Satisfactory outcomes following a second autologous hematopoietic cell transplantation for multiple myeloma in poor stem cell mobilizers: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Autologous hematopoietic cell transplants (auto-HCTs) remain the standard of care for transplant-eligible MM patients. The general practice has been to undergo upfront apheresis following induction to collect sufficient number of CD34+ cells to facilitate two auto-HCTs. However, 5-30% of MM patients do not initially mobilise a sufficient number of hematopoietic stem cells and are classified as poor mobilizers (PM).

Autologous stem cell transplantation in T-cell/histiocyte-rich large B-cell lymphoma: EBMT Lymphoma Working Party study.

Although broadly used, consolidative autologous hematopoietic stem cell transplantation (auto-HCT) for relapsed/refractory (R/R) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here, we have analyzed outcomes of auto-HCT for THRLBCL compared with diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with R/R THRLBCL and DLBCL, respectively, who underwent a first auto-HCT in a salvage-sensitive disease status as assessed by positron emission tomography-computed tomography between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation database.

Autistic Adults Avoid Unpredictability in Decision-Making.

Decision-making under unpredictable conditions can cause discomfort in autistic persons due to their preference for predictability. Decision-making impairments might furthermore be associated with a dysregulation of sex and stress hormones. This prospective, cross-sectional study investigated decision-making in 32 autistic participants (AP, 14 female) and 31 non-autistic participants (NAP, 20 female) aged 18-64 years.

Systemic and strict regulation of the glutathione redox state in mitochondria and cytosol is needed for zebrafish ontogeny.

Background: Redox control seems to be indispensable for proper embryonic development. The ratio between glutathione (GSH) and its oxidized disulfide (GSSG) is the most abundant cellular redox circuit.

Methods: We used zebrafish harboring the glutaredoxin 1-redox sensitive green fluorescent protein (Grx1-roGFP) probe either in mitochondria or cytosol to test the hypothesis that the GSH:GSSG ratio is strictly regulated through zebrafish embryogenesis to sustain the different developmental processes of the embryo.

Separable Roles for Neur and Ubiquitin in Delta Signalling in the CNS Lineages.

The execution of a Notch signal at the plasma membrane relies on the mechanical force exerted onto Notch by its ligand. It has been appreciated that the DSL ligands need to collaborate with a ubiquitin (Ub) ligase, either Neuralized or Mindbomb1, in order to exert this pulling force, but the role of ubiquitylation per se is uncertain. Regarding the Delta-Neur pair, it is documented that neither the Neur catalytic domain nor the Delta intracellular lysines (putative Ub acceptors) are needed for activity.

The meaning of ubiquitylation of the DSL ligand Delta for the development of Drosophila.

Background: Ubiquitylation (ubi) of the intracellular domain of the Notch ligand Delta (Dl) by the E3 ligases Neuralized (Neur) and Mindbomb1 (Mib1) on lysines (Ks) is thought to be essential for the its signalling activity. Nevertheless, we have previously shown that DlK2R-HA, a Dl variant where all Ks in its intracellular domain (ICD) are replaced by the structurally similar arginine (R), still possess weak activity if over-expressed. This suggests that ubi is not absolutely required for Dl signalling.

Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP).

We compared FT14 (fludarabine 150-160 mg/m, treosulfan 42 g/m) versus FB4 (fludarabine 150-160 mg/m, busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4.

Using to Analyse the Human Paralogs of the ESCRT-III Core Component Shrub/CHMP4/Snf7 and Its Interactions with Members of the LGD/CC2D1 Family.

The evolutionary conserved ESCRT-III complex is a device for membrane remodelling in various cellular processes, such as the formation of intraluminal vesicles (ILVs), cytokinesis, and membrane repair. The common theme of all these processes is the abscission of membrane away from the cytosol. At its heart in is Shrub, CHMP4 in humans, which dynamically polymerises into filaments through electrostatic interactions among the protomers.

Increasing the Batch Size of a QESD Crystallization by Using a MSMPR Crystallizer.

Quasi-emulsion solvent diffusion (QESD) crystallizations can improve the micromeritic properties of drugs and excipients. A solution is dispersed in a miscible antisolvent as a transient emulsion. Using this technique, substances that normally crystallize in the form of e.

Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).

Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule.

Complications of Autologous Stem Cell Transplantation in Multiple Myeloma: Results from the CALM Study.

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0−100 days, 101 days−1 year, and >1 year after the first transplant.

Towards a better understanding of the role of stabilizers in QESD crystallizations.

Quasi-emulsion solvent-diffusion crystallization (QESD) is a type of spherical crystallization which can be used as a particle design method to improve the flowability and micromeritic properties of drugs or excipients. Spherical particles are generated by dispersing a solvent phase in an antisolvent so that a transient emulsion is formed. Within the droplets the material can crystallize and agglomerate into spherical, hollow particles.

100% visual inspection of tablets produced with continuous direct compression and coating.

Visual appearance of tablets is an important property for patients. Since the visual appearance is most strongly influenced by the applied coating, this necessitates a high level of process control and homogeneity in the coating process. In recent years, a number of tablet coaters have been developed that can be used in combination with continuous tablet production lines.

Enabling the direct compression of metformin hydrochloride through QESD crystallization.

Metformin hydrochloride is a drug used in the treatment of type 2 diabetes. It shows very poor flowability and agglomeration under storage so that a direct compression of the material into tablets has not yet been successfully realized. In a previous study the authors showed that a quasi-emulsion solvent-diffusion (QESD) crystallization technique can be used to drastically improve the flowability and reduce storage agglomeration of this drug.

The role of ligand endocytosis in notch signalling.

The Notch signalling receptor is a mechanoreceptor that is activated by force. This force elicits a conformational change in Notch that results in the release of its intracellular domain into the cytosol by two consecutive proteolytic cleavages. In most cases, the force is generated by pulling of the ligands on the receptor upon their endocytosis.

Improving flowability and reducing storage agglomeration of metformin hydrochloride through QESD crystallization.

Metformin hydrochloride is a drug used in the treatment of type 2 diabetes and is administered orally using high-dose tablets. Due to its poor flowability and agglomeration during storage, metformin is commonly processed using an intermediate step such as granulation before the material can be compressed into tablets. Spherical crystallization is a method, which can be used to improve the flowability and tabletability of drugs and excipients.

Lethal (2) giant discs (Lgd)/CC2D1 is required for the full activity of the ESCRT machinery.

Background: A major task of the endosomal sorting complex required for transport (ESCRT) machinery is the pinching off of cargo-loaded intraluminal vesicles (ILVs) into the lumen of maturing endosomes (MEs), which is essential for the complete degradation of transmembrane proteins in the lysosome. The ESCRT machinery is also required for the termination of signalling through activated signalling receptors, as it separates their intracellular domains from the cytosol. At the heart of the machinery lies the ESCRT-III complex, which is required for an increasing number of processes where membrane regions are abscised away from the cytosol.

Unravelling of Hidden Secrets: The Tumour Suppressor Lethal (2) Giant Discs (Lgd)/CC2D1, Notch Signalling and Cancer.

The endosomal pathway plays a pivotal role upon signal transduction in the Notch pathway. Recent work on lethal (2) giant discs (lgd) points to an additional critical role in avoiding uncontrolled ligand-independent signalling during trafficking of the Notch receptor through the endosomal pathway to the lysosome for degradation. In this chapter, we will outline the journey of Notch through the endosomal system and present an overview of the current knowledge about Lgd and its mammalian orthologs Lgd1/CC2D1b and Lgd2/CC2D1a.

Multiple sclerosis and COVID-19.

This paper reviews currently available data on the novel coronavirus and clinical features of COVID-19, followed by a detailed section on possible modifications of immunomodulatory therapy in multiple sclerosis patients with COVID-19, based on what we know so far. There are discussed: (i) The COVID-19 disease (Epidemiological background SARS-CoV-1 coronavirus; Autoimmune response to COVID-19; Asymptomatic course; SARS-CoV-2 test; COVID-19 symptoms), (ii) Treatment of COVID-19 (Experimental plasma treatment; Antiviral therapy; Antimalarial treatment scheme; Biological treatment; Corticosteroid treatment; Symptomatic treatment; Vaccine preparation) and (iii) Multiple sclerosis and SARS-CoV-2 infection (Epidemiological recommendation).

Alexithymic and autistic traits: Relevance for comorbid depression and social phobia in adults with and without autism spectrum disorder.

Adults with autism often develop mental health problems such as depression and social phobia. The reasons for this are still unclear. Many studies found that alexithymia plays an important role in mental health problems like depression.

BrainSpace: a toolbox for the analysis of macroscale gradients in neuroimaging and connectomics datasets.

Understanding how cognitive functions emerge from brain structure depends on quantifying how discrete regions are integrated within the broader cortical landscape. Recent work established that macroscale brain organization and function can be described in a compact manner with multivariate machine learning approaches that identify manifolds often described as cortical gradients. By quantifying topographic principles of macroscale organization, cortical gradients lend an analytical framework to study structural and functional brain organization across species, throughout development and aging, and its perturbations in disease.

Expanding crystallization tools for nucleic acid complexes using U1A protein variants.

The major bottlenecks in structure elucidation of nucleic acids are crystallization and phasing. Co-crystallization with proteins is a straight forward approach to overcome these challenges. The human RNA-binding protein U1A has previously been established as crystallization module, however, the absence of UV-active residues and the predetermined architecture in the asymmetric unit constitute clear limitations of the U1A system.