In a circulation completely dependent on ECMO support, maximum achievable flow directly depended on the vascular factors governing venous return - i.e. closing conditions, stressed vascular volume and the elastance and resistive properties of the vasculature. Both treatments increased maximum achievable ECMO flow at stable DO2, via increases in stressed volume by different mechanisms. Vascular resistance and pump afterload decreased with Volume Expansion.

BackgroundCisplatin plus pemetrexed combination therapy is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer (NSCLC). However, advanced NSCLC has a 5-year survival rate of below 10%, which is mainly due to therapy resistance. We previously showed that the NSCLC cell line A549 harbors different subpopulations including a mesenchymal-like subpopulation characterized by increased chemo- and radiotherapy resistance. Recently, therapy resistance in hematological and solid tumors has been associated with increased mitochondrial activity. Thus, the aim of this study was to investigate the role of the mitochondrial activity in NSCLC chemotherapy resistance.MethodsBased on MitoTracker staining, subpopulations characterized by the highest 10% (Mito-High) or lowest 10% (Mito-Low) mitochondrial mass content were sorted by FACS (Fluorescence-Activated Cell Sorting) from paraclonal cultures of the NSCLC A549 cell line . Mitochondrial DNA copy numbers were quantified by real-time PCR whereas basal cellular respiration was measured by high-resolution respirometry. Cisplatin and pemetrexed response were quantified by proliferation and colony formation assay.ResultsPemetrexed treatment of parental A549 cells increased mitochondrial mass over time. FACS-sorted paraclonal Mito-High cells featured increased mitochondrial mass and mitochondrial DNA copy number compared to the Mito-Low cells. Paraclonal Mito-High cells featured an increased proliferation rate and were significantly more resistant to cisplatin treatment than Mito-Low cells. Interestingly, cisplatin-resistant, paraclonal Mito-High cells were significantly more sensitive to pemetrexed treatment than Mito-Low cells. We provide a working model explaining the molecular mechanism underlying the increased cisplatin- and decreased pemetrexed resistance of a distinct subpopulation characterized by high mitochondrial mass.ConclusionsThis study revealed that cisplatin resistant A549 lung cancer cells can be identified by their increased levels of mitochondrial mass. However, Mito-High cells feature an increased sensitivity to pemetrexed treatment. Thus, pemetrexed and cisplatin target reciprocal lung cancer subpopulations, which could explain the increased efficacy of the combination therapy in the clinical setting.

Building on recent work by Chandar et al., we construct X-ray luminosity functions (XLFs) for different classes of X-ray binary (XRB) donors in the nearby star-forming galaxy M83 through a novel methodology. Rather than classifying low- versus high-mass XRBs based on the scaling of the number of X-ray sources with stellar mass and star formation rate, respectively, we utilize multiband Hubble Space Telescope imaging data to classify each Chandra-detected compact X-ray source as a low-mass (i.e., donor mass ≲3 M ⊙), high-mass (donor mass ≳8M ⊙), or intermediate-mass XRB based on either the location of its candidate counterpart on optical color–magnitude diagrams or the age of its host star cluster. In addition to the standard (single and/or truncated) power-law functional shape, we approximate the resulting XLFs with a Schechter function. We identify a marginally significant (at the 1σ-to-2σ level) exponential downturn for the high-mass XRB XLF, at ℓ ≃ 38.48 − 0.33 + 0.52 (in log CGS units). In contrast, the low- and intermediate-mass XRB XLFs, as well as the total XLF of M83, are formally consistent with sampling statistics from a single power law. Our method suggests a non-negligible contribution from low- and possibly intermediate-mass XRBs to the total XRB XLF of M83, i.e., between 20% and 50%, in broad agreement with X-ray-based XLFs. More generally, we caution against considerable contamination from X-ray emitting supernova remnants to the published, X-ray-based XLFs of M83, and possibly all actively star-forming galaxies.

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AimTo explore the expression and clinical significance of ecotropic viral integration site-1 (EVI1) of lung squamous cell cancer (SCC).MethodsThe expression of EVI1 in SCC was detected by immunohistochemistry and the validation cohort was divided into EVI1 high-expression group and low-expression group according to the cutoff of immunohistochemical score. The correlations between EVI1 expression and the clinicopathological factors were analyzed by χ2 test. The relation between EVI1 expression and overall survival rate was evaluated by univariate analysis with Kaplan–Meier method. The independent prognostic factor was identified by multivariate analysis with Cox regression model.ResultsIn this study, the EVI1 high-expression percentage was 32.32% (53/164). EVI1 high expression was significantly associated with a poorer overall 5-year survival rate of SCC (P=0.021). Moreover, EVI1 high expression was identified as an independent prognostic factor of SCC, predicting the unfavorable prognosis (P=0.013).ConclusionHigh expression of EVI1 was significantly associated with a poorer prognosis and it was identified as an independent prognostic factor of SCC.

High central venous pressure (CVP) acutely decreases venous return. How this affects hepatic oxygen transport in sepsis remains unclear. The aim of this study was to evaluate the effects of repeated increases of CVP via standard nursing procedures (NPs) on hepato-splanchnic and renal oxygen transport in a prolonged porcine sepsis model. Twenty anesthetized and mechanically ventilated pigs with regional hemodynamics monitored were randomized to fecal peritonitis or controls (n=10 / group). Resuscitation was started after 8-hour of observation and continued for 3 days. NPs were performed at baseline and 8h, 32h, 56h and 72h after resuscitation started. NPs increased CVP by 4-7 mmHg in both groups. In controls, this was associated with less decrease in hepatic arterial (Qha, 62±70 ml/min) than portal venous flow (Qpv, 364±151 ml/min). Portal venous oxygen content, and hepatic O2 delivery (DO2) and consumption (VO2) decreased by 11±6 ml/dl, 0.9±0.3 and 0.4±0.3 ml/min/kg respectively. In septic animals, hepatic DO2 decreased more in response to increasing CVP (1.5±0.9 ml/min/kg), which was attributable to a larger fall both in Qha (88±66 ml/min) and in portal O2 content (14±10 ml/dl, all p<0.05). This resulted in numerically lower hepatic VO2 since O2 extraction did not increase significantly. In control conditions, a smaller decrease of Qha compared to Qpv helped to limit the reduction in hepatic VO2 in response to acute CVP increase. In sepsis, the contribution of Qha to maintain hepatic DO2 was reduced which jeopardized hepatic VO2 further. Renal arterial flow was similarly affected by CVP increase as Qha.

The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of NSD3-amplified LUSC. Concordantly, we showed that NSD3-amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for NSD3 and provide therapeutic rationales for NSD3-amplified squamous lung cancer.

Pericardial fluid, as a biochemical indicator of heart status, directly indicates pathological alteration to the heart. The accumulation of pericardial fluid can be attributed to an underlying systemic or local inflammatory process. However, the pericardial fluid expression of cellular surface markers, as well as several cytokines in chronic heart failure (CHF), remain unclear. In order to evaluate these issues further the pericardial fluid expression of several cytokines and the surface expression of activity markers between CHF patients and non-heart failure (NHF) patients were analyzed. The pericardial fluid expression of cytokines was measured by immunofluorescence and biomarker of plasma N-terminal propeptide of B-type natriuretic peptide (NT-proBNP), while pericardial fluid levels of soluble glycoprotein 130 (sgp130) were analyzed by ELISA in 50 CHF and 24 NHF patients. In addition, the surface expression of activation markers for T-cells was measured by immunohistochemistry. Patients with CHF demonstrated increased levels of plasma NT-proBNP and pericardial fluid sgp130. Surface expression of cellular activation markers CD25 and Foxp3 in the pericardial fluid was increased in patients with CHF. Moreover, the pro- and anti-inflammatory cytokines interferon (IFN)-γ, interleukin (IL)-6 and IL-10 in patients with CHF also demonstrated an increased expression within its pericardial fluid. In addition, there was infiltration of inflammatory cells and enhanced expression of inflammatory cytokines in the pericardial fluid of patients with CHF, which may reflect T cell activation, suggesting that systemic inflammation is important in the progression of CHF. This evidence could indicate a possible novel target for future therapeutics and prevention of CHF.