Fatty acid binding protein 5 is a novel therapeutic target for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide. Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival, growth, and evolution. Emerging evidence suggests the importance of fatty acid binding proteins (FABPs) in contribution to cancer progression and metastasis; however, how these FABPs are dysregulated in cancer cells, especially in HCC, and the roles of FABPs in cancer progression have not been well defined. AIM: To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies. METHODS: We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma (LIHC) as well as patient cohorts with other cancer types in this study. We investigated genetic alterations of FABPs in various cancer types. mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome, enriched cancer hallmarks and oncogenes previously reported for patients with HCC. We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells. RESULTS: We discovered that a gene cluster including five FABP family members (FABP4, FABP5, FABP8, FABP9 and FABP12) is frequently co-amplified in cancer. Amplification, in fact, is the most common genetic alteration for FABPs, leading to overexpression of FABPs. FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues. High FABP5 expression correlates well with worse patient outcomes (P < 0.05). FABP5 expression highly correlates with enrichment of G2M checkpoint (r = 0.33, P = 1.1e-10), TP53 signaling pathway (r = 0.22, P = 1.7e-5) and many genes in the gene sets such as CDK1 (r = 0.56, P = 0), CDK4 (r = 0.49, P = 0), and TP53 (r = 0.22, P = 1.6e-5). Furthermore, FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients (r = 0.58, P = 0; r = 0.58, P = 0; respectively). FABP5high Huh7 cells also expressed higher protein levels of p53, BIRC5, CDK1, CDK2, and CDK4 than FABP5low HepG2 cells. FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells. CONCLUSION: We discovered that FABP5 gene is frequently amplified in cancer, especially in HCC, leading to its significant elevated expression in HCC. Its high expression correlates well with worse patient outcome, enriched cancer hallmarks and oncogenes in HCC. FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells. All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.

Dual targeting of Polo-like kinase 1 and baculoviral inhibitor of apoptosis repeat-containing 5 in TP53-mutated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), often diagnosed at advanced stages without curative therapies, is the fifth most common malignant cancer and the second leading cause of cancer-related mortality. Polo-like kinase 1 (PLK1) is activated in the late G2 phase of the cell cycle and is required for entry to mitosis. Interestingly, PLK1 is overexpressed in many HCC patients and is highly associated with poor clinical outcome. Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is also highly overexpressed in HCC and plays key roles in this malignancy. AIM: To determine the expression patterns of PLK1 and BIRC5, as well as their correlation with p53 mutation status and patient clinical outcome. METHODS: The expression patterns of PLK1 and BIRC5, and their correlation with p53 mutation status or patient clinical outcome were analyzed using a TCGA HCC dataset. Cell viability, cell apoptosis, and cell cycle arrest assays were conducted to investigate the efficacy of the PLK1 inhibitors volasertib and GSK461364 and the BIRC5 inhibitor YM155, alone or in combination. The in vivo efficacy of volasertib and YM155, alone or in combination, was assessed in p53-mutated Huh7-derived xenograft models in immune-deficient NSIG mice. RESULTS: Our bioinformatics analysis using a TCGA HCC dataset revealed that PLK1 and BIRC5 were overexpressed in the same patient subset and their expression was highly correlated. The overexpression of both PLK1 and BIRC5 was more frequently detected in HCC with p53 mutations. High PLK1 or BIRC5 expression significantly correlated with poor clinical outcome. PLK1 inhibitors (volasertib and GSK461364) or a BIRC5 inhibitor (YM155) selectively targeted Huh7 cells with mutated p53, but not HepG2 cells with wild-type p53. The combination treatment of volasertib and YM155 synergistically inhibited the viability of Huh7 cells via apoptotic pathway. The efficacy of volasertib and YM155, alone or in combination, was validated in vivo in a Huh7-derived xenograft model. CONCLUSION: PLK1 and BIRC5 are highly co-expressed in p53-mutated HCC and inhibition of both PLK1 and BIRC5 synergistically compromises the viability of p53-mutated HCC cells in vitro and in vivo.

Reshaping bicuspid aortic valve stenosis with an hourglass-shaped balloon for transcatheter aortic valve replacement: A pilot study.

OBJECTIVES: We evaluated the safety and usefulness of preparatory anatomical reshaping with a geometric hourglass-shaped balloon to optimize transcatheter aortic valve replacement (TAVR) outcomes in bicuspid aortic valve (BAV) stenosis. BACKGROUND: TAVR has been increasingly performed for BAV stenosis; however, technical challenges remain. Procedural results are suboptimal given unfavorable valvular anatomies. METHODS: Eligible patients with BAV stenosis were enrolled to undergo aortic valve predilatation with the hourglass-shaped TAV8 balloon before TAVR using the self-expandable Venus A-Valve. Procedural details and outcomes were compared to a sequential group of patients with BAV who underwent TAVR with the same device following preparatory dilatation using a cylindrical balloon. RESULTS: A total of 22 patients were enrolled in the TAV8 group and 53 were included in the control group. Valve downsizing was less common in the TAV8 group (36.4 vs. 67.9%; p = .012). Stable valve release and optimal implant depth were consistently achieved in the TAV8 group with no requirement for a second valve (0 vs. 17.0%; p = .039) and with higher device success rates (100.0 vs 77.4%; p = .014). Residual aortic regurgitation graded as ≥mild was less common in the TAV8 group (13.6 vs 45.3%; p = .009). Mortality was similar (0 vs. 3.8%; p = 1); no major/disabling stroke or conversion to open-heart surgery was seen in either group within 30 days. CONCLUSIONS: Compared with standard cylindrical balloon valvuloplasty, preparatory reshaping with the hourglass-shaped balloon before self-expandable TAVR in BAV was associated with significantly better procedural results and may encourage more promising outcomes.

Tumor Mutational Burden and Genomic Alterations in Chinese Small Cell Lung Cancer Measured by Whole-Exome Sequencing.

PURPOSE: Studies on genetic alterations of the heterogenous small cell lung cancer (SCLC) are rare. We carried out the present study to clarify the genomic alterations and TMB levels of Chinese SCLC patients by whole-exome sequencing. MATERIALS AND METHODS: Whole-exome sequencing by next-generation sequencing technique was implemented on twenty SCLC samples. Significant somatic mutations and copy number variations were screened, followed by comparison with the data extracted from COSMIC. Besides, altered signaling pathways were examined in order to figure out actionable targets. RESULTS: A total of 8,062 nonsynonymous mutations were defined. The number of mutations for each case ranged from 98 to 864. As for base substitutions, a total of 15,817 substitutions were detected with C > A conversion which was correlated to smoking occupying 25.57%. The TMB values ranged from 2.51/Mb to 22.1/Mb with a median value of 9.95/Mb. RB1 was the most frequently mutated gene altered in 18 (90%) cases, followed by TP53 altered in 17 (85%) cases. Other commonly changed genes were PTEN, and RBL1, with frequencies of 55% and 50%, respectively. SOX2 significantly amplified in 6 (30%) cases and MYCN amplified in 1 (5%) patient. Notch signaling pathway and PI3K/AKT/mTOR signaling pathway were universally and significantly changed. Major genomic alterations were in consistency with data from COSMIC, but frequencies of less common mutations were different. CONCLUSION: TP53 and RB1 inactivations were universally detected in SCLC. The Notch and PI3K/AKT/mTOR signaling pathways were both significantly altered, implying potential actionable targets.

Comparative assessment of phytochemical profiles and antioxidant and antiproliferative activities of kiwifruit (Actinidia deliciosa) cultivars.

The present study was designed to analyze and compare phytochemical activities of four different cultivars of kiwifruit. Among all investigated varieties, Hua You (HY) and Cui Xiang (CUX) displayed the maximum concentration of phytochemical content, and the highest total phenolic results were observed in HY and CUX cultivars with 220.20 ± 1.12 mg GAE/100 g and 218.04 ± 1.11 mg GAE/100 g FW, respectively. Likewise, the richest total flavonoids results were estimated in red kiwifruit (RKF) and CUX varieties with 49.082 ± 0.14 mg CE/100 g FW and 48.327 ± 0.14 mg CE/100 g FW, respectively. Moreover, tests for oxygen radical scavenging capacity (ORAC) and peroxyl radical scavenging capacity (PSC) were observed maximum in RKF cultivar showing 131.229 ± 5.91 µM Trolox equivalent/g FW and 85.957 ± 11.75 µM vitamin C equivalent/g FW, respectively. Furthermore, the highest cellular antioxidant activity (CAA) with No PBS wash protocol was depicted in RKF 237.544 ± 4.12 µM QE equivalent/g FW with the lowest EC50 0.0128 mg/ml. In addition, high-performance liquid chromatography (HPLC) analysis confirmed the presence of ferulic acid, naringin, gallic acid, syringic acid, caffeic acid, rutin, protocatechuic acid, salicylic acid, and catechin in kiwifruit. Catechin as one main content in our study is consistent with the recent reports. The result suggested that the phytochemical profile and bioactivities were significantly affected by the type of cultivars. PRACTICAL APPLICATIONS: Kiwifruit is widely consumed over the world for its rich nutritious and medicinal values. Currently, phytochemicals are considered as one of the main bioactive components of kiwifruits, which are responsible for lots of bioactivities, such as antitumor, anti-inflammatory, antioxidant, hypoglycemic, and hypolipidemic activities. There are varieties of kiwifruits, and the bioactive components and bioactivities are greatly affected by the cultivars. But there have been no comparative studies on the phytochemicals from different varieties. This study aimed to make a comprehensive assessments of the free, bound, and total phenolics and flavonoids, as well as the chemical-based and cell-based antioxidant activities of four different subspecies of kiwifruit. This work would be beneficial to elucidate the function differences of different kiwifruit phytochemicals, promote its further research, as well as provide a basis for selecting cultivars.

The bifunctional SDF-1-AnxA5 fusion protein protects cardiac function after myocardial infarction.

Stromal cell-derived factor-1 (SDF-1) is a well-characterized cytokine that protects heart from ischaemic injury. However, the beneficial effects of native SDF-1, in terms of promoting myocardial repair, are limited by its low concentration in the ischaemic myocardium. Annexin V (AnxA5) can precisely detect dead cells in vivo. As massive cardiomyocytes die after MI, we hypothesize that AnxA5 can be used as an anchor to carry SDF-1 to the ischaemic myocardium. In this study, we constructed a fusion protein consisting of SDF-1 and AnxA5 domains. The receptor competition assay revealed that SDF-1-AnxA5 had high binding affinity to SDF-1 receptor CXCR4. The treatment of SDF-1-AnxA5 could significantly promote phosphorylation of AKT and ERK and induce chemotactic response, angiogenesis and cell survival in vitro. The binding membrane assay and immunofluorescence revealed that AnxA5 domain had the ability to specifically recognize and bind to cells injured by hypoxia. Furthermore, SDF-1-AnxA5 administered via peripheral vein could accumulate at the infarcted myocardium in vivo. The treatment with SDF-1-AnxA5 attenuated cell apoptosis, enhanced angiogenesis, reduced infarcted size and improved cardiac function after mouse myocardial infarction. Our results suggest that the bifunctional SDF-1-AnxA5 can specifically bind to dead cells. The systemic administration of bifunctional SDF-1-AnxA5 effectively provides cardioprotection after myocardial infarction.

Meta-Analysis of the Effectiveness and Safety of Transcatheter Aortic Valve Implantation Without Balloon Predilation.

Evidence regarding the safety and feasibility of transcatheter aortic valve implantation without balloon predilation (BP) is scarce. A literature search of PubMed, EMBASE, CENTRAL, and major conference proceedings was performed from January 2002 to July 2015. There were 18 studies incorporating 2,443 patients included in the present study. No differences were observed in the baseline characteristics between patients without BP (no-BP) and with BP. Compared with BP, no-BP had a shorter procedure time (no-BP vs BP, 124.2 vs 138.8 minutes, p = 0.008), used less-contrast medium (no-BP vs BP, 126.3 vs 156.3 ml, p = 0.0005) and had a higher success rate (odds ratio [OR] 2.24, 95% CI 1.40 to -3.58). In addition, no-BP was associated with lower incidences of permanent pacemaker implantation (OR 0.45, 95% CI 0.3 to 0.67), grade 2 or greater paravalvular leakage (OR 0.55, 95% CI 0.37 to 0.83), and stroke (OR 0.57, 95% CI 0.32 to 1.0). Furthermore, no-BP was associated with a 0.6-fold decreased risk for 30-day all-cause mortality (OR 0.60, 95% CI 0.39 to 0.92). However, the difference in the risk for permanent pacemaker implantation, grade 2, or higher aortic regurgitation, stroke was noted to be significant only in the subgroup of the CoreValve-dominating studies. In conclusion, no-BP before transcatheter aortic valve implantation was not only safe and feasible but was also associated with fewer complications and short-term mortality in selected patients especially using self-expandable valve.

Target lesion calcification and risk of adverse outcomes in patients with drug-eluting stents. A meta-analysis.

BACKGROUND: Studies focusing on the relationship between calcified lesions and adverse outcomes in the drug-eluting stent (DES) era have presented inconsistent conclusions. The aim of this study was to assess the association between target lesion calcification and adverse outcomes in patients undergoing DES implantation. METHODS: A systematic search was conducted on Medline (Ovid SP, 1946 to 28 February 2014), Embase (Ovid SP, 1974 to 28 February 2014), and the Chinese Biomedical Literature Database (CBM, 1978 to 28 February 2014). Abstracts from the 2012 and 2013 scientific meetings of the American College of Cardiology and American Heart Association were manually searched. Hazard ratios (HRs) were pooled using a fixed or random effects model in the context of heterogeneity. RESULTS: A total of 13 studies comprising 66,361 patients were included. Target lesion calcification was associated with an increased risk of all-cause mortality (HR = 1.41; 95 % CI = 1.27-1.56), cardiac death (HR = 1.97; 95 % CI = 1.68-2.31), myocardial infarction (HR = 1.33; 95 % CI = 1.13-1.57), target lesion revascularization (TLR; HR 1.47, 95 % CI 1.18-1.83), stent thrombosis (HR 1.63, 95 % CI 1.36-1.96), and major cardiovascular events (HR 1.37, 95 % CI 1.19-1.58). The results proved robust in subgroup analyses for TLR and stent thrombosis. CONCLUSION: Calcified target lesions are risk factors for adverse outcomes in the DES era. Further studies focusing on comprehensive therapy in patients with coronary calcification are urgently needed.

Percutaneous coronary intervention compared with coronary artery bypass graft in coronary artery disease patients with chronic kidney disease: a systematic review and meta-analysis.

Previous reports of percutaneous coronary intervention versus coronary artery bypass graft outcomes in coronary artery disease patients with chronic kidney disease (CKD) were inconsistent. We evaluated the optimal revascularization strategy for CKD patients. We searched Pub Med, EMBASE, and the Cochrane Central Register of Controlled Trials and scanned the references of relevant articles and reviews. All studies that compared relevant clinical outcomes between percutaneous coronary intervention and coronary artery bypass graft in CKD patients were selected. We defined short-term and long-term all-cause mortality as primary outcome, and long-term incidences of myocardial infarction and revascularization as secondary outcomes. A total of 2235 citations were retrieved, and 31 studies involving 99,054 patients, with 55,383 receiving percutaneous coronary intervention and 43,671 receiving coronary artery bypass graft, were included. In subgroup analyses of dialysis patients receiving percutaneous coronary intervention with stents versus coronary artery bypass graft, CKD patients with multivessel coronary disease, and CKD patients receiving drug-eluting stent versus coronary artery bypass graft, the pooled outcomes revealed that percutaneous coronary intervention possessed lower short-term mortality, but higher late revascularization risk. No significant differences in long-term mortality were observed between the two strategies in these subgroup analyses. In conclusion, in some specific clinical circumstances, CKD patients receiving percutaneous coronary intervention possessed lower short-term all-cause mortality, but higher long-term revascularization risk, than coronary artery bypass graft; long-term all-cause mortality was not different between the two strategies.

The impact of smoking on clinical efficacy and pharmacodynamic effects of clopidogrel: a systematic review and meta-analysis.

CONTEXT: Previous findings regarding the relationship between smoking and clopidogrel effects were considerably discrepant. OBJECTIVE: To assess the impact of smoking on clinical and pharmacodynamic response to clopidogrel. DATA SOURCES: Medline, EMBASE and the Cochrane Library through January 2013 were searched. Reference lists of pertinent literatures and abstracts of major cardiovascular conferences were screened. STUDY SELECTION: Clinical and laboratory studies, which reported major adverse cardiovascular events and on-clopidogrel platelet reactivity categorised by smoking status respectively, were selected. DATA EXTRACTION: Descriptive and quantitative data were extracted. The main analyses were performed under a random-effects model. For clinical studies, HR estimates were synthesised according to smoking status; for laboratory studies, standardised mean difference (SMD) of on-clopidogrel platelet reactivity and OR for high on-clopidogrel platelet reactivity were pooled. Heterogeneity was quantified by computing I(2) statistic. RESULTS: Of the 1869 citations retrieved, seven clinical studies and 12 laboratory studies involving 111 132 patients with established cardiovascular disease and 6658 patients with acute coronary syndrome and/or stent deployment, respectively, were included for meta-analysis. Pooled clinical results showed that an intensified antiplatelet regimen involving clopidogrel was associated with 10% reduced risk for major adverse cardiovascular events among non-current smokers (HR 0.90; 95% CI 0.85 to 0.96), while this clinical benefit was enhanced by 2.9-fold among current smokers (HR 0.71; 95% CI 0.62 to 0.80). Pooled analysis of laboratory studies revealed that current smokers had significantly lower on-clopidogrel platelet reactivity (SMD -0.30; 95% CI -0.46 to -0.15) but, notably, there was considerable inter-study heterogeneity (I(2) 76.2%; p=0.000). The analysis based on four studies (n=1423) suggested a significantly lower odds of high on-clopidogrel platelet reactivity among current smokers than those among never smokers (OR 0.33; 95% CI 0.22 to 0.43). CONCLUSIONS: Smoking appears to positively modify the relative clinical efficacy and pharmacodynamic effects of clopidogrel.

[Clinical analysis of 39 cases of heterotopic gastric mucosa in the upper esophagus].

OBJECTIVE: To determine accurately the incidence of heterotopic gastric mucosa in the upper esophagus (HGMUE) in China, and to study the macroscopic and microscopic aspects of the lesions and to evaluate the clinical importance of HGMUE. METHODS: A prospective study was made among a total of 15,228 consecutive patients, 8,573 male and 6,655 female, aged 54 (8-95), undergoing gastroscopy. Disease histories of all patients were carefully inquired, especially those regarding possible complaints including discomfort of throat and swallowing pain and so on. Special care was taken in the upper esophageal sphincter area to make sure whether the area was adequately inspected. Biopsy specimens from aberrant mucosa were obtained and the sections were stained with haematoxylin and eosin, and Giemsa stain for Helicobacter pylori. RESULTS: HGMUE was found in 39 patients (0.26%) with an average age of 50. Five patients with H. pylori infection in heterotopic gastric mucosa also presented the infection in the stomach. The gastric mucosa was gastric body type in 8 patients, transitional type in 11 patients, and antral pattern in 7 patients. Intestinal metaplasia was found in 5 patients, and mild atypical hyperplasia in 2 patients. An impressive finding was coexistent erosive gastritis in 14 patients (35.9%), Barrett's esophagus in one patient (2.6%), peptic ulcer in 8 patients (20.5%), and a patient had the complication of constriction in the upper esophagus. CONCLUSION: HGMUE is not rare in China. The presence of inlet patches is possibly correlated with specific symptoms. There are some severe complications in HGMUE, especially esophageal constriction. Close surveillance should be taken for rare cases with metaplasia or dysplasia in HGMUE.