Bi-specific antibody engagers for cancer immunotherapy.

Bispecific antibody engagers are fusion proteins composed of a nanobody that recognizes immunoglobulin kappa light chains ( ) and a nanobody that recognizes either CTLA-4 or PD-L1. These fusions show strong antitumor activity in mice through recruitment of polyclonal immunoglobulins independently of specificity or isotype. In the MC38 mouse model of colorectal carcinoma, the anti-CTLA-4 conjugate eradicates tumors and reduces the number of intratumoral regulatory T cells.

Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

Rett syndrome (RTT) and Rett-like syndromes [i.e., CDKL5 deficiency disorder (CDD) and FOXG1-syndrome] represent rare yet profoundly impactful neurodevelopmental disorders (NDDs).

Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations.

The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging.

Quantifying genome-wide transcription factor binding affinities for chromatin using BANC-seq.

Transcription factors (TFs) bind specific DNA sequences to regulate transcription. Apart from DNA sequences, local factors such as DNA accessibility and chromatin structure determine the affinity of a TF for any given locus. Including these factors when measuring TF-DNA affinities has proven difficult.

The small CRL4 ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics.

Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4).

Seasonal variation in BCG-induced trained immunity.

The Bacille Calmette-Guerin (BCG) vaccine is a well-established inducer of innate immune memory (also termed trained immunity), causing increased cytokine production upon heterologous secondary stimulation. Innate immune responses are known to be influenced by season, but whether seasons impact induction of trained immunity is not known. To explore the influence of season on innate immune memory induced by the BCG vaccine, we vaccinated healthy volunteers with BCG either during winter or spring.

LSD1/KDM1A and GFI1B repress endothelial fate and induce hematopoietic fate in induced pluripotent stem cell-derived hemogenic endothelium.

Differentiation of induced pluripotent stem cells (iPSC) into hematopoietic lineages offers great therapeutic potential. During embryogenesis, hemogenic endothelium (HE) gives rise to hematopoietic stem and progenitor cells through the endothelial- to-hematopoietic transition (EHT). Understanding this process using iPSC is key to generating functional hematopoietic stem cells (HSC), a currently unmet challenge.

Deciphering the heterogeneity of differentiating hPSC-derived corneal limbal stem cells through single-cell RNA sequencing.

A comprehensive understanding of the human pluripotent stem cell (hPSC) differentiation process stands as a prerequisite for the development of hPSC-based therapeutics. In this study, single-cell RNA sequencing (scRNA-seq) was performed to decipher the heterogeneity during differentiation of three hPSC lines toward corneal limbal stem cells (LSCs). The scRNA-seq data revealed nine clusters encompassing the entire differentiation process, among which five followed the anticipated differentiation path of LSCs.

Ferumoxtran-10-enhanced MRI for pre-operative metastatic lymph node detection in pancreatic, duodenal, or periampullary adenocarcinoma.

Objectives: To assess 3-Tesla (3-T) ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI in detecting lymph node (LN) metastases for resectable adenocarcinomas of the pancreas, duodenum, or periampullary region in a node-to-node validation against histopathology.

Methods: Twenty-seven consecutive patients with a resectable pancreatic, duodenal, or periampullary adenocarcinoma were enrolled in this prospective single expert centre study. Ferumoxtran-10-enhanced 3-T MRI was performed pre-surgery.

Repeated COVID-19 Vaccination Drives Memory T- and B-cell Responses in Kidney Transplant Recipients: Results From a Multicenter Randomized Controlled Trial.

Background: Insight into cellular immune responses to COVID-19 vaccinations is crucial for optimizing booster programs in kidney transplant recipients (KTRs).

Methods: In an immunologic substudy of a multicenter randomized controlled trial (NCT05030974) investigating different repeated vaccination strategies in KTR who showed poor serological responses after 2 or 3 doses of an messenger RNA (mRNA)-based vaccine, we compared SARS-CoV-2-specific interleukin-21 memory T-cell and B-cell responses by enzyme-linked immunosorbent spot (ELISpot) assays and serum IgG antibody levels. Patients were randomized to receive: a single dose of mRNA-1273 (100 μg, n = 25), a double dose of mRNA-1273 (2 × 100 μg, n = 25), or a single dose of adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.

Unraveling interindividual variation of trimethylamine -oxide and its precursors at the population level.

Trimethylamine -oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants.

H3K56 acetylation affects Candida albicans morphology and secreted soluble factors interacting with the host.

In recent years, epigenetics has been revealed as a mechanism able to modulate the expression of virulence traits in diverse pathogens, including Candida albicans. Indeed, epigenetic regulation can sense environmental changes, leading to the rapid and reversible modulation of gene expression with consequent adaptation to novel environments. How epigenetic changes can impact expression and signalling output, including events associated with mechanisms of morphological transition and virulence, is still poorly studied.

Detection of DNA Contamination in Prenatal Samples from Whole Exome Sequencing Data.

Background: Maternal cell contamination (MCC) in prenatal samples poses a risk for misdiagnosis, and therefore, testing for contamination is necessary during genetic analysis of prenatal specimens. MCC testing is currently performed as a method separate from the diagnostic method. With the increasing application of whole exome sequencing (WES) in prenatal diagnosis, we sought to develop a method to estimate the level of contamination from WES data, aiming to eliminate the need for a separate MCC test.

Risk factors for advanced colorectal neoplasia and colorectal cancer detected at surveillance: a nationwide study in the modern era.

Aim: Recommendations for surveillance after colonoscopy are based on risk factors for metachronous advanced colorectal neoplasia (AN) and colorectal cancer (CRC). The value of these risk factors remains unclear in populations enriched by individuals with a positive faecal immunochemical test and were investigated in a modern setting.

Methods And Results: This population-based cohort study included all individuals in the Netherlands of ≥55 years old with a first adenoma diagnosis in 2015.

SARS-CoV-2 Seroprevalence Trends in the Netherlands in the Variant of Concern Era: Input for Future Response.

Background: To inform future response planning we aimed to assess SARS-CoV-2 trends in infection- and/or vaccine-induced immunity, including breakthrough infections, among (sub)groups, professions and regions in the Dutch population during the Variant of Concern (VOC)-era.

Methods: In this prospective population-based cohort, randomly selected participants (n = 9985) aged 1-92 years (recruited early-2020) donated home-collected fingerstick-blood samples at six timepoints in 2021/2022, covering waves dominated by Alpha, Delta, and multiple Omicron (sub-)variants. IgG antibody assessment against Spike-S1 and Nucleoprotein was combined with vaccination- and testing data to estimate infection-induced (inf) and total (infection- and vaccination-induced) seroprevalence.

Temporal composition of the cervicovaginal microbiome associates with hrHPV infection outcomes in a longitudinal study.

Background: Persistent infections with high-risk human papillomavirus (hrHPV) can cause cervical squamous intraepithelial lesions (SIL) that may progress to cancer. The cervicovaginal microbiome (CVM) correlates with SIL, but the temporal composition of the CVM after hrHPV infections has not been fully clarified.

Methods: To determine the association between the CVM composition and infection outcome, we applied high-resolution microbiome profiling using the circular probe-based RNA sequencing technology on a longitudinal cohort of cervical smears obtained from 141 hrHPV DNA-positive women with normal cytology at first visit, of whom 51 were diagnosed by cytology with SIL six months later.

Developing Therapies for C3 Glomerulopathy: Report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes.

Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics.

Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce.

3D Hydrogel Coculture System Provides Mechanistic Insights into Prostate Cancer Bone Metastasis.

Patients diagnosed with advanced prostate cancer (PCa) often experience incurable bone metastases; however, a lack of relevant experimental models has hampered the study of disease mechanisms and the development of therapeutic strategies. In this study, we employed the recently established erature-based -separable () 3D cell coculture system to investigate PCa bone metastasis. Through coculturing PCa and bone cells for 7 days, our results showed a reduction in PCa cell proliferation, an increase in neovascularization, and an enhanced metastasis potential when cocultured with bone cells.

Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions.

Estrogen Receptor 1 (ESR1; also known as ERα, encoded by gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications.

CLDN1 knock out keratinocytes as a model to investigate multiple skin disorders.

The transmembrane protein claudin-1 is critical for formation of the epidermal barrier structure called tight junctions (TJ) and has been shown to be important in multiple disease states. These include neonatal ichthyosis and sclerosing cholangitis syndrome, atopic dermatitis and various viral infections. To develop a model to investigate the role of claudin-1 in different disease settings, we used CRISPR/Cas9 to generate human immortalized keratinocyte (KC) lines lacking claudin-1 (CLDN1 KO).