The Human Minor Histocompatibility Antigen1 Is a RhoGAP

The human minor Histocompatibility Antigen HMHA-1 is a major target of immune responses after allogeneic stem cell transplantation applied for the treatment of leukemia and solid tumors. The restriction of its expression to hematopoietic cells and many solid tumors raised questions regarding its cellular functions. Sequence analysis of the HMHA-1 encoding HMHA1 protein revealed the presence of a possible C-terminal RhoGTPase Activating Protein (GAP) domain and an N-terminal BAR domain. Rho-family GTPases, including Rac1, Cdc42, and RhoA are key regulators of the actin cytoskeleton and control cell spreading and migration. RhoGTPase activity is under tight control as aberrant signaling can lead to pathology, including inflammation and cancer. Whereas Guanine nucleotide Exchange Factors (GEFs) mediate the exchange of GDP for GTP resulting in RhoGTPase activation, GAPs catalyze the low intrinsic GTPase activity of active RhoGTPases, resulting in inactivation. Here we identify the HMHA1 protein as a novel RhoGAP. We show that HMHA1 constructs, lacking the N-terminal region, negatively regulate the actin cytoskeleton as well as cell spreading. Furthermore, we show that HMHA1 regulates RhoGTPase activity in vitro and in vivo. Finally, we demonstrate that the HMHA1 N-terminal BAR domain is auto-inhibitory as HMHA1 mutants lacking this region, but not full-length HMHA1, showed GAP activity towards RhoGTPases. In conclusion, this study shows that HMHA1 acts as a RhoGAP to regulate GTPase activity, cytoskeletal remodeling and cell spreading, which are crucial functions in normal hematopoietic and cancer cells

Anaesthesia during oesophagectomy

In this review, we will provide an overview of the current state of the art of perioperative practices for open and laparoscopic oesophagus surgery from the anaesthetist's perspective. Morbidity and mortality after oesophagectomy is still high despite multidisciplinary and enhanced recovery pathways showing promising results. The anaesthetist has an important role in the complex care of the oesophageal cancer patient. Minimizing unnecessary fluid administration, adequate pain management, hypotension, and protective lung ventilation are examples of proven strategies that can improve outcome after this high-risk surger

Improving the quality of drug research or simply increasing its cost? An evidence-based study of the cost for data monitoring in clinical trials

center dot Current knowledge is based on practical experience. This paper presents the first novel, quantitative and qualitative view on the efficacy of the sponsor query system widely applied in the pharmaceutical industry, used for quality control purposes by data management for clinical data. WHAT THIS STUDY ADDS center dot This study presents a structured view on the process of clinical data management and sponsor queries, the efficacy and cost effectiveness of sponsor queries and dual data entry and the conclusion to advocate a more evidence-based approach to clinical data validation. AIM Procedures for verification of data from clinical studies are intended to maintain reliability for clinical trial results. Guidelines or legislations relating to clinical data management are of limited value and no study has yet demonstrated its effectiveness. METHOD Sponsor queries and dual entry procedures from one CRO on three different phase I trials are analysed on content, impact and cost. RESULT In this study, sponsor queries and dual entry procedures proved time and cost inefficient in detecting data discrepancies. CONCLUSION We advocate a more evidence-based approach for enhancing data integrity throughout the process of clinical data management.Perioperative Medicine: Efficacy, Safety and Outcom

The use of the oesophageal Doppler in perioperative medicine: new opportunities in research and clinical practice

The oesophageal Doppler (OD) is a minimally invasive haemodynamic monitor used in the surgical theatre and the ICU. Using the OD, goal-directed therapy (GDT) has been shown to reduce perioperative complications in high-risk surgical patients. However, most GDT protocols currently in use are limited to stroke volume optimisation. In the present manuscript, we examine the conceptual models behind new OD-based measurements. These would provide the clinician with a comprehensive view of haemodynamic pathophysiology; including pre-load, contractility, and afterload. Specifically, volume status could be estimated using mean systemic filling pressure (MSFP), the pressure to which all intravascular pressures equilibrate during asystole. Using the OD, MSFP could be readily estimated by simultaneous measurements of aortic blood flow and arterial pressure with sequential manoeuvres of increasing airway pressure. This would result in subsequent reductions in cardiac output and arterial pressure and would allow for a linear extrapolation of a static MSFP value to a "zero flow" state. In addition, we also demonstrate that EF is proportional to mean blood flow velocity measured in the descending thoracic aorta with the OD. Furthermore, OD-derived indexes of blood flow velocity and acceleration, as well as force and kinetic energy, can be derived and used for continuous assessment of cardiac contractility at the bedside. Using OD-derived parameters, the different components of afterload: inertia, resistance and elastance, could also be individually determined. The integration of these additional haemodynamic parameters could assist the clinician in optimising and individualising haemodynamic performance in unstable patient

Defining fluid responsiveness: a guide to patient-tailored volume titration

Anesthesiolog