Filamin A Regulates Cardiovascular Remodeling

Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C-terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in humans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function

Ischemia causes rapidly progressive nephropathy in the diabetic rat

Ischemia causes rapidly progressive nephropathy in the diabetic rat.We examined the influence of renal ischemia in rats with diabetes mellitus (DM). Male Wistar rats were rendered diabetic by streptozotocin treatment. Two weeks later, 30 minutes of complete ischemia was induced in the left kidney of DM and non-DM animals. Both groups were evaluated functionally and morphologically four or eight weeks post-ischemia. In non-DM animals renal function and morphology showed almost complete recovery. In the DM animals, however, this comparatively short period of ischemia caused a substantial loss of renal function. Four weeks post-ischemia inulin clearance in the DM kidneys rendered ischemic was only 20% of that in the corresponding non-DM kidneys, and after eight weeks the DM kidneys were completely anuric. Extensive inflammation and tubulointerstitial fibrosis were evident in DM kidneys four weeks after ischemia and seemed to increase over time. After eight weeks, tubular atrophy was found in the ischemic DM kidneys, resulting in a substantial loss of kidney mass. We conclude that in diabetic rats renal ischemia causes rapidly progressive kidney damage that in several respects resembles diabetic nephropathy in humans. Since advanced renal lesions similar to those seen in human diabetic nephropathy never develop in the rat solely as a result of DM, the present study may provide an experimental model for further studies on renal failure in diabetes mellitus

Can a Peritoneal Conduit Become an Artery?

Objective Current vascular grafts all have limitations. This study examined peritoneum as a potential graft material and the in vivo transfer of peritoneum into a functional artery like conduit after end to end anastomosis into the common carotid artery of sheep. The aim was to investigate whether implantation of a peritoneal tube into the arterial tree results in a structure with function, histological findings, and gene expression like an artery, and whether such arterialisation occurs through a conversion of the phenotype of peritoneal cells or from host cell migration into the implant. Methods Peritoneum with adherent rectus aponeurosis from sheep was used to form tubular vascular grafts that were implanted into the common carotid artery of six sheep, then removed after five months. Two sheep received allogenic peritoneal grafts and four sheep received autologous peritoneal grafts. Results One sheep died shortly after implantation, so five of the six sheep were followed. Five months after implantation, four of the five remaining grafts were patent. Three of four patent grafts were aneurysmal. The four patent grafts had developed an endothelial layer indistinguishable from that of the adjacent normal artery, and a medial layer with smooth muscle cells with a surrounding adventitia. The new conduit displayed vasomotor function not present at the time of implantation. DNA genotyping showed that the media in the new conduit consisted of recipient smooth muscle cells. Little difference in mRNA expression was demonstrated between the post-implantation conduit and normal artery. Conclusion During a five month implantation period in the arterial system, peritoneum converted into a tissue that histologically and functionally resembled a normal artery, with a functional genetic expression that resembled that of an artery. Single nucleotide polymorphism analysis indicated that this conversion occurs through host cell migration into the graft

<i>KRAS</i> Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016–2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207–1.709, p n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124–2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148–0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC

Enhanced Mucosal Immunoglobulin A Response of Intranasal Adenoviral Vector Human Immunodeficiency Virus Vaccine and Localization in the Central Nervous System

Replication-defective adenovirus (ADV) vectors represent a promising potential platform for the development of a vaccine for AIDS. Although this vector is typically administered intramuscularly, it would be desirable to induce mucosal immunity by delivery through alternative routes. In this study, the immune response and biodistribution of ADV vectors delivered by different routes were evaluated. ADV vectors expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pol, and Env were delivered intramuscularly or intranasally into mice. Intranasal immunization induced greater HIV-specific immunoglobulin A (IgA) responses in mucosal secretions and sera than in animals with intramuscular injection, which showed stronger systemic cellular and IgG responses. Administration of the vaccine through an intranasal route failed to overcome prior ADV immunity. Animals exposed to ADV prior to vaccination displayed substantially reduced cellular and humoral immune responses to HIV antigens in both groups, though the reduction was greater in animals immunized intranasally. This inhibition was partially overcome by priming with a DNA expression vector expressing HIV-1 Gag, Pol, and Env before boosting with the viral vector. Biodistribution of recombinant adenovirus (rADV) vectors administered intranasally revealed infection of the central nervous system, specifically in the olfactory bulb, possibly via retrograde transport by olfactory neurons in the nasal epithelium, which may limit the utility of this route of delivery of ADV vector-based vaccines

Pulmonary Adenocarcinoma In Situ and Minimally Invasive Adenocarcinomas in European Patients Have Less <i>KRAS</i> and More <i>EGFR</i> Mutations Compared to Advanced Adenocarcinomas

Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (n = 10) and MIA (n = 18) and compared the number of genetic mutations with advanced ADC (n = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (p KRAS) in advanced ADC (34.6%), there was only one case of AIS with KRAS G12C mutation (3.5%; p KRAS mutation (p EGFR) mutations in advanced ADC (15.0%), the fraction of EGFR mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; p EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA

Deficiency of filamin A in endothelial cells impairs left ventricular remodelling after myocardial infarction

Aims: Actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of FLNA after myocardial infarction (MI) has not been explored. The main purpose of this study was to determine the impact of endothelial deletion of FLNA on post-MI remodelling of the left ventricle (LV). Methods and results: We found that FLNA is expressed in human and mouse endothelial cells (ECs) during MI. To determine the biological significance of endothelial expression of FLNA, we used mice that are deficient for endothelial FLNA by cross-breeding adult mice expressing floxed Flna (Flnao/fl) with mice expressing Cre under the vascular endothelial-specific cadherin promoter (VECadCre+). Male Flnao/fl and Flnao/fl/VECadCre+ mice were subjected to permanent coronary artery ligation to induce MI. Flnao/fl/VECadCre+ mice that were deficient for endothelial FLNA exhibited larger and thinner LV with impaired cardiac function as well as elevated plasma levels of NT-proBNP and decreased secretion of VEGF-A. The number of capillary structures within the infarcted areas was reduced in Flnao/fl/VECadCre+ hearts. ECs silenced for Flna mRNA expression exhibited impaired tubular formation and migration, secreted less VEGF-A, and produced lower levels of phosphorylated AKT and ERK1/2 as well as active RAC1. Conclusion: Deletion of FLNA in ECs aggravated MI-induced LV dysfunction and cardiac failure as a result of defective endothelial response and increased scar formation by impaired endothelial function and signalling