Beneficial microbiome and diet interplay in early-onset colorectal cancer.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Although the risk of developing CRC increases with age, approximately 10% of newly diagnosed cases occur in individuals under the age of 50. Significant changes in dietary habits in young adults since industrialization create a favorable microenvironment for colorectal carcinogenesis.

Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.

The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs.

Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control.

Diagnosis and prognosis prediction of gastric cancer by high-performance serum lipidome fingerprints.

Early detection is warranted to improve prognosis of gastric cancer (GC) but remains challenging. Liquid biopsy combined with machine learning will provide new insights into diagnostic strategies of GC. Lipid metabolism reprogramming plays a crucial role in the initiation and development of tumors.

APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.

The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques.

JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia.

The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche.

Hair follicle stem cells and the collapse of self-tolerance in alopecia: the interplay of barrier function, the microbiome, and immunity.

The hair follicle is thought to be a site of ‘immune privilege,’ or relative protection from autoimmune and inflammatory responses. In particular, the long-lived, quiescent hair follicle stem cells (HFSCs) are strikingly resistant to cytotoxic immune effectors such as T cells and natural killer (NK) cells, even in systems where these cells are artificially directed to attack HFSCs. Nonetheless, many forms of alopecia are associated with immune-mediated damage of the hair follicle epithelium, suggesting a failure of immune privilege.

Author Correction: Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases.

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Rett syndrome: interferon-γ to the rescue?

Rett syndrome is a severe neurodevelopmental disorder in girls, underpinned by mutations in the X-linked gene . In their recent work (Frasca et al, 2024), Frasca and colleagues identified a novel pathway involving interferon-gamma (IFNγ) that could pave the way to potential therapies.

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.

Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection.

Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA.

Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition.

Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice.

Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP.

Liver DE(HP)toxification: luteolin as "phthalates-cleaner" to protect from environmental pollution.

Environmental pollution is a major health problem that affects the health of individuals worldwide and is cumulative with other environmental stressors, contributing to the increasing prevalence of cancer, cardiometabolic, neurological and autoimmune diseases (Favé et al, 2018). Although being extensively studied, therapeutic strategies still rely primarily on exposure prevention, often with no option available to allow pollutant detoxification. In this issue of , Wang et al (Wang et al, 2024) investigated potential pharmacological strategies to allow the direct removal of phthalates, major environmental pollutants, from the liver.

Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.

Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate.