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PubMed2026

GSTT1 promotes stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 (PROM1).

Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133HighGSTT1High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1HighCD133High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.

AC133 Antigen↗

PubMed2026

Translating single-cell RNA sequencing into monocyte direct leukocyte subpopulation-transcript abundance assay ratio-based biomarkers (IFI27/PSAP or IFI27/CTSS) for clinical detection of viral infection.

A rapid method for triaging febrile patients by aetiology (e.g., viral or bacterial infection) using gene expression in peripheral blood (PB) is an intensively researched area. However, gene expression in blood represents a composite sum of gene expression of all the component cell types present in the sample. As a result, numerous genes are measured in most proposed signatures. Herein, we propose a simple ratio-based biomarker (RBB) called direct leukocyte subpopulation-transcript abundance assay (DIRECT LS-TA) that recapitulates gene expressions of a single cell type in PB (i.e., monocytes). Based on single-cell RNA sequencing (scRNAseq) data and bulk expression data, IFI27 and SIGLEC1 are found as interferon-stimulated genes (ISGs) predominantly expressed by monocytes. The DIRECT LS-TA method can use a simple ratio of two genes measured in PB as an RBB to represent the target gene expression in monocytes without the need for monocyte purification. Both scRNAseq and bulk RNA sequencing datasets were used to evaluate the correlation between ISG expression in monocytes and PB, with a particular focus on monocyte expression of IFI27. An iceberg plot of bulk transcriptome data was used to identify genes that were predominantly expressed by monocytes in PB. DIRECT LS-TA RBBs of the three genes (IFI27, IFI44L and SIGLEC1) were evaluated by group-wise comparison, receiver operating characteristic and meta-analysis. In addition, the conventional interferon (IFN) score was evaluated for comparison of diagnostic performance. In viral infection datasets, DIRECT LS-TA of IFI27 (IFI27/PSAP or IFI27/CTSS) was most intensely activated (p value by t test <1e-9) and had the best area under the curve (0.94) among the three potential monocyte ISGs analysed. DIRECT LS-TA SIGLEC1 was also another monocyte biomarker but showed a lower activation (p<9e-5). IFI27/PSAP showed better diagnostic performance than the conventional IFN score. On the other hand, IFI44L was not a predominant monocyte expression gene. DIRECT LS-TA of IFI27 (IFI27/PSAP or IFI27/CTSS) measured in PB was the best biomarker of viral infection and IFN activation among ISGs predominantly expressed by monocytes. It performed even better than the conventional IFN score which required quantification of eight genes. The results suggest that DIRECT LS-TA of IFI27 is a monocyte-informative biomarker which is easy to determine in PB without the need for cell sorting.

Humans↗

PubMed2026

Targeting SIRT6: the design and therapeutic implications of activators and inhibitors.

Sirtuin 6 (SIRT6) is an NAD+-dependent deacylase that maintains genomic stability, regulates metabolism, and influences aging, making it an attractive but challenging therapeutic target. Pharmacological modulation of SIRT6 holds promise for cancer and metabolic disorders, yet its context-dependent functions demand precise intervention strategies. Potent, selective, and drug-like chemical probes are therefore essential to dissect SIRT6 biology and to validate its therapeutic potential. This review critically evaluates recent medicinal chemistry advances in SIRT6 modulation. We focus on structure-guided design strategies and structure-activity relationships (SAR) that have transformed initial hits into optimized leads for both activators and inhibitors, highlighting the remaining challenges in achieving isoform selectivity and drug-like properties.

Sirtuins↗

PubMed2026

Clinical and endocrine correlates of genetic etiologies in severe hypospadias: Study from 34 patients.

OBJECTIVE: Hypospadias is a prevalent congenital anomaly (0.3%-1.0%); however, severe hypospadias (defined as proximal cases with the meatus at the penoscrotal junction, scrotum, or perineum) is a rare and clinically challenging entity with a multifactorial etiology. This study aimed to characterize the interrelationships among the clinical, endocrine, and genetic profiles in children with severe hypospadias. MATERIALS AND METHODS: We conducted a comprehensive analysis of 34 male patients with severe hypospadias. Preoperative hormone levels were measured using two methods: chemiluminescent immunoassay for luteinizing hormone and follicle-stimulating hormone, and liquid chromatography-tandem mass spectrometry for testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17α-hydroxyprogesterone (17α-OHP), and other steroids. Genetic analysis was conducted via whole exome sequencing. RESULTS: The diagnostic yield of clinically relevant genetic variants (including pathogenic and likely pathogenic, and variants of uncertain significance) in our cohort was 41.2% (14/34) of patients. Patients carrying these variants exhibited a more complex phenotypic profile compared to non-carriers, including a significantly higher rate of patients with ≥3 associated malformations and a greater prevalence of cryptorchidism. Furthermore, the group with clinically relevant variants showed selective elevations in adrenal-derived precursors, specifically 17α-OHP and DHEA. Correlation analysis revealed significant positive associations of both 17α-OHP levels and the T/DHT ratio with the number of associated malformations. CONCLUSION: This study reveals significant genetic heterogeneity in patients with severe hypospadias. Those carrying genetic variants was associated with more severe clinical phenotypes, while certain endocrine variations, including the elevation of adrenal-derived hormones, were also observed in this cohort.

Humans↗

PubMed2025

Patient Ethnicity and Staff Use of Restraints and Restrictive Practice in Inpatient Psychiatric Services: A Systematic Review.

Restrictive practices such as restraints, seclusion, and forced medication are only intended to be used when the threat is at a level whereby an individual is likely to inflict harm on themselves or another individual. Demographic variations, including ethnicity, may be associated with the use of these practices. However, there is no systematic review on patient ethnicity specifically. The review therefore aimed to establish whether a patient's ethnic identity was associated with staff use of restrictive practices in inpatient psychiatric services. The systematic review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Four databases were searched (PsycINFO, Medline, Embase, and CINAHL). Methodological quality was assessed using the Critical Appraisal Skills Program Checklists. Fifteen studies met the inclusion criteria. A variety of ethnicities were identified within the studies. These were driven by the location of the study. Seclusion (14 studies), forced medication (4), and physical restraint (4) were explored. There were mixed findings, with ethnicity shown to predict restrictive practices in studies having larger participant numbers, longer follow-up periods and less methodological bias. It remains unclear whether ethnicity is a genuinely independent predictor of restraint and coercive practices or interacts with other risk factors. Staff working in inpatient settings should be aware of how unconscious biases might affect clinical practice. Recruiting a diverse workforce from minority ethnic groups into inpatient psychiatric services would be a positive step. However, support for these staff members is important, and all staff should be equipped to respond to ethnic diversity. Future research should explore beyond patient-level factors.

Humans↗

PubMed2026

Pelvic lymph node dissection in prostate cancer: current evidence, controversies, and future directions.

BACKGROUND: Pelvic lymph node dissection (PLND) remains controversial in the management of prostate cancer. Although it provides the most accurate pathological staging, its therapeutic value beyond staging has long been debated due to conflicting evidence and concerns regarding procedure-related morbidity. OBJECTIVE: To critically evaluate the contemporary role of PLND, particularly extended pelvic lymph node dissection (ePLND), in prostate cancer management in the context of modern imaging, risk stratification tools, and evolving oncologic endpoints. EVIDENCE ACQUISITION: A narrative review of recent literature was conducted, focusing on high-level evidence including randomized trials, observational studies, and contemporary guideline recommendations addressing the indications, extent, oncologic outcomes, and complications of PLND. EVIDENCE SYNTHESIS: Recent randomized and observational studies suggest that ePLND improves nodal staging accuracy and may be associated with modest improvements in metastasis-free survival (MFS) in selected patients with intermediate- and high-risk prostate cancer, although the absolute benefit remains limited and causality is not definitively established. Advances in molecular imaging, particularly prostate-specific membrane antigen (PSMA) PET/CT, together with multiparametric MRI, validated nomograms, and emerging genomic classifiers, now allow more precise identification of patients most likely to benefit from ePLND. The integration of these tools supports a more individualized surgical strategy, including image-guided and sentinel lymph node approaches designed to maximize staging accuracy while minimizing unnecessary dissection. CONCLUSIONS: In the contemporary PSMA imaging era, ePLND continues to play an important role in nodal staging and may contribute to improved oncologic outcomes in carefully selected patients.

Humans↗

PubMed2026

Perinatal depression, maternal thyroid status and fetus/infant health and development: A systematic review.

BACKGROUND: Thyroid hormones are known to influence both maternal depression and child developmental outcomes, while maternal depression independently affects child outcomes. The potential interaction between thyroid dysfunction and depression in shaping child development remains insufficiently explored. The present study addresses such interplay. METHODS: Following PRISMA 2020 and JBI guidelines, three databases were searched through December 2025 for primary studies on maternal thyroid status, perinatal depression, and child development. Risk of bias (RoB) was assessed using validated tools. Due to clinical and methodological heterogeneity, data were synthesized narratively following SWiM guidelines. RESULTS: Eleven studies were included. Beyond independent risks for preterm birth and behavioral problems, limited evidence supports a synergistic model, while most studies likely reflect the simple co-occurrence of risks. Maternal thyroid peroxidase antibodies (TPO-Ab) were associated with child externalizing problems exclusively in the presence of clinical depression. High depressive symptoms also attenuated the cognitive benefits of prenatal iodine supplementation. Thyroid status appears to function as a risk moderator rather than a mediator. However, 50% of observational studies presented high RoB, primarily due to participant attrition. CONCLUSION: Findings are still scarce to support a synergistic risk model where specific maternal thyroid parameters (i.e. thyroid autoimmunity and iodine status) may moderate the impact of depressive symptoms on child development. Despite the high RoB in half of the studies, results highlight the need for integrated screening protocols. Simultaneously assessing mental health and thyroid status may optimize risk stratification for high-risk mother-infant dyads.

Female↗

PubMed2026

A chromosomal gtrB homolog and dam differentially contribute to dry-heat and high hydrostatic pressure resistance in Salmonella enterica.

Salmonella enterica can persist in low-moisture foods and shows enhanced dry-heat resistance under low water activity, posing significant food safety challenges. However, the genetic basis of extreme dry-heat resistance and its relationship with other processing stresses remain unclear. In this study, twelve S. enterica strains were screened for dry-heat treatment at 60 °C and 80 °C, with S. Infantis CICC21649 identified as the most resistant strain. Comparative genomics and transcriptional analysis identified candidate genes related to envelope integrity and regulation, including gtrB and dam. Deletion of the chromosomal gtrB homolog reduced dry-heat resistance, producing an additional 0.91-log10 reduction relative to the parent strain at 80 °C. Deletion of dam caused broader stress sensitivity, reducing resistance to both dry heat and high hydrostatic pressure, with the stronger phenotype observed under high hydrostatic pressure. Proteomic analysis of the chromosomal gtrB homolog mutant revealed broad alterations in envelope-associated proteins, transport functions, oxidative stress pathways, and central metabolism under dry-heat stress. These findings indicate that the chromosomal gtrB homolog is an important contributor to extreme dry-heat resistance, whereas dam contributes to resistance against both dry-heat and high hydrostatic pressure, likely through a broader regulatory role in stress adaptation. These results reveal distinct structural and regulatory layers underlying stress adaptation in S. enterica and provide practical guidance for low-moisture food processing by highlighting the need to account for strain-dependent and stress-specific resistance during process validation.

Hydrostatic Pressure↗

PubMed2025

Impact of stromal maturity and proportion on prognosis and immune landscape in colorectal cancer.

BACKGROUND: Tumour microenvironment and cancer cells have constant interaction affecting cancer progression. Tumour-stroma ratio (TSR) in the tumour centre and desmoplastic reaction (DR) classification at the invasive margin are prognostic factors based on stroma evaluation on H&E slides. However, their combined value and immunological associations remain poorly defined. This study examines the prognostic and immunological value of TSR, DR, and their combination in two large colorectal cancer cohorts. METHODS: Two colorectal cancer cohorts (N = 1,876) were analyzed. We introduced a three-tiered Stromal Maturity and Proportion Score (SMAPS) based on the presence of high (>50%) TSR and myxoid stroma (immature DR classification). Alcian blue staining was used to further quantify myxoid stroma. Multiplex immunohistochemistry combined with digital image analyses, was utilized to study immune cell densities associated with SMAPS, TSR, DR, and Alcian blue intensity. RESULTS: In the study cohort (N = 1,100), SMAPS was a stronger predictor of cancer-specific mortality [HR for high (vs. low) SMAPS 2.01 (95% CI 1.47-2.75), p < 0.0001] compared to TSR [HR for stroma-high (vs. stroma-low) 1.49 (95% CI 1.15-1.93), p = 0.003] and DR classification [HR for immature (vs. mature) 1.84 (95% CI 1.39-2.45), p < 0.0001]. High SMAPS, stroma-high TSR, and immature DR correlated with lower densities of CD3+ T cells, B cells, M1-like macrophages, CD66B+ granulocytes, and mast cells. Alcian blue staining was associated with immature DR and corresponding immune cells. The validation cohort (N = 776) confirmed the association of SMAPS with survival and T cell densities. CONCLUSIONS: TSR and DR are independent prognostic factors for cancer-specific survival. SMAPS is a promising prognostic tool that integrates stromal maturity at the invasive margin and stromal proportion in the tumour centre. SMAPS has stronger prognostic value compared to TSR and DR classifications alone. A high stromal proportion and myxoid content are associated with an immunosuppressive microenvironment characterized by lower densities of antitumourigenic immune cells.

Humans↗

PubMed2026

Dynamics of soil fungal communities restored with biochar from a quarry site.

Quarrying activities have intensified due to population expansion, leading to landscape degradation and ecological destruction. Quarry restoration is usually mandatory in Hong Kong, China. Although biochar is used for sustainable soil amendment, its effectiveness in restoring quarry soil with poor properties has rarely been investigated. A 24-month field study was conducted to evaluate the ecological feasibility of restoring a quarry site by using native species (that is, Castanopsis fissa and Cyclobalanopsis edithiae) and biochar amendment. The results revealed that after 24 months, the application of biochar increased the organic carbon, phosphorus and potassium of the vegetated soil by at least 120 %, 31 % and 12 %, respectively, due to higher cation exchange capacity and better plant growth. The relative abundance of Ascomycota and Basidiomycota increased by 24 % and 47 % with biochar application when C. fissa was planted, which was likely associated with the improved nutrient cycling and soil fertility. Even though adding biochar to bare soil was found to increase the complexity of fungal co-occurrence networks, biochar application only increased fungal diversity in vegetated quarry soil but usually reduced its fungal richness. Moreover, fungal co-occurrence networks in vegetated soil became less complex, suggesting that biochar potentially helped plants to assemble specific, beneficial fungal communities. This effect is most pronounced in the soil planted with C. edithiae, where the structure of fungal communities after 24 months was significantly different from that at other restoration times. This study identifies key fungal phyla enhanced by biochar in quarry soil and provides an effective strategy for facilitating the restoration and management of degraded lands, especially quarry sites.

Charcoal↗

PubMed2026

Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis.

BACKGROUND: The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials. METHODS: Participants with CKD (FLOW) or atherosclerotic cardiovascular disease (SELECT and SOUL) were randomly assigned semaglutide (once-weekly subcutaneous 1·0 mg [FLOW], once-weekly subcutaneous 2·4 mg [SELECT], or once-daily oral 14 mg [SOUL]) or matching placebo, added to standard of care. The primary outcome in this pooled analysis was time to first occurrence of a kidney composite, defined as onset of persistent 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure (persistent eGFR <15 mL/min per 1·73 m2, or initiation of kidney replacement therapy), kidney-related death, or cardiovascular-related death. Safety was also assessed. FINDINGS: The pooled participants from the trials (N=30 787) had a mean follow-up of 39·5-47·5 months. Among participants assigned to semaglutide, 973 first events of the primary kidney composite occurred compared with 1134 first events for placebo (hazard ratio [HR] 0·84 [95% CI 0·77-0·91]). First events of a narrower secondary kidney composite (excluding cardiovascular-related death from the primary outcome) were also reduced with semaglutide versus placebo (347 and 416, respectively; 0·80 [0·69-0·92]). Safety outcomes were overall similar between groups, and in line with other GLP-1 receptor agonist trials. Serious adverse events were numberically lower with semaglutide than with placebo. INTERPRETATION: Data pooled from three large phase 3 trials suggest that semaglutide reduces the risk of major kidney outcomes in a broad population with cardio-kidney-metabolic disease while having a favourable risk-benefit profile. In people with cardio-kidney-metabolic disease, with and without diabetes, semaglutide (oral or injected) prevents kidney-related and cardiovascular complications and induces adverse events in line with GLP-1 receptor agonist studies, regardless of baseline characteristics within the cardio-kidney-metabolic spectrum. This was a participant-level analysis conducted in a large database of three randomised controlled trials of similar design and examining the same treatment, but there were some differences in participants' baseline characteristics, and in the dose and route of administration of treatment. This pooled analysis adds evidence for the benefit of GLP-1 receptor agonists in general, and semaglutide in particular, in a broad population of people with cardio-kidney-metabolic disease, suggesting that the benefit of semaglutide might not be explained only by its glycaemic effects, weight-management effects, or both. FUNDING: Novo Nordisk.

Humans↗

PubMed2026

Ecotoxicological responses of aquatic macrophytes to 2,4-D: A global synthesis of species sensitivity and ecological risk.

The widespread use of 2,4-dichlorophenoxyacetic acid (2,4-D) has raised concern about its persistence, mobility, and effects on non-target aquatic vegetation in freshwater ecosystems. Here, we provide a global synthesis of the ecotoxicological responses of aquatic macrophytes to 2,4-D based on a PRISMA-guided systematic review of 86 peer-reviewed studies published between 1947 and 2025. A consistent gradient of species-specific sensitivity was observed across macrophyte growth forms. The submerged species Myriophyllum spicatum showed high susceptibility, with EC₅₀ values of 0.04-0.182 mg/L and marked growth inhibition at low concentrations, whereas floating species such as Lemna minor and Pontederia crassipes were more tolerant, requiring higher concentrations (7.08 to >100 and 8.1 mg/L, respectively) to produce comparable effects. Importantly, this sensitivity ranking was consistent across laboratory and field experimental settings. These interspecific differences likely reflect variation in herbicide uptake, translocation, and detoxification capacity associated with growth form. The overlap between EC₅₀ values for M. spicatum and regulatory thresholds for 2,4-D in surface waters suggests that current limits may be insufficient to protect sensitive submerged macrophyte communities. Regarding remediation, L. minor and Salvinia natans emerged as the most promising candidates for phytoremediation, while P. crassipes showed limited capacity to reduce herbicide concentrations in water. Despite advances, no study directly compared oxidative stress biomarkers between submerged and floating species, representing a critical gap in understanding the biochemical basis of the sensitivity gradient. Overall, this synthesis highlights the need to account for taxon-dependent sensitivity when evaluating the ecological risks of 2,4-D and provides a basis for improving regulatory frameworks and management of herbicide contamination in freshwater ecosystems.

2,4-Dichlorophenoxyacetic Acid↗

PubMed2026

Herd-level heterogeneity of antimicrobial resistance in commensal Escherichia coli: A nationwide high-throughput survey of Australian pig herds.

Antimicrobial resistance in commensal Escherichia coli provides a useful indicator for overall antimicrobial resistance burden. We applied this approach to assess antimicrobial resistance within and between commercial pig herds across Australia. A high-throughput robotic workflow was used to isolate 2730 E. coli colonies from rectal contents collected in 2022 from healthy slaughter pigs (n = 300) representing 30 herds (∼70% of national production). Up to 94 isolates per herd underwent antimicrobial susceptibility testing using the Robotic Antimicrobial Susceptibility Platform. Isolate- and herd-level antimicrobial resistance indices were calculated, weighting antimicrobials by their human health importance. Resistance to first-line agents was widespread: ampicillin 77% and tetracycline 79%. By contrast, resistance to critically important antimicrobials was rare (ciprofloxacin 0.11%; extended-spectrum cephalosporins 0.04%), and no clinical resistance to carbapenems or colistin was detected. Overall, 56.9% of isolates were multi-class resistant. Herd-level antimicrobial resistance within indices ranged from 1.51 to 5.76, revealing substantial between-herd heterogeneity. Three herds carried critically important antimicrobials-resistant isolates that would likely have been missed using conventional, lower-density sampling approaches. Whole-genome sequencing identified fluoroquinolone-resistant isolates belonging to ST10 and ST69 (both qnrS1), and ST744 (Quinolone Resistance Determining Region mutations plus blaCTX-M-27). By testing approximately tenfold more isolates than conventional surveys, we uncovered considerable antimicrobial resistance with heterogeneity within and between animals and herds, including farm-specific variability. This expanded sampling also enabled detection of critically important antimicrobial resistance at very low prevalence. In conclusion, high-throughput, high-density testing offers a practical early-warning system and herd-level benchmark to inform surveillance and targeted interventions.

Animals↗

PubMed2026

Genetic Ancestry and Carrier Variant Frequency Enrichment in a Colombian Andean Population: Insights From the Eje Cafetero.

Colombia is one of the most genetically diverse populations in Latin America, and its demographic process has promoted the persistence and local enrichment of deleterious alleles, increasing the frequency of autosomal recessive disorders, particularly in semi-isolated Andean populations such as the Eje Cafetero. However, exome-based reference data from this region remain scarce, limiting ancestry-aware variant interpretation and carrier screening strategies. We aimed to characterize the ancestry proportions of this population using exome data, and to estimate the carrier frequency and distribution of pathogenic and likely pathogenic (P/LP) variants in clinically relevant recessive genes. We conducted a cross-sectional study with whole-exome sequencing (WES) in 316 unrelated individuals from the Colombian Eje Cafetero. P/LP variants were evaluated in 454 genes associated with autosomal recessive disorders. The global ancestry proportions were estimated using a validated panel of 250 exome-compatible ancestry-informative markers. Carrier frequencies were compared against Non-Finnish Europeans (NFE) and Admixed Americans (AMX) from gnomAD v4. The cohort showed predominant European ancestry (mean 51%), followed by Native American (36%) and African (13%) components. We identified 151 carriers of 89 distinct pathogenic variants across autosomal recessive genes. The most frequent variants were SERPINA1 c.863A>T (5.5%), CFTR c.1210-11T>G (3.5%), and PYGM c.1094C>T (1.5%). Also, recurrent variants were significantly enriched compared with both NFE and AMX populations, supporting regional founder effects. This study represents one of the most comprehensive exome-based genetic characterizations of the Colombian Eje Cafetero, revealing ancestry-specific enrichment of clinically relevant autosomal recessive variants driven by founder effects.

Female↗

PubMed2026

First identification and molecular subtyping of Blastocystis spp. in donkeys in Aksaray province, Türkiye.

Blastocystis is a common intestinal protist worldwide that can infect humans and animals. Although its molecular epidemiology in Türkiye is mostly focused primarily on humans and livestock, equids have received limited attention despite their traditional roles and frequent contact with humans and other animals in rural environments. This study aimed to determine the molecular prevalence and subtype (ST) distribution of Blastocystis spp. in donkeys in Aksaray Province, providing the first molecular data on donkeys in Türkiye. A total of 182 fresh fecal samples were collected from donkeys in nine villages within Aksaray province. Genomic DNA was extracted, and the small subunit ribosomal RNA (SSU rRNA) gene fragment of Blastocystis spp. was amplified via PCR analysis. Positive isolates were sequenced bidirectionally for identification and subsequent phylogenetic analysis of Blastocystis in donkeys. The overall molecular prevalence of Blastocystis spp. in donkeys was 4.4% (8/182). The infection rate was higher in young donkeys (under 3 years old; 8.33%) than in adults (3 years or older; 2.46%). However, this difference was not statistically significant. Sequence analysis of the positive PCR products revealed the presence of one known livestock-specific subtype, ST10. Phylogenetic analysis showed that the ST10 isolates characterized in this study clustered with isolates identified from different hosts. This study provides the first molecular data on Blastocystis presence in donkeys in Türkiye. The exclusive detection of ST10 suggests potential cross-species transmission, likely facilitated by the traditional practice of co-housing donkeys with other animals in confined barns. These findings indicate that donkeys may contribute to Blastocystis transmission, underscoring the importance of a "One Health" approach in future epidemiological surveillance.

Animals↗

PubMed2026

Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial.

BACKGROUND: Stepwise treatment intensification is recommended for managing type 2 diabetes, including insulin initiation when non-insulin glucose-lowering medications are insufficient. Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk. COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications. METHODS: COMBINE 4 was a 40-week, randomised, open-label, treat-to-target, phase 3b trial conducted across 97 sites in nine countries. Adults (aged ≥18 years) with type 2 diabetes (HbA1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100. The titration target was 3·9-5·0 mmol/L (70-90 mg/dL). The primary endpoint was change in HbA1c and the secondary confirmatory endpoint was change in bodyweight, both from baseline to week 40, evaluated in all randomly allocated participants. Adverse events were recorded during weeks 0-45. This trial is registered with ClinicalTrials.gov (NCT06269107) and is complete. FINDINGS: Of 653 individuals screened between Feb 15 and Aug 6, 2024, 151 did not meet screening criteria and 17 withdrew before initiating treatment; 243 were randomised to IcoSema and 242 to glargine U100. Of the 485 randomly allocated participants, 286 (59%) were male and 199 (41%) were female, and median age was 58 years (range 26-82). For HbA1c, from baseline (9·57% for IcoSema and 9·50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3·32 vs -2·44 percentage points; estimated treatment difference [ETD] -0·88 percentage points [95% CI -1·12 to -0·63]), confirming superiority of IcoSema (p<0·001). From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0·79 vs 3·81 kg; ETD -4·61 kg [95% CI -5·46 to -3·75]), confirming superiority of IcoSema (p<0·001). Rate of combined clinically significant (blood glucose <3·0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0·29 vs 0·59 episodes per person-year of exposure; estimated rate ratio 0·56 [95% CI 0·32 to 0·97]; p=0·04). Gastrointestinal disorders were the most frequently reported adverse events with IcoSema. INTERPRETATION: Once-weekly IcoSema demonstrated superior HbA1c reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100, suggesting that IcoSema might be an effective once-weekly treatment option for insulin-naive individuals with type 2 diabetes inadequately controlled on oral glucose-lowering medications. FUNDING: Novo Nordisk.

Humans↗

PubMed2026

Screening of Estrogenic and Antiestrogenic Effects of Estradiol, Bisphenol A, and Fulvestrant Using 2D and 3D Breast Cancer Cell Systems With a Luciferase Reporter Gene Assay.

Endocrine-disrupting chemicals (EDCs) like bisphenol A (BPA) pose health risks by interfering with hormones. This study develops and utilizes in vitro 2D and 3D cell models to evaluate the estrogenic and antiestrogenic properties of compounds. Human breast cancer cell lines T47D and MCF7, stably transfected with a luciferase reporter gene (ERE-LUC), were first compared in 2D. Due to the significantly higher sensitivity and responsiveness observed in the T47D line during preliminary 2D screenings, this cell line was exclusively selected for the development of the 3D spheroid model. Cells were treated with 17β-estradiol (E2), BPA, and Fulvestrant (FUL) to assess cell viability and luciferase activity. In 2D models, T47D ERE-LUC cells showed higher responsiveness than MCF7 ERE-LUC, which failed to show significant luciferase induction with E2. In the 3D T47D model, cells exhibited significant and robust changes in luciferase activity in response to E2 and BPA, highlighting the enhanced fidelity of 3D cultures in replicating tissue conditions compared to their 2D counterparts. The study highlights the effectiveness of 3D models over 2D in evaluating estrogenic activity. Specifically, the 3D T47D ERE-LUC system serves as a superior, sensitive, and reliable platform for screening EDCs, offering benefits in cost, data speed, and reduced in vivo reliance.

Humans↗

PubMed2026

Liver transcriptome analysis revealed multiple immune processes and lipid metabolism pathways involved in the defense response of the turbot (Scophthalmus maximus) against Aeromonas salmonicida.

Aeromonas salmonicida is a significant pathogen causing notable economic losses in Scophthalmus maximus aquaculture. This study utilized Illumina sequencing technology to examine the transcriptional response characteristics of S. maximus liver at 24 h following A. salmonicida infection. A total of 2363 differentially expressed genes (DEGs) were identified when compared to the negative control group. The immunity-related Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, as well as metabolism-related PPAR signaling pathway and insulin signaling pathway, were notably enriched. Significant differences exist in the expression of key genes within the PPAR pathway, particularly cd36, acsl4a, pparαa, and plin2, all of which mediate the interaction between lipid metabolism and the immune response. These results offer valuable insights into the immunometabolic regulatory mechanism of S. maximus response to A. salmonicida infection.

Animals↗