Can Measuring the ‘Dual Anchors of Aorta’ Enhance the Success Rate of TAVR?—A Single-Center Experience

Introduction: Chronic severe aortic regurgitation (AR) has a poor long-term prognosis, especially among old-age patients. Considering their advancing age, the surgical approach of aortic valve replacement may not always be the best alternative modality of treatment in such patients. Therefore, this study’s primary goal was to provide an initial summary of the medium- and short-term clinical effectiveness of transcatheter aortic valve replacement (TAVR) guided by accurate multi-detector computed tomography (MDCT) measurements in patients with severe and chronic AR, especially in elderly patients. Methods: The study enrolled retrospectively and prospectively patients diagnosed with severe AR who eventually underwent TAVR procedure from January 2019 to September 2022 at Fuwai cardiovascular Hospital, Beijing. Baseline information, MDCT measurements, anatomical classification, perioperative, and 1-year follow-up outcomes were collected and analyzed. Based on a novel anatomical categorization and dual anchoring theory, patients were divided into four categories according to the level of anchoring area. Type 1, 2, and 3 patients (with at least two anchoring regions) will receive TAVR with a transcatheter heart valve (THV), but Type 4 patients (with zero or one anchoring location) will be deemed unsuitable for TAVR and will instead receive medical care (retrospectively enrolled patients who already underwent TAVR are an exception). Results: The mean age of the 37 patients with severe chronic AR was 73.1 ± 8.7 years, and 23 patients (62.2%) were male. The American Association of Thoracic Surgeons’ score was 8.6 ± 2.1%. The MDCT anatomical classification included 17 cases of type 1 (45.9%), 3 cases of type 2 (8.1%), 13 cases of type 3 (35.1%), and 4 cases of Type 4 (10.8%). The VitaFlow valve (MicroPort, Shanghai, China) was implanted in 19 patients (51.3%), while the Venus A valve (Venus MedTech, Hangzhou, China) was implanted in 18 patients (48.6%). Immediate TAVR procedural and device success rates were 86.5% and 67.6%, respectively, while eight cases (21.6%) required THV-in-THV implantation, and nine cases (24.3%) required permanent pacemaker implantation. Univariate regression analysis revealed that the major factors affecting TAVR device failure were sinotubular junction diameter, THV type, and MDCT anatomical classification (p &lt; 0.05). Compared with the baseline, the left ventricular ejection fraction gradually increased, while the left ventricular end-diastolic diameter remained small, and the N-terminal-pro hormone B-type natriuretic peptide level significantly decreased within one year. Conclusion: According to the results of our study, TAVR with a self-expanding THV is safe and feasible for patients with chronic severe AR, particularly for those who meet the criteria for the appropriate MDCT anatomical classification with intact dual aortic anchors, and it has a significant clinical effect for at least a year.</p

Krüppel-Like Factor 8 Is a New Wnt/Beta-Catenin Signaling Target Gene and Regulator in Hepatocellular Carcinoma

Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8

The direct effect of Focal Adhesion Kinase (FAK), dominant-negative FAK, FAK-CD and FAK siRNA on gene expression and human MCF-7 breast cancer cell tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in survival signaling. FAK has been shown to be overexpressed in breast cancer tumors at early stages of tumorigenesis.</p> <p>Methods</p> <p>To study the direct effect of FAK on breast tumorigenesis, we developed Tet-ON (tetracycline-inducible) system of MCF-7 breast cancer cells stably transfected with FAK or dominant-negative, C-terminal domain of FAK (FAK-CD), and also FAKsiRNA with silenced FAK MCF-7 stable cell line. Increased expression of FAK in isogenic Tet-inducible MCF-7 cells caused increased cell growth, adhesion and soft agar colony formation <it>in vitro</it>, while expression of dominant-negative FAK inhibitor caused inhibition of these cellular processes. To study the role of induced FAK and FAK-CD <it>in vivo</it>, we inoculated these Tet-inducible cells in nude mice to generate tumors in the presence or absence of doxycycline in the drinking water. FAKsiRNA-MCF-7 cells were also injected into nude mice to generate xenograft tumors.</p> <p>Results</p> <p>Induction of FAK resulted in significant increased tumorigenesis, while induced FAK-CD resulted in decreased tumorigenesis. Taq Man Low Density Array assay demonstrated specific induction of FAKmRNA in MCF-7-Tet-ON-FAK cells. DMP1, encoding cyclin D binding myb-like protein 1 was one of the genes specifically affected by Tet-inducible FAK or FAK-CD in breast xenograft tumors. In addition, silencing of FAK in MCF-7 cells with FAK siRNA caused increased cell rounding, decreased cell viability <it>in vitro </it>and inhibited tumorigenesis <it>in vivo</it>. Importantly, Affymetrix microarray gene profiling analysis using Human Genome U133A GeneChips revealed >4300 genes, known to be involved in apoptosis, cell cycle, and adhesion that were significantly down- or up-regulated (p < 0.05) by FAKsiRNA.</p> <p>Conclusion</p> <p>Thus, these data for the first time demonstrate the direct effect of FAK expression and function on MCF-7 breast cancer tumorigenesis <it>in vivo </it>and reveal specific expression of genes affected by silencing of FAK.</p

Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load

Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma

It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC

High-resolution magnetic resonance imaging of intracranial aneurysms treated by flow diversion

Object: Flow diverter treatment of intracerebral aneurysms is highly successful and has low rates of morbidity and mortality. Among the primary concerns after endovascular treatment are failure to achieve aneurysm obliteration and recurrence, and close imaging follow-up is required. High-resolution magnetic resonance imaging (HRMRI) is being employed in evaluation of an increasingly wide variety of pathological conditions, but investigations into its use after flow diversion for aneurysm treatment have been limited. We present a brief overview of the literature on the use of HRMRI as a follow-up tool after aneurysm treatment using flow diversion, along with a case series describing three patients in whom we used HRMRI to assess aneurysm treatment response. Case descriptions: Patient 1 presented with an ischemic stroke and was found to have an unruptured ophthalmic segment aneurysm. Patient 2 presented with subarachnoid hemorrhage from a ruptured vertebral artery pseudoaneurysm. Patient 3, on workup for possible metastatic melanoma, was found to have an unruptured posterior communicating aneurysm. All three were treated with flow diversion, and in all three cases HRMRI was used to evaluate aneurysm obliteration on outpatient follow-up. HRMRI offered excellent resolution of the parent vessel, aneurysm sac, and aneurysm wall, demonstrating decreased or loss of flow-related enhancement in the aneurysm lumen and development of aneurysm sac thrombosis. Conclusion: HRMRI is a useful tool to evaluate aneurysm treatment by flow diversion and may represent an alternative to repeat digital subtraction angiography. Keywords: High-resolution MRI, Flow diverter, Aneurys