Risks of Ventricular Tachyarrhythmia and Mortality in Patients with Amyloidosis - A Long-Term Cohort Study.

Background: The presence of ventricular tachycardia (VT) is associated with higher mortality. The annual incidence of VT after a diagnosis of amyloidosis and the associated cardiovascular (CV) outcomes have not been well assessed in a large cohort. Methods: A total of 12,139 amyloidosis patients were identified from the Taiwan National Health Insurance Research Database. Non-amyloidosis group was matched 1:1 for age, gender, hypertension, and diabetes mellitus (DM) to the amyloidosis group using a propensity score. Analysis of the risk of CV outcomes was conducted. We also analyzed the incidence of cardiac amyloidosis (CA). Results: The incidence rates of amyloidosis and CA were 6.54 and 0.61 per 100,000 person-years, respectively. Multivariable analysis revealed that the risk of VT was higher in both the amyloidosis [hazard ratio (HR): 7.90; 95% confidence interval (CI): 4.49-13.9] and CA (HR: 153.3, 95% CI: 54.3-432.7) groups. In the amyloidosis group, the risk of heart failure (HF)-related hospitalization, CV death, and all-cause death was also higher. Amyloidosis was associated with a higher CV mortality rate following VT (HR: 1.50; 95% CI: 1.07-2.12). The onset of a new VT event in patients with amyloidosis was associated with HF, DM, chronic liver disease, and anti-arrhythmic drug use. Conclusions: In this nationwide cohort study, the incidence rates of amyloidosis and CA were 6.54 and 0.61 per 100,000 person-years, respectively. The long-term risks of VT and CV mortality were higher in the patients with amyloidosis and CA. The patients with amyloidosis had a poorer prognosis following VT events, highlighting the importance of continuous monitoring in these patients.

Decreased Expression of Plakophilin-2 and αT-Catenin in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Markers for Diagnosis.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disease of the heart muscle. Clinical challenges remain, however, in identifying patients with ARVC in the early or concealed stages with subtle clinical manifestations. Therefore, we wanted to identify potential targets by immunohistochemical (IHC) analysis in comparison with controls. Pathogenic mutations were identified in 11 of 37 autopsied patients with ARVC. As observed from IHC analysis of the RV, expression of αT-catenin and plakophilin-2 is significantly decreased in autopsied patients with ARVC as compared to controls, and the decreased expression is consistent in patients with and without pathogenic mutations. Furthermore, ARVC specimens demonstrated a reduced localization of αT-catenin, desmocollin-2, desmoglein-2, desmoplakin, and plakophilin-2 on intercalated discs. These findings have been validated by comparing RV specimens obtained via endomyocardial biopsy between patients with ARVC and those without. The pathogenic mutation was present in 3 of 5 clinical patients with ARVC. In HL-1 myocytes, siRNA was used to knockdown CTNNA3, and western blotting analysis demonstrated that the decline in αT-catenin expression was accompanied by a significant decline in the expression of plakophilin-2. The aforementioned effect was directed towards protein degradation rather than mRNA stability. Plakophilin-2 expression decreases concurrently with the decline in CTNNA3 expression. Therefore, the expression of αT-catenin and plakophilin-2 could be potential surrogates for the diagnosis of ARVC.

Clinical Significance of Ventricular Tachyarrhythmias in Patients Undergoing Valve Replacement: A Nationwide Population-Based Study.

Background: The clinical significance and outcomes of ventricular tachyarrhythmias (VTa) in patients undergoing valve replacement have rarely been reported. Objective: This study aimed to investigate the incidence and outcome of VTa after surgical valve replacement. Methods: We conducted a population-based retrospective cohort study using data obtained from the Taiwan National Health Insurance Research Database. In total, 10,212 patients were selected after 1:1 propensity-score matching based on the type of prosthetic valve used (mechanical vs. bioprosthetic). Various outcomes during long-term follow-up were analyzed. Results: After a median follow-up period of 59.6 months, the crude incidence rate of VTa after surgical valve replacement was 4.8/1,000 person-years, and the cumulative incidence of VTa persistently increased after surgery. Furthermore, the occurrences of VTa after valve replacement significantly increased the risk of cardiovascular (CV) death (P < 0.001, HR 1.67, 95% CI 1.41-1.96), stroke- (P < 0.001, HR 1.66, 95% CI 1.37-2.01), atrial fibrillation- (P < 0.001, HR 2.80, 95% CI 2.42-3.24), and congestive heart failure-related hospitalization (P < 0.001, HR 2.61, 95% CI 2.30-2.95). Among patients with VTa, all-cause mortality (P = 0.001, HR 0.49, 95% CI 0.32-0.75) and CV death (P = 0.047, HR 0.58, 95% CI 0.34-0.99) in those with implantable cardioverter-defibrillator (ICD) implantation were lower than those without. Conclusion: The crude incidence rate of VTa after surgical valve replacement was 4.8/1,000 person-years, and the cumulative incidence of VTa persistently increased during follow-up. The presence of VTa after surgical valve replacement increases hospitalization and CV death, while ICD implantation reduced the mortality rate in these patients.

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

[Prediction of anti-liver fibrosis effect of Piperis Longi Fructus based on network pharmacology].

Network pharmacology and liver fibrosis(LF) model in vitro were used to analyze the underly mechanism of anti-liver fibrosis effect that induced by Piperis Longi Fructus and its major active compounds. TCMSP and TCMIP were used to search for the chemical constituents of Piperis Longi Fructus, as well as the oral bioavailability(OB), drug-likeness(DL), intercellular permeability of intestinal epithelial cells(Caco-2) and Drug-likeness grading were set as limiting conditions. The related target genes of Piperis Longi Fructus were queried by TCMSP database, while related targets of LF were screened by GeneCards databases. Interaction network was constructed using Cytoscape 3.7.1. These above data were imported into STRING database for PPI network analysis. Enrichment of gene ontology(GO) and pathway analysis(KEGG) within Bioconductor database were utilized to note functions of related targets of Piperis Longi Fructus. Finally, the core targets and pathways were preliminarily verified by in vitro experiments. The effects of piperlongumine(PL), the major active component of Piperis Longi Fructus, on proliferation of rat liver stellate cells(HSC-T6) and expression of α smooth muscle actin(α-SMA) and collagen Ⅰ were investigated. The major factors TNF-α of tumor necrosis factor(TNF) pathway and NF-κB p65, IL-6 protein expressions of LF process were examined. A total of 12 active compounds such as PL were obtained by analyzing the bioavailability and drug-like properties, which inferred to 48 targets. The functional enrichment analysis of GO obtained 1 240 GO items, mainly involving in process of biology and molecular function. A total of 99 signaling pathways were enriched in the KEGG pathway enrichment analysis, including TNF signaling pathway, cGMP-PKG signaling pathway, calcium signaling pathways. CCK-8 assay showed that PL inhibited proliferation of HSC-T6 induced by transforming growth factor-ß1(TGF-ß1). Western blot analysis found that treated with PL suppressed the protein expressions of α-SMA, collagen Ⅰ, TNF-α and p65 in HSC-T6. Enzyme linked immunosorbent assay(ELISA) showed that PL inhibited the expressions of TNF-α and IL-6 in the cluture supertant of HSC-T6 cells. In conclusion, PL could play an anti-liver fibrosis role by regulating TNF/NF-κB signaling pathway. This study provided the mechanism basis of anti-LF effects induced by Piperis Longi Fructus and its major active compounds, which might help for the further study of the mechanism and key targets of Piperis Longi Fructus.

BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy.

Zinc(II)-dipicolylamine (Zn-DPA) has been shown to specifically identify and bind to phosphatidylserine (PS), which exists in bulk in the tumor microenvironment. BPRDP056, a Zn-DPA-SN38 conjugate was designed to provide PS-targeted drug delivery of a cytotoxic SN38 to the tumor microenvironment, thereby allowing a lower dosage of SN38 that induces apoptosis in cancer cells. Micro-Western assay showed that BPRDP056 exhibited apoptotic signal levels similar to those of CPT-11 in the treated tumors growing in mice. Pharmacokinetic study showed that BPRDP056 has excellent systemic stability in circulation in mice and rats. BPRDP056 is accumulated in tumors and thus increases the cytotoxic effects of SN38. The in vivo antitumor activities of BPRDP056 have been shown to be significant in subcutaneous pancreas, prostate, colon, liver, breast, and glioblastoma tumors, included an orthotopic pancreatic tumor, in mice. BPRDP056 shrunk tumors at a lower (~20% only) dosing intensity of SN38 compared to that of SN38 conjugated in CPT-11 in all tumor models tested. A wide spectrum of antitumor activities is expected to treat all cancer types of PS-rich tumor microenvironments. BPRDP056 is a first-in-class small molecule drug conjugate for cancer therapy.

Molecular profiling of afatinib-resistant non-small cell lung cancer cells in vivo derived from mice.

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC patients with overexpressed or mutated epidermal growth factor receptor (EGFR) related to disease progression are treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Acquired drug resistance after TKI treatments has been a major focus for development of NSCLC therapies. This study aimed to establish afatinib-resistant cell lines from which afatinib resistance-associated genes are identified and the underlying mechanisms of multiple-TKI resistance in NSCLC can be further investigated. Nude mice bearing subcutaneous NSCLC HCC827 tumors were administered with afatinib at different dose intensities (5-100 mg/kg). We established three HCC827 sublines resistant to afatinib (IC50 > 1 µM) with cross-resistance to gefitinib (IC50 > 5 µM). cDNA microarray revealed several of these sublines shared 27 up- and 13 down-regulated genes. The mRNA expression of selective novel genes - such as transmembrane 4 L six family member 19 (TM4SF19), suppressor of cytokine signaling 2 (SOCS2), and quinolinate phosphoribosyltransferase (QPRT) - are responsive to afatinib treatments only at high concentrations. Furthermore, c-MET amplification and activations of a subset of tyrosine kinase receptors were observed in all three resistant cells. PHA665752, a c-MET inhibitor, remarkably increased the sensitivity of these resistant cells to afatinib (IC50 = 12-123 nM). We established afatinib-resistant lung cancer cell lines and here report genes associated with afatinib resistance in human NSCLC. These cell lines and the identified genes serve as useful investigational tools, prognostic biomarkers of TKI therapies, and promising molecule targets for development of human NSCLC therapeutics.

Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

BACKGROUND: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). METHODS AND FINDINGS: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. CONCLUSIONS: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Clinical features and diagnosis of new malignancy in patients with acute pulmonary embolism and without a history of cancer.

BACKGROUND: Pulmonary embolism (PE) is frequently associated with cancer. This study aimed to assess patients with acute PE and identify diagnostic predictors of new cancer after 1 year of follow-up. METHODS: One hundred and twenty-one patients with PE were enrolled consecutively from the emergency department of a single medical center in Taiwan. Data from computed tomography angiography, echocardiogram, electrocardiogram and for baseline comorbidities, clinical presentation, and laboratory parameters were recorded. The surviving discharged patients without a cancer diagnosis were followed-up for 1 year, and new malignancies were recorded. RESULTS: Of 121 patients with acute PE, 44 (36%) had an underlying cancer history (cancer group), and 77 (64%) did not (noncancer group). Baseline demographic characteristics, comorbidities, clinical symptoms, biochemical parameters, echocardiogram data, and electrocardiogram data of the two groups were similar except for a higher hospital mortality rate (56.8% vs 9.1%; p < 0.001), lower body mass index (22.6 ± 4.1 vs 25.5 ± 4.9; p =0.02), higher systolic blood pressure (139.7 ± 33.7 vs 125.4 ± 24.1; p = 0.02), lower low-density lipoprotein level (67.4 ± 38.3 vs 90.4 ± 33.8; p = 0.04), lower creatinine kinase (CK; 43.0 ± 43.0 vs 83.5 ± 83.1; p = 0.01), higher myocardial band (MB) form of CK ratio (0.2 ± 0.2 vs 0.1 ± 0.1; p < 0.01), higher partial pressure of arterial oxygen (122.81 ± 81.2 vs 90.2 ± 59.4; p = 0.03), and less presentation of chest pain (15.9% vs 40.3%; p = 0.01) in the cancer group. Kaplan-Meier curve analysis revealed that the 30-day survival rate was higher in the noncancer group than in the cancer group (log-rank p = 0.04). After 1 year of follow-up, 6 of 59 (10.17%) initial non-cancer-related PE survivors were diagnosed with malignancies. After multivariate analysis, only the initial CK-MB level was associated with a diagnosis of new cancer (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.029-1.811; p = 0.03). CONCLUSION: This study suggests that the CK-MB level is associated with future malignancy in patients with PE. Patients with cancer-related PE had a worse 30-day survival rate.

Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.

Electrophysiological and clinical characteristics of catheter ablation for isolated left side atrial tachycardia over a 10-year period.

AIMS: Most left atrial tachycardia (LAT) is associated with atrial fibrillation (AF). The clinical and electrophysiological characteristics and outcomes of LAT without AF have not been investigated. This study sought to determine the long-term ablation outcomes and predictors of recurrence of isolated LAT. METHODS: This is a single-center study of consecutive patients with isolated LAT. Atrial arrhythmia recurrence was determined from follow-up records of patients who underwent LAT ablation from 2008 to 2017. Clinical and electrophysiologic characteristics associated with atrial arrhythmia recurrence were identified. RESULTS: A total of 50 patients (53 ± 19 years, 46% male) with 59 LAT (1.16 ± 0.47 per patient) were enrolled. Over a mean follow-up of 37 ± 33 months, atrial arrhythmia recurrence occurred in 22 (44%) patients, 11 with atrial tachycardia (AT) only, five with AF only, and six with concurrent AT and AF. The incidence of pulmonary vein (PV) origins increased significantly in the repeat procedure (P = 0.036). Multivariate analysis identified left ventricular ejection fraction (LVEF) as the only predictor of any atrial arrhythmia recurrence and LAT recurrence, while smoking and identified macroreentrant LAT in the index procedure predicted AF recurrence. CONCLUSION: This study demonstrated a higher rate of atrial arrhythmia recurrence, including AF, among patients with initially isolated LAT. A lower LVEF predicted any atrial arrhythmia and LAT recurrence, whereas smoking and index macroreentrant AT mechanism predicted long-term AF. PV ATs were frequently observed in recurrent patients irrespective of index procedure origin.

Immunomodulatory Effects of the Stout Camphor Medicinal Mushroom, Taiwanofungus camphoratus (Agaricomycetes)-Based Health Food Product in Mice.

Taiwanofungus camphoratus is a unique medicinal mushroom endemic to Taiwan, and it is used as a folk medicine in East Asian countries. The aim of the present study was to investigate the immunomodulatory effects of "leader Antrodia cinnamomea capsule" (LAC), a health food product containing solid-state cultivated mycelial powder of T. camphoratus. For the in vivo studies, mice were orally administered LAC (76, 250, and 760 mg/kg b.w.) for 30 days, and its effects on cell-mediated humoral immune function were examined. The results of the concanavalin A-induced splenic lymphocyte proliferation test showed that LAC significantly increased splenic lymphocyte proliferation compared with the control. In addition, serum hemolysin analysis showed that LAC treatment significantly increased the half value of serum hemolysin (HC50) in mice compared with the control. Moreover, treatment with LAC significantly increased the phagocytic index as measured by carbon clearance and natural killer cell activity. Taken together, these findings provide strong evidence that LAC can modulate immune function.

Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT­8/5­Fu human colorectal cancer cell line.

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3­(4,5­dimethyl­2­thiazol)­2,5­diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT­8/5­Fu cells and provided evidence that activated nuclear factor erythroid 2­related factor (Nrf2) deficiency induced by the curcumin altered the B­cell lymphoma 2 (Bcl­2) associated X protein/Bcl­2 expression ratio, which led to the induction of apoptosis in HCT­8/5­Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

Effects of Taiwanofungus camphoratus on non-specific and specific immune activities in mice.

Taiwanofungus camphoratus is a precious medicinal fungus endemic to Taiwan and has been used as traditional medicine for a long time. Many pharmacological studies have revealed that T. camphoratus possessed various biological activities, such as immunomodulatory effects, anticancer activity and liver protective function. The aim of this study is to investigate the non-specific and antigen (ovalbumin [OVA])-specific immunomodulation effects of solid-state cultivated powder of T. camphoratus (Leader Antrodia cinnamomea [LAC]) in BABL/c male mice. In non-specific and antigen-specific immune function studies, 8-week-old mice were orally administered with LAC for 6 and 8 weeks, respectively. The results have shown that the proliferation of splenic immune cells, phagocytic activity of macrophages and cytolytic activity of natural killer cells were enhanced by LAC. Additionally, LAC increased the levels of IL-2, TNF-α, INF-γ, GM-CSF and serum OVA-IgG and OVA-IgM. These findings provided evidences that LAC had the immunomodulation effects on both antigen-specific and non-specific immune responses in mice.

Tangled history of a multigene family: The evolution of ISOPENTENYLTRANSFERASE genes.

ISOPENTENYLTRANSFERASE (IPT) genes play important roles in the initial steps of cytokinin synthesis, exist in plant and pathogenic bacteria, and form a multigene family in plants. Protein domain searches revealed that bacteria and plant IPT proteins were to assigned to different protein domains families in the Pfam database, namely Pfam IPT (IPTPfam) and Pfam IPPT (IPPTPfam) families, both are closely related in the P-loop NTPase clan. To understand the origin and evolution of the genes, a species matrix was assembled across the tree of life and intensively in plant lineages. The IPTPfam domain was only found in few bacteria lineages, whereas IPPTPfam is common except in Archaea and Mycoplasma bacteria. The bacterial IPPTPfam domain miaA genes were shown as ancestral of eukaryotic IPPTPfam domain genes. Plant IPTs diversified into class I, class II tRNA-IPTs, and Adenosine-phosphate IPTs; the class I tRNA-IPTs appeared to represent direct successors of miaA genes were found in all plant genomes, whereas class II tRNA-IPTs originated from eukaryotic genes, and were found in prasinophyte algae and in euphyllophytes. Adenosine-phosphate IPTs were only found in angiosperms. Gene duplications resulted in gene redundancies with ubiquitous expression or diversification in expression. In conclusion, it is shown that IPT genes have a complex history prior to the protein family split, and might have experienced losses or HGTs, and gene duplications that are to be likely correlated with the rise in morphological complexity involved in fine tuning cytokinin production.

Heterogeneous distribution of substrates between the endocardium and epicardium promotes ventricular fibrillation in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Aims: Whether the distribution of scar in arrhythmogenic right ventricular cardiomyopathy (ARVC) plays a role in predicting different types of ventricular arrhythmias is unknown. This study aimed to investigate the prognostic value of scar distribution in patients with ARVC. Methods and results: We studied 80 consecutive ARVC patients (46 men, mean age 47 ± 15 years) who underwent an electrophysiological study with ablation. Thirty-four patients receive both endocardial and epicardial mapping. Abnormal endocardial substrates and epicardial substrates were characterized. Three groups were defined according to the epicardial and endocardial scar gradient (<10%: transmural, 10-20%: intermediate, >20%: horizontal, as groups 1, 2, and 3, respectively). Sinus rhythm electrograms underwent a Hilbert-Huang spectral analysis and were displayed as 3D Simultaneous Amplitude Frequency Electrogram Transformation (SAFE-T) maps, which represented the arrhythmogenic potentials. The baseline characteristics were similar between the three groups. Group 3 patients had a higher incidence of fatal ventricular arrhythmias requiring defibrillation and cardiac arrest during the initial presentation despite having fewer premature ventricular complexes. A larger area of arrhythmogenic potentials in the epicardium was observed in patients with horizontal scar. The epicardial-endocardial scar gradient was independently associated with the occurrence of fatal ventricular arrhythmias after a multivariate adjustment. The total, ventricular tachycardia, and VF recurrent rates were higher in Group 3 during 38 ± 21 months of follow-up. Conclusion: For ARVC, the epicardial substrate that extended in the horizontal plane rather than transmurally provided the arrhythmogenic substrate for a fatal ventricular arrhythmia circuit.

A novel noninvasive surface ECG analysis using interlead QRS dispersion in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: This study investigated the feasibility of using the precordial surface ECG lead interlead QRS dispersion (IQRSD) in the identification of abnormal ventricular substrate in arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: Seventy-one consecutive patients were enrolled and reclassified into 4 groups: definite ARVC with epicardial ablation (Group 1), ARVC with ventricular tachycardia (VT, Group 2), idiopathic right ventricular outflow tract VT without ARVC (Group 3), and controls without VT (Group 4). IQRSD was quantified by the angular difference between the reconstruction vectors obtained from the QRS-loop decomposition, based on a principal component analysis (PCA). Electroanatomic mapping and simulated ECGs were used to investigate the relationship between QRS dispersion and abnormal substrate. RESULTS: The percentage of the QRS loop area in the Group 1-2 was smaller than the controls (P = 0.01). The IQRSD between V1-V2 could differentiate all VTs from control (P<0.01). Group 1-2 had a greater IQRSD than the Group 3-4 (V4-V5,P = 0.001), and Group 1 had a greater IQRSD than Group 3-4 (V6-Lead I, P<0.001). Both real and simulated data had a positive correlation between the maximal IQRSD (γ = 0.62) and the extent of corresponding abnormal substrate (γ = 0.71, both P<0.001). CONCLUSIONS: The IQRSD of the surface ECG precordial leads successfully differentiated ARVC from controls, and could be used as a noninvasive marker to identify the abnormal substrate and the status of ARVC patients who can benefit from epicardial ablation.

Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates.

A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.

Increased risk of ventricular tachycardia and cardiovascular death in patients with myocarditis during the long-term follow-up: A national representative cohort from the National Health Insurance Research Database.

The incidence of acute myocarditis complicated with ventricular tachycardia (VT) is unknown. This study aimed to investigate the association between myocarditis and the incidence of VT and mortality. We also aimed to determine the independent predictors that increased the VT risk in those patients. From 2000 to 2004, 13,250 patients with a history of myocarditis were identified from the Taiwan National Health Insurance Research Database. The same number of individuals without heart disease with a matched sex and underlying diseases were selected as the control group. The long-term risks of life-threatening ventricular arrhythmias and mortality in patients with a history of myocarditis were investigated by an adjusted Cox proportional hazards regression. After a mean follow-up of 10.4 ±â€Š2.94 years (interquartile range: 12, 10.19-12), the myocarditis patients showed a higher incidence of new onset VT events compared with healthy controls (5.4% [519 per 100,000 person-year] in the myocarditis group vs, 0.47% [43 per 100,000 person-year] in the healthy controls; adjusted hazard ratio [HR]: 16.1, 95% confidence interval [CI]: 12.4-20.9; P < .001). A higher incidence of cardiovascular death was noted in the myocarditis group than healthy controls (6.52% vs 3.18%; HR: 2.42, 95% CI: 2.14-2.73; P < .001) after adjusting for the multivariate confounders including sex, age, underlying comorbidities, and medications. The results of this study suggested that there was higher incidence of life-threatening VT and mortality during the very long-term follow-up in patients with a history of myocarditis. Future work should focus on an in-depth risk stratification of VT in myocarditis patients.

[Screening of small molecule inhibitors for PLK1 PBD and evaluation of antitumor activities].

With the method of fluorescence polarization (FP), we screened small molecule inhibitors for PLK1 PBD to identify the lead compounds for antitumor drugs. FP led to the identification of a potent hit, F083-0063, whose inhibition rate was (99.7 ± 0.4) % at 10 µg·mL−1. The IC50 was calculated to be 1.9 ± 0.1 µmol·L−1 using Graphpad Prism 5. The effect of the compound on cells' multiplication was measured by MTT assay which showed that F083-0063 inhibited the proliferation of many tumor cell lines. Flow cytometry analysis indicated that the F083-0063 promoted cell apoptosis and induced cell G2/M arrest. Migration abilities of cells, evaluated using scratch test, increased significantly in the presence of F083-0063 with the migration rate as low as (37.6 ± 0.7) % at 20 µmol·L−1. Molecular linkage technique found F083-0063 had good affinity with PLK1 PBD. The results of Western blotting showed that the expression of cyclin-dependent proteins was increased after treatment with F083-0063. In summary, F083-0063 has an antitumor activity and is expected to be an antitumor lead compound targeting PLK1 PBD.