Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment ...with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity.
Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or LR + exosomes (1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the perilesion BBB.
Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens 1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p < 0.05) in the exosome-treated cohort at the end of the experiment.
In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity.
Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remains a leading cause of preventable death worldwide. Mesenchymal stem cell-derived exosomes have demonstrated promise in small ...animal models of neurologic injury. To investigate the effects of exosome treatment in a clinically realistic large animal model, Yorkshire swine underwent TBI and HS. Animals were maintained in shock for 2 h before resuscitation with normal saline (NS). Animals were then resuscitated either with NS (3 × volume of shed blood) or with the same volume of NS with delayed exosome administration (1 × 10
particles/4 mL) (n = 5/cohort). Exosomes were administered 9 h post-injury, and on post-injury days (PID) 1, 5, 9, and 13. Neurologic severity scores (NSS) were assessed for 30 days, and neurocognitive functions were objectively measured. Exosome-treated animals had significantly lower NSS (p < 0.05) during the first five days of recovery. Exosome-treated animals also had a significantly shorter time to complete neurologic recovery (NSS = 0) compared with animals given NS alone (days to recovery: NS = 16.8 ± 10.6; NS + exosomes = 5.6 ± 2.8; p = 0.03). Animals treated with exosomes initiated neurocognitive testing earlier (days to initiation: NS = 9.6 ± 0.5 vs. NS + exosomes = 4.2 ± 0.8; p = 0.008); however, no difference was seen in time to mastery of tasks. In conclusion, treatment with exosomes attenuates the severity of neurologic injury and allows for faster neurologic recovery in a clinically realistic large animal model of TBI and HS.
The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic ...strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.
Members of the Cancer Target Discovery and Development Network synthesize recent insights into the different classes and characteristics of cancer therapeutic vulnerabilities.
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical ...annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
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•Acute myeloid leukemia patient cohort with clinical, molecular, drug response data•Validation and discovery of diverse biological features of drug response•Broad mapping of tumor cell differentiation state affecting response to drugs•Modeling reveals a strong and targetable determinant of clinical outcome
Bottomly et al. present a functional genomic resource composed of molecular, clinical, and drug response data on acute myeloid leukemia patient specimens. Through integration of all of these data, they identify genetic and cell differentiation state features that predict drug response, and they utilize modeling to identify targetable determinants of clinical outcome.
High-fat diets made with different fats may have distinct effects on body weight regulation and metabolism. In the present study, the metabolic effects of high-fat (HF) diets made with fish oil, palm ...oil, and soybean oil were compared with a low-fat diet in female Wistar rats that were either exercised (EX, swimming) or that remained sedentary as controls. Each adult rat was exposed to the same diet that their dams consumed during pregnancy and lactation. When they were 9 weeks old, rats began an EX regimen that lasted for 6 weeks. Twenty-four hours after the last EX bout, rats were sacrificed in a fasted state. It was observed that HF feeding of soybean oil induced more body weight and fat gain, as well as insulin resistance, as indicated by insulin/glucose ratios, than other oils. Female rats fed a HF diet made with fish oil had body weight and insulin sensitivity not different from that observed in low fat fed control rats. For rats fed HF diets made with soybean oil or palm oil, EX also exerted beneficial effects by reducing body fat %, blood insulin, triglyceride and leptin levels, as well as improving insulin sensitivity.
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