Osteoarthritis (OA) is characterized by progressive extracellular matrix (ECM) degradation, chondrocyte apoptosis, and hypertrophic differentiation, yet the molecular basis underlying the protective effects of exercise therapy remains incompletely understood. Given that periostin (POSTN) is a mechanosensitive extracellular matrix protein implicated in OA progression and that Hippo-YAP signaling is a key regulator of mechanotransduction and cartilage homeostasis, their potential involvement in exercise-mediated chondroprotection warrants investigation. This study aims to investigate the association between exercise therapy and osteoarthritis progression, with a focus on POSTN and the Hippo-YAP signaling pathway. Bioinformatics analysis was performed using the GSE169077 dataset to identify candidate genes in OA. An anterior cruciate ligament transection (ACLT)-induced rat OA model with treadmill exercise intervention and an IL-1β-induced OA-like C28/I2 chondrocyte model with cyclic tensile strain (CTS) stimulation were established. POSTN expression was detected by RT-qPCR, Western blot, and immunohistochemistry. The roles of POSTN and Hippo-YAP signaling pathways in ECM metabolism, apoptosis, hypertrophic differentiation, and YAP nuclear translocation were evaluated by POSTN overexpression and vertexporfin-mediated YAP inhibition. Bioinformatics analysis identified COL1A1, MMP2, MMP9, and POSTN as upregulated genes in OA. POSTN expression was increased in both rat OA cartilage and IL-1β-induced OA-like chondrocytes and was significantly suppressed by exercise intervention in vivo and CTS in vitro. In interleukin-1β (IL-1β)-induced OA-like chondrocytes, CTS reduced the expression of matrix degradation-related proteins (ADAMTS5 and MMP13), increased Aggrecan and Collagen II levels, inhibited apoptosis (decreased Bax, Cytochrome c, and cleaved caspase-3 and increased Bcl-2), and attenuated hypertrophic differentiation (decreased RUNX2 and COL10A1 and increased SOX9). These protective effects were partially reversed by POSTN overexpression. Mechanistically, CTS decreased the p-LATS1/LATS1 and p-YAP/YAP ratios, restored YAP expression, and promoted its nuclear translocation, whereas POSTN overexpression attenuated these effects. Furthermore, verteporfin exacerbated POSTN overexpression-induced extracellular matrix degradation and hypertrophic differentiation. Consistent with the in vitro findings, exercise intervention in vivo reduced the expression of the hypertrophic markers MMP13 and RUNX2 while restoring the expression of SOX9, Collagen II, and YAP in OA cartilage. These findings suggest that exercise therapy may be associated with changes in chondrocyte catabolic and hypertrophic processes in osteoarthritis, potentially involving the suppression of POSTN and modulation of the Hippo-YAP signaling pathway.
Cancer therapy-related cardiac dysfunction (CTRCD) remains a significant risk of contemporary cancer treatment. Despite advances in oncologic therapies, cardiac surveillance strategies have largely relied on uniform, intensive monitoring, often without consideration of individual cardiotoxicity risk. This review evaluates the rationale for transitioning from blanket surveillance to risk-based, personalized cardiac monitoring strategies, especially for HER2-targeted therapy. Evolving definitions of CTRCD and improved risk stratification tools, have highlighted substantial heterogeneity in cardiotoxicity risk. Prospective studies in low-risk patients receiving non-anthracycline HER2-targeted therapies demonstrate that reduced-frequency echocardiographic surveillance appears safe and does not compromise cardiovascular or oncologic outcomes. Similar paradigms need to be studied for other cardiotoxic therapies, including BRAF/MEK inhibitors and VEGF inhibitors, with a need for prospective validation before clinical application. Risk-adapted cardiac surveillance offers a pragmatic, evidence-based approach to optimize resource utilization while maintaining patient safety. Future research should focus on prospective validation and guideline harmonization to enable personalized cardio-oncology care.
Skeletal muscle radiodensity (SMD) is an emerging imaging-derived marker of muscle quality. Its prognostic relevance in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing [¹⁷⁷Lu]Lu-PSMA-617 radioligand therapy has not yet been systematically evaluated. This study aims to investigate the prognostic value of SMD derived from routine pretherapeutic PET/CT imaging in a large real-world mCRPC cohort treated with [¹⁷⁷Lu]Lu-PSMA-617. In this single-center study, the largest to date cohort comprising 410 mCRPC patients was analyzed. SMD was quantified automatically from the L3-level CT component of pretherapeutic [⁶⁸Ga]Ga-PSMA-PET/CT using an AI-based segmentation tool. An optimal SMD cut-off (19.26 HU) was determined for survival stratification. Associations with overall survival (OS) were assessed using multivariable Cox regression (univariable and multivariable, adjusted for baseline PSA) and Kaplan-Meier analysis. Lower SMD was associated with reduced OS (HR 1.87, P<.001). Median OS were significantly shorter in the SMD-low group compared to the SMD-high group (7.6 months vs. 12.2 months; P<.001). This prognostic stratification was seen in both, patients with or without PSA50 or PSA90 response, respectively. SMD correlated with age, albumin, and PSA, but not with BMI. SMD assessed from routine pretherapeutic PET/CT is a non-invasive prognostic biomarker in patients undergoing PSMA-targeted radioligand therapy. Integration of host-derived imaging biomarkers such as SMD with tumor-specific parameters may improve risk stratification, prehabilitation and support future individualized treatment strategies in advanced prostate cancer.
Malnutrition, whether pre-existing or acquired in the ICU, is common in critically ill children. This narrative review synthesizes current evidence on nutritional assessment and therapy, highlighting how illness phase, underlying disease, and medical interventions influence energy expenditure and nutrient requirements. International guidelines recommend comprehensive nutritional assessment and early initiation of enteral nutrition (EN) for all patients admitted to the Pediatric ICU. However, EN is frequently underutilized or insufficient to meet metabolic demands and sometimes contraindicated. Barriers to delivery persist, and parenteral nutrition (PN) may be required when EN is not feasible or adequate. Nutrition plays a crucial yet complex role in the care of critically ill children. Optimizing individualized nutrition strategies, including timely EN and appropriate PN use, is essential to improve clinical outcomes, support recovery, and enhance long-term rehabilitation, while highlighting the need for improved implementation and future research.
Concerns regarding weight changes during hormonal contraceptive use may influence health care-seeking behavior and contraceptive use patterns. While semaglutide use for weight management has increased substantially among women of reproductive age, the association of hormonal contraception use with semaglutide initiation remains unexplored. To investigate the association between hormonal contraception use and subsequent initiation of semaglutide therapy among females of reproductive age. This nested case-control study used Danish health registers to identify all females aged 12 to 49 years from January 1, 1996, to December 31, 2023. Eligible participants included females who filled their first prescription for semaglutide with no prior fill of prescriptions for drugs to lower glucose levels (semaglutide users). The date of first semaglutide prescription fill was the index date. Semaglutide users were each matched by birth year to 10 nonusers (nonuser controls) with no prior use of drugs to lower glucose levels. Data were analyzed from November 25, 2025, to May 18, 2026. Hormonal contraception use was summarized based on the chronological order of all hormonal contraceptives for which individuals had filled prescriptions from 12 years of age (or study entry) until the index date. First filled prescription of semaglutide of any dose. A total of 22 694 cases and 229 640 matched controls (249 634 participants; median age, 37 [IQR, 30-44] years) were included in the analysis. All hormonal contraception utilization patterns were associated with semaglutide initiation compared with nonuser controls. Among utilization patterns involving a single contraceptive type, adjusted hazard ratios ranged from 1.42 (95% CI, 1.34-1.51) for combined oral tablets to 1.63 (95% CI, 1.46-1.82) for progestin-only intrauterine devices. For utilization patterns involving 2 or more contraceptive types, adjusted hazard ratios ranged from 1.64 (95% CI, 1.47-1.82) for combined oral tablets followed by progestin-only oral tablets to 2.11 (95% CI, 1.97-2.25) for other utilization patterns. Adjustment for body mass index attenuated but did not eliminate associations. Subgroup analyses by age, educational attainment, income, parity, immigrant status, and semaglutide type showed consistent associations across most utilization patterns. In this nationwide case-control study, use of hormonal contraception was associated with subsequent semaglutide initiation across all utilization patterns compared with controls, highlighting a need to examine factors associated with weight management in females.
Evidence supporting the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) in individuals aged ≥ 80 years remains limited, particularly regarding treatment persistence and real-world outcomes. In this retrospective real-world study, 292 individuals with type 2 diabetes (T2D) aged ≥ 80 years who started SGLT2i (n = 155) or GLP1-RA (n = 137) after the age of 75 were stratified by age at treatment initiation (75-80 vs. > 80). Primary outcomes were all-cause mortality and treatment persistence; longitudinal renal function was also assessed. Survival analyses were performed using Cox models adjusted for confounders. Over a median follow-up of 40 (37-43) months, 47 deaths (16.1%) occurred. The incidence rate of mortality was 37.5 and 68.6 events/1000 person-years in the GLP1-RA and SGLT2i groups, respectively (adjusted HR = 0.58, 95% CI [0.28-1.21]; p = 0.148). Stratifying participants by age at first prescription, those starting either GLP1-RA or SGLT2i at age 75-80 showed similar mortality. In contrast, subjects starting GLP1-RA vs. SGLT2i after 80 years showed a higher survival rate (adjusted HR = 0.33, 95% CI [0.12-0.91]; p = 0.034); significance disappeared after further adjustment for cardiovascular burden. Treatment discontinuation was 14% with GLP1-RA and 20% with SGLT2i (HR 0.53, 95% CI [0.30-0.95]; p = 0.032), due to a better persistence in GLP1-RA of more elderly subjects. Longitudinal eGFR trajectories were similar between treatments. GLP1-RA and SGLT2i were associated with similar all-cause mortality risk when started in very late age. Kidney function over time was comparable. Persistence on SGLT2i was lower when therapy was started after the age of 80. These findings highlight the need for individualized treatment decisions in older, frail patients and for prospective studies on glucose-lowering therapies in very old populations.
Cardiometabolic diseases remain a major global health burden, and current therapies only partially address the persistent residual risk driven by chronic inflammation, hypoxia, metabolic overload, and mechanical stress. A critical need is to understand how these diverse stress signals are integrated at the cellular and molecular levels to determine whether tissues adapt or undergo pathological remodeling. This review presents a comprehensive framework of kinase-microRNA (miRNA) crosstalk as an emerging regulatory axis in cardiometabolic disease. We discuss how stress-activated kinase pathways, including ERK, p38/JNK, PI3K-Akt-mTOR/S6K2, AMPK, GSK-3, and EGFR, reprogram miRNA output through phosphorylation of key components of the miRNA machinery, including DROSHA/DGCR8, DICER-TRBP, and AGO2. These phosphorylation-dependent mechanisms influence miRNA processing, substrate selection, RISC assembly, and target repression in a context-dependent manner. We further highlight the reciprocal regulation whereby miRNAs modulate kinase signaling pathways, establishing feedback networks that regulate inflammation, apoptosis, fibrosis, angiogenesis, and metabolic adaptation across cardiac, vascular, and immune cells. Emerging technologies, including AGO2 eCLIP, phosphoproteomics, CRISPR-based perturbations, and single-cell/spatial profiling, allow causal mapping of kinase-miRNA networks. Collectively, these advances establish kinase-miRNA crosstalk as a promising mechanistic framework and therapeutic target for precision intervention in heart failure, atherosclerosis, diabetic cardiomyopathy, and related cardiometabolic diseases.
This study investigates the therapeutic efficacy of zinc sulfide nanoparticles (ZnS NPs) encapsulated within adipose-derived mesenchymal stem cell exosomes (EXO-ZnS NPs) in an imiquimod-induced rat model of psoriasis, aiming to combine nanotechnology and regenerative medicine for enhanced immune modulation and skin repair. Adipose mesenchymal stem cells (AD-MSCs) were cultured and characterized, exosomes were isolated and validated by flow cytometry and TEM. ZnS NPs were synthesized, confirmed by XRD and TEM, and encapsulated into exosomes. Release profiles, Clinical (PASI scoring), histopathological, inflammatory and proliferative markers as well as immunohistochemical analyses were evaluated across control, psoriasis, and treatment groups (EXO, ZnS NPs, and EXO-ZnS NPs). EXO-ZnS NPs exhibited a uniform nanosize with sustained ZnS NPs release (80.5% over 24 h). In vivo, EXO-ZnS NPs significantly attenuated psoriatic symptoms, and Severity Index scores, reduced inflammatory mediators (IL-23, IL-17a, TNF-α, MCP-1, NLRP3), mitigated oxidative stress, downregulated proliferative markers (Ki-67, MMP-9), and inhibited VEGF-mediated angiogenesis. collectively restored epidermal structure and improved skin architecture. EXO-ZnS NPs synergistically combine the regenerative and immunomodulatory effects of exosomes with the intrinsic anti-inflammatory and antioxidant activities of ZnS NPs, offering a novel promising, dual-action therapeutic platform for effective and sustained psoriasis management.
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Upper tract urothelial carcinoma (UTUC) requires a complex, multimodal, and guideline-based therapeutic approach. However, due to the rarity of the disease, low case numbers, and diagnostic challenges, implementation of the annually updated European Association of Urology (EAU) guidelines in daily clinical practice is often difficult. The aim of this study was to evaluate guideline-compliant care and the influence of guideline-deviating treatment decisions on oncological outcomes. In a retrospective analysis, 181 patients with UTUC who were treated at our clinic between 2011 and 2024 were examined. Diagnosis, therapy, and oncological outcome were evaluated based on the applicable EAU guidelines, and treatment courses were analyzed in relation to guideline adherence. In all, 13% of patients received nonguideline-compliant diagnosis or therapy. The main causes were lack of bladder cuff resection (52%), lack of adjuvant chemotherapy (32%, 2020-2024), lack of interdisciplinary tumor board discussion (17%), and surgical undertreatment (5%). The lack of bladder cuff resection was associated with a significantly reduced overall survival (p = 0.047) and an increased recurrence rate (p = 0.038). In addition, there were repeated deviations in the comprehensive diagnostics for the correct classification of low-risk and high-risk patients. Despite clear recommendations from the EAU, their implementation in everyday clinical practice remains challenging. However, guideline-based care is essential, as deviations are associated with significantly poorer oncological outcomes. HINTERGRUND: Das Urothelkarzinom des oberen Harntrakts (UTUC) erfordert einen komplexen, multimodalen und leitlinienbasierten Therapieansatz. Aufgrund der Seltenheit der Erkrankung, geringer Fallzahlen und diagnostischer Herausforderungen ist die Umsetzung der jährlich aktualisierten EAU-Leitlinien (European Association of Urology) im klinischen Alltag jedoch häufig erschwert. Ziel dieser Studie war die Evaluation der leitliniengerechten Versorgung sowie der Einfluss leitlinienabweichender Therapieentscheidungen auf das onkologische Outcome. In einer retrospektiven Analyse wurden 181 Patient:innen mit UTUC untersucht, die zwischen 2011 und 2024 an unserer Klinik behandelt wurden. Diagnostik, Therapie und onkologisches Outcome wurden anhand der jeweils gültigen EAU-Leitlinien bewertet und die Behandlungsverläufe in Abhängigkeit von der Leitlinientreue analysiert. Eine nicht leitlinienkonforme Diagnostik oder Therapie erhielten 13 % der Patient:innen. Hauptursachen waren die fehlende Resektion der Blasenmanschette (52 %), das Ausbleiben einer adjuvanten Chemotherapie (32 %, 2020–2024), das Fehlen einer interdisziplinären Tumorboard-Besprechung (17 %) sowie operative Untertherapie (5 %). Die fehlende Blasenmanschettenresektion war mit einem signifikant reduzierten Gesamtüberleben (p = 0,047) und einer erhöhten Rezidivrate (p = 0,038) assoziiert. Zudem zeigten sich wiederholt Abweichungen in der umfassenden Diagnostik zur korrekten Einteilung in Low-risk- und High-risk-Patient:innen. Trotz klarer Empfehlungen der EAU bleibt deren Umsetzung im klinischen Alltag herausfordernd. Eine leitliniengerechte Versorgung ist jedoch essenziell, da Abweichungen mit einem signifikant schlechteren onkologischen Outcome einhergehen.
Heart failure with reduced ejection fraction (HFrEF) represents a major clinical and economic burden in Italy, driven by an aging population. Mineralocorticoid receptor antagonists (MRAs) are a cornerstone of guideline-recommended therapy. Eplerenone has demonstrated efficacy in reducing mortality and hospitalizations but remains underutilized. This study assessed the budget impact of increasing eplerenone use in eligible patients with HFrEF from national and regional perspectives. A budget impact analysis (BIA) was conducted over a 3-year horizon from the perspective of the Italian National Health Service (INHS). Two scenarios were compared: Current (observed MRA use) and Projected (increased eplerenone uptake). Model inputs included eligible population, treatment distribution, drug acquisition costs, and clinical outcomes (all-cause mortality, hospitalizations, renal impairment, hyperkalemia, and gynecomastia) with associated costs. Clinical inputs were derived from a network meta-analysis (NMA); cost inputs from Italian literature and national tariffs. Total expenditure increased from €598.6 million (M) to €600.6 M over 3 years, corresponding to a net budget impact of + €2.01 M (+ 0.34%), with annual increments of €880,000 (year 1), €885,000 (year 2), and €245,000 (year 3). Increased eplerenone use resulted in higher costs (+ €35.07 M), driven by drug acquisition and hospitalization costs, partially offset by mortality-related savings (-€3.62 M). These were partially counterbalanced by reductions in other MRAs (spironolactone - €6.37 M, potassium canrenoate - €8.32 M, canrenone - €18.37 M), mainly due to fewer hospitalizations, renal events, and a lower drug volume. Results were primarily driven by clinical parameters for eplerenone, particularly NMA-derived hazard ratios for hospitalization and all-cause mortality. The net budget impact was modest in relative terms (< 0.4% of total MRA-related expenditure), indicating substantial budget neutrality. Greater adoption of eplerenone was associated with a modest net increase in healthcare expenditure for the INHS, corresponding to approximately €3.20 per treated patient per year and consistent with substantial budget neutrality. The budget impact reflects both treatment redistribution and differences in clinical outcomes across MRAs. Expanding eplerenone use in line with guideline-recommended therapy may be achieved at a limited additional cost, while offering a more favorable renal and selectivity profile relative to other MRAs.
Endoscopic bariatric therapies, including endoscopic sleeve gastroplasty (ESG) and intragastric balloon (IGB), are emerging as less invasive alternatives to bariatric surgery. However, their economic value relative to established treatments such as bariatric surgery and pharmacotherapy remains uncertain. This study evaluated the cost-effectiveness of endoscopic bariatric therapies compared with surgery and semaglutide from a UK health system perspective. Three state-transition Markov models compared: (1) ESG versus laparoscopic sleeve gastrectomy (LSG), (2) ESG versus semaglutide, and (3) IGB versus semaglutide. The models simulated transitions between body mass index (BMI)-defined health states over a 5-year time horizon using treatment effectiveness data derived from published studies and expert input. Outcomes were expressed as quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) from the UK National Health Service perspective. Deterministic and probabilistic sensitivity analyses explored uncertainty. For patients with class II-III obesity, LSG was cost-effective compared with ESG (£10,593/QALY). For class I and II obesity, ESG generated modestly greater QALYs than semaglutide at slightly higher cost (ICER £7,267/QALY). Semaglutide was dominant compared with IGB, producing greater health gains at lower cost. Results were most sensitive to intervention costs and assumptions regarding long-term recurrent weight gain. Endoscopic bariatric therapies may represent a cost-effective option for obesity management depending on patient characteristics and comparator treatments. LSG remains the most cost-effective intervention for severe obesity, whereas ESG may offer a cost-effective alternative to pharmacotherapy for patients with lower BMI.
Nature-based interventions (NBIs) have been identified to support a recovery-oriented approach for people experiencing mental health issues. However, there is still limited knowledge related to how mental health service users experience their recovery process when engaged in NBIs. To explore and explain how mental health service users experience the process of personal recovery from participating in a newly developed NBI. The study was conducted using constructivist grounded theory and included 20 participants. The NBI, including equine-assisted therapy, was delivered in groups at a farm-based rehabilitation centre. Purposeful sampling was used, and in-depth interviews were performed on site. Data were analysed in an iterative, comparative process. During the analysis, NVIVO 14 was used to organise and manage the data systematically. The grounded theory of the core concept 'A process of embodied recovery', described the participants' experiences of personal recovery during the NBI and included three concepts: 'Experiencing interconnection' through transactions with the environment, 'Processing inner connection' through reflection and 'Feeling intra-connected' through integration of self and body as a whole in everyday life. The NBI provides positive multisensory experiences to support personal recovery among mental health service users. The findings hold significant implications for the advancement of recovery-oriented services in mental health care, including occupational therapy.
This review paper provides an overview of contemporary research areas in the field of contact lenses, recent progress and outstanding questions. Beyond the introduction of silicone hydrogel materials and current widespread use of daily disposable soft lenses, material and design innovations over the past decade have expanded the scope of contact lens applications to include preventative strategies for myopia, drug delivery, biosensing, theranostic (diagnostic sensing and delivery of therapy in response), visual augmentation and communication. Material and nanotechnology innovations have supported drug loading and controlled drug release from contact lenses, using molecular imprinting, layer-by-layer assembly and the incorporation of colloidal and polymeric nanoparticles. Other than many optical interventions for myopia control, most applications are either in pre-clinical or clinical testing. Drug delivery and theranostic applications are likely to be advanced with standardisation of protocols and agreed outcome measures in clinical trials to support comparisons between studies and regulatory approval pathways. Development of visual augmentation, sensing and communication applications will depend on demonstration of clear benefits, affordability, comfort and wearer acceptance. While innovations beyond myopia control are largely not commercially available, the next decade is likely to translate these new technologies into broader use.
Non-pharmacological migraine treatments are commonly used for prevention, may be preferred in sensitive groups such as pregnancy, childhood, and older adults, can be applied as an adjunct to pharmacological treatment, or selected according to the patient condition/preferences. However, most studies are based on heterogeneous designs, resulting in uncertainties regarding level of evidence. This review aimed to summarize the current scientific evidence on the effectiveness of non-pharmacological interventions in migraine, and their role in clinical practice. Recent studies on acupuncture, physical therapy (PT), psychological therapies (PsyT), biofeedback, and neuromodulation point to modest but clinically significant benefits, although heterogeneity in outcomes and study designs limits the strength of recommendations. Articles were searched PubMed and Web of Science databases through November 2025 including acupuncture, PT, biofeedback, PsyT, and neuromodulation. Evidence levels were provided for headache frequency, intensity, duration, disability, and headache impact, with Grading of Recommendations Assessment, Development, and Evaluation (GRADE), where available. Acupuncture had a small effect on reducing monthly headache days with moderate GRADE. Aerobic exercise, manual therapy (with medical treatment), and yoga regarding PT, individually, ranged from moderate to large effects in reducing on monthly migraine days and a small to large effect size on pain intensity, duration, and disability, but did not have a GRADE. PsyT showed small imroving in monthly migraine, headache days, intensity, disability, medication use, and treatment response, with low GRADE. Evidence for neuromodulation treatments was not reported. Although there is limited evidence for efficacy in sensitive groups, PT and PsyT are approaches that can be considered for these groups due to potential positive treatment effects. These interventions have shown modest benefits in improving migraine symptoms, the overall quality and consistency of the evidence is limited and heterogeneous.
Heller myotomy (HM) is an effective and durable treatment for esophageal achalasia. However, some patients experience persistent or recurrent symptoms that require reintervention. Heterogeneous definitions of failure after HM limit comparability across studies and complicate clinical decision-making. This narrative review examines definitions and incidence of failure after HM, as well as risk factors for reintervention. Failure is influenced by disease severity, esophageal morphology, manometric subtype, prior endoscopic therapy, surgical technique, and center experience. Reported failure rates vary because of inconsistent definitions, follow-up durations, and patient selection. Symptom-based tools, such as the Eckardt Score, remain central but have limitations, underscoring the need for validated measures. Sigmoid esophagus and type I-III achalasia increase the risk of failure, whereas prior endoscopic therapy does not predict adverse outcomes in high-volume centers. Compared with endoscopic myotomy, HM-fundoplication may reduce postoperative reflux. Achalasia is irreversible, and treatment is palliative. Laparoscopic HM remains the gold standard, though failures occur, often due to incomplete myotomy or advanced disease. Early intervention, accurate diagnosis, and meticulous surgical technique are essential. Future research should prioritize standardized definitions of failure, subtype-specific outcome reporting, and long-term follow-up to enhance comparability and guide management.
Breast cancer remains a leading cause of cancer-related mortality among women, with prolonged exposure to endogenous estrogens recognized as a major risk factor. This study aimed to design, synthesize, and pharmacologically evaluate novel 3,3'-diindolylmethane (DIM) derivatives as multi-target modulators of estrogen-related pathways in breast cancer. A series of DIM derivatives was synthesized and structurally characterized. Their biological activities were assessed through aromatase (CYP19A1) and CYP1B1 inhibition assays, E-screen assay for estrogen receptor activity, cytotoxicity assays in breast cancer (MCF-7 BUS, MDA-MB-231) and normal breast epithelial (MCF-10 A) cells, and scratch assay for cell migration. Molecular docking and in silico ADME analyses were conducted to support experimental findings. The derivatives demonstrated significant antiestrogenic activity by targeting multiple components of estrogen signaling. One compound exhibited potent aromatase inhibition (IC₅₀ = 0.79 µM), while two derivatives showed strong CYP1B1 inhibition (IC₅₀ = 0.37 µM and 0.71 µM). Selective cytotoxicity was observed in estrogen receptor-positive cells, with reduced effects on normal cells. Additionally, selected compounds significantly inhibited cell migration. Molecular modeling revealed favorable binding interactions within target enzymes, and ADME analysis indicated acceptable drug-like properties. These findings suggest that DIM derivatives act as selective, multi-target modulators of estrogen-related pathways and may serve as promising adjuvant candidates for hormone-dependent breast cancer therapy.
To evaluate whether obstructive sleep apnea (OSA) is associated with corneal ulceration and surgical intervention, and to assess the impact of continuous positive airway pressure (CPAP) therapy on these outcomes. This retrospective cohort study used data from the TriNetX electronic health record database. Adults aged ≥ 18 years with ≥ 1 year of ophthalmology follow-up were analyzed using nearest-neighbor propensity score matching (demographics and comorbidities standardized mean differences < 0.1). Three matched analyses were performed: OSA versus controls without OSA (n = 287,572 per group), CPAP-treated OSA versus controls with OSA without CPAP treatment (n = 100,959 per group), and CPAP-treated OSA versus controls without OSA (n = 99,909 per group). Outcomes were assessed over 20 years, excluding individuals with prior diagnoses. Risk ratios (RRs) with 95% confidence intervals (CIs) and p-values were calculated. OSA was associated with higher incidence of corneal ulcer (0.98% vs 0.83%; RR 1.183, 95%CI 1.120-1.249), perforated corneal ulcer (0.15% vs 0.04%; RR 3.992, 95%CI 3.243-4.915), and keratoplasty (RR 1.556, 95%CI 1.427-1.696). Among OSA patients, CPAP was associated with lower incidence of perforated corneal ulcer (RR 0.730, 95%CI 0.584-0.913) and keratoplasty (RR 0.663, 95%CI 0.579-0.760), but higher incidence of dry eye (RR 1.189, 95%CI 1.172-1.206). Compared to controls, CPAP-treated OSA patients remained at elevated risk of corneal ulceration and surgical intervention. OSA was associated with higher incidence of corneal ulceration, severe ulcer-related sequelae, and corneal surgical interventions. CPAP was associated with fewer severe ulcer complications and reduced keratoplasty utilization, but higher dry eye burden. CPAP was associated with reduced but persistent ocular risk in patients with OSA.
Knowledge-based planning (KBP) can improve the efficiency and consistency of volumetric-modulated arc therapy (VMAT); however, the extent to which treatment-machine characteristics influence KBP model behavior remains unclear. This study aimed to clarify the dosimetric impact of machine-specific KBP models by distinguishing the contributions of model libraries and plan-generation environment. Three RapidPlan models were independently trained using 30 manually generated plans created on NovalisTx (15X), TrueBeam (10X), and Halcyon (6FFF). The models were applied to an independent cohort of 15 patients using two complementary evaluation approaches: a clinical evaluation employing each machine's native beam model and a controlled evaluation using a common TrueBeam 10X beam model with identical optimization settings. Dosimetric endpoints included planning target volume excluding the rectum (PTV-R) D2% and D98%, rectal V31/V46/V54/V58 Gy, and bladder V31/V50 Gy. In the library plans, significant differences were observed for the PTV-R metrics, rectal V54/V58 Gy, and bladder V50 Gy. Under clinical conditions, significant differences remained for the PTV-R D2% and D98% and for bladder V50 Gy, whereas rectal indices showed no significant differences. Under controlled conditions, differences in PTV-R and rectal metrics were no longer significant, whereas bladder V31 Gy and V50 Gy remained significantly different. These findings suggest that the impact of machine-specific KBP models is endpoint-dependent and reflect the combined influence of model-derived objectives and the plan-generation environment. Standardization of beam modeling and optimization conditions reduced inter-model differences for target and rectal metrics, whereas bladder-related differences persisted, indicating that KBP model management in multi-machine environments should consider endpoint-dependent behavior.
Gastric cancer is a highly prevalent malignancy of the digestive tract in China. Conventional chemotherapeutic drugs and human epidermal growth factor receptor 2 (HER2)‑targeted agents such as trastuzumab remain limited by significant challenges in the treatment of GC, including high rates of drug resistance, significant toxicity and adverse effects, and suboptimal tolerability. The advent of antibody-drug conjugates (ADCs) has marked a paradigm shift in the therapeutic landscape. This review systematically summarises the structural design, mechanisms of action, and current clinical applications of ADCs in HER2-positive or HER2-low advanced gastric cancer. The present review focuses on key clinical trial data for new-generation ADCs, specifically trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), drawing from the DESTINY-Gastric series and the RC48-C008 study. The review systematically synthesised data on efficacy, safety profiles, resistance mechanisms, and future therapeutic directions. New-generation ADCs have demonstrated significant improvements in objective response rates (ORR) and overall survival (OS) compared with traditional chemotherapy in later-line treatment settings. Emerging evidence also suggests the presence of activity in HER2-low-expressing populations. A systematic assessment of adverse drug reactions highlights both common events (e.g. gastrointestinal reactions, haematologic toxicity) and distinctive adverse events (e.g. interstitial lung disease), with corresponding management strategies. A comprehensive analysis of multiple resistance mechanisms, including HER2 heterogeneity, endocytic barriers, drug efflux, and target mutations, is conducted. The present study demonstrates that ADCs represent a transformative therapeutic modality for HER2-positive or HER2-low cases. Ongoing advancements in ADC structural optimisation, combination strategies with immune checkpoint inhibitors show great promise in terms of further improving clinical outcomes. The objective of this review is to furnish clinicians and researchers with a detailed reference for future clinical practice and investigation.