Genetic Confounding of the Association Between Age at First Hormonal Contraception and Depression.

Background: Previous research has shown that females who use hormonal contraception are at increased risk of developing depression, and that the risk is highest among adolescents. While this finding could reflect age-specific effects of exogenous hormones on mental health, genetic liability for mental disorders could be confounding the association. Our goal was to test the plausibility of this hypothesis by determining whether polygenic liabilities for major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), and attention deficit hyperactivity disorder (ADHD) are associated with younger age at hormonal contraception initiation.

DNA methylation-based analysis reveals accelerated epigenetic aging in giant cell-enriched adult-type glioblastoma.

Background: Giant cell (gc)-enriched glioblastoma (gcGB) represents a distinct histological variant of isocitrate dehydrogenase wild-type adult-type glioblastoma with notable enlarged mono- or multinuclear tumor cells. While some studies suggest a survival advantage for gcGB patients, the underlying causes remain elusive. GcGBs are associated with TP53 mutations, and gcs were shown to accumulate DNA double-strand breaks and show deficient mitosis, potentially triggering cellular senescence programs.

Null method to estimate the maximal PA at subsaturating concentrations of agonist.

The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations.

An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.

Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose.

Pathological tissue changes in brain tumors affect the pH-sensitivity of the T1-corrected apparent exchange dependent relaxation (AREX) of the amide protons.

Measuring the intracellular pH (pHi) is of interest for brain tumor diagnostics. Common metrics of CEST imaging like the amide proton transfer-weighted (APTw) MTR are pHi sensitive and allow differentiating malignant tumor from healthy tissue. Yet, the image contrast also depends on additional magnetization transfer effects and T1.

Quantitative assessment of residual tumor is a strong and independent predictor of survival in methylated glioblastoma following radiochemotherapy with CCNU/TMZ.

Background: Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The RANO resect group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol.

Inhibitory Actions of Potentiating Neuroactive Steroids in the Human α1β3γ2L γ-Aminobutyric Acid Type A Receptor.

The γ-aminobutyric acid type A (GABA) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3-hydroxy steroids inhibit, while 3-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the 13γ2L GABA receptor by the endogenous neurosteroid 3-hydroxy-5-pregnan-20-one (35P) and the synthetic neuroactive steroid 3-hydroxy-5-androstane-17-carbonitrile (ACN).

Amino acid metabolism in glioma: in vivo MR-spectroscopic detection of alanine as a potential biomarker of poor survival in glioma patients.

Purpose: Reprogramming of amino acid metabolism is relevant for initiating and fueling tumor formation and growth. Therefore, there has been growing interest in anticancer therapies targeting amino acid metabolism. While developing personalized therapeutic approaches to glioma, in vivo proton magnetic resonance spectroscopy (MRS) is a valuable tool for non-invasive monitoring of tumor metabolism.

Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1.

In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells.

Cyclohexanediamine Triazole (CHDT) Functionalization Enables Labeling of Target Molecules with AlF/Ga/In.

The AlF-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of , which allows AlF-labeling already at ambient temperature. While the suitability of for functionalization and radiofluorination of proteins is well established, its use for small molecules or peptides is less explored.

Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis.

Background: Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood.

2D H sLASER Long-TE and 3D P Chemical Shift Imaging at 3 T for Monitoring Fasting-Induced Changes in Brain Tumor Tissue.

Background: Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation.

Purpose: To design a multi-voxel H/P MR-spectroscopic imaging (MRSI) protocol for noninvasive metabolic monitoring of cerebral, fasting-induced changes on an individual patient/tumor level, and to assess its technical reliability/reproducibility.

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1.

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs).

Status epilepticus in patients with brain tumors and metastases: A multicenter cohort study of 208 patients and literature review.

Objective: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population.

Methods: This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017.

Intrathecal IgM synthesis as a diagnostic marker in patients with suspected CNS lymphoma.

For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL).

Mammalian target of rapamycin inhibition protects glioma cells from temozolomide-induced cell death.

Glioblastoma is an incurable brain tumor with a median survival below two years. Trials investigating targeted therapy with inhibitors of the kinase mTOR have produced ambiguous results. Especially combination of mTOR inhibition with standard temozolomide radiochemotherapy has resulted in reduced survival in a phase II clinical trial.

Treatment of very elderly glioblastoma patients ≥ 75 years of age: whom to treat.

Purpose: The prognosis of patients ≥ 75 years suffering from glioblastoma is poor. Novel therapies are usually reserved for patients ≤ 70 years. In an aging population, treatment of very elderly patients remains a challenge.

Gliomatosis cerebri (GC) growth pattern: A single-center analysis of clinical, histological, and molecular characteristics of GC and non-GC glioblastoma.

Background: The biological understanding of glioblastoma (GB) with gliomatosis cerebri (GC) pattern is poor due to the absence of GC-specific studies. Here, we aimed to identify molecular or clinical parameters that drive GC growth.

Methods: From our methylome database of IDH (isocitrate dehydrogenase)-wildtype GB, we identified 158 non-GC and 65 GC cases.

The proneural subtype is not associated with survival benefit from bevacizumab in newly diagnosed glioblastoma: a secondary analysis of the GLARIUS trial.

Purpose: The AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort.

Methods: We evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models.

Potentiation of the GABAR reveals variable energetic contributions by etiocholanolone and propofol.

The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor channels takes place in the context of particular models to extract parameters for functional effects. In the often-used coagonist model, the agonist generating control activity and the potentiator enhancing the control activity make additive energetic contributions to stabilize the active state of the receptor.