Human-Level Differentiation of Medulloblastoma from Pilocytic Astrocytoma: A Real-World Multicenter Pilot Study.

Medulloblastoma and pilocytic astrocytoma are the two most common pediatric brain tumors with overlapping imaging features. In this proof-of-concept study, we investigated using a deep learning classifier trained on a multicenter data set to differentiate these tumor types. We developed a patch-based 3D-DenseNet classifier, utilizing automated tumor segmentation.

Implementation of the updated Sydney system biopsy protocol improves the diagnostic yield of gastric preneoplastic conditions: Results from a real-world study.

Background: The updated Sydney system biopsy protocol (USSBP) standardizes the sampling of gastric biopsies for the detection of preneoplastic conditions (e.g., gastric intestinal metaplasia [GIM]), but the real-world diagnostic yield is not well-described.

Microenvironmental control of hematopoietic stem cell fate via CXCL8 and protein kinase C.

Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling this are poorly understood. Genetically barcoded genome editing of synthetic target arrays for lineage tracing (GESTALT) zebrafish were used to screen for factors expressed by the sinusoidal vascular niche that alter the phylogenetic distribution of the HSC pool under native conditions. Dysregulated expression of protein kinase C delta (PKC-δ, encoded by prkcda) increases the number of HSC clones by up to 80% and expands polyclonal populations of immature neutrophil and erythroid precursors.

Carbamylation of Integrin : The Mechanistic Link to Platelet Dysfunction in ESKD.

Background: Bleeding diatheses, common among patients with ESKD, can lead to serious complications, particularly during invasive procedures. Chronic urea overload significantly increases cyanate concentrations in patients with ESKD, leading to carbamylation, an irreversible modification of proteins and peptides.

Methods: To investigate carbamylation as a potential mechanistic link between uremia and platelet dysfunction in ESKD, we used liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to quantify total homocitrulline, and biotin-conjugated phenylglyoxal labeling and Western blot to detect carbamylated integrin (a receptor required for platelet aggregation).

Influence of Spine Curvature on the Efficacy of Transcutaneous Lumbar Spinal Cord Stimulation.

Transcutaneous spinal cord stimulation is a non-invasive method for neuromodulation of sensorimotor function. Its main mechanism of action results from the activation of afferent fibers in the posterior roots-the same structures as targeted by epidural stimulation. Here, we investigated the influence of sagittal spine alignment on the capacity of the surface-electrode-based stimulation to activate these neural structures.

In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets.

High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ER-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo.

CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy.

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting, and several suitable immunotargets (HAVCR2/CD33 and HAVCR2/CLEC12A) have been identified in adult AML.

Antiemetic Prophylaxis with Fosaprepitant and 5-HT-Receptor Antagonists in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Background: High-dose myeloablative conditioning prior to autologous hematopoietic stem cell transplantation (autoHSCT) in pediatric patients is usually highly emetogenic. The antiemetic neurokinin-1 receptor antagonist fosaprepitant was safe and effective in children receiving highly emetogenic chemotherapy. Data on fosaprepitant during autoHSCT in children are currently not available.

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells.

Background: Relapsed/refractory B-precursor acute lymphoblastic leukemia (BCP-ALL) remains a major therapeutic challenge in pediatric hematology. Chimeric antigen receptor (CAR) T cells targeting CD19 have shown remarkable initial response rates in BCP-ALL patients, while long-term leukemia control rate is only about 50%. So far, main mechanisms of BCP-ALL relapse after CD19-CAR T-cell therapy have been either insufficient CAR T-cell persistence in vivo or loss of surface CD19.

Leukemia-induced dysfunctional TIM-3CD4 bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients.

Interaction of malignancies with tissue-specific immune cells has gained interest for prognosis and intervention of emerging immunotherapies. We analyzed bone marrow T cells (bmT) as tumor-infiltrating lymphocytes in pediatric precursor-B cell acute lymphoblastic leukemia (ALL). Based on data from 100 patients, we show that ALL is associated with late-stage CD4 phenotype and loss of early CD8 T cells.

Efficacy, safety and feasibility of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric patients receiving moderately and highly emetogenic chemotherapy - results of a non-interventional observation study.

Background: Chemotherapy-induced nausea and vomiting (CINV) belong among the most burdensome side effects in hemato-oncology. Mostly, a combination of ondansetron and dexamethasone is used as antiemetic prophylaxis in pediatric patients undergoing emetogenic chemotherapy. However, dexamethasone is prohibited in different pediatric chemotherapy protocols.

Author Correction: Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effects of statins on multispecies oral biofilm identify simvastatin as a drug candidate targeting Porphyromonas gingivalis.

Background: Statins effectively reduce risk of cardiovascular-related morbidity and mortality in patients with hyperlipidemia, hypertension, or type 2 diabetes. In addition to lowering cholesterol levels, several studies have attributed statins with immunomodulatory and bactericidal properties. Therefore, the aim of this study was to investigate statins' antimicrobial activity against periodontal homeostasis bacteria.

Impact of fibrinogen carbamylation on fibrin clot formation and stability.

Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading to irreversible changes of protein charge, structure and function. Levels of carbamylated proteins increase significantly in chronic kidney disease and carbamylated albumin is considered as an important biomarker indicating mortality risk. High plasma concentrations and long half-life make fibrinogen a prime target for carbamylation.

CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment.

The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Recent advances marking fluorescent HSPCs have allowed exquisite visualization of HSPCs in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Here, we show that the chemokine and its receptor, , are expressed by zebrafish endothelial cells, and we identify signaling as a positive regulator of HSPC colonization.

Carbamylated LL-37 as a modulator of the immune response.

Carbamylation of lysine residues and protein N-termini is an ubiquitous, non-enzymatic post-translational modification. Carbamylation at sites of inflammation is due to cyanate formation during the neutrophil oxidative burst and may target lysine residues within the antimicrobial peptide LL-37. The bactericidal and immunomodulatory properties of LL-37 depend on its secondary structure and cationic nature, which are conferred by arginine and lysine residues.

Antibodies against carbamylated proteins are present in primary Sjögren's syndrome and are associated with disease severity.

Objectives: Herein, we investigate the presence and prognostic value of autoantibodies against carbamylated proteins (anti-CarP) in the serum of patients with primary Sjögren's syndrome (pSS).

Patients And Methods: Serum levels of anti-CarP antibodies were measured in Norwegian patients with pSS (n=78) and corresponding controls (n=74) using ELISA and analysed in relation with exocrine gland function, degree of salivary gland inflammation, signs of ectopic germinal centre (GC) formation and immunological markers. For univariate comparisons, the Mann-Whitney U test and χ(2) or Fisher's exact tests were used.

Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment.

Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients.

20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing.

Variant rs1801157 in the 3'UTR of SDF-1ß does not explain variability of healthy-donor G-CSF responsiveness.

The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3'UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3'UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism.

Carbamylation of immunoglobulin abrogates activation of the classical complement pathway.

Post-translational modifications of proteins significantly affect their structure and function. The carbamylation of positively charged lysine residues to form neutral homoitrulline occurs primarily under inflammatory conditions through myeloperoxidase-dependent cyanate (CNO-) formation. We analyzed the pattern of human IgG1 carbamylation under inflammatory conditions and the effects that this modification has on the ability of antibodies to trigger complement activation via the classical pathway.

A new workflow for whole-genome sequencing of single human cells.

Unbiased amplification of the whole-genome amplification (WGA) of single cells is crucial to study cancer evolution and genetic heterogeneity, but is challenging due to the high complexity of the human genome. Here, we present a new workflow combining an efficient adapter-linker PCR-based WGA method with second-generation sequencing. This approach allows comparison of single cells at base pair resolution.