Scientific reports
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Traumatic brain injury is a major source of global disability and mortality. Preclinical TBI models are a crucial component of therapeutic investigation. We report a tunable, monitored model of murine non-surgical, diffuse closed-head injury-modCHIMERA-characterized by impact as well as linear and rotational acceleration. modCHIMERA is based on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) platform. ⋯ Acute functional analysis revealed prolonged post-injury unconsciousness, and decreased spontaneous behavior and stimulated neurological scores. Neurobehavioral deficits were demonstrated in spatial learning/memory and socialization at 1-month. The overall injury profile of modCHIMERA corresponds with the range responsible for a substantial portion of TBI-related disability in humans. modCHIMERA should provide a reliable platform for efficient analysis of TBI pathophysiology and testing of treatment modalities.
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We measured systemic changes in the immune response in 92 patients receiving preoperative chemoradiation therapy (CRT) and subsequent surgery for rectal cancer. The peripheral blood was sampled five times from the onset of CRT until surgery. Lymphocytes decreased continuously during CRT but increased after CRT. ⋯ The predictive value of cytokines was not clear. In short, we observed that immune components in peripheral blood are affected by CRT and show dynamic changes over time. We identified biomarker candidates to predict the pathologic response in the future.
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Ischemia-reperfusion (I/R) injury is a challenging clinical problem, especially injuries involving the gastrointestinal tract. Mitochondrial DNA (mtDNA) is released upon cell death and stress, and can induce the inflammatory response. We aimed to investigate the role of mtDNA in the pathogenesis of intestinal I/R. ⋯ MtDNA was also released in a mouse model of intestinal I/R and was associated with the increased secretion of inflammatory cytokines and increased gut barrier injury compared with that of the sham group. We concluded that mtDNA contributes to I/R injury and may serve as a biomarker of intestinal I/R. We further suggest that oxidized mtDNA originated from IECs during intestinal I/R exacerbates the acute proinflammatory process by eliciting the production of proinflammatory cytokines and chemokines.
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Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood. ⋯ Analysis of the TMZ resistant (TMZres) variants in conjunction with their parental, sensitive cell lines shows that acquisition of TMZ resistance is accompanied by broad phenotypic changes, including increased proliferation, migration, chromosomal aberrations, and secretion of cytosolic lipids. Importantly, each TMZ resistant model captures a different facet of the "go" (8MGBA-TMZres) or "grow" (42MGBA-TMZres) hypothesis of GBM behavior. These in vitro model systems will be important additions to the available tools for investigators seeking to define molecular mechanisms of acquired TMZ resistance.
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The Surviving Sepsis Guidelines suggest the use of vasopressin in case of catecholamine-refractory septic shock. Terlipressin (TP) as a V1-selective AVP analogue is a potential alternative, though data regarding the first-line administration in septic shock are scarce. The present study explored and compared the effects of first-line vs. second-line infusion of TP or sole norepinephrine regarding organ function, fluid and norepinephrine requirements and survival in fulminant ovine septic shock. ⋯ No significant differences were found between groups regarding survival, haemodynamics as well as fluid- and catecholamine-requirements. Kidney function and electron microscopic kidney injury were comparable between groups. In the present model of fulminant ovine septic shock, first-line TP infusion had no significant effect on fluid and norepinephrine requirements or organ dysfunction as compared to second-line TP infusion or placebo.