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PubMed2026

Ablative radiotherapy in castration-resistant prostate cancer.

OBJECTIVE: To prove the oncological benefit of ablative radiotherapy in patients with up to five metastases from castration-resistant prostate cancer (CRPC) a single-centre randomised trial was initiated. PATIENTS AND METHODS: This monocentric, randomised, phase II clinical trial enrolled patients with up to five prostate-specific membrane antigen-positive bone or lymph node metastases developing prostate-specific antigen (PSA) progression during androgen deprivation (ADT) or ADT and androgen-receptor targeted therapy. Participants were randomised (2:1) to receive metastasis-directed therapy (MDT) or observation (OBS) without changing systemic therapy. The primary endpoint was the proportion of patients having PSA progression within 1 year, with statistical analyses conducted using intention-to-treat principles. Here, results of a planned interim analysis of the primary endpoint are reported. RESULTS: A total of 30 patients (12 in the observation arm and 18 in the MDT arm) were enrolled, PSA progression within 1 year occurred in 44% of the MDT group vs 75% in the OBS group (P = 0.14, not significant). The median time to PSA progression was significantly longer in the MDT arm (12.4 months) compared to the OBS arm (2.9 months, P = 0.03). The pre-defined criteria to discontinue the study were not met. Limitations include the single-centre design and small sample size at interim analysis. CONCLUSION: This pre-planned interim analysis of the primary endpoint did not meet the discontinuation criteria of the study protocol, suggesting that MDT in oligometastatic CRPC may extend the time to PSA progression without immediate change of systemic therapy. The continuation of the study in a multicentre setting is planned (Institutional funding by the TU Dresden, ClinicalTrials.gov identifier: NCT04141709).

Humans↗

PubMed2026

Genomic and Phenotypic Characterization of Two Novel Enterobacter Phages With EDTA-Enhanced Antibiofilm Activity.

Multidrug-resistant members of the Enterobacter cloacae complex (ECC) are increasingly linked to difficult-to-treat infections and biofilm-mediated antimicrobial tolerance. Here, two lytic phages, vB_EhoIP_HHH and vB_EluM_RZH, displaying podovirus-like and myovirus-like morphology, respectively, were isolated from the River Chelt. HHH has a 39,582 bp genome (51.2% GC, 63 ORFs), while RZH has a 174,197 bp genome (39.4% GC, 314 ORFs), with neither genome carrying antimicrobial resistance, virulence or lysogeny-associated genes. VIRIDIC and VICTOR analyses placed HHH within Kayfunavirus and RZH within Karamvirus, supporting their classification as distinct species. Both phages demonstrated rapid adsorption, short latent periods and stability across physiological pH and temperature ranges. A phage cocktail targeting MDR ECC strain was evaluated with EDTA against established biofilms. Crystal violet assays showed the greatest biomass reduction at MOI 10 with 0.5-0.75 mM EDTA. Bliss independence analysis revealed localized synergy within this window but significant overall antagonism at higher EDTA concentrations. CFU enumeration confirmed greater activity against 24 h than 48 h biofilms. The optimized combination also reduced recoverable bacteria in a fibroblast infection model while maintaining low LDH release. These findings identify two novel lytic Enterobacter phages and support a narrow EDTA concentration window for enhanced phage-mediated antibiofilm activity.

Biofilms↗

PubMed2026

Longitudinal Prediction of Retinal Sensitivity Based on Disease Progression Quantified From Optical Coherence Tomography in Geographic Atrophy.

PURPOSE: The purpose of this study was to analyze the association between disease progression of geographic atrophy (GA) from optical coherence tomography (OCT) with retinal sensitivity (RS) in microperimetry (MP) over a 2-year follow-up period. METHODS: This is a longitudinal analysis of the OAKS Phase-III clinical trial. Both study and fellow eyes with GA that underwent imaging with the Spectralis OCT and consecutive MP examination were eligible. Pointwise quantification of ellipsoid zone (EZ) thickness, EZ and retinal pigment epithelium (RPE) loss from OCT volumes was correlated with localized RS. A longitudinal predictive model using a Markov Chain framework was implemented to predict RS change over time based on OCT biomarkers. The modeling of morphological and functional progression was based on the fellow-eye cohort. RESULTS: A total of 39,681 MP points from 406 patients were analyzed. In the fellow eye cohort, baseline (BSL) EZ thickness was positively associated with RS (0.3 decibel [dB]/µm, P < 0.001). Decrease in EZ thickness between visits during follow-up was significantly associated with decrease in RS (0.1 dB / 1 µm change). RS was significantly lower in MP points within EZ loss during follow-up compared with MP points within the retina with measurable EZ (P < 0.001). The largest functional decline was observed within RPE loss, also associated with the highest probability of absolute scotoma (P < 0.001). Morphological progression to EZ and RPE loss was influenced by EZ thickness and the morphology of adjacent MP points (P < 0.001). CONCLUSIONS: Two exploratory endpoints were developed, namely quantification of EZ thickness and loss, and localized RS within high-risk OCT areas. RS decline during follow-up is associated with automatically quantified disease progression in OCT.

Humans↗

PubMed2026

Effects of exercise snacking on neuromuscular performance in insufficiently active adults: A systematic review and meta-analysis.

OBJECTIVE: To examine the effects of exercise snacking (ES) on neuromuscular performance in insufficiently active adults. METHODS: Six databases were searched from inception to July 17, 2026. Randomized controlled trials and non-randomized studies of interventions involving insufficiently active adults undertaking ES interventions were included. Outcomes were functional performance, muscular strength, and muscular power. A three-level random-effects meta-analysis was performed. Risk of bias was assessed with RoB 2 or ROBINS-I, and certainty of evidence was evaluated using GRADE. RESULTS: Nine studies (13 reports) involving 313 participants were included. In the primary three-level model, ES showed a small positive overall effect on neuromuscular performance (g = 0.37, 95% CI 0.16-0.58, p = 0.001), which remained supported under trial-clustered robust inference with small-sample adjustment. Domain-specific estimates for muscular power/velocity, functional performance, and muscular strength were positive but imprecise and were not statistically supported after small-sample robust adjustment. Robust moderator tests provided no evidence of between-subgroup differences, and the certainty of evidence was low for all outcomes. CONCLUSION: Current low-certainty evidence suggests that ES may produce a small improvement in overall neuromuscular performance. However, domain-specific effects remain uncertain because of the limited number of independent trials, and the overall prediction interval crossed zero, indicating uncertainty across future populations and settings. Larger, preregistered randomized controlled trials are needed to confirm these preliminary findings.

Adult↗

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

Effects of digital health-based exercise interventions on older adults with sarcopenia: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Sarcopenia, the progressive loss of muscle mass and function, impairs independence in older adults. Digital health exercise interventions are scalable solutions for older adults with sarcopenia. This systematic review and meta-analysis aimed to synthesize the evidence on their efficacy in populations with clinically diagnosed sarcopenia and identify influential intervention characteristics associated with treatment outcomes. METHODS: We systematically searched PubMed, EMBASE, Web of Science, Cochrane Library, CINAHL, CNKI, and Wanfang on May 20, 2026, with no date restrictions. We included randomized controlled trials involving adults aged ≥60 with sarcopenia receiving digital exercise interventions. Two reviewers independently screened studies, extracted data, and assessed risk of bias; analyses were performed using R and Review Manager. RESULTS: Fourteen trials (n = 927) were included. Digital interventions showed potential improvements in muscle mass (MD = 0.25, 95%CI:0.03-0.46, 95% PI:-0.36 to 0.85), muscle strength (MD = 2.14, 95% CI:1.18-3.11, P < 0.001), balance ability (SMD = 0.31, 95% CI:0.12-0.51, P = 0.001), walking performance (SMD = 0.55, 95% CI:0.21-0.89, 95% PI:-0.70 to 1.79), and physical function (SMD = 0.89, 95% CI:0.08-1.71, 95% PI:-2.33 to 4.12), but not quality of life (SMD = 0.08, 95% CI:-0.19 to 0.35, P = 0.53). Exploratory subgroup analyses suggested that factors such as supervision, program duration, and measurement tools may influence outcomes; however, formal tests for subgroup differences were generally non-significant, and consistent patterns across all metrics were not observed. CONCLUSION: Digital exercise interventions show potential for managing sarcopenia in older adults, though the very low to moderate certainty of evidence indicates that true effects may differ substantially from observed estimates. This review explores potential roles of intervention design, supervision, and multimodal delivery. Future research should adopt rigorous designs and longer follow-up to validate results and enhance clinical application. TRIAL REGISTRATION: PROSPERO CRD420251135174.

Humans↗

PubMed2026

Blood Bile Acids for Inflammatory Bowel Disease Diagnosis and Disease Activity Assessment: A Metabolomics Meta-Analysis.

Alterations in circulating bile acids (BAs) have been reported in inflammatory bowel disease (IBD), but the consistency of these changes across clinically relevant comparisons remains unclear. Our goal was to investigate systemic BA alterations in IBD using a metabolomics meta-analysis with an exploratory analysis of BA-related gene expression as a supporting context. A systematic review and meta-analysis of 28 metabolomics studies examined blood BA profiles associated with IBD, IBD diagnosis, and disease activity assessment. Univariate analysis and logistic regression modeling of two independent IBD cohorts explored the blood BA-related genes and IBD. Across 28 studies that comprised 5056 IBD patients, 1721 healthy controls, and 314 non-IBD patients, 131 BAs were reported. Eight predefined clinical comparisons were eligible for the meta-analysis. Lower secondary BA levels were consistently observed in IBD patients compared with controls, between UC and CD, and in active versus remission patients. Deoxycholic acid, glycodeoxycholic acid, and taurodeoxycholic acid were frequently decreased, whereas glycocholic acid was increased in certain comparisons. Transcriptomics analyses revealed differential expression of several BA-related genes in blood, including SLC51A, ABCB4, and ACOT8, across the comparisons. Our findings identify consistent circulating BA alterations in IBD and highlight the relevance of blood BA for future biomarker research in the diagnosis and disease activity assessment.

Humans↗

PubMed2026

Efferocytosis regulatory factors in atherosclerosis: A preclinical systematic review.

BACKGROUND: Impaired efferocytosis is a key driver of plaque instability during atherosclerosis progression. Efficient clearance of apoptotic cells through efferocytosis relies on the coordinated action of multiple regulatory factors. METHODS: PubMed, Web of Science, ScienceDirect, OVID MEDLINE, and Scopus were searched for studies published up to February 7, 2026. Eligible preclinical studies were systematically reviewed to identify endogenous factors that regulate efferocytosis in atherosclerosis. Clinical evidence was also incorporated to enable a preliminary translational assessment of these regulatory factors. RESULTS: Thirty-five endogenous regulatory factors were identified from 36 included studies, and their functional roles across distinct stages of efferocytosis were characterized. Notably, metabolic regulators such as PKM2, PFKFB3, GLS1, and Drp1 were involved in distinct efferocytosis stages. This suggests that metabolic reprogramming may provide the metabolic support require for efficient efferocytosis and inflammation resolution. Ten factors were supported by preliminary clinical evidence consistent with preclinical data. PKM2 was the only candidate biomarker with prospective observational data. However, its independent predictive value still requires validation in multicenter prospective studies. CONCLUSIONS: This review provides a systematic synthesis of 35 endogenous efferocytosis regulators and elucidates their regulatory network in atherosclerosis based on a functional stage framework. Metabolic reprogramming is identified as a central hub linking efferocytosis efficiency to inflammation resolution. This review offers a new theoretical basis for efferocytosis-targeted intervention strategies.

Animals↗

PubMed2026

Bone progression in multiple myeloma: Benefit of zoledronic acid for patients achieving at least Very Good Partial Response and prognostic value of bone turnover markers.

The Magnolia study demonstrated that continuation of zoledronic acid (ZOL) beyond 2 years reduces the risk of progressive bone disease (PBD) in patients with multiple myeloma (MM). This follow-up study investigated the effects of ZOL in patients achieving very good partial response (VGPR) compared to patients who did not and whether bone turnover markers could identify patients at an increased risk of PBD following treatment cessation. Two Magnolia trial subgroups were analysed: patients with VGPR or better after 2 years of ZOL, randomized to either continued treatment or observation, and patients randomized to observation in whom serial bone markers (C-terminal cross-linked telopeptide of type I collagen [CTX], procollagen type I N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BAP], tartrate-resistant acid phosphatase isoform 5b [TRAcP]) were measured for up to 4 years. Continued monthly ZOL beyond 2 years significantly reduced the risk of PBD (hazard ratio 0.40; 95% confidence interval [CI] 0.16-0.92) in patients with VGPR or better (subgroup 1). After ZOL discontinuation, bone markers increased gradually. Elevated CTX (≥0.30 μg/L) and TRAcP (≥4 U/L) levels were associated with increased 6-month PBD risk (29% and 15% respectively) (subgroup 2). Continuation of ZOL beyond 2 years seems to reduce skeletal progression risk in patients achieving VGPR or better. Elevated CTX or TRAcP levels may help identify patients who could benefit from re-initiating ZOL.

Humans↗

PubMed2026

Methyltransferase 3 promotes v-set and transmembrane domain-containing 2-like protein expression to intensify ferroptosis-mediated prostate adenocarcinoma progression through the m6A methylation modification.

BACKGROUND: Prostate adenocarcinoma (PRAD) is a common malignancy with high incidence in men. The role of v-set and transmembrane domain-containing 2-like protein (VSTM2L) in PRAD remains largely unreported. METHODS: Gene expression was analyzed using The Cancer Genome Atlas (TCGA), the Tumor Immune Estimation Resource (TIMER) 2.0, and the University of Alabama at Birmingham CANcer data analysis Portal (UALCAN) databases, and validated by quantitative real-time PCR (qRT-PCR) and western blot. Cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) staining. Apoptosis and mitochondrial membrane potential were examined by flow cytometry. Intracellular iron, Fe2+, and reactive oxygen species (ROS) levels were measured using commercial kits and flow cytometry. The role of VSTM2L in tumor growth was evaluated using xenograft mouse models, with protein expression in tumors evaluated by immunohistochemistry (IHC). The N6-methyladenosine (m6A) modification sites on VSTM2L mRNA were predicted using the sequence-based RNA adenosine methylation site predictor (SRAMP) website. The interaction between methyltransferase 3 (METTL3) and VSTM2L was confirmed by methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assay. Correlation analysis was performed using the TCGA database. RESULTS: VSTM2L was overexpressed in PRAD tissues and cell lines. Silencing VSTM2L inhibited PRAD cell proliferation, promoted apoptosis, and enhanced ferroptosis and oxidative stress in vitro. Consistently, VSTM2L knockdown suppressed tumor growth in vivo. Mechanically, METTL3 mediated m6A methylation to stabilize VSTM2L mRNA. Furthermore, METTL3 promoted proliferation and inhibited apoptosis, ferroptosis, and oxidative stress in PRAD cells via a VSTM2L-dependent manner. CONCLUSION: METTL3 promotes PRAD progression by stabilizing VSTM2L expression through m6A methylation, thereby inhibiting ferroptosis. This study establishes a direct link between RNA methylation and ferroptosis in PRAD, revealing the METTL3/VSTM2L axis as a novel regulatory pathway and a potential therapeutic target.

Male↗

PubMed2026

Diagnostic value of blood p-tau subtypes in Alzheimer's disease progression and pathology: systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and the most likely to lead to dementia. With the availability of the latest therapies, the need for Alzheimer's disease diagnosis is now gradually increasing. Whereas blood phosphorylated-tau (p-tau) has demonstrated excellent performance in the prediction and diagnosis of disease progression and Aβ positivity in AD, there are differences between different p-tau subtypes. Therefore, a pooled analysis of different blood p-tau subtypes is of more important clinical value. METHOD: Relevant literature was screened by complete search in four databases, Pubmed, Embase, Cochrane Library and Scopus. Relevant data and AUC and their confidence intervals of the included literature were extracted and analyzed by classification according to p-tau subtypes. Quality assessment was performed using the QUADAS-2 tool. RESULT: Our results reveal that p-tau217 performs better in the diagnostic performance in most stages of AD, which is consistent with the guidelines. However, our results concluded that p-tau217 has poorer diagnostic performance in the stages of cognitive unimpaired or less cognitively impaired, especially in the Aβ positivity diagnosis of SCD and CU. Head-to-head meta-analyses formally confirmed that p-tau217 significantly outperforms p-tau181 across AD dementia, Aβ positivity, tau positivity, and biological staging (all P < 0.05), whereas no significant difference was observed between p-tau231 and p-tau181. CONCLUSION: By integrating single-arm pooled AUC estimates with formal head-to-head statistical comparisons, our study provides evidence-based support for plasma p-tau217 as the subtype with the most robust diagnostic performance across AD pathology and biological staging. Head-to-head analyses formally confirmed that p-tau217 significantly outperforms p-tau181 in Aβ positivity, Tau positivity, and biological staging.

Humans↗

PubMed2026

Association Between 24-Hour Blood Pressure and Rates of Retinal Nerve Fiber Layer Progression in Glaucoma: The Vascular Imaging in Glaucoma Study.

PURPOSE: Low systemic blood pressure (BP) has been implicated as a risk factor for glaucoma progression. The purpose of this study was to investigate the association between 24-hour BP and rates of retinal nerve fiber layer (RNFL) loss in eyes with primary open-angle glaucoma. DESIGN: Prospective cohort study. PARTICIPANTS: Seventy-nine eyes from 42 subjects with glaucoma (mean age, 68.5 ± 7.6 years) enrolled in the Vascular Imaging in Glaucoma Study at the Bascom Palmer Eye Institute. METHODS: Participants underwent 24-hour ambulatory BP monitoring at baseline. Follow-up evaluations were conducted at 4-month intervals and included ophthalmic examination, BP measurement, and peripapillary RNFL thickness measurement with spectral-domain optical coherence tomography. The association between BP and RNFL loss over time was assessed using linear mixed-effects models adjusted for age, sex, race, baseline RNFL thickness, central corneal thickness, and intraocular pressure. MAIN OUTCOME MEASURES: The effect of baseline 24-hour mean arterial pressure (MAP), systolic BP (SBP), and diastolic BP (DBP) on the rate of average RNFL loss over time. RESULTS: Eyes underwent an average of 13 ± 3 optical coherence tomography exams over 43 ± 10 months of follow-up. The mean rate of RNFL loss was -0.34 ± 0.64 µm/y (median: -0.32; interquartile range: -0.66 to -0.04 µm/y). After adjusting for confounding factors, every 10 mm Hg lower in 24-hour minimum MAP, SBP, and DBP was associated with -0.542 µm/y (P < .001), -0.360 µm/y (P = .003), and -0.458 µm/y (P = .008) faster RNFL loss, respectively. Eyes in the lowest quartile of average 24-hour MAP (81-90 mm Hg) and minimum 24-hour DBP (35-47 mm Hg) experienced significantly faster progression compared to those in the highest quartile, with differences of -0.68 µm/y (P = .017) and -0.63 µm/y (P = .030), respectively. CONCLUSIONS: Lower systemic BP, especially minimum MAP, SBP, and DBP measured by 24-hour ambulatory BP monitoring, is associated with faster rates of RNFL loss in primary open-angle glaucoma eyes. 24-hour BP monitoring may help predict glaucoma patients at greater risk of progression.

Humans↗

PubMed2026

Facilitating Thought Progression via a Gamified Mobile Application for Depression: Possible Mediators of Outcomes.

Mobile health interventions represent a scalable and accessible alternative to traditional therapy, which often is out of reach due to high costs and societal stigma. Rumination is considered a key mechanism of emotional disorders and represents a potential treatment target for digital health interventions. The current study investigated the role of rumination as a mediator of the reduction in depression and anxiety reported after the use of a gamified mobile app based on the Facilitating Thought Progression (FTP) framework. One hundred-one adults with mild to moderate depression were randomized to the FTP intervention or a waitlist control group and completed weekly assessments of depression, anxiety, and rumination over 8 weeks. Multilevel structural equation modeling revealed that reduction in rumination significantly mediated decreases in depression and anxiety in the intervention group but not in the waitlist condition. These findings suggest that the FTP app targeted rumination and further highlights its role as a critical target for interventions for depression and anxiety.

Adult↗

PubMed2026

Neighborhood Hostility is Associated With the Relationship Between Park Proximity and Physical Activity Among Youth: National Evidence From Chile.

PURPOSE: Physical inactivity among youth is highly prevalent worldwide. Although proximity to parks and recreational facilities is generally associated with higher physical activity (PA), unsafe or hostile neighborhood environments may limit their use. This study examined whether neighborhood hostility moderates the association between access to recreational facilities and adherence to World Health Organization PA guidelines among Chilean youth. METHODS: This cross-sectional study analyzed data from the 2024 National Physical Activity and Sport Survey of Chile, including 3,477 urban participants stratified into childhood (5-10 years), early adolescence (11-13 years), and late adolescence (14-17 years). Built environment exposures included perceived access to recreational facilities, a cumulative neighborhood hostility score (0-5). Logistic regression models were stratified by age group and adjusted for covariates. Interaction terms assessed moderation by neighborhood hostility, and causal mediation analyses were performed. RESULTS: Adherence to World Health Organization guidelines was low (41.9% in childhood, 43.8% in early adolescence, and 43.9% in late adolescence). Greater distance to recreational facilities was associated with lower odds of meeting activity guidelines. Higher neighborhood hostility was independently associated with lower PA levels. Among adolescents, neighborhood hostility substantially attenuated the association between proximity and activity. Mediation analyses indicated partial mediation, with effective park utilization emerging as the strongest mechanism, accounting for 21.8% of the association (p < .001), followed by psychological motivation (11.9%). DISCUSSION: Proximity to recreational infrastructure alone is insufficient to promote PA in hostile neighborhoods. Policy approaches should integrate infrastructure provision with strategies addressing neighborhood safety and promoting active engagement.

Humans↗

PubMed2026

A multicenter randomized phase II/III trial of salvage treatment for refractory primary central nervous system lymphoma using tirabrutinib: JCOG2314 (ReSTART).

Primary central nervous system lymphoma (PCNSL) is an aggressive malignancy. Patients refractory to high-dose methotrexate-based induction therapy have an extremely poor prognosis. Although whole-brain radiotherapy (WBRT) is the standard salvage treatment and provides potent tumor control, early functional deterioration and late neurocognitive toxicity remain major concerns. A phase I/II trial on relapsed or refractory PCNSL demonstrated favorable efficacy and tolerability of tirabrutinib, a second-generation selective Bruton's tyrosine kinase inhibitor. Tirabrutinib's oral administration has enabled outpatient management. However, its clinical value for induction-refractory PCNSL remains uncertain. We designed a multicenter, randomized phase II/III trial (JCOG2314) to assess the non-inferiority of tirabrutinib to WBRT in overall survival and its potential to reduce functional deterioration and cognitive impairment. A total of 94 patients from 49 institutions will be enrolled over 4 years. The trial has been registered in the Japan Registry of Clinical Trials (study number: jRCT1031250645).

Humans↗

PubMed2026

Opposing kinase signaling may underlie the inverse relationship between cancer and Alzheimer's disease.

Cancer and Alzheimer's disease (AD) are leading causes of mortality and exhibit an inverse relationship, where AD patients have reduced cancer risk and vice versa. However, the molecular basis of this relationship remains poorly understood. We reanalyzed published proteomic and phosphoproteomic datasets to investigate this relationship. Differentially abundant proteins were identified in lung adenocarcinoma and glioblastoma samples relative to controls and compared with proteins altered in AD brains, revealing 37 proteins with opposing abundance patterns. Protein-protein interaction and pathway analyses revealed enrichment in kinase signaling and phosphorylation pathways. Phosphoproteomic analysis identified 52 differentially phosphorylated sites with opposing patterns, while kinase-substrate enrichment analysis identified 44 kinases with opposing inferred activity profiles. Integration of kinase activity and phosphosite data identified 29 kinase-phosphosite pairs, including 4 prioritized pairs with opposing patterns relevant to both diseases. Across seven independent cancer cohorts, 17 of 20 statistically significant phosphosite-cohort comparisons (85%) were concordant with the discovery findings, supporting reproducibility of the prioritized phosphosites. Together, these findings highlight opposing kinase signaling as a prominent feature of the inverse relationship and suggest potential biomarkers and therapeutic targets. This study provides a novel systems-level framework for investigating inverse relationships, supported by an R Shiny application for data exploration (https://advscancer.shinyapps.io/advscancer/). SIGNIFICANCE: This study presents an integrated proteomic and phosphoproteomic framework for investigating the inverse relationship between cancer and Alzheimer's disease (AD). By integrating differential protein abundance, phosphosite phosphorylation, inferred kinase activity, and curated kinase-substrate relationships, we identified opposing signaling patterns and prioritized four kinase-phosphosite pairs. Independent evaluation across seven CPTAC cancer cohorts supported the reproducibility of the prioritized phosphosite patterns. These findings provide insight into molecular processes potentially associated with the inverse relationship between cancer and AD, identify candidate biomarkers and therapeutic targets, and demonstrate the value of systems-level, data-driven approaches for investigating shared and opposing disease processes.

Humans↗

PubMed2026

A contextual activity score (CAS) for inferring ADAR-associated transcriptional activity across RNA-seq, single-cell, and spatial transcriptomics.

BACKGROUND AND OBJECTIVE: Adenosine-to-inosine RNA editing, catalyzed by Adenosine Deaminases Acting on RNA (ADARs), is a widespread modification involved in neural function, immune regulation, and cancer. The Alu Editing Index (AEI) is the standard metric to estimate ADAR activity but requires raw sequencing reads and is poorly suited for single-cell and spatial transcriptomic data. This study aimed to develop an alternative framework for inferring ADAR-associated transcriptional activity from gene expression data across diverse transcriptomic technologies. METHODS: We developed the Contextual Activity Score (CAS), a framework based on transcriptional signatures from ADAR perturbation experiments. Context-specific signatures were generated for human neurons, mouse neurons, and cancer models to infer ADAR1 and ADAR2 activity. CAS was computed from normalized gene expression matrices using regulon-based enrichment analysis. Performance was evaluated by comparing with the Alu Editing Index across bulk RNA sequencing datasets, simulated sequencing depths, and library preparation protocols. RESULTS: CAS showed strong concordance with the Alu Editing Index across multiple datasets, while remaining robust to reduced sequencing depth and different library protocols. Unlike the Alu Editing Index, CAS can be applied to single-cell and spatial transcriptomic data and enables the independent assessment of ADAR2 activity. In cancer and neuronal contexts, CAS captured biologically meaningful variations in ADAR-associated transcriptional activity at sample, cell-type, and spatial levels. CONCLUSION: CAS provides a scalable approach applicable across multiple RNA-seq protocols for estimating ADAR-associated transcriptional activity using gene expression data. This method, implemented in an open-source R package for broad adoption, expands the ability to study ADAR-associated transcriptional activity across transcriptomic modalities where direct editing quantification is challenging, such as single-cell and spatial transcriptomics.

Adenosine Deaminase↗

PubMed2026

Effects of Progressive Inspiratory Muscle Training on Lung Volume and Respiratory Strength in Patients With Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease can present changes in thoracic cavity volume and respiratory muscle weakness, even in the pre-dialysis stage. However, there is little evidence on the effects of inspiratory muscle training in these patients. METHODS: This was a randomized clinical trial which comprised patients with Chronic Kidney Disease in stages 3, 4, and 5 undergoing conservative treatment, allocated experimental group (EG) with progressive loading (up to 50% of maximal inspiratory pressure [MIP]) and control group (CG) with a fixed load (5 cmH2O) and no load progression performed daily for 8 weeks. The outcomes assessed were thoracic cavity volumes, as measured by optoelectronic plethysmography, and inspiratory and expiratory respiratory muscle strength. RESULTS: A total of 30 patients completed the study. All volumes significantly increased at the end of the protocol with a large effect size, but only the pulmonary thoracic cavity volume showed a significant interaction (F = 3.698; p = 0.042). There was an increase in inspiratory muscle strength in the EG (73.88-90.35 cmH2O; p < 0.001) and in the CG (70.85-86.92 cmH2O; p = 0.001), as well as in expiratory muscle strength in the EG (97.71-108.53 cmH2O; p = 0.001) and in the CG (80.69-94.77 cmH2O; p = 0.004). CONCLUSION: Daily IMT increased thoracoabdominal volumes, particularly pulmonary rib cage volume in the progressive-load group, as well as respiratory muscle strength in patients with pre-dialysis CKD. However, progressive-load IMT was not superior to minimal-load training.

Humans↗