-precious metal bifunctional catalysts. In this study, we found that rational design of novel nanostructures is able to increase the number of active sites, conductivity and accelerate electron transfer, thus promoting enhanced performance of the catalyst. We successfully synthesized carbon nanotubes (CNTs) containing a hollow polyhedral (CNTHPs) structure through annealing, etching and phosphating. The unique hollow shape not only provides a stable structure but also facilitates mass and charge transfer. Thus, CoP/CNTHPs can catalyze the hydrogen and oxygen evolution reactions effectively with overpotentials of 147 and 238 mV at 10 mA cm-2. Simultaneously, CoP/CNTHPs only needs a voltage of 1.54 V to attain a current density of 10 mA cm-2 in the electrocatalytic water splitting process, demonstrating its bifunctional activity. Furthermore, the electrolytic catalytic performance does not weaken significantly after 12 hours of electrolysis, demonstrating excellent stability. Overall, this research offers useful insights into rational design of high-performance non-noble metal catalysts.

Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma.

OBJECTIVES: The "incessant ovulation" hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis. METHODS: BPRN mice were treated with TAM to induce tumors at defined ages and parity status. RESULTS: BPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6-8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRNfl/+), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01). CONCLUSIONS: Our findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.

Rice straw enhancing catalysis of Pseudomonas fluorescens lipase for synthesis of citronellyl acetate.

Citronellyl acetate as an important flavor, can be effectively synthesized by lipase catalysis in nonaqueous system. But lipases usually behave low catalytic activity due to aggregation and denaturation of them in organic phase. To enhance the nonaqueous catalysis, based on the mechanism of lipases activated at water/oil (organic phase) interface, the inexpensive race straw was processed into powder and filaments on which Pseudomonas fluorescens lipase was immobilized by physical adsorption, used for synthesis of citronellyl acetate via transesterification of citronellol and vinyl acetate. Results showed that the desired loading was 10 mg lipase immobilized on 30 mg rice straw filaments or 25 mg rice straw powder. When the two immobilized lipases were employed in the reaction system consisted of 1-mL citronellol and 2-mL vinyl acetate at 37 â„ƒ and 160 rpm, the conversions all reached 99.8% after 12 h. Under the reaction condition, the conversion catalyzed by 10 mg native lipase was 85.1%. Undergoing six times of 8-h reuses in the organic system, the filament and power immobilized lipases had weak activity attenuation rates 0.36 and 0.32% h-1, lower than 1.52% h-1 of native lipase. Even at the room temperature and the static state without shaking and stirring, the rice straw filaments immobilized lipase could brought conversion 62.9% after 10 h but the native lipase only gave 37.0%. Obviously, the rice straw, especially its filaments, is an inexpensive and available natural material to prepare immobilized lipase with desired catalysis in organic phase, meant significant potential in flavor industry.

Influence of a Substituted Methyl on the Photoresponsive Third-Order Nonlinear-Optical Properties Based on Azobenzene Metal Complexes.

For studying the effect of a substituted group on the photoresponsive third-order nonlinear-optical (NLO) properties, photosensitive azobenzene derivative H2L1 was first selected to construct metal complexes {[Zn2(L1)2(H2O)3]·2DMA)}n (1) and {[Cd(L1)(4,4'-bpy)H2O]·H2O}n (2). Then H2L2 with a substituted methyl on the azobenzene ring was used to construct complexes {[Zn(L2)(4,4'-bpy)(H2O)]}n (3) and {[Cd(L2)(4,4'-bpy)(H2O)]}n (4). When the azobenzene moiety of the complexes is trans, the NLO behaviors of the complexes are the same. However, after the azobenzene moiety is excited by ultraviolet (UV) light to change from trans to cis, the substituted methyl increases the repulsion between two azobenzene rings in 3 and 4, thereby affecting their NLO behaviors. Therefore, the nonlinearity of the two types of complexes is different after UV irradiation. Density functional theory calculations support this result. The substituted methyl has a significant influence on the nonlinear absorption behaviors of 3 and 4. This work not only reports the examples of photoresponsive NLO materials based on metal complexes but also provides a new idea to deeply explore NLO properties.

Altering the Microbiome Inhibits Tumorigenesis in a Mouse Model of Oviductal High-Grade Serous Carcinoma.

Studies have shown bacteria influence the initiation and progression of cancers arising in sites that harbor rich microbial communities, such as the colon. Little is known about the potential for the microbiome to influence tumorigenesis at sites considered sterile, including the upper female genital tract. The recent identification of distinct bacterial signatures associated with ovarian carcinomas suggests microbiota in the gut, vagina, or elsewhere might contribute to ovarian cancer pathogenesis. Here, we tested whether altering the microbiome affects tumorigenesis in a mouse model of high-grade serous carcinoma (HGSC) based on conditional oviduct-specific inactivation of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes. Cohorts of control (n = 20) and antibiotic-treated (n = 23) mice were treated with tamoxifen to induce tumor formation and then monitored for 12 months. The antibiotic cocktail was administered for the first 5 months of the monitoring period in the treatment group. Antibiotic-treated mice had significantly fewer and less advanced tumors than control mice at study endpoint. Antibiotics induced changes in the composition of the intestinal and vaginal microbiota, which were durable in the fecal samples. Clustering analysis showed particular groups of microbiota are associated with the development of HGSC in this model. These findings demonstrate the microbiome influences HGSC pathogenesis in an in vivo model that closely recapitulates the human disease. Because the microbiome can modulate efficacy of cancer chemo- and immunotherapy, our genetically engineered mouse model system may prove useful for testing whether altering the microbiota can improve the heretofore poor response of HGSC to immunotherapies. SIGNIFICANCE: This study provides strong in vivo evidence for a role of the microbiome in ovarian cancer pathogenesis.

How demographic and clinical characteristics contribute to the recovery of post-stroke dysphagia?

ABSTRACT: According to the analysis to find out how demographic and clinical characteristics influent the dysphagia outcome after stroke, furthermore, giving some insights to clinical treatment.One hundred eighty post-stroke dysphagia (PSD) patients were enrolled in this retrospective study at the stroke rehabilitation department. The outcome measurements are beside water swallow test at discharge and length of stay at hospital. Twenty-five demographic and clinical variables were collected for this study. Logistic regression and multilinear regression were utilized to estimate models to identify the risk and protect predictors of PSD outcome.Mouth-opening degree, drooling severity scale (DSS) level, mini-mental state exam (MMSE) level, Barthel index and Berg balance scale were significant different between recovered and unrecovered group. Type of stroke, MMSE degree, DSS and hemoglobin level shown significant predictive value for PSD outcome in logistic regression. In addition, obstructive sleep apnea (OSA) and DSS degree were important risk factors for PSD outcome. Gender, body mass index, drinking, hypertension, recurrent stroke, water swallow test level on admission, Berg balance scale, DSS and days between onset to admission shown significant predictive value for length of stay of PSD patients.PSD outcome was influenced by type of stroke, MMSE degree, DSS and hemoglobin level significantly and obstructive sleep apnea act as an important risk role for PSD recovery.

Novel biochar@CoFe2O4/Ag3PO4 photocatalysts for highly efficient degradation of bisphenol a under visible-light irradiation.

In the study, a series of novel Z-scheme biochar@CoFe2O4/Ag3PO4 photocatalysts were synthesized and employed to degrade bisphenol A under visible light irradiation (λ ≥ 420 nm). The structural morphology, optical properties and physicochemical properties of composites were characterized by means of TEM, XRD, FT-IR, XPS, UV-Vis, BET, EIS and VSM analysis. The photocatalytic performances of the photocatalysts were evaluated systematically. The MBA-3 photocatalyst exhibited the highest photocatalytic and mineralization ability within 60 min among all photocatalysts, 91.12% and 80.23%, respectively. After four cycles, the degradation of BPA still kept the photocatalytic activity of 73.94%, and the removal rate of TOC remained 58.96%. Moreover, the active species in the photocatalytic process were evaluated, and we proposed the Z-scheme photocatalytic mechanism for highly efficient degradation of BPA. According to the GC-MS results, the photodegradation pathway of BPA is also suggested. The present study has provided a valuable way of using the magnetic biochar in the design of new and efficient system for the degradation of organic pollutions in waste water.

Murine Oviductal High-Grade Serous Carcinomas Mirror the Genomic Alterations, Gene Expression Profiles, and Immune Microenvironment of Their Human Counterparts.

Robust preclinical models of ovarian high-grade serous carcinoma (HGSC) are needed to advance our understanding of HGSC pathogenesis and to test novel strategies aimed at improving clinical outcomes for women with the disease. Genetically engineered mouse models of HGSC recapitulating the likely cell of origin (fallopian tube), underlying genetic defects, histology, and biologic behavior of human HGSCs have been developed. However, the degree to which the mouse tumors acquire the somatic genomic changes, gene expression profiles, and immune microenvironment that characterize human HGSCs remains unclear. We used integrated molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1, and Nf1 (BPRN) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features. Targeted DNA sequencing showed the mouse BPRN tumors, but not endometrioid carcinoma-like tumors based on different genetic defects (e.g., Apc and Pten), acquire somatic mutations and widespread copy number alterations similar to those observed in human HGSCs. RNA sequencing showed the mouse HGSCs most closely resemble the so-called immunoreactive and mesenchymal subsets of human HGSCs. A combined immuno-genomic analysis demonstrated the immune microenvironment of BPRN tumors models key aspects of tumor-immune dynamics in the immunoreactive and mesenchymal subtypes of human HGSC, with enrichment of immunosuppressive cell subsets such as myeloid-derived suppressor cells and regulatory T cells. The findings further validate the BPRN model as a robust preclinical experimental platform to address current barriers to improved prevention, diagnosis, and treatment of this often lethal cancer. SIGNIFICANCE: The acquired gene mutations, broad genomic alterations, and gene expression and immune cell-tumor axis changes in a mouse model of oviductal serous carcinoma closely mirror those of human tubo-ovarian high-grade serous carcinoma.

Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium.

Most high-grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal-type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal-type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi-lineage differentiation and can form glands with tubal-type epithelium. We used double transgenic Ovgp1-iCreERT2 ;R26RLSL-eYFP mice, which express an eYFP reporter protein in OVGP1-positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post-TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM-treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post-TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM-treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre-pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ARID1A-mutated ovarian cancers depend on HDAC6 activity.

ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.

High-grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease.

Recent studies have suggested that the most common and lethal type of 'ovarian' cancer, i.e. high-grade serous carcinoma (HGSC), usually arises from epithelium on the fallopian tube fimbriae, and not from the ovarian surface epithelium. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human fallopian tube epithelium (FTE). We employed Ovgp1-iCreERT2 mice to show that FTE-specific inactivation of several different combinations of tumour suppressor genes that are recurrently mutated in human HGSCs - namely Brca1, Trp53, Rb1, and Nf1 - results in serous tubal intraepithelial carcinomas (STICs) that progress to HGSC or carcinosarcoma, and to widespread metastatic disease in a subset of mice. The cancer phenotype is highly penetrant and more rapid in mice carrying engineered alleles of all four tumour suppressor genes. Brca1, Trp53 and Pten inactivation in the oviduct also results in STICs and HGSCs, and is associated with diffuse epithelial hyperplasia and mucinous metaplasia, which are not observed in mice with intact Pten. Oviductal tumours arise earlier in these mice than in those with Brca1, Trp53, Rb1 and Nf1 inactivation. Tumour initiation and/or progression in mice lacking conditional Pten alleles probably require the acquisition of additional defects, a notion supported by our identification of loss of the wild-type Rb1 allele in the tumours of mice carrying only one floxed Rb1 allele. Collectively, the models closely recapitulate the heterogeneity and histological, genetic and biological features of human HGSC. These models should prove useful for studying the pathobiology and genetics of HGSC in vivo, and for testing new approaches for prevention, early detection, and treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse.

Endometrioid carcinoma (EC) is a relatively indolent ovarian carcinoma subtype that is nonetheless deadly if detected late. Existing genetically engineered mouse models (GEMMs) of the disease, based on transformation of the ovarian surface epithelium (OSE), take advantage of known ovarian EC driver gene lesions, but do not fully recapitulate the disease features seen in patients. An EC model in which the Apc and Pten tumour suppressor genes are conditionally deleted in murine OSE yields tumours that are biologically more aggressive and significantly less differentiated than human ECs. Importantly, OSE is not currently thought to be the tissue of origin of most ovarian cancers, including ECs, suggesting that tumour initiation in Müllerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1-iCreERT2 ;Apcfl/fl ;Ptenfl/fl mice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1-iCreERT2 mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Application and Revision of Montreal Cognitive Assessment in China's Military Retirees with Mild Cognitive Impairment.

OBJECTIVE: In an effort to accommodate MOCA to better fit for the Chinese context, this study was designed to employ the MOCA criteria to screen mild cognitive impairment (MCI) and analyze associated risk factors in military retirees. METHODS: Three hundred and four retired military cadres were recruited using a random cluster sampling technique with information collected including personal, prevalence, MOCA scale, and related neuropsychiatry scale. Thirty retirees were randomly chosen to be further analyzed one month later using the revised MOCA scale. RESULTS: ①Our data indicated an incidence rate of 64.8% for mild cognitive impairment in retired military cadres. The incidence rate for MCI was significantly higher in those aged 80 or above compared with those 80 years of age or younger (P<0.05). The incidence rate of MCI was significantly higher in those with fewer than 6 years of education compared with those with over 7 years of education (P<0.05). The MCI incidence was higher for those with little exercise than those taking regular exercise (P<0.01). Moreover, the MCI incidence was higher in stroke patients than those who never had a stroke episode (P<0.05). ②There was a significant correlation between MOCA and MMSE scale scores (r = 0.81). MOCA scale scores were negatively correlated with ADL and CES-D scores (although not PSQI scores). ③ MOCA recension Cronbach's alpha value was 0.862. The related coefficient of MOCA and MOCA recension was 0.878(P<0.01). When the Score of cut-off -point of the MOCA recension was 28, the area in ROC curve analyses was 0.859, as well as the largest area. CONCLUSION: Retired cadres exhibited a greater incidence of MCI (than general population), which was closely associated with age, level of education and physical exercise and cerebral apoplexy. Revised MOCA scale displays a better validity and reaction degree of reliability and is more suitable for screening and diagnosis of MCI in the elderly in China.

Arid1a inactivation in an Apc- and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival.

Inactivation of the ARID1A tumour suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell (OCCC) carcinomas, often in conjunction with mutations activating the PI3K-AKT and/or canonical Wnt signalling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumour suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumours that reflect the biological behaviour and gene expression profiles of human OECs harbouring comparable Wnt and PI3K-AKT pathway defects, although the mouse tumours are more poorly differentiated than their human tumour counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged the survival of tumour-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of the mesenchymal markers N-cadherin and vimentin, and increased expression of the epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-epithelial transition in the Arid1a-deficient tumours. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate that the Arid1a tumour suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumour suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. Microarray data have been deposited in NCBI's Gene Expression Omnibus (GSE67695).

Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy.

Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one high-level copy-number alteration per sample (range, 0-5 and 0-6, respectively). Expression of HPV and p16 was detectable in 12% and 28% of patients, respectively. Furthermore, advanced clinical stage, lack of p16 expression, and MYC and CCND1 amplifications were significantly associated with shorter time to progression or PeSCCA-specific survival. Notably, four cases harbored EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investigational targeted therapies are available. Importantly, although paired primary tumors and lymph node metastases were largely homogeneous for relevant somatic mutations, we identified heterogeneous EGFR amplification in primary tumor/lymph node metastases in 4 of 14 cases, despite uniform EGFR protein overexpression. Likewise, activating HRAS mutations occurred in 8 of 43 cases. Taken together, we provide the first comprehensive molecular PeSCCA analysis, which offers new insight into potential precision medicine approaches for this disease, including strategies targeting EGFR.

Tissue-Specific Effects of Reduced ß-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium.

Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the ß-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding ß-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in ß-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key ß-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for ß-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for ß-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active ß-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected ß-catenin levels and some ß-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected ß-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis.