Lumping procedure for a kinetic model of catalytic naphtha reforming

A lumping procedure is developed for obtaining kinetic and thermodynamic parameters of catalytic naphtha reforming. All kinetic and deactivation parameters are estimated from industrial data and thermodynamic parameters are calculated from derived mathematical expressions. The proposed model contains 17 lumps that include the C6 to C8+ hydrocarbon range and 15 reaction pathways. Hougen-Watson Langmuir-Hinshelwood type reaction rate expressions are used for kinetic simulation of catalytic reactions. The kinetic parameters are benchmarked with several sets of plant data and estimated by the SQP optimization method. After calculation of deactivation and kinetic parameters, plant data are compared with model predictions and only minor deviations between experimental and calculated data are generally observed

Novel insights on the use of L-asparaginase as an efficient and safe anti-cancer therapy

Simple Summary L-asparaginase (L-ASNase) therapy is key for achieving the very high cure rate of pediatric acute lymphoblastic leukemia (ALL), yet its use is mostly confined to this indication. One main reason preventing the expansion of today's FDA-approved L-ASNases to solid cancers is their high toxicity and side effects, which become especially challenging in adult patients. The design of optimized L-ASNase molecules provides opportunities to overcome these unwanted toxicities. An additional challenge to broader application of L-ASNases is how cells can counter the pharmacological effect of this drug and the identification of L-ASNases resistance mechanisms. In this review, we discuss recent insights into L-ASNase adverse effects, resistance mechanisms, and how novel L-ASNase variants and drug combinations can expand its clinical applicability, with a focus on both hematological and solid tumors. L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability

Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination

T-cell acute lymphoblastic leukemia (T-ALL) is a highly malignant pediatric leukemia, where few therapeutic options are available for patients which relapse. We find that therapeutic targeting of GLI transcription factors by GANT-61 is particularly effective against NOTCH1 unmutated T-ALL cells. Investigation of the functional role of GLI1 disclosed that it contributes to T-ALL cell proliferation, survival, and dissemination through the modulation of AKT and CXCR4 signaling pathways. Decreased CXCR4 signaling following GLI1 inactivation was found to be prevalently due to post-transcriptional mechanisms including altered serine 339 CXCR4 phosphorylation and cortactin levels. We also identify a novel cross-talk between GLI transcription factors and FOXC1. Indeed, GLI factors can activate the expression of FOXC1 which is able to stabilize GLI1/2 protein levels through attenuation of their ubiquitination. Further, we find that prolonged GLI1 deficiency has a double-edged role in T-ALL progression favoring disease dissemination through the activation of a putative AKT/FOXC1/GLI2 axis. These findings have clinical significance as T-ALL patients with extensive central nervous system dissemination show low GLI1 transcript levels. Further, T-ALL patients having a GLI2-based Hedgehog activation signature are associated with poor survival. Together, these findings support a rationale for targeting the FOXC1/AKT axis to prevent GLI-dependent oncogenic Hedgehog signaling

The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL.

B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response of luciferase-positive LOUCY cells to ABT-199 monotherapy and observed specific residual disease in the splenic microenvironment. Of note, these results were confirmed by using a primary ETP-ALL patient-derived xenograft. Splenomegaly has previously been associated with poor prognosis in diverse types of leukemia. However, the exact mechanism by which the splenic microenvironment alters responses to specific targeted therapies remains largely unexplored. We show that residual LOUCY cells isolated from the spleen microenvironment displayed reduced BCL-2 dependence, which was accompanied by decreased BCL-2 expression levels. Notably, this phenotype of reduced BCL-2 dependence could be recapitulated by using human splenic fibroblast coculture experiments and was confirmed in an in vitro chronic ABT-199 resistance model of LOUCY. Finally, single-cell RNA-sequencing was used to show that ABT-199 triggers transcriptional changes in T-cell differentiation genes in leukemic cells obtained from the spleen microenvironment. Of note, increased expression of CD1a and sCD3 was also observed in ABT199-resistant LOUCY clones, further reinforcing the idea that a more differentiated leukemic population might display decreased sensitivity toward BCL-2 inhibition. Overall, our data reveal the spleen as a site of residual disease for ABT-199 treatment in ETP-ALL and provide evidence for plasticity in T-cell differentiation as a mechanism of therapy resistance

Life Cycle Assessment Applied to Naphtha Catalytic Reforming Analyse de cycle de vie appliquée au reformage catalytique du naphta

Facing the increase of environmental concerns in the oil and gas industry, engineers and scientists need information to assess sustainability of chemical processes. Among the different methods available, Life Cycle Assessment (LCA) is widely used. In this study, LCA is applied to a catalytic reforming process using the Eco- Indicator 99 as life cycle impact assessment method. The main identified environmental impacts are fossil fuels consumption, climate change and respiratory effects due to inorganics compounds. The influence of different process parameters (feed composition, reaction temperature) is determined with respect to environmental impacts. Two allocation methods are analysed (mass and exergetic allocation) and two different process versions are compared in order to determine the effect of some improvements on environmental impact. <br> Les considérations liées à l’environnement doivent de plus en plus être prises en compte par les ingénieurs et les scientifiques afin de juger de la durabilité des procédés chimiques dans l’industrie pétrolière et gazière. Parmi les différentes méthodes d’analyse environnementale, l’Analyse de Cycle de Vie (ACV) est très utilisée. Dans cette étude, l’ACV est appliquée au procédé de reformage catalytique du naphta en utilisant la méthode Eco-Indicateur 99 comme méthode d’analyse des impacts du cycle de vie. Les principaux impacts environnementaux du procédé sont la consommation de combustibles fossiles, le changement climatique et les effets sur la respiration liés aux composés organiques. L’influence de différents paramètres (composition de l’alimentation, température de réaction) sur les impacts environnementaux est testée. Deux méthodes d’allocation sont analysées (allocation massique et énergétique) et deux versions du procédé de reformage catalytique sont comparées afin de déterminer les améliorations possibles permettant de minimiser les impacts

In vivo stabilization of a less toxic asparaginase variant leads to a durable anti-tumor response in acute leukemia

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase (ASNS). Acute lymphoblastic leukemia (ALL) cells do not or minimally express ASNS which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have a significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anti-cancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have a very short half-life in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long lasting durable anti-leukemic effect between the standard-of-care PEG-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential

Management of burn wounds of the head and neck region

Management of the severely burned patient is very often a challenge, not only due to major disturbances in anatomy and physiological processes, but also because the relatively low incidence of this pathology in both civilian and military practice results in care providers' lack of experience. The purpose of this educational document is to provide doctors confronted with these formidable trauma patients with basic management guidelines as well as some practical tips. In summary, and most importantly, these patients should be treated as any other multitrauma patient. First aid is essential and can be provided by non-medical staff. Initial medical management should focus on the usual, familiar trauma algorithms of ABCDEF from the emergency management of severe burns (EMSB) manual(1) or the ABCDEs of the manual of advanced trauma life support (ATLS)(2) or advanced burn life support (ABLS). Medical care should proceed through the following steps Step one: establish a reliable intravenous infusion; step two: protect the airway; step three: establish and maintain a haemodynamic state compatible with sufficient organ perfusion in order to reduce aggravation of the burn wounds and increase overall survival likelihood; step four: provide analgesia with adequate sedation and provide anaesthesia for escharotomy, fasciotomy or other surgical injuries; step five: maintain normothermia; step six: feed the patient by starting enteral nutrition as early as possible; step seven: prevent infection using antiseptic wound management, systemic antibiotics and tetanus prophylaxis. All of these intricate steps require continuous reassessment and adjustment, but the existence of other wounds (blast injuries, penetrating and blunt trauma) even further complicates the management of bum casualties