Activation of the Epidermal Growth Factor Receptor (EGRF) is Required for CXCL12 Mediated ERK and Akt Signaling during Prostate Myofibroblast Phenoconversion

Benign prostate hyperplasia (BPH), a condition of the prostate common in aging in men, is associated with urinary voiding dysfunction, or Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal muscle contraction are known to be key players in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the differentiation of fibroblasts into myofibroblasts, which produce and secrete collagens and fibronectins that remodel the extracellular matrix (ECM). This differentiation process is usually accomplished by activation of the TGF-β/TGFβRII axis. However, in this study we report that the CXC-type chemokine, CXCL12, and its receptor, CXCR4, which are up-regulated with aging in the prostate, can drive this differentiation process as well. We have observed that CXCL12 can promote myofibroblast phenoconversion in the absence of exogenous TGF-β and can up-regulate the expression of myofibroblast genes (α-SMA, COL1, TGF-β) in primary and immortalized prostate fibroblasts. Recently we discovered that the activated CXCL12/CXCR4 axis signals through the EGFR and through downstream MEK/ERK and Akt pathways during myofibroblast differentiation, but not through Smad proteins. Smad proteins are the primary signaling proteins utilized by the TGFβRII. This suggests that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGF-β/TGFβRII axis activation or Smad signaling. Furthermore, we observed significant reduction in the activation of EGFR and ERK pathways when treating fibroblasts with an EGFR inhibitor as well as a pan-Metalloprotease inhibitor previous to chemokine treatment. Conversely, chemical inhibition of TGF-βRII or Smad3 activation did not prevent CXCL12-mediated EGFR, MEK/ERK activation or myofibroblast phenoconversion. Based on these findings, we hypothesize that EGFR activation by CXCL12/CXCR4 might be required for ERK and Akt activation during myofibroblasts conversion, and may be coupled to the shedding of extracellular ligands of EGFR by extracellular protease

Obesity-Induced Diabetes and Lower Urinary Tract Fibrosis Promote Urinary Voiding Dysfunction in a Mouse Model

Background: Progressive aging- and inflammation-associated fibrosis effectively remodels the extracellular matrix to increase prostate tissue stiffness and reduce urethral flexibility, resulting in urinary flow obstruction and Lower Urinary Tract Symptoms (LUTS). In the current study we sought to test whether senescence-accelerated mouse prone (SAMP)6 mice, which were reported to develop prostatic fibrosis, would also develop LUTS, and whether these symptoms would be exacerbated by diet-induced obesity and concurrent Type 2 Diabetes Mellitus (T2DM). Methods: To accomplish this, SAMP6 and AKR/J background strain mice were fed regular mouse chow, low fat diet chow, or high fat diet chow for 8 months, then subjected to glucose tolerance tests, assessed for plasma insulin levels, evaluated for urinary voiding function, and assessed for lower urinary tract fibrosis. Results: The results of these studies show that SAMP6 mice and AKR/J background strain mice develop diet-induced obesity and T2DM concurrent with urinary voiding dysfunction. Moreover, urinary voiding dysfunction was more severe in SAMP6 than AKR/J mice and was associated with pronounced prostatic and urethral tissue fibrosis. Conclusions: Taken together, these studies suggest that obesity, T2DM, lower urinary tract fibrosis, and urinary voiding dysfunction are inextricably and biologically linked

Polyunsaturated fatty acid metabolism in three fish species with different trophic level

Reducing the dependency of fishfeed for marine ingredients and species diversification are both considered crucial factors for the sustainable development of aquaculture. The substitution of fish oil (FO) by vegetable oils (VO) in aquafeeds is an economically feasible solution. However, such substitution may compromise the fish flesh content of essential n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFA) and, therefore, its nutritional value for human consumption. Likewise, there is a wide range of strategies to select new target species for sector diversification, among which, the capacity to biosynthesize n-3 LC-PUFA from their C18 precursors abundant in VO might be considered as a fair preliminary strategy. Therefore, the aim of the present study was to analyze the metabolic fate of [1-14C] labeled 18:2n-6, 18:3n-3, 20:5n-3 and 22:6n-3 in isolated hepatocytes and enterocytes from wild individuals of three fish species with different trophic level: the marine herbivorous salema (Sarpa salpa), the strict carnivorous sand sole (Pegusa lascaris) and the omnivorous thicklip grey mullet (Chelon labrosus). These species were selected for their phylogenetic proximity to consolidated farmed species such as gilthead seabream (Sparus aurata), senegalese sole (Solea senegalensis), and golden grey mullet (Liza aurata), respectively. The study also assessed the molecular cloning, functional characterization and tissue distribution of the fatty acyl elongase (Elovl) gene, elovl5, involved in the biosynthetic metabolism of n-3 LC-PUFA. The three species were able to biosynthesize docosahexaenoic acid (22:6n-3). S. salpa seems to have similar biosynthetic capacity than S. aurata, with a fatty acyl desaturase 2 (Fads2), with 6, 8 and 5 activities. P. lascaris showed a wider Fads2 activity repertory than S. senegalensis, including 4 and residual 6/5 activities. In C. labrosus, both 8 and 5 activities but not the 6 described for L. aurata were detected in the incubated cells. Elongation from C18 and C20 precursors to C20 and C22 products occurred in hepatocytes and enterocytes as well as in the functional characterization of Elovl5 by heterologous expression in yeast. Elovl5 showed a species specific expression pattern, with the highest rates observed in the liver, gut and brain in S. salpa and P. lascaris, and in the brain for C. labrosus. In summary, the LC-PUFA biosynthesis capacity from S. salpa, P. lascaris and C. labrosus greatly resembled that of their phylogenetic closer species. The three studied species could be further explored as candidates for the aquaculture diversification from their potential ability to biosynthesize LC-PUFA

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

“Fatty Lungs”: An uncommon case of Autoimmune Pulmonary Alveolar Proteinosis

Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease characterized by excessive accumulation of surfactant lipids and proteins in alveoli and terminal airways. It is caused by impaired GM-CSF signaling [1]. Surfactant is synthesized and secreted by alveolar type II epithelial cells, and removed by uptake and catabolism by these cells, and the alveolar macrophages. Patients with PAP usually describe gradual onset of progressive exertional dyspnea and non-productive cough. However, an asymptomatic presentation is observed in up to 25% of cases, even in the presence of diffuse radiographic changes. Three recognized subtypes exist. Autoimmune PAP is associated with neutralizing GM-CSF autoantibodies and accounts about 90% of cases. Secondary PAP may occur in the context of any disease that reduces the abundance or functionality of alveolar macrophages, resulting in impaired surfactant clearance. Congenital PAP is the result of genetic mutations that disrupt GM-CSF signaling, including mutations in the &alpha;- or &beta;-chains of the GM-CSF receptor [1-3]