A First-in-Human Study of Cinrebafusp Alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies.

Purpose: 4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, NK cells, and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.

development and process evaluation of a web-based program for persons with multiple sclerosis.

Purpose: Research shows that persons with mild to moderate multiple sclerosis are less physically active than healthy controls even though they would benefit from it. This study focusses on the feasibility testing and process evaluation of the pilot study of a twelve-week web-based program, from Ireland, to increase physical activity in this population.

Materials And Methods: The intervention was adapted to local circumstances in Hamburg, Germany and consists of eleven modules incorporating behavior change techniques.

Quantifying the contribution of transcription factor activity, mutations and microRNAs to CD274 expression in cancer patients.

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis have been remarkably successful in inducing tumor remissions in several human cancers, yet a substantial number of patients do not respond to treatment. Because this may be partially due to the mechanisms giving rise to high PD-L1 expression within a patient, it is highly relevant to fully understand these mechanisms. In this study, we conduct a bioinformatic analysis to quantify the relative importance of transcription factor (TF) activity, microRNAs (miRNAs) and mutations in determining PD-L1 (CD274) expression at mRNA level based on data from the Cancer Genome Atlas.

A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation.

Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.

Patients And Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m) or paclitaxel monotherapy in cycle 1.

AMPK activation protects astrocytes from hypoxia‑induced cell death.

Adenosine monophosphate (AMP)‑activated protein kinase (AMPK) is a major cellular energy sensor that is activated by an increase in the AMP/adenosine triphosphate (ATP) ratio. This causes the initiation of adaptive cellular programs, leading to the inhibition of anabolic pathways and increasing ATP synthesis. AMPK indirectly inhibits mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a serine/threonine kinase and central regulator of cell growth and metabolism, which integrates various growth inhibitory signals, such as the depletion of glucose, amino acids, ATP and oxygen.

Joint recommendations for a total services account as a factor in simplifying contracts.

The objective of clinical trials is to transfer findings gained from basic research to patients and to result in innovative treatment approaches. Along with basic research, results from clinical trials thus represent a core area of medical advances. As a location for clinical trials, Germany is currently well-positioned and internationally competitive.

Disruption of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α reverts key features of the neoplastic phenotype of glioma cells.

The peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a master regulator of mitochondrial biogenesis and controls metabolism by coordinating transcriptional events. Here, we interrogated whether PGC-1α is involved in tumor growth and the metabolic flexibility of glioblastoma cells. PGC-1α was expressed in a subset of established glioma cell lines and primary glioblastoma cell cultures.

Lenalidomide consolidation treatment in patients with multiple myeloma suppresses myelopoieses but spares erythropoiesis.

New drugs for the treatment of multiple myeloma (MM) comprise immunomodulatory substances such as lenalidomide and related compounds. While lenalidomide has found its way into first-line treatment as well as into relapse therapy, little is known about lenalidomide effects on normal hematopoietic stem and progenitor cells (HSPCs). In this study, we investigated whether HSPCs are influenced by lenalidomide on a phenotypic, functional and gene expression level.

Prognostic value of circulating Bcl-2/IgH levels in patients with follicular lymphoma receiving first-line immunochemotherapy.

Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.

Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion.

In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation.

Arteriolar niches maintain haematopoietic stem cell quiescence.

Cell cycle quiescence is a critical feature contributing to haematopoietic stem cell (HSC) maintenance. Although various candidate stromal cells have been identified as potential HSC niches, the spatial localization of quiescent HSCs in the bone marrow remains unclear. Here, using a novel approach that combines whole-mount confocal immunofluorescence imaging techniques and computational modelling to analyse significant three-dimensional associations in the mouse bone marrow among vascular structures, stromal cells and HSCs, we show that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow.

Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells.

Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence.

PDGFRα and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion.

The intermediate filament protein Nestin labels populations of stem/progenitor cells, including self-renewing mesenchymal stem cells (MSCs), a major constituent of the hematopoietic stem cell (HSC) niche. However, the intracellular location of Nestin prevents its use for prospective live cell isolation. Hence it is important to find surface markers specific for Nestin⁺ cells.

The tissue inhibitor of metalloproteinases-1 improves migration and adhesion of hematopoietic stem and progenitor cells.

Homing and engraftment of hematopoietic stem and progenitor cells (HSPCs) during bone marrow transplantation are critically dependent on integrins such as β1-integrin. In the present study, we show that β1-integrin and the tetraspanin CD63 form a cell surface receptor complex for the soluble serum protein tissue inhibitor of metalloproteinases-1 (TIMP-1) on human CD34⁺ HSPCs. Through binding to this receptor complex, TIMP-1 activates β1-integrin, increases adhesion and migration of human CD34⁺ cells, and protects these cells from induced apoptosis.

Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration.

Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy.

Platelet proteome analysis reveals integrin-dependent aggregation defects in patients with myelodysplastic syndromes.

Bleeding complications are a significant clinical problem in patients with myelodysplastic syndromes even at sufficient platelet counts (>50,000/μl). However, the underlying pathology of this hemorrhagic diathesis is still unknown. Here, we analyzed the platelet proteome of patients with myelodysplastic syndromes by quantitative two-dimensional difference gel electrophoresis followed by mass spectrometric protein identification.

Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation.

The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI.

Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.

Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients.

Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields.

The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF-enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization.

Natalizumab and impedance of the homing of CD34+ hematopoietic progenitors.

Background: Treatment with natalizumab, an antibody blocking the α4-integrin, is associated with increased numbers of circulating CD34+ cells in the peripheral blood of patients with multiple sclerosis.

Objective: To determine whether natalizumab mobilizes CD34+ cells from or inhibits homing to the bone marrow (BM).

Design: Fifty-two patients with relapsing-remitting multiple sclerosis treated with natalizumab were included.