Tumor organoids improve mutation detection of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) presents challenges in detecting somatic mutations due to its complex cellular composition. This study investigated the utility of patient-derived organoids (PDOs) to overcome these obstacles and enhance somatic mutation identification. Surgically resected PDAC tumors and their paired PDOs from 21 patients were examined.

The Impact of Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma.

Purpose: Unfortunately, treatment of patients with uveal melanoma (UM) with metastatic disease is limited. Twenty percent of patients with UM harbor a mutation in the splicing factor gene SF3B1, suggesting that aberrant spliceosome function plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome-compromised leukemic cells to these compounds.

B-Cell Activation Gene Signature in Blood and Liver of Hepatitis B e Antigen-Positive Patients With Immune Active Chronic Hepatitis B.

Background: Studies on chronic hepatitis B virus (HBV) infection have shown immune dysfunction involving multiple cell types, including T cells. B cells have been evaluated more recently, but in contrast to T cells, more pronounced activation of circulating B cells has been reported. To gain more insight into the activation status of B cells, we investigated gene profiles of B cells in the blood and liver of patients with chronic HBV.

Intrahepatic plasma cells, but not atypical memory B cells, associate with clinical phases of chronic hepatitis B.

Studies have traditionally focused on the role of T cells in chronic hepatitis B (CHB), but recent evidence supports a role for B cells. The enrichment of so-called atypical memory (AtM) B cells, which show reduced signaling and impaired differentiation, is believed to be a characteristic feature of CHB, potentially contributing to the observed dysfunctional anti-HBsAg B-cell responses. Our study, involving 62 CHB patients across clinical phases, identified AtM B cells expressing IFNLR1 and interferon-stimulated genes.

Whole-genome mapping of APOBEC mutagenesis in metastatic urothelial carcinoma identifies driver hotspot mutations and a novel mutational signature.

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes mutate specific DNA sequences and hairpin-loop structures, challenging the distinction between passenger and driver hotspot mutations. Here, we characterized 115 whole genomes of metastatic urothelial carcinoma (mUC) to identify APOBEC mutagenic hotspot drivers. APOBEC-associated mutations were detected in 92% of mUCs and were equally distributed across the genome, while APOBEC hotspot mutations (ApoHMs) were enriched in open chromatin.

Runx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo.

Hematopoietic stem cells (HSCs) produce all essential cellular components of the blood. Stromal cell lines supporting HSCs follow a vascular smooth muscle cell (vSMC) differentiation pathway, suggesting that some hematopoiesis-supporting cells originate from vSMC precursors. These pericyte-like precursors were recently identified in the aorta-gonad-mesonephros (AGM) region; however, their role in the hematopoietic development in vivo remains unknown.

Association of HBsAg levels with differential gene expression in NK, CD8 T, and memory B cells in treated patients with chronic HBV.

Background & Aims: HBsAg secretion may impact immune responses to chronic HBV infection. Thus, therapeutic approaches to suppress HBsAg production are being investigated. Our study aims to examine the immunomodulatory effects of high and low levels of circulating HBsAg and thereby improve our understanding of anti-HBV immunity.

Classification of Inflammation of Unknown Origin patients based on RNA-seq and SomaScan data.

A preliminary analysis was conducted on data acquired from RNA sequencing and SomaScan platforms, for the classification of patients with Inflammation of Unknown Origin. To this end, a multimodal data integration approach was designed, by combining the two platforms, in order to assess the potentiality of learning estimators, using the differentially expressed features from the independent profiling experiments of both platforms. The classification framing was the differentiation of Inflammation of Unknown Origin patients against a multitude of Systemic Autoinflammatory disease patients.

TLR9 plus STING Agonist Adjuvant Combination Induces Potent Neopeptide T Cell Immunity and Improves Immune Checkpoint Blockade Efficacy in a Tumor Model.

Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy.

Katdetectr: an R/bioconductor package utilizing unsupervised changepoint analysis for robust kataegis detection.

Background: Kataegis refers to the occurrence of regional genomic hypermutation in cancer and is a phenomenon that has been observed in a wide range of malignancies. A kataegis locus constitutes a genomic region with a high mutation rate (i.e.

Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition.

Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors.

Personalised decision making to predict absolute metastatic risk in cutaneous squamous cell carcinoma: development and validation of a clinico-pathological model.

Background: Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer, affecting more than 2 million people worldwide yearly and metastasising in 2-5% of patients. However, current clinical staging systems do not provide estimates of absolute metastatic risk, hence missing the opportunity for more personalised treatment advice. We aimed to develop a clinico-pathological model that predicts the probability of metastasis in patients with cSCC.

Single-cell RNA sequencing of liver fine-needle aspirates captures immune diversity in the blood and liver in chronic hepatitis B patients.

Background And Aims: HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing.

Evaluation of pre-processing methods for tear fluid proteomics using proximity extension assays.

Tear fluid forms a potential source for biomarker identification, and can be minimal invasively collected via Schirmer strips. The lack of knowledge on the processing of Schirmer strips however complicates the analysis and between-study comparisons. We studied two different pre-processing methods, specifically the use of punches of the strip versus elution of the strip in a buffer.

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors.

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing.

Patient-Derived Xenografts and Organoids Recapitulate Castration-Resistant Prostate Cancer with Sustained Androgen Receptor Signaling.

Castration-resistant prostate cancer (CRPC) remains an incurable and lethal malignancy. The development of new CRPC treatment strategies is strongly impeded by the scarcity of representative, scalable and transferable preclinical models of advanced, androgen receptor (AR)-driven CRPC. Here, we present contemporary patient-derived xenografts (PDXs) and matching PDX-derived organoids (PDXOs) from CRPC patients who had undergone multiple lines of treatment.

Trained Immunity in Primary Sjögren's Syndrome: Linking Type I Interferons to a Pro-Atherogenic Phenotype.

Background: Trained immunity - or innate immune memory - can be described as the long-term reprogramming of innate immune cells towards a hyperresponsive state which involves intracellular metabolic changes. Trained immunity has been linked to atherosclerosis. A subgroup of patients with primary Sjögren's syndrome (pSS) exhibits systemic type I interferon (IFN) pathway activation, indicating innate immune hyperactivation.

PDGFRβ cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny.

Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFRβ signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFRβ is involved.

Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests.

Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under investigation.

Chromosome 3p25.3 Gain Is Associated With Cisplatin Resistance and Is an Independent Predictor of Poor Outcome in Male Malignant Germ Cell Tumors.

Purpose: Cisplatin is the main systemic treatment modality for male type II germ cell tumors (GCTs). Although generally very effective, 5%-10% of patients suffer from cisplatin-resistant disease. Identification of the driving mechanisms of resistance will enable improved risk stratification and development of alternative treatments.

Stratification of hospitalized COVID-19 patients into clinical severity progression groups by immuno-phenotyping and machine learning.

Quantitative or qualitative differences in immunity may drive clinical severity in COVID-19. Although longitudinal studies to record the course of immunological changes are ample, they do not necessarily predict clinical progression at the time of hospital admission. Here we show, by a machine learning approach using serum pro-inflammatory, anti-inflammatory and anti-viral cytokine and anti-SARS-CoV-2 antibody measurements as input data, that COVID-19 patients cluster into three distinct immune phenotype groups.

Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma.

Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding the spliceosome factor , and whilst patients with such mutations generally have an intermediate risk on developing metastatic disease, a third of these patients develop early metastasis within 5 years after diagnosis. We therefore investigated whether clinical and/or genetic variables could be indicative of short progression-free survival (PFS < 60 months) or long PFS (PFS ≥ 60 months) for -mutated () UM patients. We collected 146 UM from our Rotterdam Ocular Melanoma Studygroup (ROMS) database and external published datasets.