Biology subjects

Fischer, H.

Publications and source records attributed to Fischer, H..

9 recordsLinked to original sources

bioRxiv2026

Profound CD4+ T-Cell Reprogramming by Melphalan-Driven Oxidative Stress in High-Risk Multiple Myeloma

T cell-based immunotherapies have become central to the treatment of multiple myeloma (MM), yet their efficacy depends on the functionality of endogenous T cells. How cumulative treatment exposure, particularly high-dose melphalan, together with disease-intrinsic high-risk features shapes T-cell composition and immune competence remains incompletely understood. Here, we analyzed T cell composition and function in bone marrow (BM) and peripheral blood (PB) samples from MM patients across different stages of their treatment journey using flow cytometry (BM, n=162; PB, n=1,733), single-cell RNA sequencing (n=19), and cytotoxicity assays (n=20). We reveal reduced overall T cell frequencies and CD4+/CD8+ T cell ratio, associated with lines of therapy and driven in part by depletion of naive CD4+ T cells in gene-expression defined high risk (HR) disease. Among therapeutic agents, melphalan exerted the strongest effects on T cell populations and induced pronounced redox stress in both T cells and myeloma cell lines. This oxidative stress signature was enriched in HR patients and was reversible with N-acetyl-L-cysteine treatment. Together, these findings identify immune dysregulation as a defining feature of HR MM that extends beyond tumor-intrinsic genomic alterations and is further shaped by treatment-induced remodeling of the BM microenvironment. Given the association between higher CD4+ T cell numbers and improved CAR-T cell outcomes, our data highlight the translational importance of treatment sequencing, particularly in HR MM. One Sentence SummaryMelphalan-induced redox stress depletes CD4+ naive T cells, particularly in patients with high-risk multiple myeloma.

Cancer Biology↗

bioRxiv2024

HDAC1 acts as tumor suppressor in ALK-positive anaplastic large-cell lymphoma: Implications for HDAC inhibitor therapy

Histone deacetylases (HDACs) play essential roles in T cell development, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. In this study, we investigated the effects of genetic or pharmacological HDAC inhibition on NPM-ALK positive anaplastic large cell lymphoma (ALCL) development to elucidate potential contraindications or indications for the use of HDACi for the treatment of this rare T-cell lymphoma. Short-term systemic pharmacological inhibition of HDACs using the class I-specific HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM-ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of highly homologous class I HDAC1 and HDAC2 enzymes were employed. In sharp contrast to the systemic inhibition, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM-ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. The accelerated lymphomagenesis primarily depended on the catalytic activity of HDAC1, as the expression of a catalytically inactive HDAC1 protein showed similar effects to the complete knockout. Our findings underscore the tumor-suppressive function of class I HDAC1 and HDAC2 in T cells during ALCL development, however systemic pharmacological inhibition of HDACs is still a valid treatment strategy, which could potentially improve current therapeutic outcomes.

cancer biology↗

bioRxiv2024

Altered empathy processing in frontotemporal dementiaA task-based fMRI study

A lack of empathy, and particularly its affective components, is a core symptom of behavioural variant frontotemporal dementia (bvFTD). Visual exposure to images of a needle pricking a hand (pain condition) and Q-tips touching a hand (control condition) is an established functional magnetic resonance imaging (fMRI) paradigm used to investigate empathy for pain (EFP; pain condition minus control condition). EFP has been associated with increased blood oxygen level dependent (BOLD) signal in regions known to become atrophic in the early stages in bvFTD, including the anterior insula and the anterior cingulate. We therefore hypothesized that patients with bvFTD would display altered empathy processing in the EFP paradigm. Here we examined empathy processing using the EFP paradigm in 28 patients with bvFTD and 28 sex and age matched controls. Participants underwent structural MRI, task-based and resting-state fMRI. The Interpersonal Reactivity Index (IRI) was used as a measure of different facets of empathic function outside the scanner. The EFP paradigm was analysed at a whole brain level and using two regions-of-interest approaches, one based on a metanalysis of affective perceptual empathy versus cognitive evaluative empathy and one based on the controls activation pattern. In controls, EFP was linked to an expected increase of BOLD signal that displayed an overlap with the pattern of atrophy in the bvFTD patients (insula and anterior cingulate). Additional regions with increased signal were the supramarginal gyrus and the occipital cortex. These latter regions were the only ones that displayed increased BOLD signal in bvFTD patients. BOLD signal increase under the affective perceptual empathy but not the cognitive evaluative empathy region of interest was significantly greater in controls than in bvFTD patients. The controls rating on their empathic concern subscale of the IRI was significantly correlated with the BOLD signal in the EFP paradigm, as were an informants ratings of the patients empathic concern subscale. This correlation was not observed on other subscales of the IRI or when using the patients self- ratings. Finally, controls and patients showed different connectivity patterns in empathy related networks during resting-state fMRI, mainly in nodes overlapping the ventral attention network. Our results indicate that reduced neural activity in regions typically affected by pathology in bvFTD is associated with reduced empathy processing, and a predictor of patients capacity to experience affective empathy.

neuroscience↗

bioRxiv2024

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice

BACKGROUNDImpairments in behavioral pattern separation (BPS)--the ability to distinguish between similar contexts or experiences--contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested. METHODSIn this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice. RESULTSChronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b. CONCLUSIONSThese studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

animal behavior and cognition↗

bioRxiv2022

Hypotrochoidal scaffolds for cartilage regeneration

The main function of articular cartilage is to provide a low friction surface and protect the underlying subchondral bone. The extracellular matrix composition of articular cartilage mainly consists of glycosaminoglycans and collagen type II. Specifically the collagen type II organization has a characteristic organization in three distinct zones; (1) the superficial zone which has collagen fibers oriented parallel to the surface, (2) the intermediate zone where there is no predominant orientation, and (3) the deep zone which shows a high orientation with fibers perpendicular to the underlying bone. Collagen type II fibers in these 3 zones take an arch-like organization that can be mimicked with segments of a hypotrochoidal curve. In this study, a script was developed that allowed the fabrication of scaffolds with a hypotrochoidal design. This design was investigated and compared to a regular 0-90 woodpile design. The results showed that the hypotrochoidal design was successfully fabricated. Micro-CT analyses divided the areas of the scaffold in their distinct zones. In addition, the mechanical analyses revealed that the hypotrochoidal design had a lower component Youngs modulus while the toughness and strain at yield were higher compared to the woodpile design. Fatigue tests showed that the hypotrochoidal design lost more energy per cycle due to the damping effect of the unique microarchitecture. Finite element analyses revealed that the hypotrochoidal design had an improved stress distribution compared to the 0-90 woodpile design due to the lower component stiffness. In addition, data from cell culture under dynamic stimulation demonstrated that the collagen type II deposition was improved in the hypotrochoidal design. Finally, Alcian blue staining revealed that the areas where the stress was higher during the stimulation produced more glycosaminoglycans. Our results highlight a new and simple scaffold design based on hypotrochoidal curves that could be used for cartilage tissue engineering.

bioengineering↗

bioRxiv2022

NRF2 activation induces NADH-reductive stress providing a metabolic vulnerability in lung cancer

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines--an effect that was completely rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.

molecular biology↗

bioRxiv2021

A Quantitative Data-Driven Analysis (QDA) Framework for Resting-state fMRI: a Study of the Impact of Adult Age

PurposeThe objective of this study is to introduce a new quantitative data-driven analysis (QDA) framework for the analysis of resting-state fMRI (R-fMRI) and use it to investigate the effect of adult age on resting-state functional connectivity (RFC). MethodsWhole-brain R-fMRI measurements were conducted on a 3T clinical MRI scanner in 227 healthy adult volunteers (N=227, aged 18-74 years old, male/female=99/128). With the proposed QDA framework we derived two types of voxel-wise RFC metrics: the connectivity strength index (CSI) and connectivity density index (CDI) utilizing the convolutions of the cross-correlation (CC) histogram with different kernels. Furthermore, we assessed the negative and positive portions of these metrics separately. ResultsWith the QDA framework we found age-related declines of RFC metrics in the superior and middle frontal gyrus (MFG), posterior cingulate cortex (PCC), right insula and inferior parietal lobule (IPL) of the default mode network (DMN), which resembles previously reported results using other types of RFC data processing methods. Importantly, our new findings complement previously undocumented results in the following aspects: 1) the PCC and right insula are anti-correlated and tend to manifest simultaneously declines of both the negative and positive connectivity strength with subjects age; 2) separate assessment of the negative and positive RFC metrics provides enhanced sensitivity to the aging effect; 3) the sensorimotor network depicts enhanced negative connectivity strength with the adult age. ConclusionThe proposed QDA framework can produce threshold-free, voxel-wise analysis of R-fMRI data the RFC metrics. The detected adult age effect is largely consistent with previously reported studies using different R-fMRI analysis approaches. Moreover, the separate assessment of the negative and positive contributions to the RFC metrics can enhance the RFC sensitivity and clarify some of the mixed results in the literature regarding to the DMN and sensorimotor network involvement in adult aging. HighlightsO_LIA quantitative data-driven analysis (QDA) framework was proposed to analysis resting-state fMRI data. C_LIO_LIThreshold-free resting-state functional connectivity (RFC) metrics were derived to assess brain changes with adult age. C_LIO_LISeparate assessment of the positive and negative correlations improve sensitivity of the RFC metrics. C_LIO_LIThe posterior cingulate and right insula cortices are anti-correlated and tend to manifest declines in both the negative and positive connectivity strength with adult age. C_LIO_LINegative connectivity strength enhances with adult age in sensorimotor network. C_LI

neuroscience↗

bioRxiv2018

Sleep restriction caused impaired emotional regulation without detectable brain activation changes - a functional magnetic resonance imaging study

Sleep restriction has been proposed to cause impaired emotional processing and emotional regulation by inhibiting top-down control from prefrontal cortex to amygdala. Intentional emotional regulation after sleep restriction has however never been studied using brain imaging. We here aimed to investigate the effect of sleep restriction on emotional regulation through cognitive reappraisal. Forty-seven young (age 20-30) and 33 older (age 65-75) participants (38/23 with complete data and successful sleep intervention) performed a cognitive reappraisal task during fMRI after a night of normal sleep and after restricted sleep (3h). Emotional downregulation was associated with significantly increased activity in dorsolateral prefrontal cortex (pFWE < 0.05) and lateral orbital cortex (pFWE < 0.05) in young, but not in older subjects. Sleep restriction was associated with a decrease in self-reported regulation success to negative stimuli (p < 0.01) and a trend towards perceiving all stimuli as less negative (p = 0.07), in young participants. No effects of sleep restriction on brain activity nor connectivity were found in either age group. In conclusion, our data do not support the idea of a prefrontal-amygdala disconnect after sleep restriction, and neural mechanisms underlying behavioural effects on emotional regulation after insufficient sleep require further investigation.

neuroscience↗

bioRxiv2018

Viewing pictures triggers rapid morphological enlargement in the human visual cortex

Brain morphology change over the course of weeks, days, and hours, and can be detected by non-invasive structural magnetic resonance imaging. Rapid morphological changes at scanning has yet not been investigated. In a randomized within-group study, high-resolution anatomical images were acquired during passive viewing of pictures or a fixation cross. Forty-seven individuals gray matter volume and cortical thickness were investigated, and both measures increased in the visual cortex while viewing pictures relative to a fixation cross. Thus, brain morphology enlargements were detected in less than 263 seconds. Neuroplasticity is a far more dynamic process than previously shown, suggesting that individuals current mental state affects indices of brain morphology. This needs to be taken into account in future morphology studies and in everyday clinical practice.

neuroscience↗