Plasma metabolomics identifies S-adenosylmethionine as a biomarker and potential therapeutic target for vascular aging in older adult males.

Brachial-ankle pulse wave velocity (baPWV) is a noninvasive index of vascular aging. However, the metabolic profile underlying vascular aging has not yet been fully elucidated. The current study aimed to identify circulating markers of vascular aging as assessed by baPWV and to elucidate its mechanism from a metabolomic perspective in older adults. A total of 60 and 61 Chinese male participants aged ≥80 years were recruited to the metabolome and validation cohorts, respectively. The baPWV of participants was measured using an automatic waveform analyzer. Plasma metabolic profile was investigated using ultra-performance liquid chromatography coupled with triple quadrupole linear ion trap tandem mass spectrometry. Orthogonal partial least squares (OPLS) regression modeling established the association between metabolic profile and baPWV to determine important metabolites predictive of vascular aging. Additionally, an enzyme-linked immunosorbent assay was employed to validate the metabolites in plasma and culture media of vascular smooth muscle cells in vitro. OPLS modeling identified 14 and 22 metabolites inversely and positively associated with baPWV, respectively. These 36 biomarkers were significantly enriched in seven metabolite sets, especially in cysteine and methionine metabolism (p <0.05). Notably, among metabolites involved in cysteine and methionine metabolism, S-adenosylmethionine (SAM) level was inversely related to baPWV, with a significant correlation coefficient in the OPLS model (p <0.05). Furthermore, the relationship between SAM and vascular aging was reconfirmed in an independent cohort and at the cellular level in vitro. SAM was independently associated with baPWV after adjustments for clinical covariates (ß = -0.448, p <0.001) in the validation cohort. In summary, plasma metabolomics identified an inverse correlation between SAM and baPWV in older males. SAM has the potential to be a novel biomarker and therapeutic target for vascular aging.

WAVE3 Facilitates the Tumorigenesis and Metastasis of Tongue Squamous Cell Carcinoma via EMT.

Wiskott-Aldrich syndrome protein family verprolin-homologous domain-containing protein 3 (WAVE3) is reported as an oncogene regulating cell proliferation and motility in multiple malignancies, while its role in tongue squamous cell carcinoma (TSCC) remains unknown. This study aimed to explore the expression and mechanism of WAVE3 in TSCC. We enrolled 64 TSCC patients admitted between June 2013 and February 2014 and collected their cancerous and adjacent normal tissues to determine WAVE3 expression by immunohistochemistry. The correlation of WAVE3 expression with TSCC patients' pathological characteristics was analyzed. Then, a 7-year follow-up was conducted to observe the value of WAVE3 in evaluating patient outcomes. In addition, human TSCC SCC9, SCC25, and CAL27 cells were purchased and detected by Cell Counting Kit-8 (CCK-8), Transwell, and scratch-wound assays for their proliferation, invasion, and migration capacities, while real-time quantitative PCR (qRT-PCR) and Western blotting were utilized to quantify WAVE3 and epithelial-mesenchymal transition (EMT)-related protein expression, respectively. The most active cell lines were selected to be infected with lentiviral vectors that silenced WAVE3 (named WAVE3-sh group) and overexpressed WAVE3 cDNA (named WAVE3-OE group) to observe the impacts of interfering WAVE3 expression on TSCC cell biological behavior. The positive expression of WAVE3 in TSCC tissue was found to be obviously enhanced and predominantly located in the cytoplasm. In addition, close correlations were identified between WAVE3 and T staging, clinical staging, lymphatic metastasis, distant metastasis, and differentiation degree (P < 0.05). Increased WAVE3 expression predicted an elevated risk of death, as indicated by the follow-up analysis (P < 0.05). SCC9 was selected for subsequent experiments among various TSCC cell lines studied because it showed the most potent ability to proliferate, invade, and migrate (P < 0.05). Silencing WAVE3 expression in SCC9 cells decreased cell proliferation, invasion, migration, and EMT-related protein expression (P < 0.05), while increasing WAVE3 expression promoted SCC9 viability. WAVE3, which was highly expressed in TSCC, promoted EMT in tumor cells and accelerated their proliferation, invasion, and migration, which might provide a new theoretical basis for molecular targeted therapy of TSCC in the future.

Brucea javanica oil inhibits tongue squamous cell invasion and metastasis by regulating miR-138-EZH2 pathway.

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors of head and neck. Its incidence is on the rise, and the proportion of young patients is gradually increasing, which is prone to tumor recurrence and metastasis. At present, there is no effective method to completely treat TSCC. Studies have shown that brucea javanica oil (BJO) has good antitumor activity against lung cancer and gastrointestinal tumors, but its therapeutic effect on TSCC is not clear. We have previously confirmed that oleic acid, the main component of BJO, can induce apoptosis of TSCC and reduce its invasion and metastasis ability. However, the anticancer effect and mechanism of BJO in TSCC remain unclear. In order to further explore the effects of BJO on the biological characteristics of TSCC cells, we studied the effects of different concentrations of BJO on the migration, invasion ability and epithelial mesenchymal transition (EMT) progression of TSCC cells and the possible mechanisms through in vitro experiments. We found that BJO could inhibit the invasion and metastasis of TSCC and up-regulate miR-138. After BJO treatment, the expression of E-cad was significantly increased, while the expression of EZH2, Slug, p-ERK1/2 and Vimentin was significantly decreased. EZH2 is a miR-138 target gene involved in TSCC. BJO inhibits TSCC invasion and metastasis by regulating the miR-138-EZH2 pathway. In vivo experiments have also well demonstrated the targeting effect of this pathway. This study provides a new therapeutic strategy for the treatment of TSCC.

Dengue Risk Forecast with Mosquito Vector: A Multicomponent Fusion Approach Based on Spatiotemporal Analysis.

Dengue as an acute infectious disease threatens global public health and has sparked broad research interest. However, existing studies generally ignore the spatial dependencies involved in dengue forecast, and consideration of temporal periodicity is absent. In this work, we propose a spatiotemporal component fusion model (STCFM) to solve the dengue risk forecast issue. Considering that mosquitoes are an important vector of dengue transmission, we introduce feature factors involving mosquito abundance and spatiotemporal lags to model temporal trends and spatial distributions separately on the basis of statistical properties. Specifically, we conduct multiscale modeling of temporal dependencies to enhance the forecast capability of relevant periods by capturing the historical variation patterns of the data across different segments in the temporal dimension. In the spatial dimension, we quantify the multivariate spatial correlation analysis as additional features to strengthen the spatial feature representation and adopt the ConvLSTM model to learn spatial dependencies adequately. The final forecast results are obtained by stacking strategy fusion in ensemble learning. We conduct experiments on real dengue datasets. The results indicate that STCFM improves prediction accuracy through effective spatiotemporal feature representations and outperforms candidate models with a reasonable component construction strategy.

Circulating Ceramide: A New Cardiometabolic Biomarker in Patients With Comorbid Acute Coronary Syndrome and Type 2 Diabetes Mellitus.

AIMS: This study investigated the association of circulating ceramides in patients with comorbid acute coronary syndrome and type 2 diabetes mellitus (ACS-DM). METHODS: A total of 761 patients with coronary heart disease who were admitted to the Department of Cardiology at the Chinese PLA General Hospital from March to August 2018 were enrolled in this study. Of these 761 patients, 282 were diagnosed with acute coronary syndrome (ACS). We selected 65 patients with ACS-DM (ACS-DM group; mean age 64.88 years; 38 men) and 65 patients with ACS but without any comorbidities (ACS group; mean age 64.68 years; 38 men); the two groups were matched by age and sex. We determined four circulating ceramides in 130 plasma samples: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0). The ceramides in plasma samples from patients with ACS and those from patients with ACS-DM were compared. Pearson correlation coefficients between individual ceramides and traditional cardiovascular risk factors for the whole study population were calculated. Multiple logistic regression models were used to evaluate the relativity between the ceramide and ACS-DM. RESULTS: Compared with the ACS group, the levels of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) and their ratios to Cer(d18:1/24:0) were higher in the ACS-DM group and Cer(d18:1/24:0) was lower in the ACS-DM group (P < 0.05). Correlation analysis demonstrated mild-to-moderate correlations of ceramide and traditional cardiovascular risk factors. There were relatively strong correlations of Cer(d18:1/18:0) and Cer(d18:1/24:1) with C-reactive protein, blood lipids, fasting blood glucose, and glycated hemoglobin A1c. In multiple logistic regression models, Cer(d18:1/18:0) [odds ratio (OR) 2.396; 95% confidence interval (CI) 1.103-5.205; P = 0.027], Cer(d18:1/24:1) (OR 2.826; 95% CI 1.158-6.896; P = 0.023), Cer(d18:1/18:0)/Cer(d18:1/24:0) (OR 2.242; 95% CI 1.103-4.555; P = 0.026), and Cer(d18:1/24:1)/Cer(d18:1/24:0) (OR 2.673; 95% CI 1.225-5.836; P = 0.014) were positively correlated with ACS-DM, and Cer(d18:1/24:0) (OR 0.200; 95% CI 0.051-0.778; P = 0.020) was negatively correlated with ACS-DM. CONCLUSION: Circulating ceramides are positively correlated with the risk of ACS-DM comorbidity. These results give a new insight into the pathogenesis of ACS-DM comorbidity and could provide new options for risk estimation.

Modeling and compensation of hysteresis in piezoelectric actuators.

Piezoelectric actuator has the advantages of high rigidity, wide bandwidth, fast response and high resolution. Therefore, they are widely used in many micro and nano positioning applications. However, the hysteresis characteristic in the piezoelectric actuator (PEA) seriously affects its positioning accuracy and even causes instability. In this paper, a modified Prandtl-Ishlinskii (MPI) model, which can describe the rate asymmetric hysteresis of piezoelectric actuator, is studied. The hysteresis compensation is realized by using the rate dependent Prandtl-Iishlinskii model based on the improved Prandtl-Iishlinskii hysteresis model and the hysteresis characteristics of the driver measured in the laboratory under the frequency input of up to 100 Hz. In order to further reduce the error of feedforward compensation, a sliding mode controller is designed. The stability of the control system is proved by Lyapunov theory. The experimental results show that the linear error of the system is reduced from 10% to less than 1%, and the tracking error can also be reduced by 90%.

Regulation of the cerebrovascular smooth muscle cell phenotype by mitochondrial oxidative injury and endoplasmic reticulum stress in simulated microgravity rats via the PERK-eIF2α-ATF4-CHOP pathway.

Microgravity exposure results in vascular remodeling and cardiovascular dysfunction. Here, the effects of mitochondrial oxidative stress on vascular smooth muscle cells (VSMCs) in rat cerebral arteries under microgravity simulated by hindlimb unweighting (HU) was studied. Endoplasmic reticulum (ER)-resident transmembrane sensor proteins and phenotypic markers of rat cerebral VSMCs were examined. In HU rats, CHOP expression was increased gradually, and the upregulation of the PERK-eIF2α-ATF4 pathway was the most pronounced in cerebral arteries. Furthermore, PERK/p-PERK signaling, CHOP, GRP78 and reactive oxygen species were augmented by PERK overexpression but attenuated by the mitochondria-targeting antioxidant MitoTEMPO. Meanwhile, p-PI3K, p-Akt and p-mTOR protein levels in VSMCs were increased in HU rat cerebral arteries. Compared with the control, HU rats exhibited lower α-SMA, calponin, SM-MHC and caldesmon protein levels but higher OPN and elastin levels in cerebral VSMCs. The cerebral VSMC phenotype transition from a contractile to synthetic phenotype in HU rats was augmented by PERK overexpression and 740Y-P but reversed by MitoTEMPO and the ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). In summary, mitochondrial oxidative stress and ER stress induced by simulated microgravity contribute to phenotype transition of cerebral VSMCs through the PERK-eIF2a-ATF4-CHOP pathway in a rat model.

[Clinical features and prognosis of 25 cases of breast carcinosarcoma].

OBJECTIVE: To improve the recognition, appropriate diagnosis and treatment of breast carcinosarcoma through analysis of their clinical features, diagnosis, management and prognosis. METHODS: The clinicopathological data from 25 patients with breast carcinosarcoma treated in our hospital between January 1976 and January 2008 were retrospectively reviewed. The correlation between prognosis and age, tumor size, axillary node status, and treatment modality was analyzed using the statistical software SPSS 13.0. The survival rate was calculated by Kaplan-Meier analysis and compared using log-rank test. Univariate and multivariate factors for survival were analyzed using Cox proportional hazards regression model. RESULTS: All patients were female and their median age was 56-years. The median tumor diameter was 5.1 cm. The misdiagnosis rate was high by mammography, B-ultrasound and pathological examination of needle aspiration biopsy before operation. So that the diagnosis primarily depended on postoperative histopathologic examination. The ER/PR and HER-2 positive rate of the breast carcinosarcomas was 8.3% and 7.7%, respectively. Invasive ductal carcinoma was the main malignant component accounting for 92.3%, while the sarcoma element was constitutive of fibrosarcoma with a proportion of 46.2%. The overall 5-year survival rate was 57.9% with a median survival time of 86 months after a median follow-up of 52 months. Univariate factor analysis showed that the tumor size (P = 0.012) and treatment methods (P = 0.028) were impact factors, while age and axillary lymph node status were not significantly related with prognosis. Cox multivariate analysis validated that the therapy modality was an independent prognostic factor for breast carcinosarcoma (P = 0.047). CONCLUSIONS: Breast carcinosarcoma is rare and its clinical features are not specific, so that its final diagnosis is mainly based on the postoperative pathology. Tumor size and treatment modality are independent prognostic factors, so the comprehensive therapy mainly based on radical resection is the best treatment modality. The positive expression of ER/PR and HER-2 in breast carcinosarcoma is low, while exploring new target is one of future research directions.

[Application of pedicle fat flap for defect repair in breast-conserving surgery of breast cancer].

OBJECTIVE: To evaluate the cosmetic outcomes of applying pedicle fat flap below breast fold for repairing inferior quadrant defect in breast-conserving surgery. METHODS: From May 2009 to July 2011, 18 cases of breast cancer at our hospital were recruited. All cases underwent breast-conserving procedures and achieved negative margin by frozen section examination. Then pedicle fat flap below breast fold was applied to reshape breast defect. All of them were of females with a median age of 43 years (range: 33 - 59). The median tumor size was 2.5 cm (range: 2.0 - 3.0). All tumors were located at the inferior quadrant of breast. All of them received whole breast radiotherapy and adjuvant chemotherapy. And 10 cases with positive estrogen receptor had adjuvant endocrine therapy. They were followed up at one-month postoperatively. Upon the completion of chemotherapy and radiotherapy, then follow-up was once every 4 months. The cosmetic outcomes and disease relapse were observed. RESULTS: All pedicle fat flaps survived without necrosis. After a median follow-up period of 15 months, all survived disease-free. Fat liquefaction was observed in 2 cases. The whole breast radiotherapy had no significant effect on pedicle fat flap. The rate of good cosmetics was 88.9%. And their subjective satisfactory rate was 100.0%. CONCLUSION: Both satisfactory aesthetic outcome and good efficacy are obtained with pedicle fat flap below breast fold for tumors located at the inferior quadrant of breast.

[Application of latissimus dorsi muscle flap for breast conservation in breast cancer].

OBJECTIVE: Breast conserving surgery (BCS) is one of standard treatment approaches in early breast cancer. Although most defect after BCS can be repaired, the cosmetic outcomes are unsatisfactory in the patients with poor tumor/breast ratio. Oncoplastic surgery (OPS) has emerged as a new approach for providing adequate tumor resection without compromise of aesthetic outcomes in BCS. Our purpose is to explore the cosmetic outcomes of applying latissimus dorsi (LD) muscle flap to reshape severe breast conservation deformities in breast cancer. METHODS: Totally 24 cases of breast cancer were studied. The tumor size was 3.0 - 5.5 cm (median 3.5 cm). All the cases underwent BCS and achieved negative margin by frozen sections examination. Then LD flap reshaping were performed. All the patients received whole breast radiotherapy ± chemotherapy ± endocrine therapy. RESULTS: All the LD flaps were alive without skin necrosis. After a median 23-month follow-up, all the cases were disease-free surviving. The whole breast radiotherapy had no significant effect on the LD flaps. The rate of good cosmetic results was 79.2%. The subjective satisfactory rate of the patients was 96%. CONCLUSIONS: Both satisfactory aesthetic outcome and good treatment effect were obtained using LD flap to reshape severe breast conservation deformity. OPS offers tools for breast conservation in patients otherwise destined for mastectomy or poor aesthetic outcome, such as large tumor/breast ratio, nipple-areola complex tumor, ductal carcinoma in situ, neoadjuvant chemotherapy cases and so on.

Long-term results of breast conservation in Chinese women with breast cancer.

Between July 1989 and December 2002, 172 women with Stage I/II breast cancer were treated by breast conservation therapy (BCT). All underwent quadrantectomy and axillary node clearance. Minimum follow-up was 5 years and 79 (52%) were followed for >10 years. At 5 years, local relapse-free and overall survival rates were 98.3% and 98.3%. The 10-year rates were 95% and 94%, respectively. The 10-year local recurrence rate was higher in patients with involved margins (33.3% versus 2.7%, p = 0.0272). Furthermore 10-year death rates in margin positive patients were higher (18.2% versus 2.5%, p = 0.0486). Excellent or good cosmetic results were achieved in 54%. BCT is a reasonable option for early stage breast cancer in Chinese women but margin status is the most important determinant of local recurrence. Negative margins are required for optimal local control and minimization of distant metastasis.

Differentially expressed genes between primary cancer and paired lymph node metastases predict clinical outcome of node-positive breast cancer patients.

The axillary lymph node status remains the most valuable prognostic factor for breast cancer patients. However, approximately 20-30% of node-positive patients remain free of distant metastases within 15-30 years. It is important to develop molecular markers that are able to predict for the risk of distant metastasis and to develop patient-tailored therapy strategies. We hypothesize that the lymph node metastases may represent the most metastatic fraction of the primary cancers. Therefore, we sought to identify the differentially expressed genes by microarray between the primary tumors and their paired lymph node metastases samples collected from 26 patients. A set of 79 differentially expressed genes between primary cancers and metastasis samples was identified to correctly separate most of primary cancers from lymph node metastases. And decreased expression of matrix metalloproteinase 2, fibronectin, osteoblast specific factor 2, collagen type XI alpha 1 in lymph node metastases were further confirmed by real-time RT-PCR performed on 30 specimen pairs. This set of genes also classified 35 primary cancers into two groups with different prognosis: "high risk group" and "low risk group." Patients in "high risk group" had a 4.65-fold hazard ratio (95% CI 1.02-21.13, P = 0.047) to develop a distant metastasis within 43 months comparing with the "low risk group." This suggested that the gene signature consisting of 79 differentially expressed genes between primary cancers and lymph node metastases could also predict clinical outcome of node-positive patients, and that the molecular classification based on the gene signature could guide patient-tailored therapy.

[Correlations of centrosome abnormality and genomic instability to tumor].

Genomic instability, including whole chromosome loss or gain, ploidy change, and a variety of chromosome aberration, is a characteristic of tumor cells. Centrosome abnormality is also found in several kinds of tumors. Abnormal centrosome can cause multipolar spindle formation, chromosome mis-segregation, and unequal distribution, and finally leads to cancers. Therefore, abnormal centrosome is common in tumor cells, and centrosome amplification is probably an early event in the origination and development of cancer.

[Clinical characteristics of bilateral primary breast cancer: a report of 100 cases].

BACKGROUND & OBJECTIVE: Women with breast cancer have an increased risk of new primary tumors of the contralateral breast. This study was to analyze the clinical characteristics of bilateral primary breast cancer (BPBC), and explore risk factors of BPBC. METHODS: Clinical data of 100 patients with BPBC and 200 patients with unilateral primary breast cancer (UPBC) were compared. RESULTS: The age of disease and age of menarche of BPBC patients were significantly younger than those of UPBC patients (P<0.05). Compared with UPBC patients, BPBC patients had a significantly greater prevalence of family history (15% vs. 5%, P<0.01); incidence rate of breast cancer before menopause was significantly higher in BPBC patients than in UPBC patients (70% vs. 58%, P<0.05). Pathologically positive rate of ipsilateral axillary lymph nodes was not significantly different between the 2 groups. The radiation treatment proportion in metachronous BPBC patients was not significantly different from that in UPBC patients (69% vs. 58%, P>0.05). CONCLUSIONS: Compare with UPBC patients, BPBC patients have a significantly greater prevalence of family history, and are younger. The estrogen might be closely related to BPBC, but the lymphatic metastasis ability of the first tumor in BPBC is similar to that of UPBC.

[Randomized trial on adjuvant radiotherapy for postoperative breast cancer: a 15 year experience].

OBJECTIVE: To evaluate the long term effects of adjuvant radiotherapy for postoperative breast cancer. METHODS: From 1985 to 1986, 162 patients with operable breast cancer were randomly given adjuvant radiotherapy according to clinical stage and involving condition of axillary lymph nodes (LN). The radiotherapy group (RG) was irradiated in the supraclavicular area and/or internal mammary area to 50 Gy, while the control group (CG) was not. RESULTS: The overall 5-, 10- and 15-year survival rates of the RG were 72.0%, 56.1% and 54.3%, while they were 66.3%, 51.3% and 49.4% in the CG (P > 0.05). Clinical stage I-IIIa and positive or negative LN showed no significant difference in the two groups. But in patients with LN(+) > or = 4, the 5-, 10- and 15-year survival rates of the RG were 55.6%, 38.9% and 37.1%, which were higher than the CG of 29.0%, 16.1% and 16.1% (P < 0.05). CONCLUSION: Adjuvant radiotherapy can improve the prognosis for breast cancer patients with LN(+) > or = 4, but not for LN(-).