Biology subjects

Barth, J.

Publications and source records attributed to Barth, J..

4 recordsLinked to original sources

bioRxiv2025

The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer

Nerves are an integral component of the tumor microenvironment, contributing to cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.

cancer biology↗

bioRxiv2023

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular immunity hubs defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11+ macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7+LAMP3+ dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.

immunology↗

bioRxiv2020

Development of a Coronavirus Disease 2019 Nonhuman Primate Model Using Airborne Exposure

Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comprehensive and comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to define parameters critical to disease progression and the extent to which they correlate with human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation. One Sentence SummaryNonhuman primates develop COVID-19 following airborne virus exposure.

microbiology↗

bioRxiv2019

Characterizing upper extremity motor behavior in the first week after stroke

BackgroundAnimal models of brain recovery identify the first days after lesioning as a time of great flux in sensorimotor function and physiology; these findings have implications for human stroke recovery. After rodent motor system lesioning, daily skill training in the less affected forelimb reduces skill acquisition in the more affected forelimb. We asked whether spontaneous human motor behaviors of the less affected upper extremity (UE) early after stroke resemble the animal training model, with the potential to suppress clinical recovery.\n\nMethodsThis prospective observational study used a convenience sample of patients <7 days after stroke (n=25) with a wide severity range; Controls were hospitalized for non-neurological conditions (n=12). Outcome measures were Accelerometry, Upper-Extremity Fugl-Meyer (UEFM), Action Research Arm Test (ARAT), Shoulder Abduction/ Finger Extension Test (SAFE), NIH Stroke Scale (NIHSS).\n\nResultsAccelerometry indicated total paretic UE movement was reduced compared to controls, primarily due to a 44% reduction of bilateral UE use. Unilateral paretic movement was unchanged. Movement shifted to unilateral use of the nonparetic UE, which increased by 77%. Low correlations between movement time and motor performance prompted an exploratory factor analysis (EFA) revealing a 2-component solution; motor performance tests load on one component (motor performance) whereas accelerometry-derived variables load on a second non-orthogonal component (quantity of movement).\n\nConclusionsEarly after stroke, spontaneous overall UE movement is reduced, and movement shifts to unilateral use of the nonparetic UE. Thus, spontaneously-arising UE motor behaviors early after stroke are potential substrates for two mechanisms associated with poorer motor outcomes in animal models: learned non-use and inhibition of motor recovery through training of the nonparetic side. Accurate UE motor assessment requires two independent constructs: motor performance and quantity of movement. These findings provide opportunities and measurement methods for studies to develop new behaviorally-based stroke recovery treatments that begin early after onset.

neuroscience↗