Modification of Gas6 Protein in the Brain by a Functional Endogenous Tissue Vitamin K Cycle.

The TAM receptor ligand Gas6 is known for regulating inflammatory and immune pathways in various organs including the brain. Gas6 becomes fully functional through the post-translational modification of multiple glutamic acid residues into γ-carboxyglutamic in a vitamin K-dependent manner. However, the significance of this mechanism in the brain is not known.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk.

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker.

Interaction between peripheral and central immune markers in clinical high risk for psychosis.

Neuroinflammatory events prior to the diagnosis of schizophrenia may play a role in transition to illness. To date only one study has investigated this association between peripheral proinflammatory cytokines and brain markers of inflammation (e.g.

Modifiable risk factors of dementia linked to excitation-inhibition imbalance.

Recent evidence identifies 12 potentially modifiable risk factors for dementia to which 40% of dementia cases are attributed. While the recognition of these risk factors has paved the way for the development of new prevention measures, the link between these risk factors and the underlying pathophysiology of dementia is yet not well understood. A growing number of recent clinical and preclinical studies support a role of Excitation-Inhibition (E-I) imbalance in the pathophysiology of dementia.

Association of mental disorders and psychotropic medications with bone texture as measured with trabecular bone score.

Introduction: Mental disorders and psychotropic medications are known to increase the risk of osteoporosis and fractures. However, current evidence is mostly limited to studies that used bone mineral density (BMD), which does not provide information about the texture of bone tissue and can underestimate fracture risk.

Methods: We tested the association between bone texture, as measured with lumbar spine trabecular bone score (TBS), and both diagnosed mental disorders and psychotropic medication use in a large population-based BMD registry from Manitoba, Canada.

The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling.

The homologous proteins Gas6 and protein S (ProS1) are both natural ligands for the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases. ProS1 selectively activates Tyro3; however, the precise molecular interface of the ProS1-Tyro3 contact has not been characterised. We used a set of chimeric proteins in which each of the -terminal laminin G-like (LG) domains of ProS1 were swapped with those of Gas6, as well as a set of ProS1 mutants with novel added glycosylations within LG1.

Gas6/TAM Signalling Negatively Regulates Inflammatory Induction of GM-CSF in Mouse Brain Microglia.

Microglia and astrocytes are the main CNS glial cells responsible for the neuroinflammatory response, where they release a plethora of cytokines into the CNS inflammatory milieu. The TAM (Tyro3, Axl, Mer) receptors and their main ligand Gas6 are regulators of this response, however, the underlying mechanisms remain to be determined. We investigated the ability of Gas6 to modulate the CNS glial inflammatory response to lipopolysaccharide (LPS), a strong pro-inflammatory agent, through a qPCR array that explored Toll-like receptor signalling pathway-associated genes in primary cultured mouse microglia.

Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity.

The approval of immune checkpoint inhibitors has expanded treatment options for renal cell carcinoma (RCC), but new therapies that target RCC stemness and promote anti-tumor immunity are needed. Previous findings demonstrate that doublecortin-like kinase 1 (DCLK1) regulates stemness and is associated with RCC disease progression. Herein, we demonstrate that small-molecule kinase inhibitor DCLK1-IN-1 strongly inhibits DCLK1 phosphorylation and downregulates pluripotency factors and cancer stem cell (CSC) or epithelial-mesenchymal transition (EMT)-associated markers including c-MET, c-MYC, and N-Cadherin in RCC cell lines.

Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer.

Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously considered relevant only in 0.05 to 0.5% of kidney cancers associated with germline SDH mutations.

The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

Background: Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied.

Methods: We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models.

Identification of signalling pathways activated by Tyro3 that promote cell survival, proliferation and invasiveness in human cancer cells.

Tyro3 is a member of the TAM subfamily of receptor tyrosine kinases alongside Axl and MerTK, which are activated by homologous ligands Gas6 and protein S. The TAMs activate signalling pathways that mediate diverse functions including cell survival, proliferation, phagocytosis and immune regulation, and defects in TAM-dependent processes are associated with the development of human autoimmune diseases and numerous cancers. In this study, we have focused on the signalling and functional roles of Tyro3, about which much remains unknown.

Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology.

Background: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology.

Methods: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan.

The Effect of Jazar Supplement on Quality of Life and Sexual Function in Postmenopausal Women: A Double-Blind, Randomized, Placebo-Controlled Trial.

Background: Menopause is one of the most critical stages of a woman's life and is accompanied by symptoms including hot flashes, night sweats, mood swings, sexual dysfunction, mucus atrophy, and vaginal dryness. Women tend to use complementary and alternative medicine such as herbs rather than hormone replacement therapy to alleviate these symptoms. The purpose of this study is to examine the effects of Jazar supplement (herbal supplement comprising Vitex, fennel, and carrot seeds) on sexual function, quality of life, and vaginal atrophy in postmenopausal women.

Gas6 Inhibits Toll-Like Receptor-Mediated Inflammatory Pathways in Mouse Microglia Axl and Mer.

: Microglia are well known key regulators of neuroinflammation which feature in multiple neurodegenerative disorders. These cells survey the CNS and, under inflammatory conditions, become "activated" through stimulation of toll-like receptors (TLRs), resulting in changes in morphology and production and release of cytokines. In the present study, we examined the roles of the related TAM receptors, Mer and Axl, and of their ligand, Gas6, in the regulation of microglial pro-inflammatory TNF-α production and microglial morphology.

CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown.

Immune evasion in renal cell carcinoma: biology, clinical translation, future directions.

Targeted therapies and immune checkpoint inhibitors have advanced the treatment landscape of Renal Cell Carcinoma (RCC) over the last decade. While checkpoint inhibitors have demonstrated survival benefit and are currently approved in the front-line and second-line settings, primary and secondary resistance is common. A comprehensive understanding of the mechanisms of immune evasion in RCC is therefore critical to the development of effective combination treatment strategies.

Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia.

The Gas6-TAM (Tyro3, Axl, Mer) ligand-receptor system is believed to promote central nervous system (CNS) (re)myelination and glial cell development. An additional important function of Gas6-TAM signalling appears to be the regulation of immunity and inflammation, which remains to be fully elucidated in the CNS. Here, we characterised the expression of TAM receptors and ligands in individual CNS glial cell types, observing high expression of Gas6 and the TAM receptors, Mer and Axl, in microglia, and high expression of Tyro3 in astrocytes.

Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells.

The TAM (Tyro3, Axl, MerTK) subfamily of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and protein S (ProS1), are implicated in tumorigenesis and chemoresistance in various cancers. The β-galactoside binding protein galectin-3 (Gal-3), which is also implicated in oncogenesis, has previously been shown to be a ligand for MerTK. However, the selectivity of Gal-3 for the other TAM receptors, and its TAM-mediated signalling and functional properties in cancer cells, remain to be explored.

Refractory Unforeseen Anaphylaxis Case in a Rural OR Unit.

A 35-year-old female patient with no previously documented allergies who was admitted for elective gynaecological surgery, developed rapid onset, severe anaphylaxis, with dyspnea and cardiovascular collapse, in the operating theatre after receiving routine IV cefazolin prior to induction of anesthesia. She failed to improve with two doses of intramuscular epinephrine followed by two boluses of intravenous epinephrine, but responded to an epinephrine infusion. She was assessed by Internal Medicine and discharged home the following day.