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PubMed2026

Corneal Epithelial Alterations Associated With Cyclin-Dependent Kinase 4/6 Inhibitor Therapy in Hormone Receptor-Positive Breast Cancer.

IMPORTANCE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are standard therapy for hormone receptor-positive (HR+), HER2-negative breast cancer. By blocking the G1/S cell-cycle transition, these agents may impair renewal of the corneal epithelium. No controlled study has systematically evaluated corneal epithelial changes in patients receiving CDK4/6 inhibitors. OBJECTIVE: To determine whether CDK4/6 inhibitor-based therapy is associated with cornealepithelial alterations independent of aromatase inhibitor exposure and tear film dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Retrospective comparative cross-sectional study at a tertiary ophthalmology center. A total of 132 women were enrolled: 45 receiving a CDK4/6 inhibitor plus an aromatase inhibitor (CDKAI group), 44 receiving aromatase inhibitor monotherapy (AI group), and 43 age-matched postmenopausal controls without systemic oncologic therapy. EXPOSURES: CDK4/6 inhibitor (ribociclib, palbociclib, or abemaciclib) combined with an aromatase inhibitor; aromatase inhibitor alone; or no systemic oncologic therapy. MAIN OUTCOMES AND MEASURES: Prevalence and severity of punctate epitheliopathy and vortex keratopathy, assessed by a masked ophthalmologist. Secondary outcomes included Schirmer I test, tear film break-up time, and Ocular Surface Disease Index (OSDI). RESULTS: PE was present in 44.4% of eyes in the CDKAI group vs 4.7% in the AI group and 2.3% in controls (χ² = 34.31; P < .001). All moderate (13.3%) and severe/complicated (8.9%) PE cases occurred exclusively in the CDKAI group. Vortex keratopathy was observed in 13.3% of CDKAI patients and in none of the other groups (P = .025). Schirmer values, tear film break-up time, and OSDI scores did not differ among groups (all P > .05). Within the CDKAI group, PE was not associated with treatment duration (P = .963) or tear film parameters. CONCLUSIONS AND RELEVANCE: In this comparative study, CDK4/6 inhibitor-based therapy was associated with significantly higher prevalence and severity of PE and vortex keratopathy, independent of aromatase inhibitor exposure and in the absence of measurable tear film dysfunction. These findings suggest a direct cytostatic effect on the corneal epithelium. Symptom scores were low, although OSDI interpretation was limited by incomplete responses. Proactive corneal surface evaluation with fluorescein staining may be warranted during CDK4/6 inhibitor treatment.

Humans↗

PubMed2026

A Pilot Study: Developing a Lactating Dairy Goat Model to Study Staphylococcus aureus Mastitis in Women.

INTRODUCTION: Lactational mastitis is common in lactating women, with Staphylococcus aureus as the most commonly isolated agent associated with infectious lactational mastitis. Currently, there are no evidence-based guidelines for antimicrobial treatment due to barriers in obtaining pharmacokinetic data from lactating women. To overcome this barrier, a suitable large animal model is needed. Goats are an ideal translational model for human mastitis due to their anatomical and physiological similarity to humans. The objective of this pilot study was to assess if goats would develop clinical mastitis following intramammary inoculation with a clinical human isolate of S. aureus with the goal of establishing an alternative in vivo model for future research. The hypothesis was that the infected mammary gland half would show similar clinical signs to women with mastitis and demonstrate a similar local immune response when compared to the control mammary gland half. METHODS: One half of the mammary gland of two healthy lactating does was inoculated with a clinical human isolate of S. aureus. The other half of the mammary gland was sham inoculated with sterile buffered saline. Physical examinations, mammary gland assessments, and sterile milk samples were collected every 12 hours post inoculation. At 96 hours post inoculation, the goats were euthanized, and the mammary glands were examined for pathological changes. RESULTS: Goats did not develop systemic signs of disease following inoculation. Focal infected mammary gland changes included warmth, swelling, redness, discoloration, and reduced milk production; the other mammary gland half remained normal throughout the study period. S. aureus was enumerated from only the infected mammary gland half. The microscopic findings of the infected half showed neutrophilic inflammation and cell necrosis consistent with acute mastitis. DISCUSSION: This pilot study demonstrated lactating does can develop clinical signs like those observed in women. Goats have the potential to be a promising animal model to study infectious lactational mastitis.

Animals↗

PubMed2026

Protein persulfidation emerges as a conserved component of the redox response to DNA damage.

Genotoxic stress is frequently accompanied by alterations in cellular redox homeostasis; however, the mechanisms linking redox regulation to the DNA damage response (DDR) remain incompletely understood. Here, we investigated the early redox response to DNA damage induced by methyl methanesulfonate (MMS) in Saccharomyces cerevisiae, focusing on cysteine oxidative post-translational modifications (PTM). We show that activation of the DNA damage response is accompanied by rapid redox changes that occur in the absence of a generalized oxidative stress response. MMS exposure promotes selective remodeling of cysteine oxidative modifications, characterized by decreased free thiols, robust induction of protein persulfidation, and comparatively modest changes in sulfenylation. These alterations are accompanied by increased intracellular hydrogen sulfide levels, supporting the involvement of reactive sulfur species in the cellular response to DNA damage. Proteome-wide analyses revealed that cysteine oxidative modifications preferentially target proteins involved in central metabolism, nucleotide biosynthesis, and genome maintenance. Consistent with these observations, MMS-induced genotoxic stress promotes metabolic adaptation characterized by increased mitochondrial respiration, elevated ATP production, and mitochondrial morphological remodeling, linking bioenergetic adaptation to redox regulation. Importantly, perturbation of intracellular redox balance using N-acetylcysteine compromises survival under DNA-damaging conditions, supporting a functional role for redox signaling during the DDR. Finally, MMS treatment also induces protein persulfidation in mammalian cells. Moreover, exposure to etoposide, a mechanistically distinct genotoxic agent that induces DNA double-strand breaks through topoisomerase II inhibition, showed a similar trend, suggesting that protein persulfidation may not be restricted to alkylation-induced DNA damage. Together our findings identify protein persulfidation as a prominent component of the redox response to DNA damage and provide new insight into the functional interplay between mitochondrial metabolism, cysteine-based redox regulation, and genome maintenance.

Oxidation-Reduction↗

PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗

PubMed2026

Flexible ureteroscopy with a flexible and negative suction ureteral access sheath versus traditional sheath for treatment of infectious upper urinary tract stones: A prospective, randomized controlled study.

To evaluate the efficacy and safety of the flexible ureteroscopy (fURS) with a flexible and negative suction ureteral access sheath (FANS) versus traditional sheath for patients with infectious upper urinary tract stones (IUUTS). A total of 185 patients were enrolled, with 93 assigned to the FANS group and 92 to the traditional UAS group. The primary outcome was the stone-free rate (SFR) at the first postoperative day. Secondary outcomes included the SFR at 30 days postoperatively, operative time, hemoglobin reduction, length of hospital stay, quality of life (QoL) improvement, incidence of ureteral stricture at 3 months, and surgery-related complications. No significant differences were observed between the two groups in baseline demographics or preoperative clinical characteristics (P > 0.05). The FANS group had significantly lower white blood cell count, C-reactive protein, and procalcitonin levels at 6 and 24 h postoperatively (all P < 0.05). Mean operative time was significantly shorter (P < 0.001), QoL improvement was obviously greater (P < 0.001), and average hospital stay was shorter in the FANS group (P < 0.001). The SFRs on postoperative day 1 and at 30 days were both significantly higher in the FANS group (both P < 0.05). At 3 months, ureteral strictures occurred in three patients in the traditional UAS group and one in the FANS group, a difference that was not statistically significant (P > 0.05). The overall complication rate was significantly lower in the FANS group (P < 0.05). For patients with IUUTS, fURS combined with FANS effectively improves stone clearance efficiency and reduces the risk of postoperative infection.

Humans↗

PubMed2026

Micro- and nanoplastics-induced neurotoxicity: a CNS-centered, evidence-graded adverse outcome pathway framework based on systematic weight-of-evidence assessment.

Micro- and nanoplastics (MPs/NPs) are ubiquitous anthropogenic particulate pollutants posing emerging threats to human neurological health. Severe heterogeneity in particle physicochemical properties, environmental aging status, exposure paradigms and experimental platforms has created persistent mechanistic uncertainties in MP/NP neurotoxicology, hindering reliable hazard characterization and risk translation. Here, we systematically consolidate empirical toxicological evidence and construct a dedicated central nervous system (CNS)-targeted adverse outcome pathway (AOP) network integrated with rigorous weight-of-evidence (WoE) grading to elucidate the hierarchical, particle-specific toxic cascades underlying MP/NP-induced neural injury. Our synthesis overturns the conventional linear toxicity paradigm, demonstrating that MPs/NPs trigger neurotoxicity via a complex multi-input mechanistic network. We definitively establish oxidative stress as a robust early convergent key event-rather than a universal molecular initiating event-orchestrating ROS overproduction, lipid peroxidation, mitochondrial dysfunction, and neuroinflammation to propagate neuronal damage. This core module is driven by five distinct particulate upstream triggers: particle-biomolecule interfacial perturbation, corona-facilitated cellular internalization, plastic-associated chemical leaching, aging-derived free radical reactivity, and gut-borne systemic neurotoxic signaling. Downstream pathogenic outcomes encompass glial overactivation, neurotransmitter dyshomeostasis, autophagy-lysosome dysfunction, metabolic reprogramming, regulated neuronal cell death, and behavioral impairments. Tiered WoE analysis confirms strong validation for early oxidative/inflammatory cascades, moderate support for gut-brain axis crosstalk and intracellular trafficking disruption, and nascent evidence for synaptic dysfunction and neurodegeneration-linked proteostatic defects. Extrapolation to human health risk remains constrained by the frequent use of high-dose exposure paradigms, limited validated data on internal dosimetry in the human brain, discrepancies between effective concentrations in experimental models and environmentally relevant human tissue burdens, and insufficient causal validation of distal adverse outcomes. We highlight key research priorities including aged mixed-particle exposure systems, leachate-controlled assays, quantitative internal dose evaluation, and mechanistic intervention verification. This evidence-stratified AOP framework resolves longstanding mechanistic ambiguities in particulate neurotoxicity, providing a standardized, causality-based foundation for future mechanistic exploration and health risk assessment of global plastic pollution.

Adverse outcome pathway↗

PubMed2026

Serotypic and Genomic Diversity of Vibrio anguillarum in Rainbow Trout Farms in Turkey: Implications for Vibriosis Control and Vaccine Candidate Selection.

Outbreaks of vibriosis caused by Vibrio anguillarum are a persistent constraint on rainbow trout (Oncorhynchus mykiss) aquaculture. However, information on the population structure of field strains in Turkey has been lacking. Here, we report the first systematic serotypic, proteomic, and genomic characterization of 23 V. anguillarum isolates collected over 10 years from rainbow trout farms located in six major aquaculture regions of Turkey. Serological analyses based on microagglutination, supported by ELISA characterization of hyperimmune sera, identified a clear predominance of serotype O1, whereas isolate V12 exhibited a non-agglutinating, atypical O-antigen profile. Protein profiling (SDS-PAGE) and immunoblotting showed largely conserved whole-cell protein patterns among the isolates, but distinct immunogenic bands at 14, 18, and 40 kDa were detected in isolates V18 and V21. Long-read whole-genome sequencing revealed that most Turkish isolates grouped within the global O1 clade, while V12, V25, and V28 isolates occupied more distant branches. Comparative genomics demonstrated a conserved core virulence gene set (RTX toxins, siderophore and iron-uptake systems, motility and adhesion factors, Type VI secretion system), with strain-dependent variation in accessory loci such as anguibactin and T6SS-I. Experimental infections of rainbow trout demonstrated significant differences in virulence among isolates (p < 0.05), with the V18 isolate showing high, the V15 intermediate, and the V12 low-mortality rates. By elucidating the relationship among the serotype, immunogenic protein profiles, virulence gene repertoires, and in vivo pathogenicity, this study provides a comprehensive overview of the antigenic and genomic diversity of Vibrio anguillarum isolates from Turkey. Notably, the identification of V18 and V21 as promising candidate strains for further vaccine evaluation, characterized by high virulence and unique immunogenic features, provides a scientific foundation for the development of serotype-specific vaccination strategies to mitigate vibriosis-associated losses in aquaculture.

Animals↗

PubMed2026

Transcriptomic insights into thermal stress reveal physiological trade-off between thermal stress adaptation and reproductive investment in Spodoptera litura.

Spodoptera litura, a highly polyphagous lepidopteran pest, poses a major threat to agricultural productivity due to its remarkable adaptability to diverse environmental conditions. Although heat stress is known to trigger transcriptional reprogramming in insects, the molecular mechanisms underlying thermal stress responses in S. litura remain poorly understood. In the present study, fourth-instar larvae were exposed to acute heat stress (44 °C) and compared with control conditions (27 ± 1 °C) to investigate heat-induced transcriptional alterations affecting physiology and reproduction. High-quality RNA-Seq data achieved more than 80% mapping efficiency, with a total of 15,782 transcripts were identified. Transcriptome analysis of S. litura larvae showed 323 differentially expressed genes (DEGs), of which 262 genes were significantly upregulated and 61 were downregulated in heat-stressed larvae compared to the control group. The DEGs were associated with stress response, reproduction, signalling, proteostasis, detoxification, oxidative stress, metabolism, development, and chromatin regulation. Heat shock proteins genes, including HSP70, HSP90, and HSP27, together with co-chaperones such as TRET-1, STIP1, and Starvin, were strongly upregulated, indicating enhanced cellular protection against protein damage and oxidative stress under heat stress. Conversely, key reproductive and cell cycle-related genes, including BARR, CAPD2, FEO, CDK2 and MORULA, were significantly downregulated, suggesting reproductive impairment and developmental arrest. RT-qPCR validation corroborated the RNA-Seq findings, demonstrating a heat-induced physiological trade-off that prioritizes survival over reproduction. Consistent with these molecular responses, heat-stressed insects exhibited marked reproductive impairment, including significant reductions in gonadosomatic index, eupyrene sperm bundle count, mating frequency, mating success, female calling behaviour, copulation duration, fecundity, and egg fertility. Collectively, these findings provide comprehensive insights into the molecular basis of thermal adaptation in S. litura and demonstrate that acute heat stress compromises reproductive fitness while activating conserved stress-response pathways that promote short-term survival.

Animals↗

PubMed2026

Effects of time-restricted eating on markers of glucose metabolism and regulation in individuals with prediabetes or type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.

AIMS/HYPOTHESIS: This systematic review and meta-analysis aimed to investigate the effects of time-restricted eating (TRE) on glucose metabolism and regulation in individuals with prediabetes (fasting blood glucose of 5.6-6.9 mmol/l or HbA1c of 39-47 mmol/mol [5.7-6.4%]) or type 2 diabetes (fasting blood glucose ≥7 mmol/l or HbA1c ≥48 mmol/mol [6.5%]). METHODS: A literature search was performed in MEDLINE, Embase and CENTRAL from inception to 5 August 2025. Moreover, forward and backward citation searches were performed. Eligible studies were RCTs in adults with prediabetes or type 2 diabetes, lasting ≥2 weeks, reporting markers of glucose metabolism and regulation, comparing TRE (≤12 h eating window) with a non-time-restricted control diet. Studies involving pregnancy, other fasting regimens, or non-peer-reviewed publications were excluded. Data were pooled as weighted mean differences with 95% CIs using random-effects generic inverse variance models in Cochrane Review Manager Web, and results are presented as forest plots. The certainty of evidence was defined using Grading of Recommendations, Assessment, Development and Evaluations methodology, and risk of bias was estimated by using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). RESULTS: Out of 2043 records identified through the database search, as well as 1249 from forward and backward citation searches, ten RCTs including 599 participants were included. The mean length of the studies was 4 months, and the eating windows ranged from 4 to 10 h per day. The pooled meta-analysis showed no overall effect of TRE on HbA1c (-3.33 mmol/mol; 95% CI -6.87, 0.20 (-0.30% points; -0.63, 0.02); p=0.06, moderate certainty). Nevertheless, following stratification by subgroups, TRE resulted in a reduction in HbA1c of 0.93 mmol/mol (-1.70, -0.17 [-0.09% points; -0.16, -0.02]; p=0.02) in individuals with prediabetes but not in individuals with type 2 diabetes (-4.68 mmol/mol; -10.08, 0.72 (-0.43% points; -0.92, 0.07); p=0.09). TRE reduced fasting blood glucose in the pooled analysis (-0.30 mmol/l; -0.53, -0.07; p<0.01, moderate certainty) as well as in the subgroup analyses in individuals with prediabetes (-0.14 mmol/l; -0.27, -0.01; p=0.03) and with type 2 diabetes (-0.48 mmol/l; -0.78, -0.17; p<0.01). Moreover, TRE lowered body weight by 1.6 kg (-2.2, -1.0; p<0.001) in the pooled analysis. The evidence was limited by imprecision arising from wide confidence intervals in some of the included studies, which may be due to small sample sizes. Lastly, the effects of TRE on markers of insulin sensitivity, beta cell function and continuous glucose monitoring measurements were inconclusive. CONCLUSIONS/INTERPRETATION: Moderate-certainty evidence indicates that TRE reduces fasting blood glucose but not HbA1c. The subgroup analyses revealed that TRE improved HbA1c and fasting glucose in individuals with prediabetes and improved fasting glucose in individuals with type 2 diabetes. Future large-scale studies should investigate long-term effects of TRE in prevention and treatment of type 2 diabetes. TRIAL REGISTRATION: PROSPERO CRD42024523591 FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Three authors (JS, A-DT, THA) are employed at Steno Diabetes Center Copenhagen, a public hospital and research institution under the Capital Region of Denmark, partly funded by a grant from the Novo Nordisk Foundation.

Humans↗

PubMed2026

Omics in hereditary optic neuropathies: A systematic review of clinical studies with an integrated point of view.

Hereditary optic neuropathies are characterized by bilateral visual loss due to the degeneration of retinal ganglion cells, resulting in optic nerve degeneration and atrophy. Although the genetic origin of the main isolated and syndromic hereditary optic neuropathies has been characterized, the clinical phenotypes exhibit significant and poorly understood variability in both penetrance and expressivity. Additionally, the genetic and environmental factors that influence the onset of these optic neuropathies remain poorly understood, with limited biomarkers to predict disease progression or as readouts for therapeutic trials. Data-driven omics strategies allow deep phenotyping to improve our understanding of pathophysiological mechanisms and to search for new biomarkers and therapeutic targets. We explore whether the omics strategies applied to patients with hereditary optic neuropathies have provided such new insights. MEDLINE, Web of Science and EMBASE databases were screened for studies with terms relating to hereditary optic neuropathies, transcriptomics, epigenomics, proteomics, metabolomics and lipidomics in clinical studies exploring patients' samples. Out of 1244 references identified, 22 articles were included after double-masked data curation. These articles focused only on the 3 main forms of hereditary optic neuropathies, namely, OPA1-related dominant optic atrophy (n = 4), Leber hereditary optic neuropathy (n = 13), and Wolfram syndrome (n = 5). While the methodological designs and results of these studies were highly heterogeneous, they revealed molecular alterations that we have attempted to discuss at the integrated multi-omics level. This data integration highlighted several common pathophysiological mechanisms such as energetic impairment, endoplasmic reticulum stress, proteotoxic and oxidative stresses, lipid remodeling and altered amino acid and purine metabolisms, while suggesting potential new biomarkers and therapeutic targets. These findings underscore the potential of integrated multi-omics approaches to deepen our understanding of the phenotypic complexity of hereditary optic neuropathies and to support the development of innovative diagnostic and therapeutic strategies.

Humans↗

PubMed2026

A systematic review and meta-analysis of OCT-based ophthalmic changes in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor decline and respiratory failure. Optical coherence tomography (OCT), a non-invasive imaging technique, has been explored for detecting retinal structural changes that may reflect neurodegeneration in ALS. While some studies report thinning of retinal layers, findings remain inconsistent. Therefore, a meta-analysis is needed to clarify the extent of retinal involvement and the potential of OCT as a biomarker in ALS. METHODS: A systematic literature search was conducted across PubMed, EMBASE, and Cochrane databases for studies published between 2010 and May 2025. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated through funnel plot asymmetry and Egger's test. Pooled effect sizes were calculated using random-effects models to account for between-study heterogeneity, and differences in OCT parameters between ALS patients and healthy controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Statistical heterogeneity was quantified using the I2 statistic. RESULTS: A total of 17 studies were included in the present meta-analysis. The primary unadjusted global model demonstrated significant reduction of retinal nerve fibre layer (RNFL) thickness in ALS patients compared to controls (unadjusted SMD = -0.295, 95% CI: -0.522, -0.068). Upon applying a Design Effect variance inflation model to address fellow-eye non-independence, the pooled estimate remained robustly significant across a conservative range of intraclass correlations (SMD ranged from -0.256 to -0.249). Subgroup analyses revealed that RNFL thinning was particularly pronounced in spinal-onset ALS (SMD = -0.54, 95% CI: (-0.98, -0.10). When studies were stratified by the region of conduct, RNFL and macular thinning reached statistical significance only within the non-Asian subgroup, though the formal test for subgroup differences was not significant. CONCLUSION: This meta-analysis demonstrates significant bilateral RNFL thinning in ALS, with relative preservation of the Inner Nuclear Layer and Ganglion Cell Layer - Inner Plexiform Layer, supporting retinal neurodegeneration as a feature of this multisystem disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier CRD420251076035.

Humans↗

PubMed2026

Pegcetacoplan Delivers Real-World Therapeutic Benefits and Reduces Disease Burden for Patients With Paroxysmal Nocturnal Haemoglobinuria: A Systematic Literature Review of Pegcetacoplan Real-World Clinical and Patient-Reported Outcomes.

AIMS: Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired, non-malignant haematological disorder that, if left untreated, can lead to significant morbidity. This systematic literature review (SLR) summarized real-world evidence (RWE) for pegcetacoplan, a complement 3/3b inhibitor (C3i) available since 2021. METHODS: The SLR (PROSPERO-CRD420251043506) followed 2020 PRISMA guidelines and included RW studies of pegcetacoplan (n > 1 pts.; English; to April 2025) in adults (age ≥ 18 years) with PNH. RESULTS: Of 409 identified records, 39 qualified, representing 12 distinct studies. Six studies (n = 4-39) reported median haemoglobin (Hb) with baseline 8.1-9.6 g/dL. Ending median Hb and maximum pegcetacoplan durations were: 12.0 g/dL at 12 months, 11.1-12.1 g/dL at 6 months (3 studies), and 11.1 g/dL at 3 months (1 study). In 4 other studies (n = 48-70), ending mean Hb (maximum pegcetacoplan duration) was: 11.3 g/dL (7.2 months), 11.5 g/dL (6.6 months), 11.5 g/dL (5.9 months), and 11.58 g/dL (3 months). Six studies reported reduced absolute reticulocyte count (ARC; n = 4-39) from baseline median 155-301 × 109/L to median 56-106 × 109/L from 14 days of pegcetacoplan, maintained to maximum pegcetacoplan of 1-12 months. Three studies reported lactate dehydrogenase (LDH; n = 4-62); all showed reductions from baseline median 543.0 to 161.7 U/L after 3 months, and baseline median 299.5-316.0 U/L to 193.5-187.0 U/L after 6 months of pegcetacoplan. In complement 5 inhibitor-naïve, LDH reduced from 977.8 to 358.9 U/L after 8.4 months, and 503.6 to 292.5 U/L in C5i-experienced after 7.2 months. Three studies (n = 4-63) reported reduced LDH from above the upper limit of normal levels. Six studies (n = 23-70) reported reduced red blood cell transfusions (RBCt) after maximum pegcetacoplan durations of up to 12 months, and median durations of 3.0 and 10.2 months. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale scores in 1 study increased from baseline (mean 28.4) to 38.6 at 3 months, 36.3 at 6 months, and 34.9 at 9 months of pegcetacoplan treatment. Two studies reported FACIT-Fatigue scores of 34.6-40.1 with pegcetacoplan for ≥ 1 month. EQ-5D mean utility scores (0.85-0.94) in 2 studies were comparable to population normative values. On the Short-Form 36 Health Survey, mental and physical component scores were slightly lower than US normative values. CONCLUSIONS: RWE indicates pegcetacoplan is associated with improved haematological outcomes, reduced RBCt dependence and fatigue, and enhanced HRQoL. These findings from real-world studies with diverse cohorts support generalizability and are broadly comparable with clinical trial evidence.

Humans↗

PubMed2026

Probiotic-derived extracellular vesicles as food-based nanocarriers: Mechanisms, functional applications, and future perspectives in food systems.

Probiotic-derived extracellular vesicles (PDEVs) are a promising type of postbiotic nanoparticle derived by fermentation of probiotics, and have gained growing interest as a potential application in food science and nutrition. These are lipid bilayer vesicles of nanoscale, which are naturally released by probiotic cells and contain a wide variety of bioactive molecules, such as proteins, nucleic acids, and metabolites. Moreover, PDEVs are highly stable, biocompatible, and can be easily engineered to have surfaces with high functionality, which makes them good candidates in functional engineering. In contrast to traditional live probiotics, PDEVs overcome the difficulties of preserving microbial viability during processing and storage, thus providing superior safety, stability, and predictable biological performance. This is a systematic review of the various functions of PDEVs in food systems. We conclude on the processes through which PDEVs control intestinal barrier integrity, alter gut microbiota composition, and alter host immune responses, and their potential to enhance gut health when added to functional foods. In addition to their health-promoting effects, PDEVs have shown significant potential as natural antimicrobial agents to preserve food and as effective nanocarriers of hydrophobic bioactive compounds, including fucoxanthin, to improve their stability, bioavailability, and targeted delivery. Moreover, PDEVs can be used as new regulators of microbial fermentation. However, it should be noted that a lot of the evidence that is available is still preliminary and the effectiveness of these applications in real food-processing and storage conditions has not been fully proven. Although they have potential, there are a number of challenges that still hinder the widespread use of PDEVs in the food industry. These involve the creation of scalable and cost-effective production processes, batch-to-batch consistency, vesicle stability in a variety of food matrices, and regulatory and safety considerations. Other emerging engineering approaches, such as surface functionalization and cargo loading, are also discussed in this review and could further increase the specificity, functionality, and application versatility of PDEVs in food systems. Moving forward, the incorporation of PDEVs into the next generation functional foods, novel food preservation methods, and customized nutrition plans should be prioritized in future studies. Further developments in these fields can make PDEVs useful platforms at the interface of food microbiology, nanotechnology, and human health.

Probiotics↗

PubMed2026

Analysis of end-stage renal disease mediated by cuproptosis-related genes.

OBJECTIVE: The complex pathophysiological mechanism of end-stage renal disease (ESRD) has not been fully understood. Cuproptosis is a newly discovered type of programmed cell death. Therefore, this study attempts to clarify the relationship between cuproptosis-related genes (CRGs) and the phenotype of ESRD. MATERIALS AND METHODS: The National Center for Biological Information Gene Expression Omnibus database was applied to obtain the GSE37171 dataset comprising whole-genome microarray analysis of peripheral blood samples. A 3 : 1 case-control design was employed with 75 ESRD patients and 20 healthy controls who were frequency-matched for age, sex, and ethnicity. Based on differentially expressed genes (DEGs) and genes related to cuproptosis, CRGs were identified. Thereafter, we explored two different subpopulations based on the cuproptosis gene and analyzed their expression and immune infiltration. Genes specific to the CRG cluster were identified through the weighted gene co-expression network analysis algorithm, and the best prediction model was determined and verified by four machine learning methods. RESULTS: The study identified 14 differentially expressed CRGs, among which ATP7B, SLC31A1, LIAS, LIPT1, DLD, MTF1, CDKN2A, DBT, and DLST had relatively high expression levels in the ESRD samples. Compared with the control group, expression levels of FDX1, DLAT, PDHA1, PDHB, and GLS were significantly lower in the ESRD group, and CRGs played a key role in the regulation of immune infiltration in ESRD. Two cuproptosis-related molecular clusters were identified in the ESRD samples. Cluster2 was more correlated with the immune infiltration of ESRD. By analyzing the intersection points between CRG cluster and key genes of ESRD, a total of 888 specific DEGs were identified. Functional differences related to specific DEGs were further explored using gene set variation analysis. Five significant genes (SMC5, USP47, USP53, AGA, and DMXL1) were identified by the support vector machine model as key predictors for ESRD disease risk, achieving an area under the curve (AUC) of 1.00 in internal validation. However, external validation in independent cohorts is required prior to clinical application. Individual gene analysis showed an AUC > 0.81 in discriminating ESRD patients from healthy controls, and the expression of all 5 genes in ESRD patients was significantly lower than in the control group. CONCLUSION: This study clarified the relationship between CRGs and the phenotype of ESRD, analyzed their specific roles in the immune microenvironment, and obtained a predictive model, providing new insights for the study of its potential therapeutic targets.

Humans↗

PubMed2026

Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS: ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS: 36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION: The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING: National Cancer Institute of the National Institutes of Health.

Humans↗

PubMed2026

Efficacy and safety of mitapivat in adults with transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: The absence of disease-modifying therapies for patients with α-thalassaemia and oral disease-modifying therapies for patients with β-thalassaemia has been a substantial unmet need in these patients. We assessed the efficacy and safety of mitapivat, an oral allosteric activator of pyruvate kinase, in adults with transfusion-dependent thalassaemia. METHODS: ENERGIZE-T is a global, double-blind, randomised, placebo-controlled, phase 3 trial, conducted across 19 countries in North America, Europe, Asia-Pacific, South America, and the Middle East. Patients aged 18 years or older with transfusion-dependent α-thalassaemia or β-thalassaemia were randomly allocated (2:1) with a central interactive response technology system, stratified by geographical region and thalassaemia genotype, to receive 100 mg mitapivat or placebo orally twice a day for 48 weeks. The primary endpoint was transfusion reduction response (TRR), defined as a reduction of at least 50% in transfused red blood cell units with a reduction of at least two units in any consecutive 12-week period until week 48 compared with baseline. Efficacy was analysed in the full analysis set, comprising all randomly allocated patients. Type, severity, and relationship of adverse events and serious adverse events were assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT04770779) and is active but not recruiting. FINDINGS: Between Nov 30, 2021 and May 2, 2023, 305 patients were screened, of whom 258 were randomly allocated (median age 33·5 years [IQR 27·0-44·0]; 136 [53%] female and 122 [47%] male participants). Of 258 patients allocated, 238 (92%) completed the double-blind treatment period. All patients were required to have a safety follow-up approximately 4 weeks after the final dose of study drug, regardless of completion of the double-blind period or continuation into the open-label extension period. In the full analysis set, TRRs occurred in 52 (30%) of 171 patients in the mitapivat group and 11 (13%) of 87 in the placebo group (adjusted difference 18 percentage points [95% CI 8-27]; two-sided p=0·0003). The safety analysis set comprised 172 patients in the mitapivat group (including one patient allocated to the placebo group who received one dose of mitapivat in error) and 85 in the placebo group. Adverse events were reported in 155 (90%) patients treated with mitapivat and 71 (84%) treated with placebo; the most common events with mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhoea, and fatigue. Serious adverse events were reported in 19 (11%) patients treated with mitapivat and 13 (15%) treated with placebo. Ten (6%) patients who received mitapivat and one (1%) who received placebo discontinued study treatment due to adverse events. No deaths were reported. INTERPRETATION: Mitapivat significantly reduced the transfusion burden and was generally well tolerated, showing a favourable benefit-risk profile. These findings support mitapivat as the first oral disease-modifying therapy for adults with transfusion-dependent α-thalassaemia or β-thalassaemia, providing a new treatment option to reduce transfusion burden in this patient population. FUNDING: Agios Pharmaceuticals, Inc.

Adult↗

PubMed2026

Factors Associated With Accelerated Fracture Healing in Patients With Traumatic Brain Injury and Extremity Comminuted Fractures: A Retrospective Case-Control Study.

OBJECTIVE: Although traumatic brain injury (TBI) has been clinically associated with accelerated bone healing, the factors that determine which patients experience this phenomenon remain poorly defined, and previous findings are conflicting. This study aimed to investigate the clinical factors associated with accelerated fracture healing in patients with TBI combined with comminuted fractures of the limbs, so as to provide an evidence-based foundation for elucidating the clinical phenomenon of TBI-promoted fracture healing. METHODS: A retrospective case-control study design was employed. Patients between January 2020 and April 2024 with concurrent diagnoses of TBI and comminuted fractures were included. Based on radiographic findings and RUST/mRUST scores, patients were divided into an accelerated healing group (AHG) and a normal/delayed healing group (NDHG). Clinical data including demographics (age, sex, BMI), TBI characteristics (injury site, GCS score), admission laboratory indices (blood count, coagulation function, inflammatory markers), and fracture site/local soft tissue conditions, as well as functional outcomes assessed by the Short Musculoskeletal Function Assessment (SMFA) questionnaire at final follow-up were collected. Univariate analysis and multivariate logistic regression analysis were used to identify independent factors influencing accelerated fracture healing. Receiver operating characteristic (ROC) curves were plotted to evaluate their predictive value. RESULTS: A total of 119 patients were included, with 69 in the AHG and 50 in the NDHG. Significant differences were observed between the two groups in terms of age, BMI, GCS score, and platelet count (p < 0.05). Univariate analysis showed that age, BMI, GCS score, red blood cell count, and platelet count were associated with accelerated fracture healing (p < 0.20). Multivariate logistic regression analysis indicated that younger age (OR = 0.875, 95% CI: 0.821-0.934) and lower GCS score (indicating more severe TBI; OR = 0.490, 95% CI: 0.339-0.707) were independent predictors of accelerated fracture healing. ROC curve analysis showed that the area under the curve (AUC) for age and GCS score in predicting accelerated healing were 0.893 and 0.851, respectively. CONCLUSIONS: In patients with TBI combined with comminuted fractures, younger age and greater TBI severity (lower GCS score) are independent predictors of accelerated fracture healing. These findings assist clinicians in the early identification of patients with high healing potential to optimize treatment strategies, facilitate the early identification of high-risk patients, and provide clinical clues for further exploration of the molecular mechanisms underlying neurohumoral regulation of bone regeneration.

Humans↗

PubMed2026

Insights into the fate and dynamics of antibiotic resistance in multidrug-resistant Bacillus cereus during in vitro simulated gastrointestinal digestion.

Bacillus cereus, an important pathogen responsible for causing foodborne diseases worldwide, releases pore-forming enterotoxins, which target host epithelial cells, leading to osmotic lysis and ultimately manifesting as diarrheal syndrome. Moreover, some B. cereus strains carry antimicrobial resistance genes that confer multidrug resistance against a spectrum of antibiotics. Characterizing the survival traits of multidrug-resistant (MDR) B. cereus strains in the intestinal microenvironment is essential for developing targeted strategies to effectively manage diarrheal foodborne diseases caused by this pathogen. This study used whole-genome sequencing (WGS) to evaluate the pre- and post-digestion toxigenic potential, antimicrobial resistance profiles, and genetic diversity of MDR B. cereus strains isolated from food samples in Guangdong Province, China. The four B. cereus isolates investigated in this study exhibited a genetic diversity, as determined by multilocus sequence typing analysis of WGS data. All four isolates produced the diarrheal toxins Hbl, Nhe, and CytK to varying levels, indicative of their potential to cause outbreaks of foodborne diseases. Each of the four isolates exhibited resistance to more than three classes of antibiotics, fulfilling the criterion for multidrug resistance. At an initial concentration of 9 log colony-forming units (CFU)/mL, the intestinal concentration of these four isolates crossed the threshold required to induce widespread diarrhea in the general population. Under rice slurry protection, all tested isolates maintained intestinal concentration beyond the threshold when the initial concentration was increased to ≥8 log CFU/mL. Moreover, the upregulations of genes associated with acid tolerance, bile tolerance and stress response were observed in the surviving MDR B. cereus isolates. Digestion markedly altered the antibiotic resistance profiles of the MDR B. cereus isolates. In the absence of a food matrix, the MDR isolates lost their resistance to imipenem, meropenem, amoxicillin-clavulanic acid, and trimethoprim-sulfamethoxazole post-digestion and was influenced by the initial concentration of the strains. In the presence of food matrix rice slurry, the effects of digestion on the antibiotic resistance of MDR B. cereus isolates can be mitigated, enabling them to maintain their antibiotic resistance to the greatest extent. Most remarkably, after digestion, the isolates Bce055 and Bce166 exhibited newly emergent resistance to cefotetan and trimethoprim-sulfamethoxazole, respectively. Our findings clarify the fate of MDR B. cereus isolates in the gastrointestinal tract and inform the development of prevention and control strategies for foodborne diseases caused by this pathogen.

Drug Resistance, Multiple, Bacterial↗