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PubMed2026

Liquid biopsy-based detection of circulating and exfoliated cholangiocarcinoma tumor cells from blood and bile using heparan sulfate octasaccharides on integrated microfluidic systems.

Early diagnosis of cholangiocarcinoma (CCA) remains challenging because existing diagnostic approaches often lack sufficient sensitivity for reliable detection of early-stage disease. Circulating tumor cells (CTCs) in blood and exfoliated tumor cells (ETCs) in bile represent valuable targets for liquid biopsy-based detection; however, their low abundance and the complexity of clinical sample analysis pose substantial technical challenges for reliable enrichment and identification. Herein, we present a reproducible workflow for isolating and identifying CCA tumor cells from blood for CTCs and bile for ETCs using synthetic cell-surface heparan sulfate (HS) octasaccharide-functionalized magnetic beads (MBs) on integrated microfluidic systems. The method combined sample pre-processing, magnetic bead-based enrichment, controlled low-shear mixing and immunofluorescence-based identification into a unified workflow compatible with distinct clinical sample types. Key operational parameters, including MB concentration, mixing frequency, and pressure settings, were detailed to facilitate consistent performance. Using this workflow, tumor cell capture rates of approximately 70% in bile (for ETCs) and blood (for CTCs) were achieved, with a total processing time of 60-90 min per sample under clinically relevant low-abundance conditions. The platform enables reliable detection of as few as 1 tumor cell per mL of blood or bile. This method provides a practical and adaptable strategy for glycosaminoglycan-mediated liquid biopsy applications and may be extended to other tumor-cell enrichment workflows involving heterogeneous cell-surface interactions.

Humans↗
PubMed2026

EZH1/2 inhibition selectively targets SMARCA4/2 co-deficient lung cancer cells by suppressing stemness and proliferation.

SMARCA4-deficient thoracic malignancies comprise biologically heterogeneous tumors, ranging from conventional non-small cell lung cancer with SMARCA4 alterations to thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), an aggressive entity frequently associated with concomitant SMARCA2 loss. However, the extent to which SMARCA4-deficient lung cancer cell lines recapitulate SMARCA4-UT-like biology remains incompletely defined. Here, we characterized lung cancer cell lines across distinct SMARCA4 and SMARCA2 states and identified a subgroup with SMARCA4/2 co-deficiency that exhibited reduced expression of epithelial lineage markers and transcriptional similarity to SMARCA4-UT and other SWI/SNF-deficient malignancies. The EZH1/2 inhibitor HM97662 selectively suppressed growth in SMARCA4/2-deficient cells, with limited effects in SMARCA2-proficient cells. EZH1/2 inhibition broadly reduced H3K27me3 and induced derepression of PRC2 targets regardless of drug sensitivity. However, its biological effects were most pronounced in SMARCA4/2-deficient cells, where it promoted apoptosis, reduced stemness marker expression, attenuated the SMARCA4-UT-associated transcriptional signature, and suppressed proliferative and mTORC1-related programs. Chromatin accessibility analysis further revealed cell-line-specific patterns of accessibility loss, with reduced accessibility at stemness-associated transcription factor motif-enriched regions coupled with transcriptional repression of nearby genes in SMARCA4/2-deficient cells. These findings support dual EZH1/2 inhibition as a potential therapeutic vulnerability in SMARCA4/2-deficient, SMARCA4-UT-like lung cancer cells.

Humans↗
PubMed2026

A Letter Matters: ADRB2 rs1042713 c.46A Modulates Anti-osteogenic Effect of Epinephrine in Human Mesenchymal Stem Cells.

Osteoporosis (OP) is a systemic bone disease affecting millions worldwide, characterized by long-term asymptomatic development that manifests in low-energy fractures. Due to their high stability, genetic markers represent a promising strategy for early diagnostics. The ADRB2 rs1042713 polymorphism is one such marker, considered as a potential predictor for OP. Although the anti-osteogenic role of the β2-adrenergic receptor is well-established, debate continues on which allele (G or A) of this polymorphism drives bone deterioration. In this study, we examined the influence of the ADRB2 rs1042713 G/G and A/A variants on osteogenic differentiation in patient-derived mesenchymal stem cells (MSCs) under treatment with the endogenous agonist epinephrine. We show that epinephrine (whose levels are often elevated in comorbid conditions) drastically impairs osteogenic differentiation, specifically at the matrix mineralization stage in MSCs A/A. Epinephrine fails to activate the canonical β2-adrenergic receptor pathway and promotes receptor perinuclear and nuclear localization in MSCs A/A. Crucially, metformin, a common anti-diabetic drug, rescues this anti-osteogenic effect. These results open new perspectives for early diagnostics by identifying epinephrine sensitivity as a critical factor, while also suggesting a potential therapeutic strategy to counteract epinephrine detrimental effect in individuals carrying the ADRB2 rs1042713 A-allele.

Humans↗
PubMed2026

Effect of adding umbilical cord blood derived stem cells to haploidentical stem cell transplant (haplo-cord) on post-transplant survival and graft-versus-host disease in patients with hematological malignancies: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Haploidentical stem cell transplantation (haplo-SCT) carries a substantial risk of graft-versus-host disease (GvHD), whereas umbilical cord blood (UCB) transplantation offers lower GvHD risk but slower engraftment. The haplo-cord approach combines both graft sources, aiming to mitigate GvHD while ensuring timely engraftment. This meta-analysis compares haplo-cord transplantation with haplo-SCT alone for the treatment of hematological malignancies. METHODS: Four electronic databases and two clinical trial registries were systematically searched. Effect sizes from eligible studies were pooled using odds ratios (ORs) for dichotomous outcomes and hazard ratios (HRs) for time-to-event outcomes. RESULTS: Twelve studies met the inclusion criteria. Haplo-cord was associated with a statistically significant reduction in chronic GvHD (OR = 0.62, 95%-CI: 0.42-0.93), while no significant difference was observed for grade II-IV acute GvHD (OR = 0.75, 95%-CI: 0.52-1.09). Survival outcomes favored haplo-cord, with lower HRs for overall survival (HR = 0.68, 95%-CI: 0.53-0.86) and event-free survival (HR = 0.61, 95%-CI: 0.52-0.72), while non-relapse mortality was not significant. Relapse at 3 years was significantly lower with haplo-cord (OR = 0.54, 95%-CI: 0.35-0.82). Haplo-cord also demonstrated higher day-30 engraftment, along with lower relapse-related and GvHD-related mortality, while CMV and EBV viremia showed no difference between groups. CD34 selection in the haplo graft significantly influenced effect sizes and heterogeneity in both subgroup analyses and meta-regression for acute GvHD. CONCLUSION: Haplo-cord transplantation improves GvHD outcomes, survival, and relapse risk compared with haplo-SCT alone. However, whether protocol optimization, possibly via CD34 selection, confers additional benefit remains uncertain and requires confirmation in future studies.

Humans↗
PubMed2026

Frequent mutations in the BIRC3 gene promote metastatic potential of nasopharyngeal carcinoma cells through the TRAF2-NF-κB pathway.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer characterized by highly locoregionally invasive behavior attributable to the latent infection with Epstein-Barr virus (EBV) and genomic instability. It is well established that EBV-encoded oncogenic molecules actively contribute to the malignant behavior of NPC cells. However, the mechanism by which aberrant genomic alterations enable NPC cells to become aggressive remains largely unknown. In the present study, whole-exome sequencing (WES) revealed that the gene encoding the baculoviral IAP repeat-containing 3 (BIRC3) protein was frequently mutated in circulating tumor cells (CTCs) but not in paired primary tumor cells from patients with metastatic NPC. A minigene assay indicated that the c.637 A > G mutation disrupted normal mRNA splicing, resulting in the partial deletion of Exons 2 and 3 and altered stability of BIRC3 mRNA. In vitro experiments demonstrated that ectopic expression of the BIRC3c.637A>G mutant enhanced NPC cell invasive properties, including proliferation, resistance to apoptosis, migration, and invasion. Furthermore, overexpression of wild-type BIRC3 promoted invasive characteristics in NPC cells through the TRAF2-NF-κB signaling axis. In summary, BIRC3 acts as a regulator of the malignant features of NPC cells. Frequent BIRC3 mutations in CTCs, such as the c.637 A > G mutation, further enhance the metastatic potential of disseminated NPC cells by inducing aberrant alternative splicing. These findings suggest the therapeutic feasibility of targeting the BIRC3/TRAF2/NF-κB axis in the treatment of NPC.

Humans↗
PubMed2026

Novel environmental contaminant 6PPD-quinone promotes malignant phenotypes in colorectal cancer cells and identifies candidate response-associated genes.

6PPD-quinone (6PPDQ), an oxidative transformation product of the widely used tire antioxidant 6PPD, is a ubiquitous environmental contaminant with bioaccumulation potential and widespread human exposure. Recent epidemiological evidence indicates a positive association between urinary 6PPDQ levels and colorectal cancer (CRC) risk; however, its biological effects on CRC-related phenotypes and associated molecular responses remain unclear. We integrated bioinformatics analysis, prognostic modeling, molecular docking and dynamics simulations, and in vitro experiments to investigate cellular and molecular responses to 6PPDQ in CRC models. Predicted 6PPDQ targets were intersected with CRC prognosis-related genes from The Cancer Genome Atlas, followed by functional enrichment and LASSO regression to construct a prognostic risk model, with 1-, 3-, and 5-year AUC values of 0.727, 0.754, and 0.778, respectively. Molecular docking and 100-ns molecular dynamics simulations suggested interactions between 6PPDQ and candidate proteins, including CPT2, SHC2, SRMS, and STK35. Functional assays showed that 6PPDQ exposure altered proliferation, wound-closure capacity, and invasion in Caco-2 and HCT116 cells across the nanomolar concentration range, with non-monotonic and cell-line-dependent responses. In contrast, NCM460 cells showed no increase in EdU incorporation at 10 or 100 nM, whereas reduced proliferation at higher concentrations was accompanied by increased LDH release. 6PPDQ also altered the expression of several prognosis-associated candidate genes. These findings identify cellular phenotypes and candidate molecular responses associated with 6PPDQ exposure under the tested in vitro conditions, but do not establish their causal roles or in vivo relevance. Further mechanistic and in vivo studies are required.

Humans↗
PubMed2026

Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.

Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.

Humans↗
PubMed2026

Orbital involvement in sickle cell disease: A systematic review.

Orbital involvement in sickle cell disease (SCD) is rare but potentially vision-threatening and is often misdiagnosed due to overlap with infectious orbital disease. We conducted a systematic review of case reports and series describing orbital complications in patients with confirmed SCD, following PRISMA and MOOSE guidelines. Across 53 studies, 76 cases were identified. Patients were predominantly male (77.6%), with an average age of 13.2 years. Orbital disease was the initial SCD manifestation in 6.6%. Presentations included periorbital edema in all, proptosis in 64.1%, restricted ocular motility in 56.5%, reduced visual acuity in 28.1%, and bilateral involvement in 38.2%. Laboratory findings commonly included leukocytosis (73%) and raised inflammatory markers (86.7%). Radiologically, orbital subperiosteal hematoma were observed in 70%, combined orbital bone infarction and hematoma in 38.2%, and orbital bone infarction alone in 19.7%. Magnetic resonance imaging is critical for accurate diagnosis. Intracranial hemorrhage was present in 9.2%. Less frequent manifestations included orbital apex syndrome, lacrimal gland disease, and nonspecific soft tissue swelling. Management was primarily conservative (82.9%), and surgery was reserved for vision-threatening or intracranial complications. Complete recovery was achieved in 93.1% of cases. While severe vision-threatening complications are uncommon, early recognition remains critical to optimising outcomes in sickle cell orbitopathy.

Humans↗
PubMed2026

Decoding bipotency: a transient regulatory state bridging totipotency and lineage commitment.

Early mammalian embryogenesis entails a coordinated transition from totipotency to the first lineage bifurcation, giving rise to embryonic lineages and the extra-embryonic trophectoderm. The mechanisms by which totipotency is resolved into lineage-primed states remain incompletely understood. Emerging evidence supports a non-binary model in which cells traverse a continuum of potency states, passing through a transient bipotent intermediate that retains both embryonic and extra-embryonic potential while exiting totipotency. Here, we synthesize recent advances in the mechanisms that establish, maintain, and resolve bipotency. We emphasize the coordinated roles of transposable elements, transcription factors, and signaling pathways in regulating this transition. We also highlight newly developed bipotent stem cell models and their implications in generating advanced embryo models in vitro. Notably, current insights are largely derived from mouse systems; given key differences between mouse and human early embryogenesis, extending these findings to human models remains a critical next step.

Animals↗
PubMed2026

The effects of cold temperature on the development, microbiome, and transcriptome of the sea anemone Nematostella vectensis.

Thermal conditions impact essentially all aspects of the physiology for ectotherms. While the effects of high temperatures have been widely studied, cold temperature effects on aquatic invertebrates and their microbial communities have been poorly characterized. To determine the diverse effects of exposure to cold temperatures, we assessed acute and long-term impacts of ecologically relevant low temperatures on the development, microbiome, and gene expression of the sea anemone Nematostella vectensis. Two hours post fertilization, embryos were exposed to temperatures from 4°C to 35°C and development rate to the juvenile stage was quantified. We found temperature impacts the development rate of embryos, where lower temperatures extended development time and resulted in mortality below 10°C. For both microbiome and host transcriptomic responses, anemones were held at 20°C, 10°C, and 0°C and compared at 24 hours and 7 days. Extended exposures to colder temperatures caused restructuring of the host-associated microbiome, with the loss of common taxonomic groups from the class Bacteroidia and Bacilli. Lastly, cold stress induced significant changes in gene expression, which were more pronounced at the 10°C than 0°C but showed little change over time in each temperature. Interestingly, expression of genes associated with innate immunity were among the most differentially expressed genes including heat shock proteins and innate immune genes providing a potential host-imposed mechanism to explain the shift in the microbiome. Overall, cold temperatures have broad effects on many facets of this sea anemone and its microbial community and indicate the importance of cold temperature events when characterizing how ectotherms acclimate to thermal variation.

Animals↗
PubMed2026

RPLP0 drives diffuse large B-cell lymphoma cell proliferation through reactive oxygen species-dependent AKT/mTOR activation and inhibition of stress-induced autophagy.

Diffuse large B-cell lymphoma (DLBCL) is a common, aggressive subtype of non-Hodgkin lymphoma with poor outcomes. Identifying the primary molecular causes of DLBCL remains key. The present study examined the function of ribosomal protein lateral stalk subunit P0 (RPLP0) in DLBCL pathogenesis. The Cancer Genome Atlas-DLBCL and GSE12453 datasets overlapping differentially expressed genes were identified. Hub genes were identified via protein-protein interaction network analysis. DLBCL cells were subjected to functional tests following RPLP0 overexpression or knockdown. Reverse transcription-quantitative PCR, western blotting, flow cytometry, transmission electron microscopy, colony formation assay and biochemical analysis were among the tests performed. N-acetylcysteine (NAC), rapamycin (RAPA) and 3-MA were among the medication therapies. In the DLBCL datasets, six ribosome-associated genes were differentially expressed. RPLP0 knockdown inhibited the proliferation of DLBCL cells and caused G2-phase arrest, without impacting apoptosis. Thioredoxin, heat shock protein family A member 1A and heat shock protein family B member 1 expression was downregulated by RPLP0 knockdown, which also increased the NAD+/NADH ratio, promoted reactive oxygen species (ROS) accumulation and caused mitochondrial membrane potential depolarization. Meanwhile, 3-MA reversed the effects of RPLP0 knockdown, which encouraged LC3-II accumulation, autophagy-related gene 5 (ATG5) overexpression and an increase in autophagic vesicles. Autophagy-related indicators were decreased, and AKT/mTOR phosphorylation was increased by RPLP0 overexpression, which RAPA inhibited. NAC therapy preserved the viability of RPLP0-silenced cells, restored p-AKT/p-mTOR levels and restored normal LC3 and ATG5 expression. These findings suggest that RPLP0 regulates stress-induced autophagy through ROS-dependent AKT/mTOR signaling and may represent a potential therapeutic target for DLBCL.

AKT/mTOR signaling pathway↗
PubMed2026

Identification of elements determining KIR gene demethylation at the CD56-bright stage of NK cell development.

The variegated expression of the KIR family of class I MHC receptors generates specialized natural killer (NK) cells capable of allele-specific HLA recognition. Understanding the mechanism of KIR gene activation will lead to improved methods for the generation of fully functional NK cells. A central RUNX-binding site in the KIR proximal promoter is required for gene activation. RUNX proteins recruit ten-eleven translocation (TET) proteins that generate 5-hydroxymethylcytosine (5hmC) and drive DNA demethylation. Assessment of 5-methylcytosine (5mC) and 5hmC residues at four stages of NK cell development reveals deposition of 5hmC primarily in a CREB site next to the RUNX site at the CD56Bright stage but not the subsequent CD56Dim stage representing fully mature NK cells. KIR promoter demethylation is delayed relative to other lineage-associated genes, indicating a high threshold for KIR gene demethylation in developing NK cells, and a window of opportunity for RUNX/TET-dependent KIR gene activation in CD56Bright NK cells.

6-base sequencing↗
PubMed2026

The Potential Role of Mesenchymal Stem Cell Therapy for Moderate-to-Severe Atopic Dermatitis: A Systematic Review and Meta-Analysis of Human Clinical Trials.

Despite currently available treatment options for moderate-to-severe atopic dermatitis (AD), some patients fail to achieve adequate disease control. Emerging evidence suggests that mesenchymal stem cells (MSCs) may represent a promising therapeutic option. This systematic review and meta-analysis included four randomized controlled trials (RCTs) and one non-randomized clinical trial. Eligible studies evaluated patients with moderate-to-severe AD treated with MSCs derived from human umbilical cord blood, autologous adipose tissue, and allogeneic bone marrow. PubMed, Embase, and Cochrane were searched from inception to December 2025. Primary outcomes included the proportion of patients achieving ≥50% and ≥75% improvement from baseline in the Eczema Area and Severity Index (EASI) and safety outcomes. The meta-analysis included 236 participants. The pooled EASI-50 response rate at week 12 was 46.76% (95% confidence interval [CI]: 32.36% to 61.72%). EASI-75 response rates were 17.41% (95% CI: 5.56% to 43.03%) at week 12 and 23.97% (95% CI: 16.48% to 33.50%) at week 16. The pooled incidence of treatment-emergent adverse events was 26.86% (95% CI: 19.56% to 35.68%), with infections and infestations 7.97% (95% CI: 4.11% to 14.88%) and gastrointestinal disorders 3.52% (95% CI: 1.33% to 9.01%) being the most frequently reported. MSC-based therapy shows early promise as a potential treatment for moderate-to-severe AD, offering a possible alternative to traditional therapies. However, the current evidence is largely based on small clinical trials, underscoring the necessity for large-scale RCTs to establish the efficacy and safety of MSC-based therapy in broader patient populations.

Humans↗
PubMed2026

A proteomic analysis of the PHF-forming tau fragment (tau297-391) following uptake into differentiated human neuronal SHSY5Y cells.

Tau self-assembly and intracellular deposition are associated with a group of neurodegenerative diseases called tauopathies, which include Alzheimer's disease (AD) and Pick's disease. Here, we measured the proteome response in human neuronal cells (differentiated SH-SY5Y) following the addition of a spontaneously amyloidogenic region of tau known as dGAE (tau297-391), which forms AD-like paired helical filaments in vitro, and proteomic analysis showed increased endogenous tau expression. Further interactome analysis uncovered increased association between tau and proteins associated with nuclear chromatin, the nucleolus, and the spliceosome, as well as the thiol-peroxidase, PRDX6, alongside an increase in reactive oxygen species. The present work highlights a method to identify proteome pathways that may play an important role in the development of tau pathology and reveals an oxidative stress response to dGAE.

Humans↗
PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗
PubMed2026

Delayed maturation of the milk microbiome in women with type 1 diabetes.

AIMS/HYPOTHESIS: The breastmilk microbiome plays a crucial role in gut microbial colonisation and immune development, but little is known about how it is influenced by type 1 diabetes. METHODS: We conducted a longitudinal 16S rRNA gene sequencing study of milk from women with type 1 diabetes (n=69 pregnancies; 174 samples) and women who did not have type 1 diabetes (n=49 pregnancies; 123 samples), collected at seven timepoints from birth to 15 months postpartum. Alpha diversity (richness, inverse Simpson evenness) was analysed by generalised linear mixed models, beta diversity was analysed by Bray-Curtis dissimilarities and PERMANOVA, and differential abundance was analysed by limma. Additionally, we examined associations with maternal genetic risk score (GRS), maternal HLA type, glycaemic management (HbA1c) and breastmilk secretory IgA (sIgA), and performed a parallel analysis for the infant stool microbiome. RESULTS: A significant interaction between type 1 diabetes status and timepoint was observed for alpha diversity, both richness (p=0.01) and inverse Simpson diversity (p=0.003), indicating distinct temporal trajectories between women with and without type 1 diabetes. In those without type 1 diabetes, richness increased significantly between birth and 1 week postpartum, but this early increase was delayed in women with type 1 diabetes to between 1 week and 3 months postpartum (p=0.002). Beta diversity analysis revealed earlier and more extensive compositional shifts in women without type 1 diabetes compared to those with type 1 diabetes. These differences persisted after adjusting for Caesarean delivery, BMI, parity and infant sex, and were not attributable to a delay in initiating breastfeeding. Taxa with delayed enrichment in women with type 1 diabetes included Streptococcus spp. and Rothia mucilaginosa, which metabolise human milk oligosaccharides to short-chain fatty acids to promote development of the infant's gut barrier and immune system. Maternal GRS, HLA, HbA1c or sIgA were not associated with milk microbiota diversity trajectories. In infant stool samples, alpha diversity did not differ between exposure groups, and showed no evidence of delayed maturation. Beta diversity revealed an early compositional shift between birth and 1 week postpartum only in infants born to women without type 1 diabetes. Similarly, significant taxonomic changes between birth and 1 week postpartum were detected only in infants born to women without type 1 diabetes, but with some taxa differing between exposure groups at 1 week. CONCLUSIONS/INTERPRETATION: Maternal type 1 diabetes is associated with delayed early maturation of the breastmilk microbiome. Early compositional differences in microbiota restructuring were also observed in the infant gut, partially mirroring the pattern in the milk microbiome; however, sustained differences in infant gut microbiota diversity were not detected. Further investigation could determine whether these changes affect development of the infant's gut and immune system.

Humans↗
PubMed2026

Metabolic ketosis attenuates NLRP3 inflammasome activation and is associated with improvements in hepatic steatosis and liver stiffness in MASLD: a pilot randomized controlled trial.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic metabolic-inflammatory disorder in which metabolic stress and innate immune activation, particularly through the NLRP3 inflammasome, contribute to disease progression. Metabolic ketosis, characterized by increased levels of circulating ketone bodies, especially &#x3b2;-hydroxybutyrate, has emerged as a promising strategy to modulate substrate utilization, inflammatory signaling, and hepatic injury. However, clinical evidence integrating molecular, metabolic, and hepatic outcomes remains limited. METHODS: In this pilot randomized controlled trial, 20 participants with newly diagnosed MASLD were randomly assigned to either a 3-month intervention with a daily C8-enriched medium-chain fatty acid formulation (m-CAP; meta-Capridin, providing approximately 20 g/day of C8) or a standardized low-carbohydrate dietary protocol. Metabolic indices, inflammatory mediators, adipokines, and hepatic enzymes were assessed. The expression of key inflammasome components (NLRP3, caspase-1, and ASC) was evaluated in peripheral blood mononuclear cells, and hepatic steatosis and liver stiffness were measured via transient elastography. RESULTS: The C8-enriched intervention was associated with increased circulating &#x3b2;-hydroxybutyrate levels, indicating the achievement of nutritional ketosis. Changes over time were observed in metabolic parameters, including fasting serum glucose (p < 0.05), HOMA-IR (p < 0.05), body fat percentage (p < 0.05), and BMI (p < 0.05). Alterations in inflammatory mediators and adipokine-related outcomes were also observed following the intervention. At the molecular level, changes in inflammasome-related markers were detected, including caspase-1 mRNA expression (p < 0.05) and NLRP3 expression at the transcriptional (p < 0.05) and protein levels (p < 0.01), whereas ASC expression remained unchanged. Changes in hepatic steatosis (p < 0.01) and liver stiffness measurements were observed following the intervention. Given the absence of significant Group &#xd7; Time interactions for several secondary outcomes, these findings should be interpreted as exploratory and hypothesis-generating. CONCLUSIONS: Induction of metabolic ketosis was associated with changes in metabolic, inflammatory, and hepatic parameters in patients with MASLD. The observed associations between ketosis, inflammasome-related markers, and noninvasive liver outcomes warrant further investigation of ketosis-based interventions as adjunctive approaches in MASLD. Larger and longer-term clinical trials are needed to confirm these findings and to determine whether short-term changes in liver stiffness reflect sustained alterations in hepatic status rather than structural fibrosis regression. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT); Unique identifier: IRCT20170315033086N12; Registration date: 19 September 2024; Registry URL: https://www.irct.ir. IRCT is a primary registry in the WHO Registry Network (https://www.who.int/tools/clinical-trials-registry-platform/network/primary-registries).

Humans↗
PubMed2026

Real-World Efficacy and Safety of Standard-of-Care Chimeric Antigen Receptor T-Cell (CART) and Bispecific T-Cell Engager (TCE) Therapies in Relapsed/Refractory Multiple Myeloma (RRMM).

We aimed to evaluate the real-world (RW) efficacy and safety of standard-of-care CART versus TCE therapies in relapsed/refractory myeloma (RRMM), to assess utilization, outcomes, and tolerability of these therapies in a RW oncology in the US. Data were derived from the US-based, electronic health record-derived deidentified Flatiron Health Research Database, 2021-2024. A total of 419 patients (CART n&#x2009;=&#x2009;220; TCE n&#x2009;=&#x2009;199) with a confirmed diagnosis of myeloma who received CART or TCE as a standard-of-care treatment after at least 2 prior lines of therapy were included. Patients in the CART cohort were younger, had better ECOG PS, and a higher receipt of a prior autologous stem cell transplant versus bispecific TCE cohort. In CART versus TCE cohort, the overall response rates (ORR) were 83.3% versus 66.3%, median duration of response 7.9&#x2009;months versus 4.3&#x2009;months, progression free survival (PFS) 13.6&#x2009;months versus 10.5&#x2009;months, and overall survival (OS) of 29.8&#x2009;months versus 21.9&#x2009;months, respectively. A higher percentage of hematologic toxicity, infections, and cytokine release syndrome (CRS) were noted in the CART versus TCE cohort. This study provides insights on the RW effectiveness of CART versus TCE in the treatment of RRMM; highlights the differences in patient selection, clinical responses, treatment duration, and toxicity profiles.

CART↗