Non-Hypertensive Effects of Aldosterone.

Aldosterone, the primary adrenal mineralocorticoid hormone, as an integral part of the renin-angiotensin-aldosterone system (RAAS), is crucial in blood pressure regulation and maintaining sodium and potassium levels. It interacts with the mineralocorticoid receptor (MR) expressed in the kidney and promotes sodium and water reabsorption, thereby increasing blood pressure. However, MRs are additionally expressed in other cells, such as cardiomyocytes, the endothelium, neurons, or brown adipose tissue cells.

Are the content and usability of a new direct observation tool adequate for assessing competency in delivering person-centred care: a think-aloud study with patients and healthcare professionals in Sweden.

Objective: To evaluate the content and usability of a new direct observation tool for assessing competency in delivering person-centred care based on the Gothenburg Centre for Person-Centred Care (gPCC) framework.

Design: This is a qualitative study using think-aloud techniques and retrospective probing interviews and analyzed using deductive content analysis.

Setting: Sessions were conducted remotely via Zoom with participants in their homes or offices.

What We Know about and What Is New in Primary Aldosteronism.

Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension.

Do the Outcomes of Clinical Efficacy Trials Matter in Regulatory Decision-Making for Biosimilars?

Background: There is an increasing body of evidence supporting a more flexible approach in clinical data requirements for the approval of more complex biosimilar substances such as monoclonal antibodies (mAbs).

Objective: The aim of this paper is to further analyse the role of quality/chemistry, manufacturing and controls (CMC) and clinical data for the conclusion on biosimilarity and the decision on marketing authorisation (MA).

Methods: In the present study, we analysed the MA applications (MAAs) of all 33 mAbs and three fusion proteins evaluated by the European Medicines Agency (EMA) between July 2012 and November 2022 with special emphasis on all submitted rituximab (four products) and trastuzumab (seven products) biosimilar candidates, including withdrawn applications.

Regulatory Evaluation of Biosimilars: Refinement of Principles Based on the Scientific Evidence and Clinical Experience.

The World Health Organization (WHO) guidelines on evaluation of similar biotherapeutic products (SBPs; also called biosimilars) were adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2009. In 2019, the ECBS considered that a more tailored and potentially reduced clinical data package may be acceptable in cases where this was clearly supported by the available scientific evidence. The goal of this publication is to review the current clinical experience and scientific evidence and to provide an expert perspective for updating the WHO guidelines to provide more flexibility and clarity.

WHO informal consultation on revision of guidelines on evaluation of similar biotherapeutic products, virtual meeting, 30 June - 2 July 2021.

The WHO informal consultation was held to promote the revision of WHO guidelines on evaluation of similar biotherapeutic products (SBPs) adopted by the Expert Committee on Biological Standardization (ECBS) in 2009. It was agreed in the past consultations that the evaluation principles in the guidelines are still valid, but a review was recommended to provide more clarity and case-by-case flexibility. The opportunity was therefore taken to review the experience and identify areas where the current guidance could be more permissive without compromising its basic principles, and where additional explanation could be provided regarding the possibility of reducing the amount of data needed for regulatory approval.

Observable indicators of person-centred care: an interview study with patients, relatives and professionals.

Objective: To identify key observable indicators of person-centred care (PCC) from interviews with patients, relatives and professionals with experience of receiving or working with PCC.

Design: A qualitative interview study using deductive content analysis.

Setting: Primary and hospital care settings in Western Sweden.

A state-of-the-art review of direct observation tools for assessing competency in person-centred care.

Background: Direct observation is a common assessment strategy in health education and training, in which trainees are observed and assessed while undertaking authentic patient care and clinical activities. A variety of direct observation tools have been developed for assessing competency in delivering person-centred care (PCC), yet to our knowledge no review of such tools exists.

Objective: To review and evaluate direct observation tools developed to assess health professionals' competency in delivering PCC.

High School Students' Experiences in School Toilets or Restrooms.

Previous research about school toilets is based on studies of children in elementary school. Thus, the aim of this study was to explore the experiences when using the school toilets reported by students aged 16-18 years. Qualitative interviews with 21 students were conducted and analyzed using content analysis.

Biosimilar regulation in the EU.

In the EU, the EMA has been working with biosimilars since 1998. This experience is crystallized in the extensive set of guidelines, which range from basic principles to details of clinical trials. While the guidance may appear complicated, it has enabled the development of biosimilars, of which 21 have managed to get marketing authorization.

Biosimilars: what clinicians should know.

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product.

LKB1 in endothelial cells is required for angiogenesis and TGFbeta-mediated vascular smooth muscle cell recruitment.

Inactivation of the tumor suppressor kinase Lkb1 in mice leads to vascular defects and midgestational lethality at embryonic day 9-11 (E9-E11). Here, we have used conditional targeting to investigate the defects underlying the Lkb1(-/-) phenotype. Endothelium-restricted deletion of Lkb1 led to embryonic death at E12.

LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis.

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps, raising the possibility of non-epithelial origins in tumorigenesis.

The LKB1 tumor suppressor kinase in human disease.

Inactivating germline mutations in the LKB1 gene underlie Peutz-Jeghers syndrome characterized by hamartomatous polyps and an elevated risk for cancer. Recent studies suggest the involvement of LKB1 also in more common human disorders including diabetes and in a significant fraction of lung adenocarcinomas. These observations have increased the interest towards signaling pathways of this tumor suppressor kinase.

Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2.

The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2.

Bmx tyrosine kinase transgene induces skin hyperplasia, inflammatory angiogenesis, and accelerated wound healing.

The Bmx gene, a member of the Tec family of nonreceptor protein tyrosine kinases, is expressed in arterial endothelium and in certain hematopoietic and epithelial cells. Previous in vitro studies have implicated Bmx signaling in cell migration and survival and suggested that it contributes to the progression of prostate carcinomas. However, the function of Bmx in normal tissues in vivo is unknown.

Etk/Bmx transactivates vascular endothelial growth factor 2 and recruits phosphatidylinositol 3-kinase to mediate the tumor necrosis factor-induced angiogenic pathway.

Tumor necrosis factor (TNF), via its receptor 2 (TNFR2), induces Etk (or Bmx) activation and Etk-dependent endothelial cell (EC) migration and tube formation. Because TNF receptor 2 lacks an intrinsic kinase activity, we examined the kinase(s) mediating TNF-induced Etk activation. TNF induces a coordinated phosphorylation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Etk, which is blocked by VEGFR2-specific inhibitors.

p130Cas Couples the tyrosine kinase Bmx/Etk with regulation of the actin cytoskeleton and cell migration.

Bmx/Etk, a member of the Tec/Btk family of nonreceptor kinases, has recently been shown to mediate cell motility in signaling pathways that become activated upon integrin-mediated cell adhesion (Chen, R., Kim, O., Li, M.

Bmx tyrosine kinase has a redundant function downstream of angiopoietin and vascular endothelial growth factor receptors in arterial endothelium.

The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with the lacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype.

The Bmx tyrosine kinase is activated by IL-3 and G-CSF in a PI-3K dependent manner.

Cytoplasmic protein tyrosine kinases play crucial roles in signaling via a variety of cell surface receptors. The Bmx tyrosine kinase, a member of the Tec family, is expressed in hematopoietic cells of the granulocytic and monocytic lineages. Here we show that Bmx is catalytically activated by interleukin-3 (IL-3) and granulocyte-colony stimulating factor (G-CSF) receptors.

The Bmx tyrosine kinase induces activation of the Stat signaling pathway, which is specifically inhibited by protein kinase Cdelta.

Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway.

Bmx tyrosine kinase is specifically expressed in the endocardium and the endothelium of large arteries.

Background: The growth and differentiation of endothelial cells are regulated by signal transduction through tyrosine protein kinases. Recently, a novel cytoplasmic tyrosine kinase gene, Bmx (Bone Marrow tyrosine kinase gene in chromosome X), was identified in human bone marrow RNA and found to be expressed predominantly in myeloid hematopoietic cell lineages. Our preliminary analyses indicated that the Bmx gene was also highly expressed in human heart.