Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity.

The DNA-incorporating nucleoside analogs azacytidine (AZA) and decitabine (DEC) have clinical efficacy in blood cancers, yet the precise mechanism by which these agents kill cancer cells has remained unresolved - specifically, whether their anti-tumor activity arises from conventional DNA damage or DNA hypomethylation via DNA methyltransferase 1 (DNMT1) inhibition. This incomplete mechanistic understanding has limited their broader therapeutic application, particularly in solid tumors, where early clinical trials showed limited efficacy. Here, through the assessment of drug sensitivity in over 600 human cancer models and comparison to a non-DNA-damaging DNMT1 inhibitor (GSK-3685032), we establish DNA hypomethylation, rather than DNA damage, as the primary killing mechanism of AZA and DEC across diverse cancer types.

CYLD-TRAF6 interaction promotes ADP-heptose-induced NF-κB signaling in H. pylori infection.

The inflammatory response associated with Helicobacter pylori (H. pylori) infection causes a multitude of alterations in the gastric microenvironment, leading to the slow and steady disruption of the gastric epithelial barrier. Activation of NF-κB during H.

ALPK1-Dependent cIAP1 Degradation Regulates Helicobacter pylori-Induced Apoptosis.

Helicobacter pylori infection poses a significant risk for disrupting the gastric epithelium by inducing inflammation and apoptosis. Here, we identify alpha kinase 1 (ALPK1) as essential in H. pylori-induced apoptosis.

CSN-CRL Complexes: New Regulators of Adipogenesis.

Recent discoveries revealed mechanistic insights into the control of adipogenesis by the Constitutive Photomorphogenesis 9 Signalosome (CSN) and its variants, CSN and CSN, which differ in the paralog subunits, CSN7A and CSN7B. CSN and CSN variants form permanent complexes with cullin-RING-ubiquitin ligases 3 and 4A (CRL3 and CRL4A), respectively. These complexes can be found in most eukaryotic cells and represent a critical reservoir for cellular functions.

Staphylococcal SplA and SplB serine proteases target ubiquitin(-like) specific proteases.

Staphylococcus aureus is a Gram-positive opportunistic pathogen that has colonized nearly 30% of the human population and can cause life-threatening infections. S. aureus exports a variety of virulence factors, such as a novel set of extracellular serine protease-like proteins (Spls).

The enigma of maladaptation in gastric pathophysiology.

Despite a decline in global incidence, gastric cancer (GC) remains a major health concern. The development of GC is a sequential, multistage maladaptive process involving numerous different factors. Understanding the complexity of GC development is crucial for early detection, effective treatment, and, ultimately, prevention.

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters control.

In atopic dermatitis (AD), lesional skin is frequently colonized by , which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate . Therefore, repolarization of macrophages toward the M1 phenotype may foster control of .

Dysregulation of deubiquitinylases: a linchpin of gastrointestinal diseases.

Ubiquitinylation of proteins regulates manifold processes and is reversed by deubiquitinylating enzymes (DUBs), which are therefore implicated in a plethora of cellular processes. DUBs are frequently upregulated in many diseases, while in a few cases downregulation of DUBs is associated with disease progression. This review focuses on the involvement of DUBs in the development and progression of gastrointestinal diseases with a particular emphasis on hepatic steatosis and hepatocellular, cholangio-, esophageal, gastric, colorectal, and pancreatic ductal carcinomas.

Activation and Reactivity of the Deubiquitinylase OTU Cezanne-2 from MD Simulations and QM/MM Calculations.

Cezanne-2 (Cez2) is a deubiquitinylating (DUB) enzyme involved in the regulation of ubiquitin-driven cellular signaling and selectively targets Lys11-linked polyubiquitin chains. As a representative member of the ovarian tumor (OTU) subfamily DUBs, it performs cysteine proteolytic isopeptide bond cleavage; however, its exact catalytic mechanism is not yet resolved. In this work, we used different computational approaches to get molecular insights into the Cezanne-2 catalytic mechanism.

Differential expression of the ubiquitin-editing enzyme A20 in gastric biopsies indicates the severity of disease.

A20, an ubiquitin-editing enzyme, plays a pivotal role in regulating cell signaling and immune responses. Dysregulated A20 expression has been associated with various pathological conditions, including inflammatory diseases and malignancies, where its expression levels often correlate with differing prognoses in solid tumors. This study aimed to explore the expression and cellular localization of A20 in both nonpathological and diseased human gastric tissues to gain deeper insights into its involvement in gastric pathologies.

Ascorbate: a forgotten component in the cytotoxicity of Cu(II) ATCUN peptide complexes.

In 1983, Linus Pauling and colleagues reported about enhanced antitumor activity of the Cu(II) complex of the simplest ATCUN (amino terminal Cu(II) and Ni(II)-binding motif) peptide (NH-Gly-Gly-His-COOH, GGH) in the presence of ascorbate as an additive. In the following 4 decades, structural modifications of this complex were implemented, however, anticancer activity could not be significantly increased. This has led to neglecting the ATCUN motif and its Cu(II) complexes as potential chemotherapeutic agents.

Monolithic Hybrid Abutment Crowns (Screw-Retained) Versus Monolithic Hybrid Abutments With Monolithic Crowns (Adhesively Cemented): Three-Year Data of a Prospective Clinical Split-Mouth Study.

Objectives: This study compares the restoration of single-tooth implants with screw-retained lithium-disilicate hybrid-abutment crowns and single-tooth lithium-disilicate crowns adhesively bonded to hybrid abutments with regard to objective clinical and subjective patient-specific evaluation criteria over a time of observation of 3 years.

Materials And Methods: Two bone-level implants were placed in contralateral sides of the same jaw in 10 patients, each with two single-tooth gaps. After osseointegration, implants were uncovered and an impression was taken.

Cortactin-dependent control of Par1b-regulated epithelial cell polarity in infection.

Cell polarity is crucial for gastric mucosal barrier integrity and mainly regulated by polarity-regulating kinase partitioning-defective 1b (Par1b). During infection, the carcinogen hijacks Par1b via the bacterial oncoprotein CagA leading to loss of cell polarity, but the precise molecular mechanism is not fully clear. Here we discovered a novel function of the actin-binding protein cortactin in regulating Par1b, which forms a complex with cortactin and the tight junction protein zona occludens-1 (ZO-1).

Harnessing gastrointestinal organoids for cancer therapy.

Gastrointestinal organoids have emerged as a model system that authentically recapitulates the in vivo situation. Despite biomedical and technical challenges, self-assembled 3D structures derived from pluripotent stem cells or healthy and diseased tissues have proved to be invaluable tools for cancer drug discovery, disease modeling, and studying infection with carcinogenic pathogens.

Gastric Epithelial Barrier Disruption, Inflammation and Oncogenic Signal Transduction by Helicobacter pylori.

Helicobacter pylori exemplifies one of the most favourable bacterial pathogens worldwide. The bacterium colonizes the gastric mucosa in about half of the human population and constitutes a major risk factor for triggering gastric diseases such as stomach cancer. H.

Fault roughness controls injection-induced seismicity.

Surface roughness ubiquitously prevails in natural faults across various length scales. Despite extensive studies highlighting the important role of fault geometry in the dynamics of tectonic earthquakes, whether and how fault roughness affects fluid-induced seismicity remains elusive. Here, we investigate the effects of fault geometry and stress heterogeneity on fluid-induced fault slip and associated seismicity characteristics using laboratory experiments and numerical modeling.

Inhibition of EIF2α Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma.

Drug resistance is a common cause of therapy failure in head and neck squamous cell carcinoma (HNSCC). One approach to tackling it is by targeting fundamental cellular processes, such as translation. The eukaryotic translation initiation factor 2α (EIF2α) is a key player in canonical translation initiation and integrates diverse stress signals; when phosphorylated, it curbs global protein synthesis.

Evaluating the prospective crown-root ratio after extrusion and crown lengthening procedures in vitro.

For restoration of extensively damaged teeth preprosthetic treatment measures are necessary. Crown lengthening and extrusion affect the prospective crown-root ratio (CRR). The subject of this in vitro study was to compute CRRs for both treatment approaches.

Decreased eukaryotic initiation factors expression upon temozolomide treatment-potential novel implications for eIFs in glioma therapy.

Purpose: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment.

Forced Orthodontic Extrusion to Restore the Unrestorable: A Proof of Concept.

The purpose of this clinical study was to assess the feasibility of forced orthodontic extrusion with the Tissue Master Concept to retain subgingivally fractured teeth as abutments for which extraction and replacement would be equal treatment opportunities. Participants were recruited from a group of consecutive patients in need of prosthodontic rehabilitation. In total, 36 deeply destroyed teeth in 31 patients underwent forced orthodontic extrusion with forces exceeding 50 g to reestablish biologic width and ensure a 2-mm dentin-ferrule design prior to single-crown restoration.

Root-analogue implants compared to forced orthodontic extrusion: a retrospective analysis of clinical, radiological and esthetic outcomes after restoration.

Objectives: To assess clinical, radiological and esthetic outcomes of restorations supported by root-analogue implants (RAIs) or roots of severely damaged teeth after forced orthodontic extrusion (FOE).

Materials And Methods: Clinical data regarding milled one-piece (titanium/zirconia roots and zirconia abutments) RAIs (REPLICATE™ System) and FOE were recorded and retrospectively evaluated for 40 patients by two investigators. Strict inclusion and exclusion criteria were applied.