Tonabersat enhances temozolomide-mediated cytotoxicity in glioblastoma by disrupting intercellular connectivity through connexin 43 inhibition.

Glioblastoma cells rely on connexin 43 (Cx43)-based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood-brain-barrier-penetrating drug with GJ-inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks.

Individual differences in functional connectivity during suppression of imagined threat.

Functional magnetic resonance imaging studies typically rely on between-person analyses. To examine individual differences in functional connectivity, we used Group Iterative Multiple Model Estimation and its subgrouping function to analyze functional magnetic resonance imaging data of 54 participants who were suppressing imagined future threat. A two-stage random-effects meta-analytic approach was employed to examine individual differences.

[Prolonged weaning after long-term ventilation due to SARS-CoV-2 infection: a multicenter retrospective analysis].

Unlabelled: Some of the patients with SARS-CoV-2 infection (COVID-19) received invasive ventilation during inpatient care. Weaning from ventilation was difficult for some patients (so-called prolonged weaning).

Patients: Patients (n=751) with prolonged weaning (reason for ventilation "pneumonia" and "acute respiratory failure") from four centers for the period 2011-23 from the "WeanNet" registry were used as a matched group.

Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial homeostasis and increases antitumor activity against glioblastoma.

He, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis.

Suppressing PD-L1 Expression via AURKA Kinase Inhibition Enhances Natural Killer Cell-Mediated Cytotoxicity against Glioblastoma.

Immunotherapies have shown significant promise as an impactful strategy in cancer treatment. However, in glioblastoma multiforme (GBM), the most prevalent primary brain tumor in adults, these therapies have demonstrated lower efficacy than initially anticipated. Consequently, there is an urgent need for strategies to enhance the effectiveness of immune treatments.

Mindfulness as a therapeutic option for obsessive-compulsive disorder.

Introduction: Obsessive-compulsive disorder (OCD) is a prevalent mental health issue characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions) that can cause significant life impairment. Despite cognitive-behavioral therapy (CBT) being the most effective treatment, some individuals experience insufficient symptom reduction or relapse.

Areas Covered: This special report explores the potential of mindfulness-based interventions as complementary treatments for OCD, examining the specific techniques used and their practical application.

Novel Approaches Toward Studying Change: Implications for Understanding and Treating Psychopathology.

In this article, the authors critically evaluate contemporary models of psychopathology and therapies, underscoring the limitations of traditional symptom-based classification approaches in mental health. The authors introduce a paradigm shift in the field, toward a process-oriented and dynamic systems approach to psychotherapy that offers deeper insights into the complex interplay of symptoms and individual experiences in psychopathology. These approaches offer a more personalized and effective understanding and treatment of mental health issues, moving beyond static and 1-dimensional views.

BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac Ca1.

Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature.

Introduction: The causes of diaphragmatic paresis are manifold. An association between neuralgic amyotrophy (NA) and hepatitis E virus (HEV) infection has been reported. We wondered about the prevalence of diaphragmatic disfunction and hepatitis E infection in our clinic.

Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes.

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied.

Psychological flexibility and cognitive-affective processes in young adults' daily lives.

Psychological flexibility plays a crucial role in how young adults adapt to their evolving cognitive and emotional landscapes. Our study investigated a core aspect of psychological flexibility in young adults: adaptive variability and maladaptive rigidity in the capacity for behavior change. We examined the interplay of these elements with cognitive-affective processes within a dynamic network, uncovering their manifestation in everyday life.

[Curriculum "Tracheostomy management in dysphagia therapy"].

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation.

The Alcatraz-Strategy: a roadmap to break the connectivity barrier in malignant brain tumours.

In recent years, the discovery of functional and communicative cellular tumour networks has led to a new understanding of malignant primary brain tumours. In this review, the authors shed light on the diverse nature of cell-to-cell connections in brain tumours and propose an innovative treatment approach to address the detrimental connectivity of these networks. The proposed therapeutic outlook revolves around three main strategies: (a) supramarginal resection removing a substantial portion of the communicating tumour cell front far beyond the gadolinium-enhancing tumour mass, (b) morphological isolation at the single cell level disrupting structural cell-to-cell contacts facilitated by elongated cellular membrane protrusions known as tumour microtubes (TMs), and (c) functional isolation at the single cell level blocking TM-mediated intercellular cytosolic exchange and inhibiting neuronal excitatory input into the malignant network.

The Potential Role of the Extracellular Matrix Glycoprotein Reelin in Glioblastoma Biology.

Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a successful containment strategy can be found. Reelin, an extracellular matrix glycoprotein, plays an important role in neuronal migration and serves here as a natural stop signal.

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the α-ketoglutarate dehydrogenase (OGDH) gene, which encodes an enzyme that is part of the tricarboxylic acid (TCA) cycle, as essential for GBM growth. Moreover, by combining transcriptome and metabolite screening analyses, we discovered that loss of function of OGDH by the clinically validated drug compound CPI-613 was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3 mimetic, ABT263) in patient-derived xenografts as well neurosphere GBM cultures.

Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro.

Background: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide.

Drug safety in older patients with alcohol use disorder: a retrospective cohort study.

Background: Older patients with alcohol use disorder are at particular risk of developing adverse drug reactions due to multimorbidity, polypharmacy, and altered organ function.

Objectives: In this study, we investigated the frequency and characteristics of potentially serious alcohol-medication interactions, potentially inappropriate medications (PIMs) for older adults, and potential drug-drug interactions (pDDIs) in a population of older patients with alcohol use disorder over a 10-year period.

Design: Retrospective monocentric cohort study.

Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors.

The ion-conducting IKs channel complex, important in cardiac repolarization and arrhythmias, comprises tetramers of KCNQ1 α-subunits along with 1-4 KCNE1 accessory subunits and calmodulin regulatory molecules. The E160R mutation in individual KCNQ1 subunits was used to prevent activation of voltage sensors and allow direct determination of transition rate data from complexes opening with a fixed number of 1, 2, or 4 activatable voltage sensors. Markov models were used to test the suitability of sequential versus allosteric models of IKs activation by comparing simulations with experimental steady-state and transient activation kinetics, voltage-sensor fluorescence from channels with two or four activatable domains, and limiting slope currents at negative potentials.

[Curriculum "Tracheostomy management in dysphagia therapy"].

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation.

Inhibition of Survivin Homodimerization Decreases Neuroblastoma Cell Growth.

Increased expression of BIRC5/survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB), the most common extracranial tumor of childhood. Transcriptional inhibitors of survivin have been tested in adult cancers and inhibitors of survivin homodimerization are emerging. We compared genetic inhibition of survivin transcription with the inhibition of survivin homodimerization by S12 and LQZ-7I, chosen from a larger panel of survivin dimerization inhibitors with activity against NB cells.

[Non-invasive Mechanical Ventilation in Acute Respiratory Failure. Clinical Practice Guidelines - on behalf of the German Society of Pneumology and Ventilatory Medicine].

The guideline update outlines the advantages as well as the limitations of NIV in the treatment of acute respiratory failure in daily clinical practice and in different indications.Non-invasive ventilation (NIV) has a high value in therapy of hypercapnic acute respiratory failure, as it significantly reduces the length of ICU stay and hospitalization as well as mortality.Patients with cardiopulmonary edema and acute respiratory failure should be treated with continuous positive airway pressure (CPAP) and oxygen in addition to necessary cardiological interventions.

Alveolar gradients in breath analysis. A pilot study with comparison of room air and inhaled air by simultaneous measurements using ion mobility spectrometry.

Analyzing exhaled breath samples, especially using a highly sensitive method such as MCC/IMS (multi-capillary column/ion mobility spectrometry), may also detect analytes that are derived from exogenous production. In this regard, there is a discussion about the optimal interpretation of exhaled breath, either by considering volatile organic compounds (VOCs) only in exhaled breath or by additionally considering the composition of room air and calculating the alveolar gradients. However, there are no data on whether the composition and concentration of VOCs in room air are identical to those in truly inhaled air directly before analyzing the exhaled breath.