Biology subjects

Neuhaus, R.

Publications and source records attributed to Neuhaus, R..

7 recordsLinked to original sources

bioRxiv2025

Focal adhesion pathway inhibition is the central axis of macrophage phenotypic responses to monoclonal antibody therapy in aggressive lymphoma via high-throughput screening and high-content imaging

High-grade B-cell lymphoma (HGBCL) frequently arises as a refractory or relapsed state of diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes due to multi-drug resistance and hallmark oncogenic translocations. To identify novel therapeutic strategies, we developed a dual high-throughput screening (HTS) and high-content imaging (HCI) macrophage-tumour co-culture platform that quantifies antibody-dependent and antibody-independent cellular phagocytosis (ADCP/AICP) across a 1,241-compound library. Using GFP+ HGBCL cells and mCherry+ macrophages, we validated our methodology through time-resolved phenotypic profiling, Euclidean distance-based analysis, and hit compound prioritisation. Pathway interrogation revealed focal adhesion as a central hub of macrophage phenotypic modulation, highlighting focal adhesion kinase (FAK/PTK2) as a candidate therapeutic target. Pharmacological inhibition with PF-562271 enhanced phagocytic activity, altered macrophage morphology, and synergised with anti-CD20 monoclonal antibodies in vitro and ex vivo. In vivo, Rituximab plus PF-562271 significantly reduced lymphoma burden and prolonged survival in xenograft models. Collectively, our work demonstrates that HTS/HCI-driven phenotypic profiling of tumour-associated macrophages can uncover actionable therapeutic combinations and nominates FAK inhibition as a promising strategy to potentiate antibody immunotherapy in HGBCL.

cell biology↗

bioRxiv2025

A lipidomic exploration of the effects of high-intensity interval exercise in healthy men after metformin intake

We have previously found that high-intensity interval exercise (HIIE) affected metformin pharmacokinetics, causing higher maximal plasma concentration compared with rest. In this scenario, changes in individual lipids could play an important role. The prolonged responses of the lipidome to HIIE have not been explored. Thus, this study aimed to explore differences in the plasma lipidomic profiles between HIIE and rest, both under metformin treatment. Nine healthy males participated in two sessions where they received 1,000 mg of metformin. In session A, they performed HIIE at an average intensity of 67% of maximum heart rate for a total duration of 76 min, whereas in session B they rested. Plasma was collected before taking metformin and during each session (in total 14 time points spanning 12 h). Samples were analysed through lipidomics using mass spectrometry. Paired Wilcoxon tests between sessions were applied for statistics. We found several variations in the lipid profiles due to HIIE, which persisted until 4 h post-exercise. The main discriminant lipid classes were fatty acids, acyl carnitines, glycerophosphocholins, sphingomyelins, and triglycerides. These changes were followed in time up to 12 h, showing the effect of the meals taken during the session. We hypothesize the changes are a synergic effect of HIIE and metformin in the lipidome with the effect of HIIE being the predominant. These findings provide important insights into the dynamic and complex physiological response of humans to intensive exercise under metformin intake.

systems biology↗

bioRxiv2020

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

Chemoimmunotherapy (CIT) is the standard of care in B-cell malignancies. It is relying on synergistic effects of alkylating chemotherapy and monoclonal antibodies via secretory crosstalk with effector macrophages. Here, we observed that loss of p53 function mediates resistance to CIT by suppressing macrophage phagocytic function. Loss of p53 leads to an upregulation of PDL1 and an increased formation of extracellular vesicles (EVs). EVs directly inhibit macrophage phagocytosis by PDL1 surface expression. Suppression of phagocytic function by lymphoma cell-derived EVs could be abrogated by pre-incubation of EVs with anti-PDL1 antibodies, CRISPR-KO of PDL1 and abrogation of EV formation by RAB27A-KO in lymphoma cells. Immune checkpoint inhibition represents a viable strategy to overcome EV-mediated resistance to chemoimmunotherapy in lymphoma. SignificanceLoss of TP53 mediates cell autonomous resistance to genotoxic chemotherapy, moreover non-cell autonomous effects may cause therapy resistance mediated by the tumor microenvironment. We identify a TP53-dependent mechanism that mediates resistance to synergistic chemoimmunotherapy by increasing formation of EVs and expression of the PDL1 immune checkpoint. PDL1 on EVs is directly responsible for macrophage suppression, preventing the exertion of the essential effector function of antibody-dependent cellular phagocytosis. This novel mechanism of resistance is in turn targetable by PDL1 checkpoint inhibition. Enhanced EV-release and immune checkpoint expression in lymphoma are novel mechanisms of macrophage modulation in the lymphoma microenvironment. We provide a novel principle of resistance to chemoimmunotherapy (CIT) representing of immediate relevance to treatment of refractory B-cell lymphoma. HighlightsO_LILoss of TP53 in B-cell lymphoma induces resistance towards chemoimmunotherapy (CIT) by inhibition of macrophage effector function through PDL1 upregulation C_LIO_LILoss of TP53 increases formation of extracellular vesicles (EVs) carrying PDL1 C_LIO_LIEVs inhibit antibody-mediated cellular phagocytosis (ADCP), a key macrophage effector function in CIT C_LIO_LITargeting PDL1 on EVs with immune checkpoint inhibitors overcomes TP53-mediated resistance to CIT C_LI

cell biology↗

bioRxiv2020

ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation

Genotoxin-based cancer therapies trigger a DNA damage response (DDR) to eliminate cancer cells but similarly exert profound alterations to the immune cell compartment. Macrophages in the tumor microenvironment are important and multifaceted components in actively sustaining tumor progression but also in clearance of tumor cells and play an important role in the outcome of chemotherapy. Here, we report that post neo-adjuvant chemotherapy macrophages in tumor samples display elevated expression of the immune checkpoint PD-L1. We determined that chemotherapy or direct application of DNA damage to macrophages in vitro triggers a specific MDDR polarization phenotype characterized by increased phagocytic activity, elevated PD-L1 expression, and induction of endotoxin tolerance. Phospho-proteomics analysis revealed epigenetic alterations and ATM-dependent induction of senescence in macrophages upon DNA damage. We propose that ATM-induced senescence and PD-L1 immune checkpoint induction mediate a specific MDDR macrophage polarization that might contribute to chemotherapy responses. Furthermore, our results clarify the functional role of tumor associated macrophages in the context of DNA damage and combination therapies including checkpoint inhibition.

immunology↗

bioRxiv2019

Associations between Processing Speed and Psychopathology in a Transdiagnostic, Pediatric Sample

ObjectiveThe present study sought to examine the relationships between processing speed (PS), mental health disorders, and learning disorders. Prior work has tended to explore relationships between PS deficits and individual diagnoses (i.e., anxiety, autism, ADHD, depressive) in isolation of one another, often relying on relatively modest sample sizes. In contrast, the present work simultaneously investigated associations between PS deficits and these diagnoses, along with specific learning disabilities (i.e., reading, math), in a large-scale, transdiagnostic, community self-referred sample.\n\nMethodA total of 843 children, ages 8-16 were included from the Healthy Brain Network (HBN) Biobank. Given the presence of four PS tasks in HBN, principal component analysis (PCA) was employed to create a composite measure that represented the shared variance of the four PS tasks, referred to as PC1. Intraclass correlation coefficient (ICC) between the four PS measures, as well as PC1, were calculated to assess reliability. We then used multiple linear regression models to assess specific relationships between PS deficits and psychiatric diagnoses.\n\nResultsICCs were moderate between WISC-V tasks (0.663), and relatively modest between NIH Toolbox Pattern Comparison and other PS scales (0.14-0.27). Regression analyses revealed specific significant relationships between PS and reading and math disabilities, ADHD-inattentive type (ADHD-I), and ADHD-combined type (ADHD-C). Secondary analyses accounting for inattention dimensionally diminished associations with ADHD-C, but not ADHD-I or specific learning disability subtypes. The present study did not find a significant relationship with Autism Spectrum Disorder after accounting for inattentive symptoms. Consistent with prior work, demographic variables, including sex, socioeconomic status, and motor control exhibited independent relationships with PC1 as well.\n\nDiscussionThis study provided a comprehensive examination of PS, mental health disorders, and learning disabilities through a transdiagnostic approach. Implications for understanding how PS interacts with a highly heterogeneous childhood sample, as well as the need for increased focus on detection of affected populations are discussed.

developmental biology↗

bioRxiv2018

Targeting a Therapy-Resistant Cancer Cell State Using Masked Electrophiles as GPX4 Inhibitors

We recently discovered that inhibition of the lipid peroxidase GPX4 can selectively kill cancer cells in a therapy-resistant state through induction of ferroptosis. Although GPX4 lacks a conventional druggable pocket, covalent small-molecule inhibitors are able to overcome this challenge by reacting with the GPX4 catalytic selenocysteine residue to eliminate enzymatic activity. Unfortunately, all currently-reported GPX4 inhibitors achieve their activity through reactive chloroacetamide groups. We demonstrate that such chloroacetamide-containing compounds are poor starting points for further advancement given their promiscuity, instability, and low bioavailability. Development of improved GPX4 inhibitors, including those with therapeutic potential, requires the identification of new electrophilic chemotypes and mechanisms of action that do not suffer these shortcomings. Here, we report our discovery that nitrile oxide electrophiles, and a set of remarkable chemical transformations that generates them in cells from masked precursors, provide an effective strategy for selective targeting of GPX4. Our results, which include structural insights, target engagement assays, and diverse GPX4-inhibitor tool compounds, provide critical insights that may galvanize development of improved compounds that illuminate the basic biology of GPX4 and therapeutic potential of ferroptosis induction. In addition, our discovery that nitrile oxide electrophiles engage in highly selective cellular interactions and are bioavailable in their masked forms may be relevant for targeting other currently undruggable proteins, such as those revealed by recent proteome-wide ligandability studies.

biochemistry↗

bioRxiv2017

The Healthy Brain Network Biobank: An open resource for transdiagnostic research in pediatric mental health and learning disorders

Technological and methodological innovations are equipping researchers with unprecedented capabilities for detecting and characterizing pathologic processes in the developing human brain. As a result, ambitions to achieve clinically useful tools to assist in the diagnosis and management of mental health and learning disorders are gaining momentum. To this end, it is critical to accrue large-scale multimodal datasets that capture a broad range of commonly encountered clinical psychopathology. The Child Mind Institute has launched the Healthy Brain Network (HBN), an ongoing initiative focused on creating and sharing a biobank of data from 10,000 New York area participants (ages 5-21). The HBN Biobank houses data about psychiatric, behavioral, cognitive, and lifestyle phenotypes, as well as multimodal brain imaging (resting and naturalistic viewing fMRI, diffusion MRI, morphometric MRI), electroencephalography, eye-tracking, voice and video recordings, genetics, and actigraphy. Here, we present the rationale, design and implementation of HBN protocols. We describe the first data release (n = 664) and the potential of the biobank to advance related areas (e.g., biophysical modeling, voice analysis).

neuroscience↗