Biology subjects

Neff, C.

Publications and source records attributed to Neff, C..

4 recordsLinked to original sources

bioRxiv2024

Multi-omics analysis in mouse primary cortical neurons reveals complex positive and negative biological interactions between constituent compounds in Centella asiatica

BackgroundA water extract of the Ayurvedic plant Centella asiatica (CAW) improves cognitive function in mouse models of aging and Alzheimers disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plants therapeutic benefit. MethodsMouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses respectively. ResultsExtensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicate the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8) and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA, and possible compound interactions at this level. ConclusionsFour gene expression modules and two metabolite modules were altered by the four types of treatments applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.

neuroscience↗

bioRxiv2023

Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic responses

Intracranial tumors present unique challenges for immunotherapy. These can include both local and systemic modes of immune suppression whose mechanistic underpinnings are incompletely understood. Here, we reveal that tumors harbored intracranially elicit systemic increases to circulating catecholamine levels, with the resultant chronic sympathetic hyperactivity driving T cell dysfunction and limiting immunotherapeutic success. Conversely, treatment with {beta}-adrenergic blockade increases NF-{kappa}B activity in immune cells, restores T cell polyfunctionality, modifies the tumor microenvironment, and licenses immune-based therapies in murine models of glioblastoma (GBM) to extend survival. Extended survival is also observed in GBM patients having received {beta}-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received {beta}-blockade alongside concomitant immune checkpoint inhibition. While {beta}-blockade also impacts outcomes in the setting of extracranial disease, the benefits are especially pronounced in patients harboring intracranial disease burdens. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors, specifically and advance a role for {beta}-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.

immunology↗

bioRxiv2022

SARS-CoV-2-specific T cells associate with reduced lung function and inflammation in pulmonary post-acute sequalae of SARS-CoV-2

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had up to 34-fold higher frequencies of IFN-{gamma}- and TNF--producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF--producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-{gamma}-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden. Author SummaryLong COVID-19 or post-acute sequelae of SARS-CoV-2 (PASC) impacts 20-30% of those infected with SARS-CoV-2 and is characterized by COVID-19 symptoms exceeding 4 weeks from symptom onset. While those with PASC experience a wide variety of persistent symptoms including shortness of breath, cough, chest pain, irregular heartbeat, brain fog, fatigue, and intermittent fever, lung-related conditions are the most common. Although, infection with SARS-CoV-2 is clearly the inciting factor for PASC, the mechanisms responsible for long-term lung dysfunction are unclear and current treatments are ineffective at resolving pulmonary symptoms. Generalized PASC has been associated with SARS-CoV-2-specific T cells, a component of adaptive immunity, suggesting that residual virus may persist. Here, we investigated the frequency and function of virus-specific T cells in the blood of individuals with pulmonary PASC and correlated their presence with systemic inflammation and lung function. Our findings demonstrated that T cells specific for SARS-CoV-2 are elevated in the blood of those with pulmonary PASC and are associated with increased IL-6, a cytokine strongly associated with COVID-19 severity, and decreased lung function. These findings provide mechanistic insight into the pathophysiology of pulmonary PASC needed for the development of new treatments to improve quality of life for those affected.

immunology↗

bioRxiv2018

Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors

Due to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.\n\nKey messageWe quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the \"my choice\" HRD score in collaboration with Myriad Genetics.\n\nThese confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.

cancer biology↗