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PubMed2026

Pharmacological therapies for the prevention of fractures in men.

RATIONALE: Pharmacological therapies for fracture prevention usually target osteoporosis, a skeletal disorder characterised by compromised bone mass or quality (or both). As most participants in osteoporosis trials are women, a review of pharmacological therapies for fracture prevention in men was warranted. OBJECTIVES: To determine the benefits and harms of bisphosphonates, parathyroid (PTH) or parathyroid-related protein (PTHrP) analogues, denosumab, and romosozumab therapy for the prevention of fractures in men. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and WHO ICTRP) until 14 October 2025, with no restrictions on date or language of publication. ELIGIBILITY CRITERIA: We included randomised controlled trials that compared bisphosphonates, PTH or PTHrP analogues, denosumab, or romosozumab (alone or with calcium or vitamin D, or both) with placebo, other drugs, or non-pharmacological therapies in men aged 50 years or older. Our primary comparison was bisphosphonates versus placebo. OUTCOMES: Critical outcomes were incidence of hip fractures, symptomatic vertebral fractures, other (not hip or vertebral) fractures, disability, participants with adverse events, study withdrawals due to adverse events, and participants with serious adverse events. Our primary time point was the final time point reported in the trials. RISK OF BIAS: We used Cochrane's RoB 2 tool to assess risk of bias. SYNTHESIS METHODS: We used a random-effects model for meta-analysis employing the Mantel-Haenszel approach, and the DerSimonian and Laird method to estimate between-trial variance. We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: Seventeen trials (4132 participants) met our inclusion criteria. The average age of participants ranged from 52 to 73 years. Twelve trials used a placebo comparator versus bisphosphonate (7 trials, 2548 participants), PTH or PTHrP analogues (4 trials, 569 participants), denosumab (1 trial, 240 participants), and romosozumab (1 trial, 244 participants). For the other planned comparisons, a bisphosphonate was compared to vitamin D/vitamin D analogues (2 trials, 434 participants), to calcitonin (1 trial, 32 participants), to PTH or PTHrP analogues (1 trial, 19 participants), or to another bisphosphonate (1 trial, 301 participants), and one trial compared a bisphosphonate plus calcium to calcium tablets alone (46 participants). SYNTHESIS OF RESULTS: Placebo-controlled trials were largely susceptible to bias in selection of the reported result (83%), while most trials without a placebo control were also susceptible to bias arising from the randomisation process (100%) and in measurement of the outcome (80%). We are very uncertain about the effect of bisphosphonates on the incidence of hip fractures, symptomatic vertebral fractures, or other (non-hip non-vertebral) fractures compared to placebo at the final follow-up (up to two years). We downgraded the certainty of evidence once for risk of bias, twice for imprecision (very low event rates), and once for suspected publication bias. The certainty of evidence for incidence of other fractures was further downgraded for indirectness, as it was unclear if hip fractures were also included in the outcome. At up to two years, 2/875 participants (2 per 1000) in the bisphosphonate group reported hip fractures compared with 2/760 (3 per 1000) in the placebo group (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.06 to 8.51; I² = 36%; 4 trials, 1635 participants); 5/1021 (4/1000) participants in the bisphosphonate group had a symptomatic vertebral fracture compared to 7/855 (8/1000) participants in the placebo group (RR 0.49, 95% CI 0.14 to 1.74; I² = 0%; 5 trials, 1876 participants); 25/1130 participants (16/1000) in the bisphosphonate group reported other (non-hip non-vertebral) fractures compared to 19/913 participants (21/1000) in the placebo group (RR 0.78, 95% CI 0.42 to 1.45; I² = 0%; 6 trials, 2043 participants). Bisphosphonates probably do not increase the risk of adverse events: 1024/1374 participants (746/1000) receiving bisphosphonates reported adverse events compared to 826/1174 participants (704/1000) receiving placebo (RR 1.06, 95% CI 0.93 to 1.19; I² = 75%; 7 trials, 2548 participants; moderate-certainty evidence) or serious adverse events: 329/1329 participants (272/1000) receiving bisphosphonate reported serious adverse events compared to 323/1128 participants (286/1000) receiving placebo (RR 0.95, 95% CI 0.84 to 1.08; I² = 0%; 6 trials, 2457 participants; moderate-certainty evidence). We downgraded the certainty of evidence once due to potential bias for adverse events and serious adverse events. We are very uncertain if bisphosphonates result in more withdrawals due to adverse events: 41/1374 participants (25/1000) in the bisphosphonate group withdrew due to adverse events compared with 43/1174 participants (37/1000) in the placebo group (RR 0.68, 95% CI 0.39 to 1.18; I² = 37%; 7 trials, 2548 participants; very low-certainty evidence). We downgraded the certainty of evidence once for risk of bias, once for indirectness, and once for imprecision. No trial reported disability. We are very uncertain about the effects of PTH or PTHrP analogues, denosumab, or romosozumab compared to placebo on fracture outcomes. We are very uncertain about the effects of PTH/PTHrP analogues on total adverse events, withdrawals due to adverse events, and serious adverse events. Denosumab may not increase the risk of adverse events or serious adverse events compared to placebo, while the evidence for withdrawals due to adverse events is very uncertain. Romosozumab probably does not increase the risk of adverse events and may not increase the risk of serious adverse events or result in more withdrawals due to adverse events. AUTHORS' CONCLUSIONS: We are very uncertain about the effects of bisphosphonates compared to placebo on the incidence of hip fractures, symptomatic vertebral fractures, or other (non-hip non-vertebral) fractures in men at up to two years of use. Bisphosphonates probably do not increase the risk of adverse events or serious adverse events, and we are very uncertain if they result in more withdrawals due to adverse events. We downgraded the certainty of evidence for indirectness, imprecision (low event rate), and serious risk of bias in selection of the reported result, as it was unclear if all studies fully reported every fracture. We found similar results for PTH or PTHrP analogues, denosumab, or romosozumab versus placebo. Larger, longer placebo-controlled studies are needed to determine whether pharmacological therapies are beneficial for reducing fractures in men. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol (2021): https://doi.org/10.1002/14651858.CD014707.

Humans↗

PubMed2026

Gout and allopurinol adherence in newly diagnosed patients and the risk of fractures: a nationwide cohort study.

INTRODUCTION / OBJECTIVES: The association between gout and fractures remains controversial due to the competing effects of uric acid's antioxidant properties and gout-induced chronic inflammation. Our study aimed to evaluate the risk of fractures in newly diagnosed gout patients and to analyze the impact of Allopurinol medication adherence on this risk. METHODS: This nationwide cohort study utilized the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) database (2002-2019). We identified 4,107 patients newly diagnosed with gout who remained on continuous allopurinol therapy during the 24-month medication assessment period and matched them 1:3 with 12,321 non-gout controls using propensity score matching. Allopurinol adherence was assessed via the Medication Possession Ratio (MPR) over a 24-month period and categorized into three groups: MPR < 0.3, 0.3 ≤ MPR < 0.8, and MPR ≥ 0.8. Multivariable Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for fractures (vertebral, hip, and distal radius). RESULTS: Gout patients demonstrated a significantly higher risk of overall fractures compared to the non-gout group (aHR 5.52; 95% CI 4.19-7.26). A significant inverse linear relationship was observed between allopurinol adherence and fracture risk (P for trend < .001). The risk was highest in the low-adherence group (MPR < 0.3; aHR 5.91; 95% CI 4.40-7.93) and relatively lower in the high-adherence group (MPR ≥ 0.8; aHR 4.77; 95% CI 2.94-7.72). Consistent trends were observed for vertebral (aHR 5.68) and hip (aHR 4.22) fractures. These associations remained consistent across all subgroups, including age, sex, and comorbidities. CONCLUSION: Newly diagnosed gout is associated with a substantially increased risk of fractures. Higher adherence to Allopurinol therapy is correlated with a significant reduction in this risk, suggesting that consistent urate-lowering therapy may mitigate gout-related bone fragility. Key Points • Newly diagnosed gout patients have a significantly higher risk of major osteoporotic fractures compared to the non-gout population. • A significant inverse linear relationship exists between Allopurinol adherence and fracture risk, with the highest adherence group (MPR ≥ 0.8) showing a relatively lower risk. • Consistent urate-lowering therapy (ULT) may mitigate bone fragility in gout patients by reducing systemic inflammatory burden caused by urate crystal deposition.

Humans↗

PubMed2026

Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine versus Abraxane + Gemcitabine Alone in a Phase II, Open-Label, Randomized Study.

PURPOSE: Transforming growth factor β (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in the disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human mAb targeting TGFβ, demonstrated antifibrotic and immunomodulatory activity in preclinical models and early-phase trials. PATIENTS AND METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve patients with metastatic PDAC (mPDAC) to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel (or Abraxane)/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cell-free DNA profiling, and plasma proteomics. RESULTS: NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of cancer-associated fibroblast markers (Acta2, Fap) and collagen-related signatures. Despite proof of mechanism, clinical efficacy was not observed: Median PFS and OS were comparable or numerically worse in the NIS793 arm versus control (HR for OS in NIS793 + ABRA/GEM vs. ABRA/GEM: 1.32; 95% confidence interval, 0.84-2.07). The safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes after treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stromal remodeling but failed to improve outcomes in mPDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition.

Humans↗

PubMed2026

Randomized phase-II trial of surufatinib plus FOLFOX/FOLFIRI versus FOLFOXIRI as second-line therapy for metastatic colorectal cancer.

BACKGROUND: Second-line treatment for metastatic colorectal cancer (mCRC) typically involves oxaliplatin- or irinotecan-based doublet chemotherapy with or without anti-angiogenic antibodies. Triplet regimens such as FOLFOXIRI have demonstrated synergy and improved efficacy as first-line therapy. Surufatinib, an oral multi-kinase inhibitor targeting VEGFR1-3, FGFR1, and CSF-1R, may enhance chemotherapy efficacy. We evaluated surufatinib combined with doublet (FOLFOX/FOLFIRI) versus triplet (FOLFOXIRI) chemotherapy as second-line treatment for mCRC. PATIENTS AND METHODS: This multicentre, open-label, randomized phase-II trial used Simon's minimax two-stage design. Eligible patients had mCRC progressing on or within 6 months after first-line doublet chemotherapy. Patients were randomized 1:1 to surufatinib 250 mg once daily plus either mFOLFOX6/FOLFIRI (doublet cohort, selected based on prior regimen) or FOLFOXIRI (triplet cohort). The primary endpoint was objective response rate (ORR). RESULTS: From September 2021 to November 2023, 57 patients were randomized (28 per cohort after one withdrawal). In the doublet cohort, ORR was 35.7% (95% CI: 18.6-55.9), median progression-free survival (PFS) was 5.4 months (95% CI: 3.8-7.0), and median overall survival (OS) was 19.0 months (95% CI: 9.2-28.8). In the triplet cohort, ORR was 39.3% (95% CI: 21.5-59.4), median PFS was 5.8 months (95% CI: 3.3-8.2), and median OS was 10.9 months (95% CI: 6.0-15.8). Grade ≥3 treatment-emergent adverse events occurred more frequently in the triplet (71.4%) versus doublet (57.1%) cohort, with higher rates of treatment delays (89.3% versus 72.0%) and discontinuations (25.0% versus 14.3%). CONCLUSIONS: Surufatinib plus doublet chemotherapy showed encouraging antitumor activity and acceptable tolerability in second-line mCRC, warranting further evaluation in a larger randomized trial. In contrast, surufatinib plus triplet chemotherapy was associated with increased toxicity, more frequent treatment delays or discontinuations, and shorter overall survival; this combination is not recommended for further investigation in this setting.ClinicalTrials.gov: NCT04734249Date of registration: January 31, 2021.

Humans↗

PubMed2026

Suppression of HIV-1 replication in CEM-A cell cultures by trans-splicing group I introns targeting PAS/PBS sequences and conditionally expressing ΔN-Bax.

Anti-HIV group I introns containing antisense guide sequences directed against the HIV-1 primer activation signal and primer-binding site (PAS/PBS) were designed and evaluated. Because PAS/PBS sequences are present in the viral RNA species examined, these RNAs can serve as trans-splicing substrates. The introns were active against both artificial target RNAs and viral RNA generated during infection. Cleavage and degradation of targeted viral RNA may have contributed to suppression, whereas inclusion of a 3' exon encoding the proapoptotic protein ΔN-Bax was associated with increased programmed cell death and may have augmented suppression of viral replication. In cultured CEM-A cells, transgene expression of these introns markedly suppressed HIV-1 replication, with p24 levels falling below the assay detection limit in selected clones. RESULTS: RT-PCR and sequence analysis detected splice products containing the expected PAS/PBS junctions. In the dual-luciferase assay, intron expression reduced normalized Gaussia luciferase signal by approximately 70% relative to the negative control. Qualitative Annexin V imaging and caspase-3 assays were consistent with infection-dependent apoptosis after ΔN-Bax splice-product formation. Transient expression of each intron in HEK293T cells followed by infection with VSV-G-pseudotyped HIV-1NL4-3 at an MOI of 2 reduced p24 levels by approximately 50% at 4 days post-infection. Construct 128L produced the strongest RT-PCR band under the tested conditions and was selected for subsequent experiments. A canonical splice product and a low-abundance noncanonical splice product were detected; both involved the intended HIV-derived target RNA, although transcriptome-wide off-target splicing was not assessed. Heterogeneous transformed HEK293T populations showed an approximately 2-log10 reduction in p24. In selected clonal HEK293T and CEM-A lines, p24 was below the assay detection limit at the measured endpoints, including up to 90 days after infection in some CEM-A clones. CONCLUSIONS: PAS/PBS-targeting group I introns suppressed HIV-1-associated p24 production in the tested cell-culture models. Linking the introns to a ΔN-Bax 3' exon was associated with infection-dependent apoptosis and may further limit viral replication and spread. The use of highly conserved, functionally constrained target sequences may reduce the likelihood of escape, but viral evolution and transcriptome-wide off-target effects were not assessed. This conditional death-upon-infection strategy warrants further evaluation in primary-cell and in vivo models.

Humans↗

PubMed2026

DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.

Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.

Humans↗

PubMed2026

Whole cell inactivated poly-bacterial preparation MV130 effect on nasal mucosal immunity and experimental human pneumococcal carriage: double-blind randomised controlled trial with controlled human infection model.

BACKGROUND: Bacterial mucosal immunotherapy has shown protection of children and adults from both viral and bacterial respiratory infections, offering the potential to reduce antimicrobial use, and hence also control antimicrobial resistance (AMR). Pneumococcal carriage of vaccine type Streptococcus pneumoniae remains high in Malawi despite infant conjugate vaccination and AMR is increasing. We compared nasal inflammation following sublingual bacterial immunotherapy including S. pneumoniae (MV130, Inmunotek, Spain) or placebo and determined the effect in an experimental human pneumococcal carriage model. METHODS: A double-blind, randomised, placebo-controlled trial in healthy adult volunteers was conducted at Queen Elizabeth Central Hospital in Blantyre, Malawi. Participants were randomly allocated to receive MV130 or placebo sublingually once daily for 42 days. Mucosal inflammation (neutrophil to T cell ratio, NTR) was measured in nasal micro-biopsies. Post-treatment, participants were challenged with 160,000 CFU/naris S. pneumoniae 6B (Spn6b). Experimental pneumococcal carriage rates post inoculation were compared between the two arms. All participants completing the study were included in the analysis. Prospective trial registration: PACTR202403820001276. FINDINGS: 107 participants were enrolled and randomised to MV130/placebo between May and December 2024. There were no serious adverse events, complete compliance was good (72%) and all adverse events were mild. 96 participants (53 male, 43 female) completed the study with 52 participants randomised to MV130 and 44 to placebo. There was no difference in mucosal inflammation (neutrophil to T cell ratio) at day 14 of the intervention MV130 NTR median = 0.737 (IQR 0.294, 2.059) and placebo NTR = 0.831 (IQR 0.450, 2.073), p = 0.64. Secondary analyses showed a rise in mucosal neutrophils after MV130 treatment and after experimental pneumococcal inoculation. There was no difference in nasal or serum anti-pneumococcal immunoglobulin or in experimental pneumococcal carriage proportion between MV130 (12/52, 23%) and placebo (10/44, 23%) groups (unadjusted risk ratio 1.02 (CI 0.49-2.12) p = 1.0). INTERPRETATION: MV130 induced non-specific mild neutrophil inflammation of the nasal mucosa but had no protective effect against experimental human pneumococcal carriage. FUNDING: Wellcome Trust.

Humans↗

PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗

PubMed2026

From host response to genomic targets: electrochemical biosensing of tuberculosis biomarkers.

Tuberculosis (TB) remains one of the leading causes of death from a single infectious agent worldwide, with timely diagnosis continuing to be a major challenge, particularly in resource-limited settings. Conventional TB diagnostic methods are limited by low sensitivity, long turnaround times, and an inability to reliably differentiate latent from active disease. Biomarker-based diagnostic strategies have therefore gained increasing attention as they offer the potential to improve early detection, disease differentiation, and treatment monitoring. Herein, we examine electrochemical biosensing strategies for TB diagnostics using a biomarker-class-driven framework, covering host-response biomarkers (IFN-γ and TNF-α), pathogen-derived antigens (ESAT6, CFP10, CFP10-ESAT6, MPT64, Ag85, HspX and LpqH), cell-wall signatures and whole-cell markers (LAM and whole cell Mtb), and genomic markers (Mtb DNA and IS6110). Through structured comparison of recognition elements, biointerface designs, signal amplification strategies, electrochemical techniques, matrices, and validation levels, this review identifies the most promising technical approaches for different TB biomarker classes. It further highlights key translational bottlenecks, including limited clinical validation, buffer-based testing, complex multistep amplification, redox-probe dependence, matrix fouling, and insufficient evidence of manufacturability. This review therefore provides practical guidance for developing electrochemical TB biosensors that are analytically sensitive, clinically relevant, and suitable for decentralized diagnostic applications.

Biosensing Techniques↗

PubMed2026

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans↗

PubMed2026

Bacterially produced dsRNA targeting SePGRP-LB reduces population fitness of Spodoptera exigua (Lepidoptera: Noctuidae) and increases its susceptibility to SeMNPV.

The beet armyworm, Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae), is an important agricultural pest, and S. exigua multiple nucleopolyhedrovirus (SeMNPV) is a host-specific biological control agent. However, baculovirus efficacy can be limited by host antiviral responses. S. exigua peptidoglycan recognition protein LB (SePGRP-LB) has been identified as an antiviral immune factor, suggesting that its suppression may increase larval susceptibility to SeMNPV. In this study, bacterially produced double-stranded RNA targeting SePGRP-LB (bac-dsPGRP-LB) was orally delivered to larvae to induce RNA interference. Feeding bac-dsPGRP-LB reduced SePGRP-LB transcript levels by 24.0% to 65.7% over 7 d. SePGRP-LB knockdown prolonged fifth-instar larval development, reduced female pupal weight, shortened male adult longevity and the oviposition period, and decreased fecundity by approximately 51%. Life table analysis further showed significant reductions in the intrinsic rate of increase (r), finite rate of increase (λ), and net reproductive rate (R0) following bac-dsPGRP-LB treatment. During SeMNPV infection, co-feeding with bac-dsPGRP-LB significantly suppressed SePGRP-LB expression, increased the SeMNPV genomic load, and reduced larval survival compared with the SeMNPV + bac-dsGFP treatment. These findings identify SePGRP-LB as a promising RNAi target for simultaneously reducing S. exigua fitness and enhancing its susceptibility to SeMNPV under laboratory conditions.

SePGRP-LB↗

PubMed2026

Fluoride as a Modifier of Metallome Homeostasis: A Systematic Review of Animal Studies.

Fluoride is widely used for caries prevention due to its effects on mineralized tissues, yet its potential role as a modifier of systemic metal homeostasis remains insufficiently explored. This systematic review synthesizes preclinical evidence on the association between fluoride exposure and changes in metal and semi-metal concentrations across biological matrices. A comprehensive search strategy was conducted across major databases without language or date restrictions, following SyRF, CAMARADES and PRISMA 2020 guidelines. Thirty-one animal studies were included, encompassing multiple species, exposure conditions and analytical approaches. Despite substantial methodological heterogeneity, consistent patterns emerged. Fluoride exposure was associated with element-specific redistribution of the metallome rather than uniform change. Essential elements were predominantly depleted, most consistently zinc, copper and manganese, whereas the toxic metals lead and cadmium tended to be retained. This contrast between homeostatically regulated essential elements that are lost and non-regulated toxic metals that accumulate supports the hypothesis that fluoride differentially modifies the distribution and retention of co-existing elements. The novelty of this review lies in integrating metallomic outcomes across experimental models, highlighting fluoride as a potential systemic modulator rather than a tissue-specific agent. Although variability in study design and risk of bias limits causal inference, the consistent directionality of findings across models reinforces their biological plausibility and translational relevance.

Animals↗

PubMed2026

The Complete Mitochondrial Genome of a Newly Recorded Chinese Species of Diglyphus sabulosus (Hymenoptera: Eulophidae) and Insights into Its Phylogenetic Position.

Diglyphus Walker, 1844 is an economically important genus which many species acting as biocontrol agents against agromyzid leafminer pests, but there is a lack of mitogenomic data on the evolutionary relationships within this genus, hindering a comprehensive understanding of its evolutionary history. We used traditional morphological methods to identify species, and present the first complete mitochondrial genome sequence and characterization of features of Diglyphus sabulosus and further infer its phylogenetic position based on the amino acid sequences of 13 protein-coding genes (PCGs). The complete mitochondrial genome of D. sabulosus is 15,690 bp in length, including 13 PCGs, 22 transfer RNA genes, 2 ribosomal RNA genes and a control region. The AT content of the whole genome sequence was 81.0%, indicating a significant AT bias. All protein-coding genes have the typical ATN as the start codon and TAA as the stop codon. Phylogenetic analysis inferred from the amino acid sequences of 13 PCGs revealed that all species within the family Eulophidae constituted a monophyletic clade, supporting the monophyly of this family. D. sabulosus and D. poppoea form a well-supported sister group, representing the species with the closest phylogenetic relationship within the analyzed taxa. In this study, the mitogenome structure was analyzed and the taxonomic status of D. sabulosus was clarified, thus providing a theoretical basis for understanding the phylogenetic relationships of Diglyphus.

Animals↗

PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗

PubMed2026

Proteomic responses of the oil palm pest Metisa plana (Psychidae) to farnesyl acetate exposure.

Metisa plana Walker (Lepidoptera: Psychidae) is a major defoliator of oil palm in Malaysia, causing substantial economic losses. Farnesyl acetate (FA), a sesquiterpenoid compound, has been proposed as a potential insecticidal agent against M. plana, yet its molecular impact on larval physiology remains poorly understood. Here, we employed label-free quantitative proteomics, functional enrichment analysis, and targeted transcript assessment to characterize the temporal proteomic response of M. plana larvae at 7 and 14 days after treatment (DAT) with FA. Principal component analysis revealed robust separation between treated and control samples at both time points, indicating sustained treatment-driven proteomic restructuring. Early exposure (7 DAT) elicited a heterogeneous response involving stress-associated proteins, redox enzymes, and cytoskeletal regulators, whereas later exposure (14 DAT) produced a consolidated profile characterized by metabolic reprogramming, downregulation of ribosomal proteins, induction of heat shock proteins, and enrichment of RNA surveillance and mitochondrial pathways. Targeted transcript analysis qualitatively supported proteomic trends for HSP83 and aldehyde dehydrogenase X, although limited amplification precluded quantitative inference. Collectively, these findings demonstrate that FA exposure drives a shift from acute proteomic perturbation toward a maintenance-oriented physiological state, prioritizing proteostasis, energy management, and stress adaptation over growth and development. This integrated molecular perspective provides mechanistic insight into the chronic effects of FA, highlighting its potential to suppress larval performance and informing the development of biorational, physiology-based pest management strategies in non-model insects.

Animals↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2026

Strategy for enhanced production of A40926B0 in Nonomuraea gerenzanensis using an efficient CRISPR/AsCas12f1 system.

The global emergence of vancomycin-resistant Gram-positive pathogens underscores the urgent need for efficient production of novel lipoglycopeptide antibiotics. Dalbavancin, a last-resort therapeutic agent, relies on its key biosynthetic precursor A40926B0, whose industrial manufacture is severely limited by the low yield of wild-type Nonomuraea gerenzanensis and inefficient genetic tools for this rare actinomycete. Here, we developed a high-efficiency CRISPR/AsCas12f1 genome editing system and applied systematic metabolic engineering to boost A40926B0 biosynthesis. First, conjugation conditions were optimized to elevate the transfer efficiency in N. gerenzanensis D11. The hypercompact AsCas12f1 nuclease showed markedly lower cytotoxicity than SpCas9 and enabled 100% gene deletion efficiency with preferred PAMs (TTTG, CTTG, GTTG). Second, we strengthened the shikimate pathway via multiple genetic strategies: overexpressing feedback-resistant DAHP synthase (aroG fbr ) and chorismate mutase/prephenate dehydrogenase (tyrA fbr ), as well as knocking out pheA. This manipulation blocks the phenylalanine synthetic branch and redirects metabolic flux toward the l-tyrosine branch. Third, we engineered the branched-chain fatty acid (BCFA) pathway via promoter replacement of bkdA2B2C2, LipAB, fabF and deletion of acdH to enhance isododecanoyl side-chain supply. The combinatorial engineering yielded strain B-13, which produced 1740 mg/L A40926B0 in shake flasks. Finally, 50-L fed-batch fermentation with continuous maltodextrin feeding further increased the titer to 1817 mg/L, the highest reported titer to date. This work establishes a robust CRISPR editing tool for N. gerenzanensis and provides valuable engineering references for precursor-oriented strain improvement targeting lipoglycopeptide antibiotics, offering insights for the industrial scale production of A40926B0.

A40926B0↗

PubMed2026

Misalignment between ultra-processed status and 'better for you' claims on premix alcohol products.

BACKGROUND: Premix alcohol products (also known as ready-to-drink beverages) are a rapidly expanding alcohol category and frequently marketed using 'better for you' claims (e.g., 'Low sugar', 'Natural'). Little is known about the extent to which these products are ultra-processed or whether marketing claims align with ultra-processed status. This study aimed to address this evidence gap by auditing ingredient disclosure on premix products, assessing the ultra-processed status of these products, and determining the prevalence of 'better for you' claims with a particular focus on claims relating to ultra-processed status. METHODS: 534 premix alcohol products sold in major Australian retail outlets were assessed. Products were evaluated for compliance with mandatory ingredient disclosure, classified according to ultra-processed status based on the presence of indicators of ultra-processing (additives and other industrial ingredients), and analysed to determine the prevalence and types of 'better for you' marketing claims. RESULTS: Only 79% of assessed products displayed an ingredients list. Among compliant products, 98% contained at least one additive or ingredient indicative of ultra-processing, most commonly flavours, carbonating agents, colours, and sweeteners. One-third (33%) of products containing an ultra-processing indicator displayed a claim suggesting naturalness or minimal processing. Substantially higher proportions of ultra-processed products than non-ultra-processed products carried health-related claims. DISCUSSION AND CONCLUSIONS: Premix beverages available in Australia are overwhelmingly ultra-processed, yet many are marketed in ways that may mislead consumers about their composition and healthfulness. Stronger regulatory oversight of ingredient disclosure and marketing claims in this sector is urgently needed to support informed consumer decision-making.

Alcoholic Beverages↗