Untersuchung des Verhaltens zirkulierender epithelialer Tumorzellen und ihrer Her2-Amplifikation bei Mammakarzinompatientinnen unter Trastuzumabtherapie in der adjuvanten Situation und nach Rezidiv

Bei 79 Mammakarzinompatientinnen wurde die CETC-Zahl mehrfach bestimmt und bei 48 dieser Patientinnen zusätzlich die Her2-Amplifikation in den CETC meist mehrfach erhoben. Die CETC-Quantifizierung erfolgte immunfluorometrisch mit dem Laser Scanning Cytometer. Lagen ausreichend viele CETC vor, erfolgte eine Her2-Analyse mittels Fluoreszenz-in-situ-Hybridisierung (FISH). Steigende Zellzahlen sind gegenüber stabilen eindeutig assoziiert mit einem verkürzten Gesamtüberleben bei Rezidivtherapie. Bisher vernachlässigte man zudem den Einfluss des Verabreichungsmodus von Trastuzumab auf dessen Wirksamkeit. Diese Studie zeigt deutlich, dass sich die gleichzeitige adjuvante Chemo- und Trastuzumabtherapie im Vergleich zur sequentiellen Therapie nachteilig auf das krankheitsfreie Überleben und die Rezidivhäufigkeit auswirkt. Die Etablierung der FISH an CETC gelang sicher. Die entdeckten CETC-Amplifikationssubgruppen besitzen ein unterschiedliches Verhalten unter Therapie. Die Ergebnisse sprechen für die Möglichkeit einer wechselseitigen Inhibierung von Chemotherapeutika und Trastuzumab. Die Schwankungen der hochamplifizierten Zellen korrelieren mit steigenden Zellzahlen und einer schlechteren Prognose. Diese Zellpopulation mit vermutlich erhöhter Proliferationsaktivität ist somit auch für die Überwachung der Trastuzumabwirkung und einer Resistenzentwicklung interessant. Dominanz der niedrig- und mittelgradig amplifizierten CETC bedeutet ein signifikant verkürztes krankheitsfreies Überleben. Alarmierend ist das regelhafte Auftreten amplifizierter Zellen bei primär Her2-negativen Patientinnen. Die in dieser Arbeit präsentierten Ergebnisse sprechen für die Einführung einer regelmäßigen Reevaluation des Her2-Status im Krankheitsverlauf, um die Fraktion Her2-positiver Zellen zu beobachten, die Wirksamkeit der Trastuzumabtherapie individuell und aktuell einzuschätzen und einer auf Anstieg oder Änderung der Zellpopulationen beruhenden Tumorprogression zeitig therapeutisch zu begegnen

Long-term changes of parvalbumin- and somatostatin-positive interneurons of the primary motor cortex after chronic social defeat stress depend on individual stress-vulnerability

Chronic stress is a major risk factor for developing mental illnesses and cognitive deficiencies although stress-susceptibility varies individually. In a recent study, we established the connection between chronic social defeat stress (CSDS) and impaired motor learning abilities accompanied by chronically disturbed structural neuroplasticity in the primary motor cortex (M1) of mice. In this study, we further investigated the long-term effects of CSDS exposure on M1, focusing on the interneuronal cell population. We used repeated CSDS to elicit effects across behavioral, endocrinological, and metabolic parameters in mice. Susceptible and resilient phenotypes were discriminated by symptom load and motor learning abilities were assessed on the rotarod. Structural changes in interneuronal circuits of M1 were studied by immunohistochemistry using parvalbumin (PV+) and somatostatin (SST+) markers. Stress-susceptible mice had a blunted stress hormone response and impaired motor learning skills. These mice presented reduced numbers of both interneuron populations in M1 with layer-dependent distribution, while alterations in cell size and immunoreactivity were found in both susceptible and resilient individuals. These results, together with our previous data, suggest that stress-induced cell loss and degeneration of the GABAergic interneuronal network of M1 could underlay impaired motor learning, due to their role in controlling the excitatory output and spine dynamics of principal neurons required for this task. Our study further highlights the importance of long-term outcomes of chronically stressed individuals which are translationally important due to the long timecourses of stress-induced neuropsychiatric disorders

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation

Glia: A Neglected Player in Noninvasive Direct Current Brain Stimulation

Noninvasive electrical brain stimulation by application of direct current (DCS) promotes plasticity in neuronal networks in vitro and in in vivo. This effect has been mainly attributed to the direct modulation of neurons. Glia represents approximately 50% of cells in the brain. Glial cells are electrically active and participate in synaptic plasticity. Despite of that, effects of DCS on glial structures and on interaction with neurons are only sparsely investigated. In this perspectives article we review the current literature, present own dose response data and provide a framework for future research from two points of view: first, the direct effects of DCS on glia and second, the contribution of glia to DCS related neuronal plasticity

Safety of ipsilesional anodal transcranial direct current stimulation in acute photothrombotic stroke: implications for early neurorehabilitation

Abstract Early rehabilitation in the acute phase of stroke, that bears unique neuroplastic properties, is the current standard to reduce disability. Anodal transcranial direct current stimulation can augment neurorehabilitation in chronic stroke. Studies in the acute phase are sparse and held back by inconclusive preclinical data pointing towards potential negative interaction of the excitability increasing tDCS modality with stroke-induced glutamate toxicity. In this present study, we aimed to evaluate structural and behavioral safety of anodal tDCS applied in the acute phase of stroke. Photothrombotic stroke including the right primary motor cortex was induced in rats. 24 h after stroke anodal tDCS was applied for 20 min ipsilesionally at one of four different current densities in freely moving animals. Effects on the infarct volume and on stroke induced neuroinflammation were assessed. Behavioral consequences were monitored. Infarct volume and the modified Neurological Severity Score were not affected by anodal tDCS. Pasta handling, a more sensitive task for sensorimotor deficits, and microglia reactivity indicated potentially harmful effects at the highest tDCS current density tested (47.8 A/m2), which is more than 60 times higher than intensities commonly used in humans. Compared to published safety limits of anodal tDCS in healthy rats, recent stroke does not increase the sensitivity of the brain to anodal tDCS, as assessed by lesion size and neuroinflammatory response. Behavioral deficits only occurred at the highest intensity, which was associated with increased neuroinflammation. When safety limits of commonly used clinical tDCS are met, augmentation of early neurorehabilitation after stroke by anodal tDCS appears to be feasible