The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression

Elevated plasma CXCL12 alpha is associated with a poorer prognosis in pulmonary arterial hypertension.

Recent work in preclinical models suggests that signalling via the pro-angiogenic and proinflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortalit

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

NETs and CF Lung Disease: Current Status and Future Prospects

Cystic Fibrosis (CF) is the most common fatal monogenic disease among Caucasians. While CF affects multiple organ systems, the principle morbidity arises from progressive destruction of lung architecture due to chronic bacterial infection and inflammation. It is characterized by an innate immune defect that results in colonization of the airways with bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa from an early age. Within the airway microenvironment the innate immune cells including epithelial cells, neutrophils, and macrophages have all been implicated in the host defense defect. The neutrophil, however, is the principal effector cell facilitating bacterial killing, but also participates in lung damage. This is evidenced by a disproportionately elevated neutrophil burden in the airways and increased neutrophil products capable of tissue degradation, such as neutrophil elastase. The CF airways also contain an abundance of nuclear material that may be originating from neutrophils. Neutrophil extracellular traps (NETs) are the product of a novel neutrophil death process that involves the expulsion of nuclear material embedded with histones, proteases, and antimicrobial proteins and peptides. NETs have been postulated to contribute to the bacterial killing capacity of neutrophils, however they also function as a source of proteases and other neutrophil products that may contribute to lung injury. Targeting nuclear material with inhaled DNase therapy improves lung function and reduces exacerbations in CF and some of these effects may be due to the degradation of NETs. We critically discuss the evidence for an antimicrobial function of NETs and their potential to cause lung damage and inflammation. We propose that CF animal models that recapitulate the human CF phenotype such as the CFTR−/− pig may be useful in further elucidating a role for NETs

Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD).

Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a potentially treatable risk factor for frequent COPD exacerbations; testing for antibody deficiency should be considered in difficult to manage frequently exacerbating COPD patients. Further prospective studies are warranted to further test this hypothesis

Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat

This is a panel discussion of: Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat / S. Christiansen, M. Scholze, M. Axelstad, J. Boberg, A. Kortenkamp, U. Hass.Summary of main paper:The incidence of hypospadias is increasing in young boys, but it remains unclear whether human exposure to endocrine disrupting chemicals plays a role. Risk assessment is based on estimation of no-observed-adverse-effect levels for single compounds, although humans are exposed to combinations of several anti-androgenic chemicals. In a mixture (MIX) study with three androgen receptor antagonists, vinclozolin, flutamide and procymidone, rats were gavaged during gestation and lactation with several doses of a MIX of the three chemicals or the chemicals alone. External malformations of the male reproductive organs were assessed on PND 47 using a score from 0 to 3 (normal to marked) for hypospadias. Markedly increased frequencies were observed after exposure to a MIX of the three chemicals compared to administration of the three chemicals alone. Anogenital distance at PND 1, nipple retention at PND 13, and dysgenesis score at PND 16 were highly correlated with the occurrence of hypospadias, and MIX effects were seen at doses where each of the individual chemicals caused no observable effects. Therefore, the results indicate that doses of anti-androgens, which appear to induce no hypospadias when judged on their own, may induce a very high frequency of hypospadias when they interact in concert with other anti-androgens

Helsingin hotellien kannattavuuden kehittäminen benchmarkkauksen avulla

Opintojemme aikana tutustuimme kolmeen toimintamalliin, joiden näimme olevan sidoksissa katetuottolaskennan kolmeen osa-alueeseen: myynnin lisäämiseen, katteen parantamiseen ja kiinteiden kustannusten alentamiseen. Yksi toimintamalleista oli lentoyhtiöiden käytössä, toi-nen osa kansainvälistä kehitysprojektia ja kolmas oli käytössä hotelleissa Suomen ulkopuolel-la. Huomasimme, ettei mitään näistä toimintamalleista oltu vielä hyödynnetty Helsingin alueen hotelleissa, minkä vuoksi päätimme lähteä tutkimaan opinnäytetyössämme niiden soveltu-vuutta kyseisen alueen toimipaikoissa. Tämän opinnäytetyön tavoitteena on benchmarkkauksen avulla tuoda esille toimintatapoja, joilla uskomme olevan vaikutusta kannattavuuden paranemiseen Helsingin hotelleissa. Tavoitteena on selvittää, kuinka toimivina Helsingin alueen hotellien ylin johto ne näkee. Työn tietoperustassa perehdytään toimintaympäristön nykytilaan ja käsitellään kannattavuuteen liittyvät keskeisimmät asiat. Kannattavuuden parantamisen osalta työ on rajattu koskemaan myynnin lisäämistä, myyntihinnan korotusta ja kiinteiden kustannusten pienentämistä. Osana tietoperustaa esitellään benchmarkkauksen kohteena olevat toimintamallit, jotka ovat The Plusgrade –sovellusalusta, Geneva Transport Card ja automatisoitu sisäänkirjautuminen. Opinnäytetyön tutkimusongelma on, voidaanko Helsingin hotellien kannattavuutta parantaa tässä opinnäytetyössä esitettyjen benchmarkattujen toimintamallien avulla. Tutkimusongelma on täsmennetty vielä alaongelmiksi. Niiden avulla pyritään löytämään vastaus siihen, kuinka toimiviksi nämä toimintatavat tutkimukseen osallistuneissa hotelleissa nähdään. Lisäksi selvitetään, miksi toimintatavat eivät toimisi tutkimukseen osallistuneissa hotelleissa ja mitä haasteita toimintatapoihin liittyy. Tutkimusstrategiaksi tässä työssä valikoitui kvalitatiivinen tutkimus ja sen tutkimusmetodiksi teemahaastattelu. Tutkimusta varten haastateltiin viittä Helsingin alueella toimivaa hotellinjohtajaa. Haastattelut tehtiin helmi-maaliskuussa vuonna 2016. Tutkimustuloksista ilmeni, että The Plusgrade -sovellusalustaa voitaisiin hyödyntää lähes ainoastaan kausiluontoisesti eikä sen kannattavuudesta oltu varmoja. Geneva Transport Card sai varovaisimman vastaanoton, koska sille ei nähty varsinaista tarvetta, rahoitus olisi haastavaa ja käyttöönotto edellyttäisi laajaa yhteistyötä eri toimijoiden välillä. Automatisoitu sisäänkirjautuminen sen sijaan kiinnosti haastateltavia eniten kaikesta kolmesta toimintamallista, sillä kyseessä on lähitulevaisuudessa tapahtuva muutos

GOLD classification in patients with COPD, including those who were treated with antibiotics versus immunoglobulin replacement.

<p>GOLD classification in patients with COPD, including those who were treated with antibiotics versus immunoglobulin replacement.</p