Evaluation and Application of Ultra-Low-Resolution Pressure Reactivity Index in Moderate or Severe Traumatic Brain Injury

Background: The pressure reactivity index (PRx) has emerged as a surrogate method for the continuous bedside estimation of cerebral autoregulation and a predictor of unfavorable outcome after traumatic brain injury (TBI). However, calculation of PRx require continuous high-resolution monitoring currently limited to specialized intensive care units. The aim of this study was to evaluate a new index, the ultra-low-frequency PRx (UL-PRx) sampled at ∼0.0033 Hz at ∼5 minutes periods, and to investigate its association with outcome. Methods: Demographic data, admission Glasgow coma scale, in-hospital mortality and Glasgow outcome scale extended at 12 months were extracted from electronic records. The filtering and preparation of time series of intracranial pressure (ICP), mean arterial pressure and cerebral perfusion pressure (CPP), and calculation of the indices (UL-PRx, Δ-optimal CPP), were performed in MATLAB using an in-house algorithm. Results: A total of 164 TBI patients were included in the study; in-hospital and 12-month mortality was 29.3% and 38.4%, respectively, and 64% of patients had poor neurological outcome at 12 months. On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month mortality. After adjusting for age, Glasgow coma scale, ICP and CPP, mean UL-PRx and UL-PRx thresholds of 0 and +0.25 remained associated with 12-month mortality. Similar findings were obtained for in-hospital mortality. For mean UL-PRx, the area under the receiver operating characteristic curves for in-hospital and 12-month mortality were 0.78 (95% confidence interval [CI]: 0.69-0.87; P<0.001) and 0.70 (95% CI: 0.61-0.79; P<0.001), respectively, and 0.65 (95% CI: 0.57-0.74; P=0.001) for 12-month neurological outcome. Conclusions: Our findings indicate that ultra-low-frequency sampling might provide sufficient resolution to derive information about the state of cerebrovascular autoregulation and prediction of 12-month outcome in TBI patients

Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients

In Search for the Missing Link in APECED-like Conditions: Analysis of the AIRE Gene in a Series of 48 Patients

Autoimmune diseases are a heterogeneous group of disorders of the immune system. They can cluster in the same individual, revealing various preferential associations for polyendocrine autoimmune syndromes. Clinical observation, together with advances in genetics and the understanding of pathophysiological processes, has further highlighted that autoimmunity can be associated with immunodeficiency; autoimmunity may even be the first primary immunodeficiency manifestation. Analysis of susceptibility genes for the development of these complex phenotypes is a fundamental issue. In this manuscript, we revised the clinical and immunologic features and the presence of AIRE gene variations in a cohort of 48 patients affected by high polyautoimmunity complexity, i.e., APECED-like conditions, also including patients affected by primary immunodeficiency. Our results evidenced a significant association of the S278R polymorphism of the AIRE gene with APECED-like conditions, including both patients affected by autoimmunity and immunodeficiency and patients with polyautoimmunity compared to healthy controls. A trend of association was also observed with the IVS9+6 G&gt;A polymorphism. The results of this genetic analysis emphasize the need to look for additional genetic determinants playing in concert with AIRE polymorphisms. This will help to improve the diagnostic workup and ensure a precision medicine approach to targeted therapies in APECED-like patients

Additional file 1 of Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups

Additional file 1. Additional Methods