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PubMed2026

Time-varying hazard rates reveal patterns of progression in HR+/HER2- metastatic breast cancer: Towards risk-adapted monitoring.

BACKGROUND: optimal imaging intervals for patients with hormone receptor-positive/HER2-negative metastatic breast cancer (MBC) remains undefined. Aim of this study was to analyze the temporal patterns of disease progression to identify high risk subgroups that may benefit from intensified monitoring. METHODS: we analyzed 149 hormone receptor-positive/HER2-negative MBC patients prospectively enrolled in the MAGNETIC.1 trial (NCT05814224) and treated with first line endocrine therapy. Hazard rates (HR) for disease progression were determined according to clinico-pathological and liquid biopsy features. RESULTS: in the overall population, two distinct progression-risk peaks emerged at 2-3 months (32.9/1000 person-months) and at 24 months (28.0/1000). Higher risk of progression was observed in lobular carcinoma (61.1) [HR 61.12 per 1000 person month (pm)], progesterone receptor-negative status (HR 39.07), fulvestrant-based treatment (HR 46.88), liver metastases (HR 59.00), and presence of ≥ 3 metastatic sites (HR 40.10). CONCLUSIONS: Hazard distribution in hormone receptor-positive/HER2-negative MBC is biphasic and modulated by readily available clinical variables. High-risk subgroups may benefit from intensified radiologic and liquid-biopsy surveillance during the first three months and around two years after treatment start.

Breast cancer↗

PubMed2026

Distress Intolerance, Social Anxiety, and Depressive Symptoms in Adolescents: Evidence from Random-Intercept Cross-Lagged Panel and Cross-Lagged Panel Network Analyses.

Social anxiety and depressive symptoms frequently co-occur during adolescence, yet the mechanisms underlying their longitudinal associations remain insufficiently understood. Distress intolerance has been proposed as a transdiagnostic risk factor implicated across internalizing symptoms. However, it remains unclear whether distress intolerance is predicted by social anxiety and depressive symptoms, as well as the underlying mechanisms among these three constructs. The specific symptoms most centrally involved in these cross-domain associations remain poorly understood. The present study investigated the longitudinal associations among distress intolerance, social anxiety, and depressive symptoms using a dual-method framework combining random-intercept cross-lagged panel models (RI-CLPM) and cross-lagged panel network (CLPN) analyses. A total of 1,378 Chinese adolescents (Mage = 12.57, SDage = 0.63; 50.4% female) were assessed at three time points with six-month intervals between waves. The RI-CLPM analyses revealed that higher distress intolerance prospectively predicted subsequent increases in both social anxiety and depressive symptoms, whereas elevated social anxiety and depressive symptoms in turn predicted subsequent increases in distress intolerance. Moreover, distress intolerance mediated the longitudinal associations between social anxiety and depressive symptoms. Additionally, distress intolerance was also indirectly associated with its own subsequent levels through social anxiety and depressive symptoms. The CLPN analyses revealed that fear of negative evaluation and fatigue were the strongest predictors of other network nodes from T1 to T2 and from T2 to T3, respectively. In contrast, distress intolerance symptoms were predominantly predicted by other nodes in both cross-lagged networks. These findings extend prior views of distress intolerance as a unidirectional vulnerability by showing that distress intolerance is also predicted by social anxiety and depressive symptoms and accounts for part of their longitudinal associations across adolescence.

Humans↗

PubMed2026

Molecular Landscape and Advanced Diagnostic Technologies for BRAF Mutations in Cancer: From Quantitative PCR and ddPCR to CRISPR-Based Platforms.

BRAF mutations are key oncogenic alterations across multiple malignancies, including melanoma, thyroid carcinoma, colorectal cancer, non-small cell lung cancer, glioma, and hairy cell leukemia. The most prevalent variant, BRAF-V600E, induces constitutive activation of the MAPK signaling pathway, promoting tumor progression and influencing therapeutic responsiveness. Accurate detection of BRAF alterations is therefore essential for molecular classification, prognostic assessment, treatment selection, and resistance surveillance. This review summarizes the molecular heterogeneity of BRAF mutations and critically evaluates current diagnostic methodologies. Conventional approaches such as allele-specific PCR and Sanger sequencing are compared with advanced quantitative platforms, including high-resolution melting analysis, droplet digital PCR, and next-generation sequencing, with emphasis on analytical sensitivity, mutation coverage, and clinical applicability. Emerging technologies such as CRISPR-based assays, rolling circle amplification systems, and nanoparticle-based biosensors and point-of-care diagnostic platforms are also discussed for their potential to enhance ultra-sensitive detection, particularly in liquid biopsy settings. These emerging tools are highlighted for their potential to enable ultra-sensitive, rapid, and decentralized mutation detection, particularly in liquid biopsy settings. Key challenges, including intratumoral heterogeneity, low allele-frequency variants, FFPE-associated artifacts, and clonal evolution under therapeutic pressure, are examined within a translational framework. In addition, we examine critical barriers to clinical implementation, including standardization, cost, and global accessibility of molecular diagnostics, and outline potential solutions through scalable technologies and decentralized testing strategies. We propose that optimal BRAF testing requires a mutation subclass-informed and clinically integrated strategy combining comprehensive baseline profiling with longitudinal molecular monitoring. Future diagnostic paradigms will likely integrate multi-omics data and artificial intelligence (AI)-assisted interpretation to refine precision oncology implementation. Looking forward, we propose that optimal BRAF testing will require integration of multi-omics profiling with AI-assisted interpretation, enabling automated variant classification, real-time clinical decision support, and improved prediction of therapeutic response and resistance.

Humans↗

PubMed2026

Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.

Theta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes. Sixty male participants with OUD were randomized to receive 20 min of active or sham 6 Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using time × group interaction models to examine (1) modulation of drug cue-related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior. (1) A significant Time × Group interaction revealed decreased post-stimulation opioid cue-related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected α = 0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement (β = 2.63, p= 0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum (β = 1.99, p= 0.037) and left medial amygdala (β = 1.97, p= 0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r = 0.43, p= 0.02). Together, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical-subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction.

Humans↗

PubMed2026

Precision targeting of teacher burnout using network-informed ecological momentary interventions.

Teacher well-being affects classroom functioning and workforce stability, yet generic digital programs rarely use person-specific affect dynamics to select support. This cluster-randomised trial evaluated whether micro-interventions selected from high expected influence (EI) nodes in teachers' contemporaneous affect networks produced larger changes in burnout-related EI and everyday happiness than content-matched random allocation. The objectives were to estimate allocation effects on changes in estimated network summaries and happiness, evaluate network change as a statistical mediator, examine personality moderation, and benchmark simpler allocation rules. A two-arm cluster randomised platform trial was conducted in 84 public schools across four urban districts in H Province. After a 14 day baseline of ecological momentary assessment (EMA), person specific partial correlation networks were estimated for happiness, exhaustion, detachment, efficacy and rumination. An optimisation engine prioritised three brief micro-intervention types per teacher according to baseline EI, while the active control received the same library without network information. EMA continued for 8 weeks; Bayesian multilevel models, permutation-based mediation, and benchmarking analyses were applied. EI-based targeting produced larger reductions in the composite EI-change index than active control (mean difference 0.11, 95% credible interval 0.08 to 0.14) and higher week 7 EMA happiness (4.4 points on a 0 to 100 scale, 95% credible interval 2.7 to 6.0), with a positive arm by week slope difference of 0.62 points per week (95% credible interval 0.39 to 0.85). Model-based mediation estimates were consistent with approximately one half of the happiness difference being statistically associated with change in the composite EI-change index (average conditional mediation estimate 3.5 points, 95% credible interval 2.0 to 5.2). Benchmarking showed smaller gains under severity, threshold, or group-level centrality rules. Effects were stronger among teachers higher in conscientiousness. The findings indicate that integrating EMA, network modelling, and EI-driven optimisation yields measurable gains beyond content-matched exposure, providing a proof of concept for district-scale precision mental health that requires prospective implementation testing. Replication in additional regions, expanded node sets, and longer follow up are warranted to assess durability and generalisability.

Female↗

PubMed2026

The glucagon and GLP-1 receptor dual agonist DD01 for metabolic dysfunction-associated steatotic liver disease and steatohepatitis (DD01-DN-02): 12-week results from a randomised, double-blind, multicentre, placebo-controlled, phase 2 trial.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS: DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS: Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION: In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING: D&D Pharmatech, Neuraly.

Humans↗

PubMed2026

Ribosomal protein S3: a critical regulator of human disease mechanisms.

Ribosomal protein S3 (RPS3) is an essential structural component of the 40S ribosomal subunit, yet growing evidence highlights crucial extraribosomal roles in genome maintenance, cell-cycle control, and immune signaling. Dysregulation of RPS3 contributes to diverse human disorders, including cancer, inflammatory diseases, neurodegeneration, and resistance to antimicrobial and anticancer therapies. As a cofactor of NF-κB and a participant in DNA damage responses, RPS3 occupies a node that integrates stress signaling with transcriptional reprogramming, enabling both protective and pathological outcomes. The present review critically evaluates mechanistic insights into RPS3 biology, emphasizing recent findings that delineate its context-dependent effects, discrepancies across models, and remaining gaps that restrict translational applications. Understanding these complexities is essential to assess RPS3's potential as a biomarker and therapeutic target.

Humans↗

PubMed2026

Comparative Effectiveness of Exercise Interventions for Hamstring Injury Prevention in Football Players: A Systematic Review and Network Meta-analysis.

BACKGROUND: Hamstring strain injury is a leading time-loss injury in football, yet trials have evaluated diverse exercise-based prevention programs with limited direct head-to-head evidence. This systematic review and network meta-analysis aimed to compare the effectiveness of exercise-based interventions for preventing hamstring injuries in football players using exposure-adjusted incidence rate ratios. METHODS: We conducted a PRISMA-aligned systematic review and random-effects network meta-analysis of randomized controlled trials in football players comparing exercise-based interventions to prevent hamstring injuries. Searches covered PubMed, Cochrane Library, Embase and Web of Science from inception to January 5, 2026. Interventions were modeled as separate nodes (Nordic hamstring exercise [NHE], FIFA 11, FIFA 11 + , FIFA 11 + Kids, bounding exercise program [BEP], usual training). The primary effect measure was incidence rate ratio (IRR) versus usual training, with ranking by P-scores; exploratory subgroup analyses were conducted by sex-restricted male-only evidence and age group. RESULTS: Eleven randomized controlled trials involving 9,282 participants were included. The network was connected but largely star-shaped, with most evidence comparing active interventions against usual training and no direct active-active comparisons. FIFA 11 + showed the most consistent exposure-adjusted association with reduced hamstring injury incidence versus usual training (IRR = 0.55, 95% CI 0.31-0.98; P-score = 0.84). FIFA 11 + Kids showed a favorable but imprecise estimate, whereas NHE showed a modest non-significant reduction and FIFA 11 and BEP showed no clear benefit. Male-only findings were broadly consistent with the primary analysis. Age-stratified analyses suggested that the apparent hierarchy was not fully identical across age strata, but subgroup networks were sparse and exploratory. RoB 2 judged three studies as high risk and eight as having some concerns; no trial was judged as overall low risk. Between-study heterogeneity was substantial, and treatment rankings were, therefore, interpreted cautiously. CONCLUSIONS: In this IRR-based network meta-analysis, FIFA 11 + showed the most consistent exposure-adjusted association with reduced hamstring injury incidence compared with usual training. However, certainty across the primary comparisons ranged from low to very low because of clinical and methodological heterogeneity, sparse direct evidence for several nodes, reliance on indirect active-active comparisons, substantial between-study heterogeneity, and moderate-to-high risk of bias across the included studies. The treatment hierarchy should, therefore, be interpreted as a low-to-very-low-certainty, population-level summary rather than as a basis for firm recommendations. Further well-reported, age- and population-specific head-to-head trials with consistent exposure, injury-definition, adherence, and intervention-dose reporting are needed. Registration Systematic review registration PROSPERO (CRD420251243576).

FIFA 11 + ↗

PubMed2026

Hierarchical modeling of tumor subtypes in cell lines using large-scale genomic datasets.

Cancer cell lines (CLs) are widely used to study tumor biology and drug response, yet their translational relevance is often limited by inaccurate subtype annotations. Existing CL-tumor matching approaches are frequently constrained by flat classification schemes, weak subtype definitions, and the exclusion of normal tissue references, leading to potential confounding of tumor-specific and tissue-of-origin signals. To address these limitations, a hierarchical classification (HC) framework is presented in which CLs are aligned with patient tumors across biological resolutions, from organ to molecular subtype. Gene expression profiles from 802 CLs, 5,612 tumors from The Cancer Genome Atlas (TCGA) , and 8,939 non-cancerous tissues were integrated to separate oncogenic signals from tissue-specific signals. Node-specific features were selected using maximum relevance minimum redundancy, and balanced accuracies of 89% in cross-validation and 75%, and 80% on external datasets were achieved. Through the framework, 43 CLs were reassigned, and clinically relevant underrepresented subtypes were identified.

cancer cell lines↗

PubMed2026

Integrated proteomic and acetylomic analyses reveal the metabolic reprogramming associated with increased tylosin-equivalent concentration in Streptomyces xinghaiensis sf106-B1.

Deciphering the metabolic basis of high-yield antibiotic production in Streptomyces is crucial for strain optimization. Atmospheric and room-temperature plasma (ARTP) mutagenesis of Streptomyces xinghaiensis sf106 generated a mutant with a 30% increase in tylosin-equivalent concentration (μg/mL). 4D-FastDIA quantitative proteomics identified 279 differentially abundant proteins enriched in the Type I polyketide synthase (PKS) pathway, with increased abundance of key macrolide-biosynthesis-related proteins. Lysine-acetylome profiling identified 1152 differentially abundant acetylation sites and revealed altered acetylation of enzymes involved in fatty acid metabolism and the tricarboxylic acid (TCA) cycle, suggesting adjustments in central metabolism associated with acyl-CoA precursor availability and energy generation. Integration of proteomic and acetylomic data suggests coordinated changes in protein abundance and lysine acetylation associated with the increased tylosin-equivalent concentration. These results highlight candidate nodes for rational metabolic engineering of S. xinghaiensis.

Streptomyces↗

PubMed2026

Effects of different training modalities on lower-limb explosive power, acceleration, 20-m sprint performance, and change-of-direction ability in youth soccer players: a systematic review and network meta-analysis.

BACKGROUND: Youth soccer players repeatedly perform explosive actions, short accelerations, linear sprints, decelerations, and multidirectional movements. However, the comparative effects of different structured physical-conditioning programmes remain uncertain. METHODS: Seven databases were searched from inception to 3 July 2026 using a final expanded search strategy encompassing plyometric, strength or resistance, sprint, acceleration, speed, change-of-direction, neuromuscular, multicomponent, and combined training. Randomised controlled trials involving healthy youth soccer players were eligible. Intervention arms were classified using operational, content-based node definitions. Construct-restricted primary networks and expanded sensitivity networks were analysed using frequentist random-effects network meta-analysis. Hedges' adjusted g was preferentially calculated from post-intervention or final-follow-up means, standard deviations, and sample sizes. Estimates were presented so that positive values indicated better performance. P-scores were treated as descriptive ranking summaries. Risk of bias was assessed using an adapted study-level application of the five-domain RoB 2 framework, and confidence in the evidence was assessed using CINeMA. A post hoc strict-age sensitivity analysis excluded two age-boundary studies. RESULTS: Eighty-nine studies were included in the expanded quantitative analysis, of which 74 contributed to at least one construct-restricted primary network. The primary lower-limb explosive-power, acceleration, 20-m sprint, and planned change-of-direction networks included 55, 20, 25, and 38 studies, respectively. Compared with usual soccer training, plyometric training combined with sprint and/or change-of-direction training showed favourable estimates for lower-limb explosive power (SMD 0.79, 95% CI 0.55 to 1.03), acceleration (1.19, 0.90 to 1.49), 20-m sprint performance (0.80, 0.33 to 1.28), and planned change-of-direction ability (1.46, 1.13 to 1.80). Corresponding I² values were 34.6%, 21.8%, 65.0%, and 41.0%. Between-design inconsistency was detected in the 20-m sprint (P = 0.0036) and change-of-direction (P = 0.0007) networks. CINeMA confidence for these four comparisons was low, low, very low, and low, respectively. Expanded sensitivity networks showed substantially greater heterogeneity. The highest-ranked intervention differed across outcome domains but remained consistent within each outcome across the three analysis sets. Excluding the two age-boundary studies did not materially alter the principal estimates. CONCLUSIONS: Plyometric training combined with sprint and/or planned change-of-direction training produced favourable comparative estimates across the four performance outcomes. However, evidence for several nodes and active-versus-active comparisons was sparse, heterogeneity in programmes and outcomes was present, inconsistency was detected in some networks, and confidence in the evidence was low or very low. These limitations do not support a conclusion that any training category is universally superior. The findings should be interpreted as provisional category-level signals rather than definitive training prescriptions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420261347297, registered on 21 March 2026, https://www.crd.york.ac.uk/PROSPERO/view/CRD420261347297 .

Change-of-direction ability↗

PubMed2026

Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.

TECPR2 is a key regulator of autophagy, encoded by the TECPR2 gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report a teenage female with a syndromic intellectual disability disorder associated with neuromuscular abnormalities. Multi-omics analysis including genomics, transcriptomics, and proteomics, together with muscle biopsy from the affected individual, were used in this clinical case. Through trio exome sequencing we identified two heterozygous variants in the TECPR2 gene, NM_014844.4: c.480G>A; p.(Gln160=) and c.2846C>A; p.(Ala949Glu). Both were classified as variants of uncertain significance due to the lack of supporting evidence for pathogenicity. Subsequent long-read sequencing phased the variants and confirmed they were in trans. Additional functional studies using RNAseq and proteomics analyses verified the pathogenicity of the variants. This case study demonstrated the value of a multi-omics assisted analysis, which complemented the traditional phenotype-first approach in reaching a definitive clinical diagnosis.

Humans↗

PubMed2026

Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial.

BACKGROUND: Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS: In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS: Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION: Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING: None.

Humans↗

PubMed2026

Topical Carboxytherapy as an Adjunct to Skin Recovery Post-CO2 Laser Fractional Resurfacing.

BACKGROUND: Topical carboxytherapy, a transcutaneous carbon dioxide (CO2) delivery system, may support skin repair and regeneration, yet its role as an adjunct to fractional laser treatment remains underexplored. OBJECTIVE: To investigate the effectiveness and safety of topical CO2 mask (CO2Lift® Carboxy Gel, Lumisque Skincare) in supporting skin recovery and improving clinical outcomes following fractional CO2 laser resurfacing. METHOD: This 12-week randomized, placebo-controlled trial evaluated mild-to-moderate photoaging (n=6 females only). Participants received either topical carboxytherapy (n=4) or standard care (n=2). Assessments included VISIA-CR imaging, biophysical measurements, investigator ratings, and paired (baseline and 4-week) skin biopsies. RESULTS: Topical carboxytherapy accelerated recovery and was well-tolerated, with no major adverse events. VISIA-CR imaging showed accelerated erythema resolution, transepidermal water loss normalized more rapidly, and pH remained stable. Skin histology at week 4 revealed epidermal thickening and rete ridge formation with topical carboxytherapy vs placebo. Investigator ratings demonstrated significantly improved healing, global assessment, and global aesthetic improvement scale scores, with trends toward improvement in photodamage, rhytides, and pigmentation. CONCLUSION: Adjunctive topical carboxytherapy after fractional CO2 resurfacing accelerated healing, improved barrier recovery, and overall aesthetic outcomes. Larger studies are needed to confirm these findings.

Humans↗

PubMed2026

Influenza as a Less Commonly Recognized Cause of Hemophagocytic Lymphohistiocytosis: A Systematic Review of Case Reports and Case Series.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory condition that can be triggered by viral infections. However, influenza is not commonly recognized as a cause of HLH, and there is no comprehensive synthesis of influenza-associated HLH in the literature to guide clinicians. We conducted a systematic search of Pubmed and Embase to identify case reports and case series on influenza-associated HLH, and included 29 articles involving 47 patients. Their age ranged from 2 months to 72 years. 67% were males. Influenza A accounted for 91.3% of the cases, predominantly H1N1 (90.2%). All patients had fever, 60% had anemia, 69.7% had thrombocytopenia, 46.6% had leukopenia, 61.3% had splenomegaly, 71.4% had hypertriglyceridemia, and 94.7% had elevated ferritin levels. 97.6% had hemophagocytosis on biopsy. Antiviral therapy was administered in 89.5% of patients. HLH-directed therapy included corticosteroids (77%), intravenous immunoglobulin (36%), and etoposide (23.1%). Intensive care was required in 95.2% of cases. Overall survival was 53.2%. Survival rate was 50% among patients who received either antiviral therapy alone or HLH-directed therapy alone, compared with 65.4% among those who received both. Further studies are necessary to establish standardized diagnostic and therapeutic protocols for influenza-associated HLH.

Humans↗

PubMed2026

Context matters: coordinated transcriptional regulation and root plasticity under multinutrient conditions.

Plants often encounter simultaneous imbalances in multiple nutrients, but the regulatory logic coordinating their responses remains poorly understood. We aimed to uncover shared transcriptional programs and regulatory nodes underpinning multinutrient adaptation in Arabidopsis thaliana roots. We analyzed publicly available RNA-seq datasets spanning 15 nutrient and beneficial element conditions using differential expression, co-expression network (WGCNA), and gene regulatory network analysis. Selected transcription factors (TFs) were validated via root phenotyping, suberin staining, and ionomic profiling under two-nutrient stress conditions. We identified a core set of 2050 genes responsive to multiple nutrient treatments, enriched for suberin biosynthesis, and structured into modular co-expression clusters. Eight prioritized candidate TFs (ARR10, GBF3, HHO5, NAC32, NF-YA3, NF-YB2, SARD1, and WRKY33) were shown to modulate root system architecture under specific nutrient combinations. WRKY33 and NF-YB2, in particular, regulated nutrient-responsive suberin deposition and ionomic plasticity. These findings reveal suberin remodeling as a shared downstream process in multinutrient responses and suggest that plasticity is not a fixed trait but a modular, polygenic, and context-dependent outcome. Repurposed TFs with pleiotropic functions coordinate structural and physiological traits, providing regulatory entry points for improving nutrient resilience.

Plant Roots↗

PubMed2026

Comparative genomics and full-length transcriptome profiling of wing morphs in Tetrix grossus (Orthoptera: Tetrigidae).

Wing polymorphism represents a paradigmatic dispersal-reproduction trade-off, yet its molecular basis remains uncharacterised in the phylogenetically distant pygmy grasshoppers (Tetrigidae). Here we integrate comparative genomics across ten orthopteran species with full-length transcriptomics of long-winged (FL) and short-winged (FS) Tetrix grossus. OrthoFinder recovered 118 orthogroups specific to T. grossus. Against a backdrop of pronounced gene-family contraction (36 expansions versus 222 contractions; net -186, mirrored at the ancestral Tetrix node, +37/-140), we identified an ancestral, Tetrix-specific expansion of hormone-regulation (12 genes; fold enrichment 7.93) and lipid/carbohydrate-metabolic families organised into syntenic clusters, alongside 513 positively selected genes enriched for integrin-mediated cell adhesion (6 genes), a process relevant to epithelial and appendage morphogenesis. Full-length transcriptomics of one long-winged (FL) and one short-winged (FS) adult female detected 7530 (FL) and 7515 (FS) expressed genes, with 794 FL- and 776 FS-restricted transcriptome-derived SNP-associated genes. The FL morph was enriched for an EGFR/Ras-Rho developmental-patterning axis and neuromuscular flight genes, whereas the FS morph was enriched for insulin/peptide-hormone response and growth-regulatory loci. Overall, we present genomic resources and testable hypotheses concerning the evolution and regulation of wing morphs in Tetrigidae rather than a validated genetic architecture of wing-morph determination.

Animals↗

PubMed2026

Integrative multi-omics reveals a fibroblast-centered, ZFHX3-prioritized regulatory framework linking sick sinus syndrome and atrial fibrillation.

OBJECTIVE: To define shared genetic and multi-scale mechanisms underlying comorbidity between sick sinus syndrome (SSS) and atrial fibrillation (AF). METHODS: We integrated genome-wide association study (GWAS) summary statistics for SSS and AF with Genotype-Tissue Expression (GTEx) expression and splicing quantitative trait loci (eQTL/sQTL), atrial single-cell and spatial transcriptomics, and epigenomics. We identified trait-relevant tissues and pathways, prioritized shared cell types, quantified genome-wide and local genetic sharing, detected joint loci by cross-trait meta-analysis, and linked loci to regulatory programs via colocalization and cell-prioritized co-expression networks. RESULTS: Both traits showed strongest enrichment in cardiac tissue, especially Heart Atrial Appendage. Fibroblasts from the left atrial appendage were consistently prioritized as the key shared cell population. SSS and AF displayed significant positive genome-wide genetic correlation, with multiple locally shared regions, including six major loci. Cross-trait meta-analysis identified eight joint-phenotype SNPs implicating four susceptibility genes. ZFHX3 was the leading tissue-cell-gene candidate, acting as a hub in fibroblast co-expression modules and colocalizing with cardiac regulatory signals. CONCLUSION: Shared liability for SSS and AF is highly tissue- and cell-specific, converging on regulatory networks in atrial appendage fibroblasts, with ZFHX3 serving as a central mechanistic and biomarker node.

Humans↗