Programmed cell death protein ligand 1 (PD-L1) blockade has emerged as a key therapy for advanced non-small cell lung cancer (NSCLC). Unfortunately, one of the key barriers in the treatment is the acquired resistance to PD-L1, even though after the initial response to the treatment, more than 60% of the patients develop acquired resistance. In a study published in the Cancer Cell journal by Memon et al. (2024), a cohort of 1,201 patients with NSCLC was analyzed to evaluate the relapse mechanism. They identified subtypes with persistent or upregulated interferon γ (IFNγ) signaling, immune dysfunction, and antigen presentation defects. Murine models exposed to chronic IFNγ recapitulated these features, highlighting that a chronically inflamed microenvironment drives resistance. These insights underscore the need for adaptive therapies that dynamically target evolving tumor-immune interactions.

Aim: This study aimed to explore the correlation between peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and diabetic kidney disease (DKD) susceptibility in the Han Chinese population.

Methods: The distribution of Gly482Ser (rs8192678) and its relationship with blood PGC-1α messenger RNA (mRNA) expression were examined in healthy volunteers, patients with type 2 diabetes mellitus (T2DM), and those with DKD. The single-nucleotide polymorphism was genotyped using a DNA extraction kit and TaqMan-minor groove binder (MGB) probe real-time polymerase chain reaction.

Results: We enrolled 574 subjects: 212 healthy controls, 186 with T2DM, and 176 with DKD. The rs8192678 AA genotype was more frequent in controls than in T2DM or DKD groups (P < 0.001). Under additive, dominant, and recessive models, the GG genotype was linked to higher T2DM risk after age and sex adjustment (P < 0.001), but not to progression from T2DM to DKD. PGC-1α mRNA levels were also higher in AA carriers than in GG carriers across all groups (P < 0.05).

Conclusion: Our study identifies the G allele of PPARGC1A rs8192678 as a risk factor for T2DM, but its role in DKD is context-dependent. Although not a risk factor in the general T2DM population, this allele is linked to higher DKD risk specifically in patients with normal triglyceride levels. This association was driven by the GA and AA genotypes, not the GG genotype, highlighting the complex interplay between genetics and metabolic state in DKD.

To elucidate the etiology of recurrent fetal brain developmental malformations accompanied by other structural ultrasound anomalies in a Chinese non-consanguineous couple, we performed a comprehensive evaluation of prenatal ultrasound phenotypes across their two consecutive pregnancies. Copy number variation sequencing and exome sequencing were applied to the amniotic fluid sample obtained from the affected pregnancy. One copy number variation and four candidate missense variants in three genes identified in the initial analysis were reassessed and reclassified according to current clinical and genetic evidence. Our results demonstrated that a maternal mosaic c.7G>A(p.Glu3Lys) variant in the tubulin alpha 1a (TUBA1A) gene was the underlying cause of the couple’s recurrent adverse pregnancy outcomes. These findings enrich the database of pathogenic TUBA1A variants, expand the spectrum of associated prenatal ultrasound phenotypes, and provide valuable insights into the underlying pathogenic mechanisms.

The use of autologous haematopoietic stem cell gene therapy is increasingly recognised as a promising treatment option for severe combined immunodeficiency diseases (SCID). This approach seeks to correct the underlying genetic cause of SCID conditions, potentially allowing a single treatment to restore a healthy immune system for the lifespan of the patient. To date, such gene therapy has relied on the use of gamma-retroviruses or lentiviruses to deliver genetic material to a patient’s haematopoietic stem cells before reinfusion. This approach has had notable successes in the clinic for conditions including X-linked severe combined immunodeficiency (SCID-X1), Artemis-SCID, and adenosine deaminase-SCID. However, significant hurdles have been met when using viral-mediated gene addition, primarily linked to the potential risk of insertional mutagenesis; however, for certain SCID forms, there are also limitations associated with the regulation and levels of gene expression achievable. This has driven the development of new gene editing technologies for the treatment of SCID conditions. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9), base editing and prime editors are all actively under investigation, mainly in the preclinical stage to understand their potential applications. In this review, we explore gene editing approaches that are in development for the treatment of SCID. While initial results look promising, significant challenges need to be overcome before their clinical use. Such technologies represent an exciting new wave of treatment options for SCID patients.

Aim: Illicit etomidate (ET) use in e-cigarettes has increased recently, but its effects on the oral microbiome remain unknown. This study investigates oral microbiota alterations in chronic ET users.

Methods: Saliva from 45 ET users and 44 controls underwent 16S ribosomal RNA (rRNA) sequencing. We compared microbial diversity, composition, predicted functions, and co-occurrence networks between groups, and developed 12 machine learning models to classify ET users based on microbial features.

Results: Chronic ET-containing e-cigarette use was strongly associated with significant oral microbial dysbiosis. Species richness and diversity were significantly lower in the ET group. ET users exhibited proliferation of taxa associated with oral diseases, including Actinomyces, Rothia, and Atopobium. PICRUSt2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2) predicted enhanced carbohydrate and amino acid metabolism in the ET group, while controls showed greater abundance of biotin and fatty acid metabolism pathways. Network analysis revealed reduced complexity and stability in the ET group. The ensemble model GLMBoost (generalized linear model boosting) + Random Forest achieved an area under the curve (AUC) of 1.00 and 100% accuracy on the test set. Seven key genera were identified as discriminative biomarkers: Prevotella_7, Rothia, Neisseria, Veillonella, Haemophilus, Actinomyces, and Fusobacterium.

Conclusion: Chronic use of ET-containing e-cigarettes is linked to altered homeostasis of the oral microbiota, providing a deeper understanding of how substance addiction impacts oral microbial ecology and highlights the potential of machine learning-derived microbial signatures as non-invasive tools for accurately distinguishing ET-containing e-cigarette users from non-users.

Receptor activator of nuclear factor-κB ligand (RANKL) is indispensable for osteoclast differentiation, activation, and bone resorption. While the relative contributions of membrane-bound RANKL (mRANKL) and soluble RANKL were historically debated, evidence from the past decade increasingly establishes mRANKL as the primary driver of osteoclastogenesis. However, a systematic literature synthesis integrating these diverse cellular sources and structural modalities remains lacking. It has also not been systematically defined which cellular sources of RANKL - arising from bone marrow mesenchymal lineage cells or hematopoietic lineage cells - play dominant roles in driving osteoclast activation. Clarifying these distinct forms and sources of RANKL will refine the conceptual framework of osteoclast regulation and provide a mechanistic basis for next-generation antiresorptive therapies that selectively target specific RANKL modalities to achieve more durable skeletal protection.