Cellular Therapeutics (United Kingdom)

Caspase-8 is a cysteine protease historically regarded as anti-neoplastic protein, thanks to its role in apoptosis. However, Caspase-8 expression is retained or even enhanced in several tumors, including glioblastoma (GBM), where it plays pro-tumor functions. We previously reported that it is a negative prognostic factor and contributes to resistance against DNA damaging agents, such as ionizing radiations (IR) and Temozolomide, commonly used in standard GBM treatment. We therefore investigated whether Caspase-8 may sustain DNA repair pathways proficiency in GBM. Here we uncover a novel role of Caspase-8 as promoter of the Homologous Recombination Repair (HRR). Importantly, IR promote Caspase-8 transient nuclear translocation and its recruitment to the chromatin. Moreover, Caspase-8 sustains the expression and the recruitment to the chromatin upon IR of RAD51 and CtIP, two key players of the HRR. Consistently, we identify a synthetically lethal interaction between Caspase-8 and PARP inhibition, that may enhance GBM sensitivity to IR. Remarkably, by using Caspase-8-/- murine embryo fibroblasts and a Drosophila melanogaster Caspase-8 mutant, we demonstrate that Caspase-8 plays an evolutionary conserved role in DNA repair.

<h3>Background</h3> Previous analyses from the AX8–003 clinical study indicated that in patients with refractory or unexplained chronic cough (RCC/UCC) and throat discomfort (baseline visual analogue scale [VAS] score ≥55 mm), the TRPM8 agonist AX-8 reduced bout frequency (cough bouts are defined as clusters of ≥2 coughs separated by ≤2 seconds),¹ more effectively than cough frequency. This study further explores how AX-8 preferentially targets bouts, examining detailed count- and duration-based metrics. <h3>Methods</h3> This was a randomized, double-blind, placebo-controlled crossover study of RCC/UCC patients (≥1 year cough duration, cough severity VAS score ≥40 mm, and 24h cough frequency ≥10 coughs/h at screening). In the throat discomfort subgroup (n=24), we compared the effect of AX-8 (40 mg orally disintegrating tablet BID) versus placebo on cough and bout frequencies, as previously, as well as on single and bout cough frequencies, mean number of coughs per bout, and total and mean bout durations. Analyses below focus on the 4-hour period following the first dose on day 1. <h3>Results</h3> AX-8 showed a non-significant decrease in single cough frequency (15.5%, p&gt;0.2) but significantly reduced bout cough frequency (50.4%, p=0.001) without affecting the number of coughs per bout (p&gt;0.2). Placebo, conversely, moderately reduced the number of coughs per bout. In terms of cough duration, AX-8 significantly lowered the total bout duration (51.4%, p&lt;0.01), primarily by reducing bout frequency (p&lt;0.001) but not the mean bout duration (p&gt;0.1). In contrast, placebo’s small benefit arose from shortening the mean bout duration. <h3>Conclusion</h3> These data demonstrate that AX-8 selectively targets the initiation of bouts rather than single coughs, which are less important for RCC/UCC patients. The different effects of AX-8 and placebo on bout characteristics may reflect distinct underlying neurophysiological mechanisms. <h3>Clinical Trial Registry</h3> NCT04866563 <h3>Reference</h3> Holt KJ, <i>et al. ERJ Open Res.</i> 2024;<b>10</b>(6):00316–2024. https://doi.org/10.1183/23120541.00316-2024

Severe refractory alloimmune thrombocytopenia is a challenging and life-threatening complication in patients with hematologic disorders who are undergoing allogeneic hematopoietic stem cell transplantation. This study aimed to investigate the utility of continuous intravenous immunoglobulin and platelet transfusions as a therapeutic approach for alloimmune thrombocytopenia in patients undergoing allogeneic transplants. A single-center retrospective analysis was conducted of ten adult allogeneic transplant patients hospitalized with transfusion-refractory alloimmune thrombocytopenia. Intravenous immunoglobulin (2 g/kg) was administered as a slow continuous infusion over 48 h along with a continuous apheresis platelet infusion (one apheresis unit over eight hours). Clinical response was defined as the resolution of bleeding or patients being able to undergo the required procedure without bleeding complications. The median time after the transplant was 27.5 (range: 7-299) days. Myeloablative and reduced-intensity conditioning were performed in 5 (50 %) and 5 (50 %) patients, respectively. The median platelet count at the time of infusion was 4.5 × 109/L. All patients were able to achieve clinical response with the median maximum platelet count within ten days of the infusion being 41.0 × 109/L. The median time to best response was three days with a median platelet count of 27.0 × 10⁹/L. Continuous intravenous immunoglobulin and platelet infusions over 48 h may be able to overcome life-threatening refractory alloimmune thrombocytopenia in transplant patients and may provide a bridging measure until platelet engraftment or for life-threatening hemorrhage or invasive procedures with high bleeding risk.

Abstract Manganese dioxide is a material that is more and more used in its particular form, for many industrial applications such as chemical catalysis or for batteries. Thus, workers can be exposed to this particulate chemical. It is known that overexposure to manganese leads to a brain disease called manganism. However, manganese is also known to impact the pulmonary function, which is important as pulmonary exposure is of prime importance for workers. We thus investigated the effects of manganese dioxide on macrophages, i.e. the scavenger cells that take particulates in charge in our bodies. To this purpose, we used a combination of proteomic and targeted approaches, in order to obtain a wide view of the cellular responses to manganese dioxide. We also used a repeated exposure mode, in order to better mimic occupational exposure. Our results point out the fact that manganese oxide nanoparticles are rather toxic for macrophages and induce mitochondrial dysfunction, oxidative stress and a pro-inflammatory response. Environmental significance Manganese dioxide is more and more used in batteries, so that workers in batteries factories are exposed to this metallic oxide. As always for particulate materials, macrophages are the first line of defense of the organism. We thus investigated the effects of manganese dioxide on macrophages, using a repeated exposure scheme to mimic occupational exposure, and the effects were documented by a combination of proteomic and targeted approaches. The functional effects include mitochondrial dysfunction, oxidative stress and inflammation.