A non-conditioned bone marrow transplantation mouse model to study clonal hematopoiesis and myeloid malignancies.

Clonal hematopoiesis of indeterminate potential (CHIP) is a condition where blood or bone marrow cells carry mutations associated with hematological malignancies. Individuals with CHIP have an increased risk of developing hematological malignancies, atherosclerotic cardiovascular disease, and all-cause mortality. Bone marrow transplantation (BMT) of cells carrying CHIP mutations into irradiated mice are useful procedures to investigate the dynamics of clonal expansion and potential therapeutic strategies, but myeloablative conditioning can induce confounding effects.

A HER2 Specific Nanobody-Drug Conjugate: Site-Selective Bioconjugation and In Vitro Evaluation in Breast Cancer Models.

A human epidermal growth factor receptor 2 (HER2)-specific nanobody called 2Rs15d, containing a His3LysHis6 segment at the C-terminus, was recombinantly produced. Subsequent site-selective acylation on the C-terminally activated lysine residue allowed installation of the cytotoxin monomethyl auristatin E-functionalized cathepsin B-sensitive payload to provide a highly homogenous nanobody-drug conjugate (NBC), which demonstrated high potency and selectivity for HER2-positive breast cancer models.

Second primary non-myeloid malignancies following intensive treatment for adult acute myeloid leukaemia: a Danish population-based cohort study.

Background: Second primary malignancies (SPMs) are a well-known, long-term complication of antineoplastic treatment. This nationwide cohort study examined the risk of non-myeloid SPMs in survivors of adult acute myeloid leukaemia (AML) treated with intensive chemotherapy and, in some cases, allogeneic stem cell transplantation (alloSCT), compared to a matched general population.

Methods: Patients with incident AML between 2000 and 2018, alive and aged 18-70 years two years after start of intensive chemotherapy, were included and matched 1:10 to comparators from the general Danish population on sex, age, and the Nordic Multimorbidity Index.

Nuclear N-WASP Induces Actin Polymerization in the Nucleus with Cortactin as an Essential Factor.

Nuclear actin polymerization was reported to control different nuclear processes, but its regulation is poorly understood. Here, we show that N-WASP can trigger the formation of nuclear N-WASP/F-actin nodules. While a cancer hotspot mutant of N-WASP lacking the VCA domain (V418fs) had a dominant negative function on nuclear F-actin, an even shorter truncation mutant found in melanoma (R128*) strongly promoted nuclear actin polymerization.

Molecularly redefining small bowel adenocarcinoma to accelerate precision patient care - protocol of a multicenter observational cohort biomarker study.

Background: Small Bowel Adenocarcinoma (SBA) is a rare gastrointestinal cancer with a limited understanding of the molecular pathology. This study aims to bridge the knowledge gap, providing a robust molecular foundation for SBA and addressing the clinical challenges inherent in treating this orphan disease. The study proposes to redefine the clinical management for SBA patients through advanced molecular profiling techniques to improve potential precision medicine.

Machine Learning identifies remodeling patterns in human lung extracellular matrix.

Organ function depends on the three-dimensional integrity of the extracellular matrix (ECM). The structure resulting from the location and association of ECM components is a central regulator of cell behavior, but a dearth of matrix-specific analysis keeps it unresolved. Here, we deploy a high-resolution, 3D ECM mapping method and design a machine-learning powered pipeline to detect and characterize ECM architecture during health and disease.

Overlapping DNA methylation changes in enhancers in clonal cytopenia of undetermined significance and myelodysplastic neoplasm patients with , , or mutations.

Not available.

Orthotopic meningioma rat model exhibits morphological and immunohistochemical congruency and epigenetic concordance with benign primary patient-derived tumors.

Meningiomas are the most common primary central nervous system tumor. Clinical trials have failed to support effective medical treatments, despite initially promising animal studies. A key issue could be that available experimental models fail to mimic the clinical situation.

Mutational signatures define immune and Wnt-associated subtypes of ampullary carcinoma.

Background And Objective: Ampullary carcinoma (AMPAC) taxonomy is based on morphology and immunohistochemistry. This classification lacks prognostic reliability and unique genetic associations. We applied an approach of integrative genomics characterising patients with AMPAC exploring molecular subtypes that may guide personalised treatments.

AXL in myeloid malignancies - an elusive target?

The TAM receptor tyrosine kinase family member AXL plays critical roles in tissue homeostasis, survival, chemoresistance, and motility. This study investigates the receptor expression in six AML cell lines and bone marrow myeloblasts from 25 patients with myeloid neoplasms. We found that AXL expression was generally absent or very low in AML myeloblasts.

Using GeoMx DSP Spatial Proteomics to Investigate Immune Infiltration of NOD Mouse Islet and Exocrine Compartments.

Purpose: Type 1 Diabetes (T1D) pathogenesis involves immune cells infiltrating pancreatic Islets of Langerhans, leading to T cell activation, beta cell destruction, and impaired insulin production. However, infiltration has a heterogenic nature that isn't described in detail, as not all islets are infiltrated. The aim of this study was to investigate if the observed heterogeneity is coupled to differences in immune and/or dysfunctional status of islets or exocrine cells, and if specific markers could elucidate mechanistic details of T1D pathogenesis.

Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy.

Reporter Mice for Gene Editing: A Key Tool for Advancing Gene Therapy of Rare Diseases.

Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have been generated which, by expression of reporter genes, indicate the efficiency of precise and imprecise gene editing.

How to manage patients with germline variants: Recommendations from the Nordic working group on germline predisposition for myeloid neoplasms.

Increasing recognition of germline variants in patients with hematological malignancies prompted us to provide -specific recommendations for diagnosis, surveillance, and treatment. Causative germline variants in the predispose to the development of myeloid neoplasms (MNs), especially myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Almost 3%-5% of all patients with MDS or AML carry a pathogenic or likely pathogenic germline variant, while half of them acquire a somatic second hit in the other allele.

Endomucin marks quiescent long-term multi-lineage repopulating hematopoietic stem cells and is essential for their transendothelial migration.

Endomucin (EMCN) currently represents the only hematopoietic stem cell (HSC) marker expressed by both murine and human HSCs. Here, we report that EMCN long-term repopulating HSCs (LT-HSCs; CD150CD48LSK) have a higher long-term multi-lineage repopulating capacity compared to EMCN LT-HSCs. Cell cycle analyses and transcriptional profiling demonstrated that EMCN LT-HSCs were more quiescent compared to EMCN LT-HSCs.

TPPP-BRD9 fusion-related gallbladder carcinomas are frequently associated with intracholecystic neoplasia, neuroendocrine carcinoma, and a distinctive small tubular-type adenocarcinoma commonly accompanied with a syringomatous pattern.

A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors' database.

A proteomics-based survey reveals thrombospondin-4 as a ligand regulated by the mannose receptor in the injured lung.

Receptor-mediated cellular uptake of specific ligands constitutes an important step in the dynamic regulation of individual protein levels in extracellular fluids. With a focus on the inflammatory lung, we here performed a proteomics-based search for novel ligands regulated by the mannose receptor (MR), a macrophage-expressed endocytic receptor. WT and MR-deficient mice were exposed to lipopolysaccharide, after which the protein content in their lung epithelial lining fluid was compared by tandem mass tag-based mass spectrometry.

Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L.

RNase L is an endoribonuclease of higher vertebrates that functions in antiviral innate immunity. Interferons induce oligoadenylate synthetase enzymes that sense double-stranded RNA of viral origin leading to the synthesis of 2',5'-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L remodels the host cell transcriptome.