Control of positive end-expiratory pressure (PEEP) for small animal ventilators

Background  

The positive end-expiratory pressure (PEEP) for the mechanical ventilation of small animals is frequently obtained with water seals or by using ventilators developed for human use. An alternative mechanism is the use of an on-off expiratory valve closing at the moment when the alveolar pressure is equal to the target PEEP. In this paper, a novel PEEP controller (PEEP-new) and the PEEP system of a commercial small-animal ventilator, both based on switching an on-off valve, are evaluated.     

Analysis of heart rate deflection points to predict the anaerobic threshold by a computerized method

Many studies have used the heart rate deflection points (HRDPs) during incremental exercise tests, because of their strong correlation with the anaerobic threshold. The aim of this study was to evaluate the profile of the HRDPs identified by a computerized method and compare them with ventilatory and lactate thresholds. Twenty-four professional soccer players (age, 22 ± 5 years; body mass, 74 ± 7 kg; height 177 ± 7 cm) volunteered for the study. The subjects completed a Bruce-protocol incremental treadmill exercise test to volitional fatigue. Heart rate (HR) and alveolar gas exchange were recorded continuously at ≥1 Hz during exercise testing. Subsequently, the time course of the HR was fit by a computer algorithm, and a set of lines yielding the lowest pooled residual sum of squares was chosen as the best fit. This procedure defined 2 HRDPs (HRDP1 and HRDP2). The HR break points averaged 43.9 ± 5.9 and 89.7 ± 7.5% of the VO2peak. The HRDP1 showed a poor correlation with ventilatory threshold (VT; r = 0.50), but HRDP2 was highly correlated to the respiratory compensation (RC) point (r = 0.98). Neither HRDP1 nor HRDP2 was correlated with LT1 (at VO2 = 2.26 ± 0.72 L·min(-1); r = 0.26) or LT2 (2.79 ± 0.59 L·min(-1); r = 0.49), respectively. LT1 and LT2 also were not well correlated with VT (2.93 ± 0.68 L·min(-1); r = 0.20) or RC (3.82 ± 0.60 L·min(-1); r = 0.58), respectively. Although the HR deflection points were not correlated to LT, HRDP2 could be identified in all the subjects and was strongly correlated with RC, consistent with a relationship to cardiorespiratory fatigue and endurance performance.     

Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer

The aggressiveness of pancreatic ductal adenocarcinoma (PDA) is characterized by its high metastatic potential and lack of effective therapies, which is the result of a lack of understanding of the mechanisms involved in promoting PDA metastases. We identified Annexin A2 (ANXA2), a member of the Annexin family of calcium-dependent phospholipid binding proteins, as a new molecule that promotes PDA invasion and metastases. We found ANXA2 to be a PDA-associated antigen recognized by post-treatment sera of patients who demonstrated prolonged survival following treatment with a PDA-specific vaccine. Cell surface ANXA2 increases with PDA development and progression. Knockdown of ANXA2 expression by RNA interference or blocking with anti-ANXA2 antibodies inhibits in vitro invasion of PDA cells. In addition, post-vaccination patient sera inhibits in vitro invasion of PDA cells, suggesting that therapeutic anti-ANXA2 antibodies are induced by the vaccine. Furthermore, cell-surface localization of ANXA2 is tyrosine 23 phosphorylation-dependent; and tyrosine 23 phosphorylation is required for PDA invasion. We demonstrated that tyrosine 23 phosphorylation resulting in surface expression of ANXA2 is required for TGFβ-induced, Rho-mediated epithelial-mesenchymal transition (EMT), linking the cellular function of ANXA2 which was previously shown to be associated with small GTPase-regulated cytoskeletal rearrangements, to the EMT process in PDA. Finally, using mouse PDA models, we showed that shRNA knock-down of ANXA2, a mutation at tyrosine 23, or anti-ANXA2 antibodies, inhibit PDA metastases and prolong mouse survival. Thus, ANXA2 is part of a novel molecular pathway underlying PDA metastases and a new target for development of PDA therapeutics.     

A Preclinical Murine Model of Hepatic Metastases

Numerous murine models have been developed to study human cancers and advance the understanding of cancer treatment and development. Here, a preclinical, murine pancreatic tumor model of hepatic metastases via a hemispleen injection of syngeneic murine pancreatic tumor cells is described. This model mimics many of the clinical conditions in patients with metastatic disease to the liver. Mice consistently develop metastases in the liver allowing for investigation of the metastatic process, experimental therapy testing, and tumor immunology research.     

Characterization of extracellular proteins in members of the Paracoccidioides complex

Paracoccidioides is a thermodimorphic fungus that causes Paracoccidioidomycosis (PCM) – an endemic systemic mycosis in Latin America. The genus comprises several phylogenetic species which present some genetic and serological differences. The diversity presented among isolates of the same genus has been explored in several microorganisms. There have also been attempts to clarify differences that might be related to virulence existing in isolates that cause the same disease. In this work, we analyzed the secretome of two isolates in the Paracoccidioides genus, isolates Pb01 and PbEpm83, and performed infection assays in macrophages to evaluate the influence of the secretomes of those isolates upon an in vitro model of infection. The use of a label-free proteomics approach (LC-MS^E) allowed us to identify 92 proteins that are secreted by those strains. Of those proteins, 35 were differentially secreted in Pb01, and 36 in PbEpm83. According to the functional annotation, most of the identified proteins are related to adhesion and virulence processes. These results provide evidence that different members of the Paracoccidioides complex can quantitatively secrete different proteins, which may influence the characteristics of virulence, as well as host-related processes.