Longitudinal Goal Attainment With Repeat Injections of AbobotulinumtoxinA in Adults With Lower Limb Spasticity: Results From a Prospective Observational Study.

Objective: To assess longitudinal goal attainment with repeat abobotulinumtoxinA (AboBoNT-A) injections for lower limb spasticity (LLS) over 16 months.

Design: Prospective, longitudinal, international, multicenter, observational study (NCT04050527).

Setting: Specialist neurorehabilitation centers.

Prevalence and management of hypertensive patients in clinical practice: Cross-sectional registry in five countries outside the European Union.

Inadequate blood pressure (BP) control may be linked with poor adherence to guidelines by the treating physician. This study aimed at assessing the rates of controlled hypertension as per the 2009 Reappraisal of the 2007 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines in 2185 hypertensive adults across five countries (Algeria, Pakistan, Ukraine, Egypt and Venezuela). The rates of controlled hypertension according to physician perception, type of therapy and risk factors were evaluated.

GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin's B lymphomas via NF-κB-dependent induction of HIF-1α.

Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma.

GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death.

Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell death (CICD). Escape from CICD is particularly relevant in the context of cancer as apoptosis inhibition only is often not sufficient to allow oncogenic transformation.

Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response.

Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice.

Severe thymic atrophy in a mouse model of skin inflammation accounts for impaired TNFR1 signaling.

Transgenic mice expressing the caspase-cleaved form of the tyrosine kinase Lyn (LynΔN) develop a TNFα-dependent skin disease that accurately recapitulates human psoriasis. Participation of lymphocytes in this disease was confirmed by backcrossing LynΔN mice on a Rag-1 deficient background. The present study was therefore conducted to analyze whether modification of lymphocyte homeostasis does occur and participate in the phenotype of LynΔN mice.

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.

We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing.

Mitochondrial control of caspase-dependent and -independent cell death.

Mitochondria control whether a cell lives or dies. The role mitochondria play in deciding the fate of a cell was first identified in the mid-1990s, because mitochondria-enriched fractions were found to be necessary for activation of death proteases, the caspases, in a cell-free model of apoptotic cell death. Mitochondrial involvement in apoptosis was subsequently shown to be regulated by Bcl-2, a protein that was known to contribute to cancer in specific circumstances.

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation.

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis.

Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells.

Imatinib mesylate is widely used for the treatment of patients with chronic myelogenous leukemia (CML). This compound is very efficient in killing Bcr-Abl-positive cells in a caspase-dependent manner. Nevertheless, several lines of evidence indicated that caspase-mediated cell death (i.

Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway.

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is known to protect tumor cells from apoptosis and more specifically from the Fas-mediated apoptotic signal. The antitumoral agent edelfosine sensitizes leukemic cells to death by inducing the redistribution of the apoptotic receptor Fas into plasma membrane subdomains called lipid rafts. Herein, we show that inhibition of the PI3K signal by edelfosine triggers a Fas-mediated apoptotic signal independently of the Fas/FasL interaction.

Dominant-negative Fas mutation is reversed by down-expression of c-FLIP.

Fas triggering by agonistic antibodies or by its cognate ligand, FasL, induces apoptotic cell death, whereas mutation in the Fas death domain is associated with lymphoma progression. On prolonged culture in the presence of an agonistic anti-Fas antibody, we raised a Jurkat cell line resistant to agonistic antibodies but still sensitive to soluble FasL, which carried at the heterozygous state, a point mutation into the Fas death domain. Down-modulation of c-FLIP expression reversed the blockade of the Fas pathway.

In vitro endothelial cell susceptibility to xenobiotics: comparison of three cell types.

In three different endothelial cell (EC) cultures (primary human umbilical cord vein, so-called HUVEC; and immortalized cell lines HBMEC and EA-hy-926), the effects of different xenobiotics were studied in order to standardize vascular EC models for in vitro pharmacotoxicological studies. Cell characteristics were first investigated by the production and the mRNA levels of known endothelial markers in the three EC culture models. EC secretory products, tissue plasminogen activator (tPA) and von Willebrand factor (vWF), were present in the supernatant of the immortalized cell lines.

Cutting edge: SDS-stable Fas microaggregates: an early event of Fas activation occurring with agonistic anti-Fas antibody but not with Fas ligand.

The 45 kDa Fas or CD95 receptor triggers apoptosis via the caspase cascade when stimulated by its ligand FasL or by agonistic Abs. Activated Fas receptors seem to oligomerize very early into SDS-stable and reducing agent-resistant microaggregates of 200-250 kDa on SDS-PAGE. However, these microaggregates have so far only been reported using agonistic anti-Fas Abs, and no results have been reported using FasL.