Intensive Lipid-Lowering Therapy as per the Latest Dyslipidemia Management Guideline in Predicting Favorable Long-Term Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Grafting: A Retrospective Cohort Study.

Background There are limited data on low-density lipoprotein cholesterol (LDL-C) goal achievement per the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidemia management guidelines and its impact on long-term outcomes in patients undergoing coronary artery bypass grafting (CABG). We investigated the association between LDL-C levels attained 1 year after CABG and the long-term outcomes. Methods and Results A total of 2072 patients diagnosed with multivessel coronary artery disease and undergoing CABG between 2011 and 2020 were included. Patients were categorized by lipid levels at 1 year after CABG, and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs) was evaluated. The goal of LDL-C <1.40 mmol/L was attained in only 310 patients (14.9%). During a mean follow-up of 4.2 years after the index 1-year assessment, 25.0% of the patients experienced MACCEs. Multivariable-adjusted hazard ratios (95% CIs) for MACCEs, cardiac death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and cardiac rehospitalization were 1.94 (1.41-2.67), 2.27 (1.29-3.99), 2.45 (1.55-3.88), 1.17 (0.63-2.21), 2.47 (1.31-4.66), and 1.87 (1.19-2.95), respectively, in patients with LDL-C ≥2.60 mmol/L, compared with patients with LDL-C <1.40 mmol/L. The LDL-C levels at 1-year post-CABG were independently associated with long-term MACCEs. Conclusions This retrospective analysis demonstrates that lipid goals are not attained in the vast majority of patients at 1 year after CABG, which is independently associated with the increased risk of long-term MACCEs. Further prospective, multicenter studies are warranted to validate if intensive lipid management could improve the outcomes of patients undergoing CABG.

Changes of ubiquitylated proteins in atrial fibrillation associated with heart valve disease: proteomics in human left atrial appendage tissue.

Background: Correlations between posttranslational modifications and atrial fibrillation (AF) have been demonstrated in recent studies. However, it is still unclear whether and how ubiquitylated proteins relate to AF in the left atrial appendage of patients with AF and valvular heart disease. Methods: Through LC-MS/MS analyses, we performed a study on tissues from eighteen subjects (9 with sinus rhythm and 9 with AF) who underwent cardiac valvular surgery. Specifically, we explored the ubiquitination profiles of left atrial appendage samples. Results: In summary, after the quantification ratios for the upregulated and downregulated ubiquitination cutoff values were set at >1.5 and <1:1.5, respectively, a total of 271 sites in 162 proteins exhibiting upregulated ubiquitination and 467 sites in 156 proteins exhibiting downregulated ubiquitination were identified. The ubiquitylated proteins in the AF samples were enriched in proteins associated with ribosomes, hypertrophic cardiomyopathy (HCM), glycolysis, and endocytosis. Conclusions: Our findings can be used to clarify differences in the ubiquitination levels of ribosome-related and HCM-related proteins, especially titin (TTN) and myosin heavy chain 6 (MYH6), in patients with AF, and therefore, regulating ubiquitination may be a feasible strategy for AF.

Case Report: 3D Printing Guided Cardiac Autotransplantation for Treatment of a Giant Complex Primary Left Atrial Tumor.

Primary cardiac tumors are rare and complete surgical resection is the optimal treatment. However, it is a great challenge to resect some malignant or complex benign left-sided cardiac tumors situated on the posterior aspect of the heart using conventional surgical resection techniques. Previous studies reported that cardiac autotransplantation is a feasible and safe technique for resection of such cardiac tumors. We report a successful case of cardiac autotransplantation with 3-dimensional (3D) printing technique for complete resection of a giant complex primary left atrial tumor.

Evaluation of the "safe multidisciplinary app-assisted remote patient-self-testing (SMART) model" for warfarin home management during the COVID-19 pandemic: study protocol of a multi-center randomized controlled trial.

BACKGROUND: Warfarin treatment requires frequent monitoring of INR (international normalized ratio) to adjust dosage in a therapeutic range. In China, patients living in small towns usually go to tertiary hospitals to get warfarin monitoring and dosing, resulting in low frequencies of follow-ups and high incidence of complications. Influenced by the COVID-19 pandemic, patients on warfarin have further reduced their visits to healthcare institutions. While patient self-testing (PST) via using a point-of-care testing device for INR measuring at home has been widely used in developed countries and demonstrated improved clinical outcomes compared to usual care in clinics, it is rarely applied in developing countries, including China. This proposed study will develop and assess the "Safe Multidisciplinary App-assisted Remote patient-self-Testing (SMART) model" for warfarin home management in China during the COVID-19 pandemic. METHODS: This is a multi-center randomized controlled trial. We will carry out the study in three county hospitals, three small tertiary hospitals and three large tertiary hospitals with anticoagulation clinics in Hunan province of China. Eligible patients will be randomly assigned to the SMART model group (n = 360) or the control group (usual care clinic group, n = 360; anticoagulation clinic group, n = 120). Patients in the SMART model group do PST at home once every two to 4 weeks. Controls receive usual care in the clinics. All the patients will be followed up through outpatient clinics, phone call or online interviews at the 3rd, 6th, 9th and 12th month. The percentage of time in therapeutic range (TTR), incidence of warfarin associated major bleeding and thromboembolic events and costs will be compared between the SMART model group and control groups. DISCUSSION: Patients in the SMART model group would show improved TTR, lower incidence of complications and better quality of life compared to the control groups. Our design, implementation and usage of the SMART model will provide experience and evidence in developing a novel model for chronic disease management to solve the problem of healthcare service maldistribution, an issue particularly obvious in developing countries during the COVID-19 pandemic. TRIAL REGISTRATION: ChiCTR, ChiCTR 2000038984 . Registered 11 October, 2020.

A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced AAA in ApoE-/- mice were investigated. AAA was induced in ApoE-/- mice with infusion of AngII for 28 days. BP-1-102 was administrated orally to mice every other day. Mice were sacrificed on day 7, day 14, and day 28 to evaluate the treatment effects. BP-1-102 markedly decreased AAA incidence and aortic diameter, maintained elastin structure and volume, reduced the expression of pro-inflammatory cytokines and MMPs, and inhibited inflammatory cells infiltration. Moreover, BP-1-102 dramatically reduced the expression of JAK2, p-STAT3, p-NF-κB, and Bcl-xL but maintained the expression of LC3B and Beclin in AAA tissues. In vitro, vascular smooth muscle cells (VSMCs) were treated with AngII and/or BP-1-102 at indicated time and concentration. BP-1-102 inhibited AngII-induced JAK2/STAT3 and NF-κB signaling activation and maintained autophagy-related proteins expression in VSMCs. Taken together, our findings suggest that BP-1-102 inhibits vascular inflammation and AAA progression through decreasing JAK2/STAT3 and NF-κB activation and maintaining autophagy.

Percutaneous gallbladder drainage as a bridge to concomitant coronary artery bypass grafting and laparoscopic cholecystectomy.

A 74-year-old woman with left main and three-vessel coronary artery disease was scheduled for off-pump coronary artery bypass grafting and developed acute severe cholecystitis preoperatively. Percutaneous gallbladder drainage was placed to achieve gallbladder decompression and infection control. Two weeks later, CABG and laparoscopic cholecystectomy were successfully performed at the same time.

Mesenchymal stem cell-derived conditioned medium attenuate angiotensin II-induced aortic aneurysm growth by modulating macrophage polarization.

Mesenchymal stem cells (MSCs) exhibit therapeutic benefits on aortic aneurysm (AA); however, the molecular mechanisms are not fully understood. The current study aimed to investigate the therapeutic effects and potential mechanisms of murine bone marrow MSC (BM-MSCs)-derived conditioned medium (MSCs-CM) on angiotensin II (AngII)-induced AA in apolipoprotein E-deficient (apoE-/- ) mice. Murine BM-MSCs, MSCs-CM or control medium were intravenously administrated into AngII-induced AA in apoE-/- mice. Mice were sacrificed at 2 weeks after injection. BM-MSCs and MSCs-CM significantly attenuated matrix metalloproteinase (MMP)-2 and MMP-9 expression, aortic elastin degradation and AA growth at the site of AA. These treatments with BM-MSCs and MSCs-CM also decreased Ly6chigh monocytes in peripheral blood on day 7 and M1 macrophage infiltration in AA tissues on day 14, whereas they increased M2 macrophages. In addition, BM-MSCs and MSCs-CM reduced MCP-1, IL-1Ra and IL-6 expression and increased IL-10 expression in AA tissues. In vitro, peritoneal macrophages were co-cultured with BM-MSCs or fibroblasts as control in a transwell system. The mRNA and protein expression of M2 macrophage markers were evaluated. IL-6 and IL-1ß were reduced, while IL-10 was increased in the BM-MSC systems. The mRNA and protein expression of M2 markers were up-regulated in the BM-MSC systems. Furthermore, high concentration of IGF1, VEGF and TGF-ß1 was detected in MSCs-CM. Our results suggest that MSCs-CM could prevent AA growth potentially through regulating macrophage polarization. These results may provide a new insight into the mechanisms of BM-MSCs in the therapy of AA.

Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial.

OBJECTIVE: Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. METHODS: This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders. RESULTS: A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. CONCLUSIONS: Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).

Diverse roles of macrophage polarization in aortic aneurysm: destruction and repair.

Aortic aneurysm (AA) is defined as an enlargement of the aorta greater than 1.5 times its normal size. Early diagnosis of AA is challenging and mortality of AA is high. Curative pharmacological treatments for AA are still lacking, highlighting the need for better understanding of the underlying mechanisms of AA progression. Accumulating studies have proven that the polarization state of circulating monocyte-derived macrophages plays a crucial role in regulating the development of AA. Distinct macrophage subtypes display different functions. Several studies targeting macrophage polarization during AA formation and progression showed potential treatment effects. In this review, we focus on the recent advances of research on macrophage polarization in the progression of AA and propose that targeting macrophage polarization could hold great promise for preventing and treating AA.

Effects of David I operation in the treatment of aortic root disease combined with aortic insufficiency.

BACKGROUND: We compared the effects of the new David I operation and classical Bentall operation in the treatment of aortic root disease combined with aortic insufficiency. METHODS: A total of 60 cases of patients with aortic root disease combined with aortic insufficiency diagnosed at our hospital from January 2010 to January 2016 were analyzed retrospectively, including 32 cases of aortic root aneurysm, 18 cases of aortic dissection, 5 cases of hypertension combined with atherosclerosis, 2 cases of retrogression, 2 cases of rheumatic heart disease and 1 case of Takayasu arteritis. Twenty-four cases that underwent the David I operation and 36 cases that underwent the Bentall operation were selected and their therapeutic effects were compared. The operation success rate, operation time, cardiopulmonary bypass time, cross-clamp time and blood infusion of both groups were compared; there were no significant differences (P>0.05). RESULTS: Two patients in the David I group and 3 patients in the Bentall operation group died of multiple organ dysfunction. The LVEDd and LVEF of both groups postoperation had no difference when compared with those parameters of before operation. The diameter of the valve annulus after the operation was shorter than before the operation. The severity of valve regurgitation of both groups had no difference. However, the ratio of severe regurgitation of the David I group increased and the mild regurgitation decreased. The incidence rate of complications of the David I group was significantly lower than that of the Bentall operation group. The differences were statistically significant (P<0.05). CONCLUSIONS: Both David I operation and Bentall operation have better short-term and long-term effects in the treatment of aortic root disease when combined with aortic insufficiency; however, David I operation had less long-term complications.

Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways.

Aortic valve calcification (AVC), which used to be recognized as a passive and irreversible process, is now widely accepted as an active and regulated process characterized by osteoblastic differentiation of aortic valve interstitial cells (AVICs). Apelin, the endogenous ligand for G-protein-coupled receptor APJ, was found to have protective cardiovascular effects in several studies. However, the effects and mechanisms of apelin on osteoblastic differentiation of AVICs have not been elucidated. Using a pro-calcific medium, we devised a method to produce calcific human AVICs. These cells were used to study the relationship between apelin and the osteoblastic calcification of AVICs and the involved signaling pathways. Alkaline phosphatase (ALP) activity/expression and runt-related transcription factor 2 (Runx2) expression were examined as hallmark proteins in this research. The involved signaling pathways were studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, and the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002. The results indicate that apelin attenuates the expression and activity of ALP, the expression of Runx2, and the formation of mineralized nodules. This protective effect was dependent on the dose of apelin, reaching the maximum at 100 pM, and was connected to activity of ERK and Akt (a downstream effector of PI3-K). The activation of ERK and PI3-K initiated the effects of apelin on ALP activity/expression and Runx2, but PD98059 and LY294002 abolished the effect. These results demonstrate that apelin attenuates the osteoblastic differentiation of AVICs via the ERK and PI3-K/Akt pathway.

MicroRNAs: Novel Players in Aortic Aneurysm.

An aortic aneurysm (AA) is a common disease with potentially life-threatening complications. Despite significant improvements in the diagnosis and treatment of AA, the associated morbidity and mortality remain high. MicroRNAs (miRNAs, miR) are small noncoding ribonucleic acids that negatively regulate gene expression at the posttranscriptional level by inhibiting mRNA translation or promoting mRNA degradation. miRNAs are recently reported to be critical modulators for vascular cell functions such as cell migration, contraction, differentiation, proliferation, and apoptosis. Increasing evidences suggest crucial roles of miRNAs in the pathogenesis and progression of cardiovascular diseases such as coronary artery disease, heart failure, arterial hypertension, and cardiac arrhythmias. Recently, some miRNAs, such as miR-24, miR-155, miR-205, miR-712, miR-21, miR-26a, miR-143/145, miR-29, and miR-195, have been demonstrated to be differentially expressed in the diseased aortic tissues and strongly associated with the development of AA. In the present paper, we reviewed the recent available literature regarding the role of miRNAs in the pathogenesis of AA. Moreover, we discuss the potential use of miRNAs as diagnostic and prognostic biomarkers and novel targets for development of effective therapeutic strategies for AA.

A decline of LAMP- 2 predicts ursodeoxycholic acid response in primary biliary cirrhosis.

Biochemical response to ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) is variable. We have previously reported that augmented expression of lysosome-associated membrane protein 2 (LAMP-2) was correlated with the severity of PBC. This study aimed to determine whether serum LAMP-2 could serve as a predictor of biochemical response to UDCA. The efficiency of serum LAMP-2 to predict biochemical response was assessed after 1 year of UDCA treatment in PBC patients by a retrospective analysis. We found that the basal serum LAMP-2 level was increased in PBC, especially in patients with stage III-IV (p = 0.010) or TBIL > 1 mg/dL (p = 0.014). Baseline serum LAMP-2 was higher in non-responders than that in responders, but the difference was statistically insignificant. However, after UDCA treatment, serum LAMP-2 level decreased prominently in the first 3 months, which was more obvious in responders. Further studies showed that the 35% decline of LAMP-2 after treatment for 3 months could be stated as an indicator of UDCA response with the sensitivity of 62.9% and specificity of 75.0% by Paris criteria. Meanwhile the specificity and sensitivity were identified as 63.5% and 64.1% by Barcelona criteria. Together, a decline in LAMP-2 might help to predict the response to UDCA.

The association between bile salt export pump single-nucleotide polymorphisms and primary biliary cirrhosis susceptibility and ursodeoxycholic acid response.

BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic and progressive cholestasis liver disease. Bile salt export pump (BSEP) is the predominant bile salt efflux system of hepatocytes. BSEP gene has been attached great importance in the susceptibility of PBC and the response rate of ursodeoxycholic acid (UDCA) treatment of PBC patients. METHODS: In this study, TaqMan assay was used to genotype four variants of BSEP, and the Barcelona criteria were used for evaluating the response rate of UDCA treatment. RESULTS: Variant A allele of BSEP rs473351 (dominant model, OR = 2.063; 95% CI, 1.254-3.393; P = 0.004) was highly associated with PBC susceptibility. On the contrary, variant A allele of BSEP rs2287618 (dominant model, OR = 0.617; 95% CI, 0.411-0.928; P = 0.020) provided a protective role and Barcelona evaluation criterion indicated that the frequency of variant allele at BSEP rs2287618 was significantly decreased in UDCA-responsive PBC patients (P = 0.021). CONCLUSION: These results suggested that BSEP rs473351 was closely associated with the susceptibility of PBC and if people with BSEP rs2287618 were diagnosed as PBC, the UDCA treatment was not satisfactory. Larger studies with mixed ethnicity subjects and stratified by clinical and subclinical characteristics are needed to validate our findings.

Primary leiomyoma: a rare space occupying lesion in the right ventricle.

A case of primary cardiac leiomyoma arising from the infundibulum of the right ventricle of a 24-year-old woman is presented. The mass protruded into the cavity of the right ventricle and caused severe right ventricular outflow tract obstruction. We resected the tumor under cardiopulmonary bypass successfully, and confirmed it histologically to be a benign leiomyoma. To the authors' knowledge, this is the first case report of a primary cardiac leiomyoma in an adult woman.

Polymorphisms in the vitamin D receptor gene and risk of primary biliary cirrhosis: a meta-analysis.

BACKGROUND AND AIM: Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic autoimmune liver disease. Although many studies have evaluated the association between many functional polymorphisms in the vitamin D receptor (VDR) gene and PBC risk, debates still exist. Our aim is to evaluate the association between VDR gene polymorphisms, including TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232), and the risk of PBC by a systematic review. METHODS: We searched literatures in PubMed, SCOPUS, and EMBASE until July 2013. We calculated pooled odds ratios (OR) and 95% confidence intervals (CIs) using a fixed effects model or a random effects model for the risk to PBC associated with different VDR gene polymorphisms. And the heterogeneity assumption decided the effect model. RESULTS: A total of six relevant studies, with 1322 PBC cases and 2264 controls, were included in this meta-analysis. The results indicated that TaqI (rs731236) polymorphism was significantly associated with PBC risk (for T vs t OR = 0.75, 95% CI 0.63, 0.89, Pz = 0.001; TT + Tt vs tt OR = 0.62, 95% CI 0.44, 0.86, Pz = 0.005; OR = 0.74, 95% CI 0.58, 0.94, Pz = 0.016 for recessive model), while ApaI (rs7975232) or BsmI (rs1544410) polymorphism did not. CONCLUSION: Based on current evidences from published studies, the cumulative effect of TaqI polymorphism in VDR was significantly associated with PBC. Larger studies with mixed ethnicity subjects and stratified by clinical and sub clinical characteristics are needed to validate our findings.

Prevalence of minimal hepatic encephalopathy and quality of life evaluations in hospitalized cirrhotic patients in China.

AIM: To investigate the prevalence of minimal hepatic encephalopathy (MHE) and to assess corresponding health-related quality of life (HRQoL) in hospitalized cirrhotic patients in China. METHODS: This multi-center cross-sectional study included 16 teaching hospitals, which were members of "Hepatobiliary Cooperation Group, Society of Gastroenterology, Chinese Medical Association", from different areas of China carried out between June and October in 2011. All the eligible hospitalized cirrhotic patients (n = 538) were required to complete triplicate number connection tests combined with one digit symbol test for diagnosing MHE. Patients' clinical examination data were complemented by a modified questionnaire assessing HRQoL. Written informed consent was obtained from each patient. RESULTS: Male was predominant (68.6%) in 519 patients who met the criteria of the study, with a mean age of 49.17 ± 11.02 years. The most common cause of liver cirrhosis was chronic hepatitis B (55.9%). The prevalence of MHE was 39.9% and varied by Child-Pugh-Classification score (CPC-A: 24.8%, CPC-B: 39.4% and CPC-C: 56.1%, P < 0.01). MHE (P < 0.01) and higher CPC scores (P < 0.01) were associated with a high HRQoL scores (reflecting poorer quality of life). The prevalence of MHE was proportionate to CPC (P = 0.01) and high quality of life scores (P = 0.01). CONCLUSION: Hospitalized cirrhotic patients have a high prevalence of MHE that is proportionate to the degree of liver function and HRQoL impairment.

Cytochrome P450 oxidoreductase genetic polymorphisms A503V and rs2868177 do not significantly affect warfarin stable dosage in Han-Chinese patients with mechanical heart valve replacement.

PURPOSE: To investigate the influence of cytochrome P450 oxidoreductase (POR) polymorphisms (A503V and rs2868177) on warfarin stable dosage (WSD) in Han-Chinese patients with mechanical heart valve replacement (MHVR). METHODS: Three hundred and seventeen Han-Chinese MHVR patients on stable maintenance dose of warfarin were enrolled. Blood samples were collected for genotyping analyses of VKORC1 -1639G>A, CYP2C9 *3, CYP4F2 rs2108622 and POR (A503V and rs2868177). Average WSD of carriers with variant POR genotypes or haplotypes were compared. Association analyses were performed by single and multiple linear regression analysis. RESULTS: The variant allele frequencies of POR polymorphisms (A503V and rs2868177) were 38.8 % and 44.8 %, respectively. D' between POR A503V and rs2868177 was 0.855, r(2) was 0.375, and the frequencies of the four POR haplotypes were 42.3 % for CG, 36.3 % for TA, 18.9 % for CA, and 2.5 % for TG, respectively. There were no significant differences in average WSD among carriers with three variant POR A503V genotypes or among carriers with three variant POR rs2868177 genotypes (both P > 0.05). Similarly, there were no significant differences in average WSD among carriers with variant POR haplotypes (all P > 0.05). Neither single nor multiple linear regression analyses showed significant effects of POR A503V or POR rs2868177 polymorphisms on WSD. CONCLUSION: POR polymorphisms (A503V and rs2868177) do not appear to significantly influence WSD in Han-Chinese patients with MHVR.

Reduced leaflet stress in the stentless quadrileaflet mitral valve: a finite element model.

BACKGROUND: Failure of bioprosthetics is usually caused by calcification of the leaflets as a consequence of high tensile stresses. The stentless valve resembles native mitral valve anatomy, has a flexible leaflet attachment and a suspension at the papillary muscles, and preserves annuloventricular continuity. In this study, the effects of the stentless valve design on leaflet stress were investigated with a finite element model. METHODS: Finite element models of the stentless quadrileaflet mitral valve were created in the close and open configurations. The geometry of the stented trileaflet mitral valve was also analyzed for comparative purposes. Under the designated pressures, the regional stresses were evaluated, and the distributions of stresses were assessed. RESULTS: Regardless of whether the valve is in the open or close configuration, the maximum first principal stress was significantly lower in the stentless valve than in the stented valve. For the stentless valves, limited stress concentration was discretely distributed in the papillary flaps under both close and open conditions. In contrast, in the stented valve, increased stress concentration was evident at the central belly under the open condition and at the commissural attachment under close condition. In either configuration, the maximum second principal stress was markedly lower in the stentless valve than in the stented valve. CONCLUSIONS: The stentless valve was associated with a significant reduction in leaflet stress and a more homogeneous stress distribution compared to the stented valve. These findings are consistent with recent reports of the clinical effectiveness of the stentless quadrileaflet mitral valve.

Identification of anaplastic lymphoma kinase as a potential therapeutic target in ovarian cancer.

Ovarian cancer is the leading cause of death from gynecologic cancer. Improvement in the clinical outcome of patients is likely to be achieved by the identification of molecular events that underlie the oncogenesis of ovarian cancer. Here we show that the anaplastic lymphoma kinase (ALK) is aberrantly activated in ovarian cancer. Using an unbiased and global phosphoproteomic approach, we profiled 69 Chinese primary ovarian tumor tissues and found ALK to be aberrantly expressed and phosphorylated in 4 tumors. Genetic characterization of these ALK-positive tumors indicated that full-length ALK expression in two serous carcinoma patients is consistent with ALK gene copy number gain, whereas a stromal sarcoma patient carries a novel transmembrane ALK fusion gene: FN1-ALK. Biochemical and functional analysis showed that both full-length ALK and FN1-ALK are oncogenic, and tumors expressing ALK or FN1-ALK are sensitive to ALK kinase inhibitors. Furthermore, immunohistochemical analysis of ovarian tumor tissue microarray detected aberrant ALK expression in 2% to 4% serous carcinoma patients. Our findings provide new insights into the pathogenesis of ovarian cancer and identify ALK as a potential therapeutic target in a subset of serous ovarian carcinoma and stromal sarcoma patients.