Biology subjects

Larsen, K.

Publications and source records attributed to Larsen, K..

5 recordsLinked to original sources

bioRxiv2026

Nephrotoxicity of Immune Checkpoint Inhibitors in Mice with a Human Immune System

IntroductionImmune checkpoint inhibitors (ICIs) enhance antitumor responses by blocking inhibitory receptors, including PD-1 and CTLA-4. Overactivation can trigger systemic toxicity akin to autoimmune diseases, including kidney manifestations. We sought to 1) profile immune signaling and 2) interrogate potential mechanisms of ICI-related kidney injury in a Human Immune System (HIS) tumor-bearing mouse model treated with nivolumab and ipilimumab. MethodsImmunodeficient BRGS (BALB/c-Rag2nullIl2r{gamma}nullSirpNOD) neonates were engrafted with human CD34+ cells to generate HIS-BRGS mice. Human MDA-MB-231 tumor cells were implanted subcutaneously; once tumors reached [~]150 mm3, mice received weekly intraperitoneal vehicle (PBS) or ICI (nivolumab 20 mg/kg + ipilimumab 10 mg/kg) for 4 weeks (Veh BRGS n=4; ICI BRGS n=6; Veh HIS-BRGS n=7; ICI HIS-BRGS n=7). Kidneys were evaluated by histopathology (H&E, TEM), flow cytometry for human immune phenotypes, multiplex ELISA (80 human proteins; 10 injury biomarkers), bulk RNA sequencing, and targeted qPCR. Pearson correlations identified predictors of histopathological injury. ResultsRenal vasculitis and interstitial nephritis were observed only in ICI-treated HIS-BRGS mice. These kidneys showed a shift toward CD4+ T-cell enrichment with an increased TNF- production capacity compared to CD8+ counterparts. Toxicity was accompanied by increased renal concentrations of human cytokines, chemokines, and soluble receptors. ICI treatment significantly elevated serine proteases (Granzyme A/B) and NGF-{beta}, while decreasing IL-4. Interstitial nephritis correlated with renal PD-1 and MIF. Renal vasculitis correlated with kidney PD-1, CCL1, MIF, Granzyme A, IL-15, and BAFF. Traditional injury biomarkers (KIM-1, NGAL) remained unchanged; however, a trending decrease in EGF was observed. ConclusionsOur study suggests that shifts in human T-cell populations and specific immune proteins could serve as promising biomarkers and mechanistic targets for ICI nephrotoxicity. The tumor-bearing HIS-BRGS mouse model reproducibly recapitulates the histopathological and immunological features of human ICI-induced nephrotoxicity and represents a validated preclinical platform for testing novel therapeutic interventions to preserve kidney function during cancer immunotherapy. Translational StatementImmune checkpoint inhibitor (ICI)-associated nephrotoxicity occurs in up to 25% of treated patients, yet the immunological mechanisms driving renal injury remain poorly characterized due to the scarcity of human biopsy material and the absence of robust preclinical models that recapitulate human immune responses. This study demonstrates that tumor-bearing humanized immune system (HIS) mice treated with combined nivolumab and ipilimumab reproducibly develop renal vasculitis and interstitial nephritis mediated by a human CD4+ T cell-dominant infiltrate, mirroring the clinicopathological features reported in patients with ICI-associated acute kidney injury. By integrating histopathology, flow cytometry, multiplex proteomics, and transcriptomics, we identify a coordinated immune network, including IL-15, CCL1, MIF, GZMA, and BAFF, that correlates with the severity of renal pathology and represents tractable mechanistic targets and candidate biomarkers. These findings provide a validated preclinical platform for dissecting irAE mechanisms and testing novel therapeutic strategies to preserve kidney function during cancer immunotherapy.

pharmacology and toxicology↗

bioRxiv2026

Psilocybin acutely reduces low-frequency BOLD power and frequency-specific connectivity

Psilocybin and other serotonergic drugs acutely alter human brain function and large-scale connectivity as measured with BOLD fMRI, but whether these effects are frequency-specific remains unknown. We applied multitaper spectral and cross-spectral analyses to resting-state fMRI data from 28 healthy volunteers scanned multiple times acutely following oral psilocybin administration (0.2 - 0.3 mg/kg), together with plasma psilocin measurements, to estimate psilocin associations with temporal frequency-specific activity and connectivity. Psilocybin produced a selective reduction in low-frequency spectral power (0.01 - 0.06Hz) and an increase in spectral entropy, with the strongest effects in transmodal networks. We also observed a reduction in low-frequency connectivity energy explained by the unimodal/transmodal axis. These findings demonstrate that psilocin induces spatially distributed, frequency-dependent alterations, suggesting that broadband fMRI analyses may obscure low-frequency dynamics. Frequency-resolved approaches may offer greater sensitivity for characterizing psychedelic effects on brain activity.

neuroscience↗

bioRxiv2025

Pitfalls of mapping functional and molecular human brain imaging data from separate cohorts

It has become increasingly common to probe correlations between human brain imaging measures of receptor/protein binding and function using population-level brain maps drawn from independent cohorts, estimating correlations across regions. This strategy raises issues of interpretation that we highlight here with a multimodal brain imaging dataset and simulation studies. Twenty-four healthy participants completed neuroimaging with both [11C]Cimbi-36 positron emission tomography and magnetic resonance imaging scans to estimate receptor binding potential (BP) and cerebral blood flow (CBF), respectively, in 18 cortical/subcortical regions. Correlations between BP and CBF were estimated in three ways: 1) Pearson correlation across regions of mean regional BP and CBF ({rho}l), to mimic studies using data from independent cohorts; 2) Pearson correlation between BP and CBF across participants in each region ({rho}2); or 3) the correlation between BP and CBF across participants across all regions within a single linear mixed effects model ({rho}3). We observed a significant positive correlation across regions ([Formula]l = 0.672; p = 0.0023). Region-specific correlations across participants were substantively lower and not statistically significant ([Formula]2: mean = 0.140, range = -0.112 to 0.336; all p > 0.10), nor when estimated simultaneously within a linear mixed model ([Formula]3 = 0.138, p = 0.26). Our simulation study illustrated that regional differences in BP or CBF mean and variance can bias across regions correlations by 1000% or create a type-1 error of 100%. Our observations that both the estimated correlation and the statistical significance can differ greatly highlights that inferring across region correlation as evidence for correlation across participants is erroneous. Without validated methods that limit confounding and other biases, we discourage future studies from inferring across region correlation of population-level brain maps from independent cohorts in this manner.

neuroscience↗

bioRxiv2020

Reef Cover: a coral reef classification for global habitat mapping from biophysical remote sensing.

Coral reef management and conservation stand to benefit from improved high-resolution global mapping. Yet classifications employed in large-scale reef mapping to date are typically poorly defined, not shared or region-specific. Here we present Reef Cover, a new coral reef geomorphic zone classification, developed to support global-scale coral reef habitat mapping in a transparent and version-based framework. We developed scalable classes by focusing on attributes that can be observed remotely, but whose membership rules also reflect knowledge of reef formation, growth and functioning. Bridging the divide between earth observation data and geo-ecological knowledge of reefs, Reef Cover maximises the trade-off between applicability at global scales, and relevance and accuracy at local scales. We use the Caroline and Mariana Island chains in the Pacific as a case study to demonstrate use of the classification scheme and its scientific and conservation applications. The primary application of Reef Cover is the Allen Coral Atlas global coral reef mapping project, but the system will support bespoke reef mapping conducted at a variety of spatial scales.

systems biology↗

bioRxiv2020

Scoping reviews in medical education: A scoping review

PurposeThe purpose of this study was to characterize the extent, range, and nature of scoping reviews published in core medical education journals. In so doing, the authors identify areas for improvement in the conduct and reporting of scoping reviews, and highlight opportunities for future research. MethodThe authors searched PubMed for scoping reviews published between 1999 through April 2020 in 14 medical education journals. From each review, the authors extracted and summarized key bibliometric data, the rationales given for conducting a scoping review, the research questions, and key reporting elements as described in the PRISMA-ScR reporting guidelines. Rationales and research questions were mapped to the reasons for conducting a scoping review, as described by Arksey and OMalley. ResultsOne hundred and one scoping reviews were included. On average 10.1 scoping reviews (MED=4, SD=13.08) were published annually with the most reviews published in 2019 (n=42) in 13 of the included 14 journals reviewed. Academic Medicine published the most scoping reviews (n=28) overall. Authors described multiple reasons for undertaking scoping reviews, including to: summarize and disseminate research findings (n=77); examine the extent, range, and nature of research activity in a given area (n=74); and to analyze an emerging topic or heterogenous literature base (n=46). In 11 reviews there was alignment between the rationales for the scoping review and the stated research questions. No review addressed all elements of the PRISMA-ScR, with only a minority of authors publishing a protocol (n=2) or including stakeholders (n=20). Authors identified several shortcomings of scoping review methodology, including being unable to critically assess the included studies. ConclusionsMedical educators are increasingly conducting scoping reviews with a desire to characterize the literature on a topic. There is room for improvement in the reporting of scoping reviews, including the alignment of research questions, the creation and publishing of protocols, and the inclusion of external stakeholders in published works.

scientific communication and education↗