Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

A clinician’s guide to management of intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Measurement of jet-substructure observables in top quark, W boson and light jet production in proton-proton collisions at √s=13 TeV with the ATLAS detector

A measurement of jet substructure observables is presented using data collected in 2016 by the ATLAS experiment at the LHC with proton-proton collisions at s√ = 13 TeV. Large-radius jets groomed with the trimming and soft-drop algorithms are studied. Dedicated event selections are used to study jets produced by light quarks or gluons, and hadronically decaying top quarks and W bosons. The observables measured are sensitive to substructure, and therefore are typically used for tagging large-radius jets from boosted massive particles. These include the energy correlation functions and the N-subjettiness variables. The number of subjets and the Les Houches angularity are also considered. The distributions of the substructure variables, corrected for detector effects, are compared to the predictions of various Monte Carlo event generators. They are also compared between the large-radius jets originating from light quarks or gluons, and hadronically decaying top quarks and W bosons

Search for large missing transverse momentum in association with one top-quark in proton-proton collisions at s√=13 TeV with the ATLAS detector

This paper describes a search for events with one top-quark and large missing transverse momentum in the final state. Data collected during 2015 and 2016 by the ATLAS experiment from 13 TeV proton–proton collisions at the LHC corresponding to an integrated luminosity of 36.1 fb−1 are used. Two channels are considered, depending on the leptonic or the hadronic decays of the W boson from the top quark. The obtained results are interpreted in the context of simplified models for dark-matter production and for the single production of a vector-like T quark. In the absence of significant deviations from the Standard Model background expectation, 95% confidence-level upper limits on the corresponding production cross-sections are obtained and these limits are translated into constraints on the parameter space of the models considered

Functional abdominal wall reconstruction improves core physiology and quality-of-life

Introduction One of the goals of modern ventral hernia repair (VHR) is restoring the linea alba by returning the rectus muscles to the midline. Although this practice presumably restores native abdominal wall function, improvement of abdominal wall function has never been measured in a scientific fashion. We hypothesized that a dynamometer could be used to demonstrate an improvement in rectus muscle function after open VHR with restoration of the midline, and that this improvement would be associated with a better quality-of-life. Methods Thirteen patients agreed to dynamometric analysis before and 6 months after an open posterior component separation (Rives-Stoppa technique complimented with a transversus abdominis muscle release) and mesh sublay. Analysis done using a dynamometer (Biodex 3, Corp, Shirley, NY) included measurement of peak torque (PT; N*m) and PT per bodyweight (BW; %) generated during abdominal flexion in 5 settings: Isokinetic analysis at 45°/s and 60°/s as well as isometric analysis at 0°, -15°, and +15°. Power (W) was calculated during isokinetic settings. Quality-of-life was measured using our validated HerQles survey at the time of each dynamometric analysis. Results Thirteen patients (mean age, 54 ± 9 years; mean body mass index, 31 ± 7 kg/m2) underwent repair with restoration of the midline using the aforementioned technique. Mean hernia width was 12.5 cm (range, 5-19). Improvements in PT and PT/BW were significant in all 5 settings (P &lt;.05). Improvement in power during isokinetic analyses at 45°/s and 60°/s was also significant (P &lt;.05). All patients reported an improvement in quality-of-life, which was associated positively with each dynamometric parameter. Conclusion Restoration of the linea alba during VHR is associated with improved abdominal wall functionality. Analysis of rectus muscle function using a dynamometer showed statistical improvement by isokinetic and isometric measurements, all of which were associated with an improvement in quality-of-life

Intra-abdominal hypertension and abdominal compartment syndrome after abdominal wall reconstruction : quaternary syndromes?

Background and Aims: Reconstruction with reconstitution of the container function of the abdominal compartment is increasingly being performed in patients with massive ventral hernia previously deemed inoperable. This situation places patients at great risk of severe intra-abdominal hypertension and abdominal compartment syndrome if organ failure ensues. Intra-abdominal hypertension and especially abdominal compartment syndrome may be devastating systemic complications with systematic and progressive organ failure and death. We thus reviewed the pathophysiology and reported clinical experiences with abnormalities of intra-abdominal pressure in the context of abdominal wall reconstruction. Material and Methods: Bibliographic databases (1950-2015), websites, textbooks, and the bibliographies of previously recovered articles for reports or data relating to intra-abdominal pressure, intra-abdominal hypertension, and the abdominal compartment syndrome in relation to ventral, incisional, or abdominal hernia repair or abdominal wall reconstruction. Results: Surgeons should thus consider and carefully measure intra-abdominal pressure and its resultant effects on respiratory parameters and function during abdominal wall reconstruction. The intra-abdominal pressure post-operatively will be a result of the new intra-peritoneal volume and the abdominal wall compliance. Strategies surgeons may utilize to ameliorate intra-abdominal pressure rise after abdominal wall reconstruction including temporizing paralysis of the musculature either temporarily or semi-permanently, pre-operative progressive pneumoperitoneum, permanently removing visceral contents, or surgically releasing the musculature to increase the abdominal container volume. In patients without complicating shock and inflammation, and in whom the abdominal wall anatomy has been so functionally adapted to maximize compliance, intra-abdominal hypertension may be transient and tolerable. Conclusions: Intra-abdominal hypertension/abdominal compartment syndrome in the specific setting of abdominal wall reconstruction without other complication may be considered as a quaternary situation considering the classification nomenclature of the Abdominal Compartment Society. Greater awareness of intra-abdominal pressure in abdominal wall reconstruction is required and ongoing study of these concerns is required