In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic leukemia xenografts.

The overall survival rate of patients with T-cell acute lymphoblastic leukemia (T-ALL) is now 90%, although patients with relapsed T-ALL face poor prognosis. The ubiquitin-proteasome system maintains normal protein homeostasis, and aberrations in this pathway are associated with T-ALL. Here we demonstrate the in vitro and in vivo activity of ixazomib, a second-generation orally available, reversible, and selective proteasome inhibitor against pediatric T-ALL cell lines and patient-derived xenografts (PDXs) grown orthotopically in immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJAusb (NSG) mice. Ixazomib was highly potent in vitro, with half-maximal inhibitory concentration (IC50) values in the low nanomolar range. As a monotherapy, ixazomib significantly extended mouse event-free survival of five out of eight T-ALL PDXs in vivo.

In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts.

BACKGROUND: Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs). PROCEDURES: Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+ ) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event-free survival and stringent objective response measures. RESULTS: PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values <.0001). Duvelisib was well-tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent. CONCLUSIONS: Duvelisib demonstrated limited in vivo activity against ALL PDXs.

Conducting a conventional multi-casualty incident in COVID-19 personal protective equipment - a semi-structured interview.

BACKGROUND: The risk of COVID-19 transmission to healthcare professionals is likely to continue for the foreseeable future. The wearing of personal protective equipment (PPE) presents a number of potential challenges to responders that may impact upon the management of patients in a multi-casualty incident. This report describes a multi-agency multi-casualty incident. It identifies learning points specifically related to the challenges of conducting a conventional multi-casualty incident in COVID-19 PPE. CASE: The multi casualty incident in Reading, UK on the 20 June 2020 involved six stab injury victims and was attended by four pre-hospital critical care teams. This was the first conventional multi-casualty incident that pre-hospital critical care teams had attended during the COVID-19 era and it was conducted in COVID-19 PPE (1). The scene was an urban park where three patients were confirmed to be in Traumatic Cardiac Arrest (TCA) from stab wounds and another three patients had also suffered stab injuries. By the time the incident had concluded three patients were pronounced dead at the scene. Two patients were transported to the local trauma unit and one patient was transported to the regional Major Trauma Centre depending on the severity of their injuries. CONCLUSIONS: We conducted a semi structured telephone interview with the critical care clinicians who were involved in the incident. The interviews focused specifically on the challenges of responding whilst wearing COVID-19 PPE, rather than the wider challenges of responding to such an incident. The key learning points identified were: Improving the identifiability of clinicians in level 3 PPE wearing identification tabards using visible labelling on PPE suits Improving communication by radio using a belt to carry the radio using an earpiece and push to talk system. Training in conducting multi casualty incidents in level 3 PPE.

Characterisation and management of concrete grinding residuals.

Concrete grinding residue is the waste product resulting from the grinding, cutting, and resurfacing of concrete pavement. Potential beneficial applications for concrete grinding residue include use as a soil amendment and as a construction material, including as an additive to Portland cement concrete. Concrete grinding residue exhibits a high pH, and though not hazardous, it is sufficiently elevated that precautions need to be taken around aquatic ecosystems. Best management practices and state regulations focus on reducing the impact on such aquatic environment. Heavy metals are present in concrete grinding residue, but concentrations are of the same magnitude as typically recycled concrete residuals. The chemical composition of concrete grinding residue makes it a useful product for some soil amendment purposes at appropriate land application rates. The presence of unreacted concrete in concrete grinding residue was examined for potential use as partial replacement of cement in new concrete. Testing of Florida concrete grinding residue revealed no dramatic reactivity or improvement in mortar strength.

Coherent X-ray imaging: bridging the gap between atomic and micro-scale investigations.

We present a review of state-of-the art X-ray imaging techniques based on partially coherent synchrotron radiation. Full-field X-ray tomography, X-ray ptychography, scanning small-angle X-ray scattering, and scanning transmission X-ray microscopy are imaging techniques that gather structural information at spatial resolution ranging from several microns to a few tens of nanometers in both real- and reciprocal space. These methods exploit contrast mechanisms based on absorption, phase, and spectroscopic signals. We provide examples of how these techniques can be applied to address scientific questions ranging from imaging of biological samples, to foam rheology, and cement composition.

Coherent X-ray Imaging: Bridging the Gap between Atomic and Micro-scale Investigations.

We present a review of state-of-the art X-ray imaging techniques based on partially coherent synchrotron radiation. Full-field X-ray tomography, X-ray ptychography, scanning small-angle X-ray scattering, and scanning transmission X-ray microscopy are imaging techniques that gather structural information at spatial resolution ranging from several microns to a few tens of nanometers in both real- and reciprocal space. These methods exploit contrast mechanisms based on absorption, phase, and spectroscopic signals. We provide examples of how these techniques can be applied to address scientific questions ranging from imaging of biological samples, to foam rheology, and cement composition.