1. Abstract Poly Cystic Ovarian Syndrome (PCOS) is one of the most common metabolic and reproductive disorders among women of reproductive age. Women suffering from PCOS present with a constellation of symptoms associated with menstrual dysfunction and androgen excess, which significantly impacts their quality of life. They may be at increased risk of multiple morbidities, including obesity, insulin resistance, type II diabetes mellitus, cardiovascular disease, infertility, cancer, and psychological disorders. This review summarizes what the literature has so far provided from guidelines to diagnosis of PCOS. It will also present a general overview about the morbidities associated with this disease, specifically with its more severe classic form. Finally, the review will stress on the various aspects of treatment and screening recommendations currently used in the management of this condition.

Although the impact of Th17 cells on autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We discovered soluble N-ethylmaleimide–sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of β1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or K_V1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although K_V1.3 is not expressed in CNS tissue, intrathecal administration of a K_V1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that β1-integrin– and K_V1.3 channel–dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.

Communication signals and signaling pathways are often studied in different physiological systems. However, it has become abundantly clear that the immune system is not self-regulated, but functions in close association with the nervous system. The neural–immune interface is complex; its balance determines cancer progression, as well as autoimmune disorders. Immunotherapy remains a promising approach in the context of glioblastoma multiforme (GBM). The primary obstacle to finding effective therapies is the potent immunosuppression induced by GBM. Anti-inflammatory cytokines, induction of regulatory T cells, and the expression of immune checkpoint molecules are the key mediators for immunosuppression in the tumor microenvironment. Immune checkpoint molecules are ligand–receptor pairs that exert inhibitory or stimulatory effects on immune responses. In the past decade, they have been extensively studied in preclinical and clinical trials in diseases such as cancer or autoimmune diseases in which the immune system has failed to maintain homeostasis. In this review, we will discuss promising immune-modulatory targets that are in the focus of current clinical research in glioblastoma, but are also in the precarious position of potentially becoming starting points for the development of autoimmune diseases like multiple sclerosis.

Glioblastoma multiforme is the most common and devastating form of brain tumor for which only palliative radio- and chemotherapy exists. Although some clinical studies on vaccination approaches have shown promising efficacy due to their potential to generate long-term immune surveillance against cancer cells, the evasion mechanisms preventing therapy response are largely uncharacterized. Here, we studied the response of glioblastoma-propagating cells (GPCs) to clinically relevant doses of γ radiation. GPCs were treated with 2.5 Gy of γ radiation in seven consecutive cellular passages to select for GPCs with increased colony-forming properties and intrinsic or radiation-induced resistance (rsGPCs). Quantitative proteomic analysis of the cellular signaling platforms of the detergent-resistant membranes (lipid rafts) in GPCs vs. rsGPCs revealed a downregulation of the MHC class I antigen-processing and -presentation machinery. Importantly, the radio-selected GPCs showed reduced susceptibility towards cytotoxic CD8+ T-cell-mediated killing. While previous studies suggested that high-dose irradiation results in enhanced antigen presentation, we demonstrated that clinically relevant sub-lethal fractionated irradiation results in reduced expression of components of the MHC class I antigen-processing and -presentation pathway leading to immune escape.