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Abstract Introduction. The digital transformation in health drives the increase of new software, aligned with the dynamics of the development of information and communications technologies (ICTs). Objective. 1) To justify the benefits of using digital medical technologies -ERGOCID, METALYZER, MOVICORDE and CARDIOTRAINING-CIDC- in the biomedical monitoring of Cuban high-performance athletes. 2) To present the innovations that are carried out in ergometry and field tests during the cardiovascular medical monitoring of Cuban athletes. Method. Prospective, longitudinal study of innovation and development between January 2018 and December 2023. The universe consisted of 490 athletes from national teams in the different Olympic competition sports. The selective and intentional sample was made up of athletes, both men and women, from combat sports: judo, wrestling, boxing, taekwondo, karate, and fencing. 187 athletes were studied: 101 men and 86 women. The ages of the participants ranged between 17 and 34 years old. Results. Ergometry-specific protocols were designed, which constitute a technological innovation, for wrestling, judo, boxing, and taekwondo. Telemetric studies were carried out with MOVICORDE during training in taekwondo, karate, and fencing. The CARDIOTRAINING-CIDC software was created and used. Conclusion. The use of digital technologies has been very beneficial in the medical monitoring and sport performance of athletes. The innovations made, the design of gesture-specific ergometric protocols, and the creation of the VBA CARDIOTRAINING-CIDC macro were very useful in sports biomedical control.

Resumen Introducción. La transformación digital en salud impulsa el aumento de nuevos softwares, alineada con la dinámica del desarrollo de las tecnologías de la información y las comunicaciones (TICs). Objetivos. 1) Fundamentar los beneficios de la utilización de las tecnologías médicas digitales -ERGOCID, METALYZER, MOVICORDE y CARDIOTRAINING-CIDC- en el control biomédico de los deportistas de alto rendimiento cubano. 2) Presentar las innovaciones que se realizan en la ergometría y pruebas de terreno durante el seguimiento médico cardiovascular del deportista cubano. Método. Se realizó un estudio prospectivo, longitudinal, de innovación y desarrollo, entre enero de 2018 y diciembre de 2023. El universo quedó constituido 490 deportistas de los equipos nacionales en los diferentes deportes de competición olímpica. La muestra selectiva e intencional la conformaron los deportistas, tanto hombres como mujeres, de los deportes de combate: judo, lucha, boxeo, taekwondo, kárate y esgrima. Fueron estudiados 187 deportistas; 101 varones y 86 féminas. Las edades de los participantes oscilaron entre 17 y 34 años. Resultados. Se diseñaron protocolos ergométricos gesto-específicos que constituyen una innovación tecnológica, para lucha, judo, boxeo y taekwondo. Se realizaron estudios telemétricos con MOVICORDE durante el entrenamiento de taekwondo, kárate y esgrima. Fue creado y utilizado el software CARDIOTRAINING-CIDC. Conclusión. El uso de tecnologías digitales resultó muy beneficioso en el seguimiento médico y del rendimiento atlético de los deportistas. Las innovaciones realizadas, el diseño de protocolos ergométricos gesto-específicos y la creación de la macro VBA CARDIOTRAINING-CIDC resultaron de gran utilidad en el control biomédico deportivo.

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Abstract Background. Obesity is a multifactorial disease that affects overall health and is associated with several conditions, including cardiovascular disease, diabetes, and metabolic disorders. Adipose tissue, particularly visceral adipose tissue, significantly contributes to chronic inflammation that exacerbates these comorbidities. In addition, the prevalence of heart failure and obesity in patients is high. Objective. To determine the prevalence and factors associated with excess weight in patients with heart failure. Methods. A descriptive cross-sectional study was conducted with patients diagnosed with heart failure and enrolled in a cardiac rehabilitation program at a clinic in Cali, Colombia. The study included sociodemographic and clinical variables, functional aerobic capacity measured by the 6-minute walk test, quality of life assessed using the Minnesota Living with Heart Failure Questionnaire (MLFHQ), and depression evaluated by the Patient Health Questionnaire-9 (PHQ-9). Results. A total of 300 participants were involved in the study, including 152 individuals without excess weight and 148 with excess weight. Statistically significant results (p < 0.05) revealed that hypertension (OR = 1.81; CI [1.23-3.85]), elevated triglyceride levels (OR = 1.84; CI [1.08-3.13]), and a mild PHQ-9 score (OR = 1.91; CI [1.04-3.49]) were associated with a higher likelihood of excess weight. Conclusion. Patients with HF aged under 65 years and with reduced or moderate left ventricular ejection fraction show a lower probability of excess weight. In contrast, those with hypertension, elevated triglyceride levels, and a mild PHQ-9 score are more likely to present excess weight.

Resumen Antecedentes. La obesidad es una enfermedad multifactorial que afecta la salud en general y se asocia a varias enfermedades, como las cardiovasculares, la diabetes y los trastornos metabólicos. El tejido adiposo, en particular el visceral, contribuye significativamente a la inflamación crónica que agrava estas comorbilidades. Además, la prevalencia de la insuficiencia cardiaca y la obesidad en los pacientes es elevada. Objetivo. Determinar la prevalencia y los factores asociados al exceso de peso en pacientes con insuficiencia cardiaca. Método. Se realizó un estudio descriptivo transversal con pacientes diagnosticados de insuficiencia cardiaca e inscritos en un programa de rehabilitación cardiaca en una clínica de Cali, Colombia. El estudio incluyó variables sociodemográficas y clínicas, capacidad aeróbica funcional medida mediante la prueba de caminata de 6 minutos, calidad de vida evaluada con el instrumento Minnesota Living with Heart Failure Questionnaire (MLFHQ) y depresión evaluada por el Patient Health Questionnaire-9 (PHQ-9). Resultados. Participaron 300 personas: 152 de sin exceso de peso y 148 con exceso de peso. Los resultados fueron estadísticamente significativos (p<0,05). Los siguientes factores se asociaron a una mayor probabilidad de exceso de peso en personas con IC: hipertensión arterial (OR = 1,81; IC [1,23-3,85]), niveles elevados de triglicéridos (OR = 1,84; IC [1,08-3,13]) y una puntuación leve en el cuestionario PHQ-9 (OR = 1,91; IC [1,04-3,49]). Conclusión. Los pacientes con IC menores de 65 años y con una fracción de eyección ventricular izquierda reducida o moderada presentan una menor probabilidad de exceso de peso. Por el contrario, aquellos con hipertensión, niveles elevados de triglicéridos y una puntuación PHQ-9 leve muestran una mayor probabilidad de exceso de peso.

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Fusobacterium nucleatum (Fn), an intratumoral pathogenic bacterium, is confirmed to be associated with tumor progression in colorectal cancer (CRC). To evaluate CD8+ T cell function against CRC cells, their cytotoxicity was determined via live/dead staining and ELISA, while proliferation was assessed using the CFSE assay. CD274 (PD-L1) expression in CRC was quantified by qPCR, flow cytometry, and immunofluorescence. Lactate accumulation in CRC cells was measured using LDHA and lactate assay kits. Histone lactylation levels were analyzed by Western blot. Chromatin immunoprecipitation was applied to examine the abundance of H3K18 lactylation (H3K18la) at the CD274 promoter region. Finally, Annexin V/PI staining was employed to analyze the apoptosis rate of CRC cells. Fn treatment inhibited the anti-tumor immune capacity of CD8+ T cells against CRC cells and increased PD-L1 expression. Fn stimulation promoted lactate accumulation in CRC cells and enhanced H3K18la levels. Mechanistic studies revealed enrichment of H3K18la. Fn treatment induced H3K18la of PD-L1, upregulating its expression, suppressing CD8+ T cell immune activity, and promoting immune escape in CRC. This study demonstrates that Fn is crucial in CRC immune escape, proposing that regulating Fn abundance represents a novel strategy to enhance immunotherapy effectiveness.

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Ischemia-reperfusion injury, a critical pathophysiological phenomenon in multiple organ systems, remains a formidable therapeutic challenge in clinical practice. As the third endogenously produced gaseous signaling molecule, hydrogen sulfide (H2S) has emerged as a pivotal regulator of diverse physiological processes and pathological cascades. Accumulating evidence indicates that H2S exerts cytoprotective effects against cerebral, cardiac, hepatic, renal, and pulmonary ischemia-reperfusion injuries through multifaceted mechanisms involving mitigation of inflammatory responses, suppression of oxidative stress, modulation of autophagic processes, and inhibition of apoptotic pathways. This comprehensive review systematically examines the endogenous biosynthesis and metabolic regulation of H2S, while elucidating the molecular mechanisms underlying its organ protective effects during ischemia-reperfusion injury. Particular emphasis is placed on the therapeutic potential of H2S synthase isoforms and bioactive metabolites in ischemic pathophysiology. Notably, recent advances in H2S pharmacology have catalyzed the development of novel H2S donors and slow-releasing compounds, including HSDF-NH2, S-allyl cysteine, S-propargyl cysteine, and S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-L-cysteine. These pharmacological innovations demonstrate enhanced tissue specificity and controlled release kinetics, paving the way for clinical translation of H2S-based therapeutics in ischemia-reperfusion injury management. Future research directions should focus on optimizing drug delivery systems and elucidating the spatiotemporal dynamics of H2S signaling in organ-specific ischemia-reperfusion pathologies.

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Long-term oxygen therapy is used to treat of chronic respiratory diseases with chronic hypoxia. To date, long-term oxygen therapy has significantly contributed to the relief of dyspnea in the daily life of patients with chronic respiratory disease and chronic hypoxemia. Chronic hypoxia is a possible cause of cognitive impairment, and patients with chronic respiratory disease using long-term oxygen therapy with severe chronic hypoxia may be at a higher risk of cognitive impairment than patients using non-long-term oxygen therapy. Cognitive impairment in patients with chronic respiratory disease can lead to a decline in treatment adherence, including medication usage, health care check-ups, and smoking cessation efforts, which contribute to disease progression. In addition, patients using long-term oxygen therapy require oxygen delivery equipment. Operating oxygen delivery equipment is difficult for patients with cognitive impairment, and the inability to use long-term oxygen therapy properly is a serious challenge that can affect their life expectancy. Patients with chronic respiratory disease who use long-term oxygen therapy may be more affected by cognitive impairment than non-long-term oxygen therapy patients. Several review articles have addressed cognitive impairment in patients with chronic respiratory disease; however, none specifically focus on patients with chronic respiratory disease using long-term oxygen therapy. This narrative review describes the current knowledge and future issues regarding cognitive impairment in patients with chronic respiratory disease using the long-term oxygen therapy.

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Sonodynamic therapy has emerged as a novel non-invasive treatment for cancer with limited single effects. To achieve optimal therapeutic efficacy, sonodynamic therapy frequently needs to be combined with other therapeutic strategies. By exploiting the biological properties of specific gas molecules, gas therapy is an emerging tumor treatment that exerts direct or indirect inhibitory effects on tumor cells. This review systematically examines the rationales, methodologies, and outcomes of sonodynamic therapy and gas therapy combinatorial strategies for malignant tumors. There is a synergistic effect between sonodynamic therapy and gas therapy in tumor treatment. The ultrasound-induced cavitation enhances tissue permeability for improved gas delivery, while gas molecules concurrently sensitize sonodynamic reactions and ameliorate tumor hypoxia. The interaction significantly enhances the therapeutic effect of tumors. Moreover, the combination of sonodynamic therapy with other therapeutic modalities can significantly enhance the anti-tumor efficacy, improve the therapeutic precision and safety, while improve the tumor microenvironment. This combined treatment strategy can also reduce side effects and has a broad clinical application perspective.

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FactsGas therapy represents a novel and promising therapeutic paradigm for intervertebral disc degeneration, utilizing bioactive gases to modulate oxidative stress, inflammation, and extracellular matrix metabolism.Certain gas therapies, such as medical ozone and hyperbaric oxygen, have already been translated into clinical use for intervertebral disc degeneration, demonstrating efficacy in pain alleviation, disinfection, and improving functional outcomes through minimally invasive delivery.The core mechanisms of gas therapeutics involve the restoration of disc microenvironment homeostasis via specific actions, including reactive oxygen species scavenging, suppression of inflammatory cytokines, inhibition of inflammasome activity, and enhancement of collagen synthesis.Combination strategies integrating gas therapy with other regenerative approaches-such as stem cell transplantation, bioactive scaffolds, or drug delivery systems-exhibit synergistic potential for amplifying anti-inflammatory, antioxidant, and anabolic effects in disc repair.Open questionsWhat are the precise molecular mechanisms and signaling pathways (e.g., hydrogen-mediated nuclear factor erythroid 2-related factor 2 activation, hydrogen sulfide-dependent extracellular matrix regulation) through which gaseous mediators exert their therapeutic effects in human disc cells under pathological microenvironments?How can physiologically relevant disease models-such as human disc organoids or large animal models under biomechanical loading-be developed and utilized to better recapitulate human intervertebral disc degeneration pathophysiology and improve the translational validity of preclinical gas therapy research?What is the clinical efficacy and safety of gas therapeutic protocols in large-scale, multicenter randomized controlled trials? How can standardized treatment parameters and personalized regimens be established for different subtypes and etiologies of intervertebral disc degeneration? Environmental gaseous molecules extensively participate in human physiological and pathological regulation through differential biological effects. Gas transmitter-based therapeutic strategies, as emerging intervention modalities, have demonstrated significant translational value in intervertebral disc degeneration management. The intervertebral disc degeneration susceptibility to progressive degenerative pathology stems from its unique avascular nature and complex biomechanical microenvironment, while conventional therapies face limitations in efficacy and carry invasive risks. This review systematically delineates innovative applications of gaseous therapeutics for intervertebral disc degeneration, encompassing clinically established ozone and hyperbaric oxygen therapies alongside preclinical-stage hydrogen, hydrogen sulfide, and nitric oxide interventions. Comprehensive analyses address molecular properties, biological functions, and mechanistic actions. Current evidence indicates that gas therapies significantly alleviate pain and improve functional impairment through targeted modulation of oxidative stress-inflammation-apoptosis cascades and extracellular matrix metabolic dysregulation. Their minimally invasive precision delivery capabilities and multimodal bio-regulatory advantages offer groundbreaking diagnostic and therapeutic strategies for intervertebral disc degeneration, exhibiting well-defined clinical translation potential.

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Conventional antibiotic therapies often fail to eradicate biofilms, which can lead to persistent infections and significant clinical challenges. Gas therapy, which utilizes the unique properties of gas molecules such as nitric oxide, carbon monoxide, hydrogen, and hydrogen sulfide, is emerging as a promising and innovative strategy to address these challenges. This review first highlights gas signaling in bacterial biofilms. It then goes on to list four types of gas therapy in detail: photothermal-enhanced gas therapy, photodynamic-activated gas therapy, micro/nanobubble-mediated gas therapy, and gas-based synergistic therapy. Their potential applications and future directions are also fully discussed. Due to its unique bioactivity, low resistance, and synergy with existing treatments, gas therapy has demonstrated significant potential in the prevention and treatment of biofilm-associated infections. However, overcoming delivery challenges, validating efficacy in large-scale trials, and developing standardized protocols are essential for its clinical translation. Future efforts should prioritize the integration of nanotechnology and mechanistic studies to unlock broader therapeutic utility.

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BACKGROUND: The North Central London (NCL) Cancer Alliance carried out a quality improvement (QI) project to fill a distinct knowledge gap regarding the quality of clinical coded data in a primary care electronic health care record system across the whole cancer pathway. OBJECTIVE: This study aims to establish the quality of cancer-related clinical coding in NCL primary care, encompassing both quantitative measures (eg, coding completeness and diversity) and qualitative dimensions such as clinical relevance and workflow alignment. METHODS: This was a mixed methods QI project in which we combined an observational dataset review and qualitative data from stakeholder interviews, workshops, and discussions. In the dataset review, we evaluated completeness, diversity, validation, and granularity in cancer clinical coding along the patient cancer pathway, which was split into three domains: (1) patient characteristics and risk factors, (2) cancer screening attendance, and (3) living with cancer. It was conducted in NCL primary care electronic health record systems, covering a population of over 1.4 million adults across 5 boroughs. RESULTS: Cancer-related clinical coding in NCL primary care revealed significant gaps despite high completeness for ethnicity (912,679/1,055,083, 86.5%) and language (898,023/1,307,601, 68.7%). Employment status (29,848/1,229,644, 2.4%) and family history of cancer (183,424/1,236,580, 14.8%) were underrecorded, with wide variation in coding practices. Screening data showed good alignment with national datasets for cervical and bowel screening but fragmented and inconsistent breast screening data due to a lack of standardized codes. Cancer diagnosis coding was incomplete (4604/5260, 87.5% recorded), and treatment and staging data were almost entirely absent, limiting proactive management of long-term consequences. Stakeholder input highlighted inconsistent template use, limited data updates, and insufficient incentives as key barriers to better coding. CONCLUSIONS: The QI project has provided a detailed insight into the many dimensions of cancer coding and sheds light on many factors that underpin variation and coding preference. We offer a number of recommendations. The prioritized ones include the need for a cancer clinical coding data framework for primary care supported by appropriate funding and incentivization; improvements in the breast screening pathway and its interface with primary care; improvements in the quality of secondary care information that is sent to primary care; and dissemination of the importance of coding of cancer activity in primary care.

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BACKGROUND: The pathological and physiological state of patients with intracerebral hemorrhage (ICH) after minimally invasive surgery (MIS) is a dynamic evolution, and the traditional models cannot dynamically predict prognosis. Clinical data at multiple time points often show the characteristics of different categories, different numbers, and missing data. The existing models lack methods to deal with imbalanced data. OBJECTIVE: This study aims to develop and validate a dynamic prognostic model using multi-time point data from patients with ICH undergoing MIS to predict survival and functional outcomes. METHODS: In this study, 287 patients who underwent MIS for ICH were retrospectively collected on the day of surgery, days 1, 3, 7, and 14 after surgery, and the day of drainage tube removal. Their general information, vital signs, laboratory test findings, neurological function scores, head hematoma volume, and MIS-related indicators were collected. In addition, this study proposes a multistep attention model, namely the MultiStep Transformer. The model can simultaneously output 3 types of prediction probabilities for 30-day survival probability, 180-day survival probability, and 180-day favorable functional outcome (modified Rankin Scale [mRS] 0-3) probability. Five-fold cross-validation was used to evaluate the performance of the model and compare it with mainstream models and traditional scores. The main evaluation indexes included accuracy, precision, recall, and F1-score. The predictive performance of the model was evaluated using receiver operating characteristic (ROC) curves; its calibration was assessed via calibration curves; and its clinical utility was examined using decision curve analysis (DCA). Attributable value analysis was conducted to assess the key predictive features. RESULTS: The 30­day survival rate, 180­day survival rate, and 180­day favorable functional outcome rate among 287 patients were 92.3%, 88.8%, and 52.3%, respectively. In terms of predictive efficacy for survival and functional outcomes, the MultiStep Transformer model showed a remarkable superiority over traditional scoring systems and other deep learning models. For these three outcomes, the model achieved areas under the receiver operating characteristic curves (AUROCs) of 0.87 (95% CI 0.82-0.92), 0.85 (95% CI 0.77-0.93), and 0.75 (95% CI 0.72-0.78), with corresponding Brier scores of 0.1041, 0.1115, and 0.231. DCA confirmed that the model provided a definite clinical net benefit when threshold probabilities ranged within 0.06-0.26, 0.04-0.5, and 0.21-0.71. CONCLUSIONS: The MultiStep Transformer model proposed in this study can effectively use imbalanced data to construct a model. It possesses good dynamic prediction ability for short-term and long-term survival and functional outcome of patients with ICH undergoing MIS, providing a novel tool for individualized assessment of prognosis among patients with ICH undergoing MIS.

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Drug-induced liver injury (DILI) represents a critical pharmacotherapeutic challenge requiring novel interventions. The hepatoprotective mechanisms of Gypenoside XLIX (GYP XLIX) against liver injury remain underexplored. This study establishes GYP XLIX as a hepatoprotective agent against diclofenac (DF)-induced liver injury through integrated experimental approaches. Male Wistar rats were used in this investigation and grouped randomly into four groups: the control group, the DF group (50 mg/kg), the GYP XLIX group (30 mg/kg), the DF + XLIX group, and the DF + silymarin group for 7 days. Human liver cell line L02 was used for further study. The analytical methods used included network pharmacology analysis, molecular docking, H&E staining, qPCR, enzyme activity assay, and Western blot. GYP XLIX significantly ameliorated DF-induced hepatic damage, as evidenced by reduced serum ALT, AST, and ALP levels, attenuated histopathological abnormalities, enhanced antioxidant capacity (elevated SOD and GSH, decreased MDA), and suppressed pro-inflammatory cytokine release. Mechanistically, GYP XLIX targeted the AKT/NLRP3 pathway, promoting AKT phosphorylation and inhibiting NLRP3 inflammasome activation, confirming its role in alleviating hepatotoxicity through antioxidative and anti-inflammatory mechanisms. In L02 cells, GYP XLIX exerts a protective effect against DF-induced liver injury through the AKT/NLRP3 axis, and this mechanism has been further confirmed. This work supports GYP XLIX as a promising multi-target therapeutic candidate for chemical hepatotoxicity, providing new insights for clinical prevention and treatment of DILI.

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system mediated by autoimmune demyelination. While treatments targeting the peripheral immune system have been effective in reducing relapse risks for MS patients, the neuroinflammation within the central nervous system, which is believed to contribute to neurodegeneration, has not been successfully addressed. Human Dental Pulp Stem Cells (hDPSCs) have shown potential in entering the CNS and exerting anti-inflammatory effects, making them a promising candidate for treating neurological disorders. In experimental autoimmune encephalomyelitis (EAE) models, intravenously administered hDPSCs ameliorated clinical scores, decreased demyelinated lesion volume, and reduced inflammatory infiltration. Given the established safety profile, hDPSCs could potentially be developed as a new approach to combat disease progression of MS by inhibiting compartmentalized neuroinflammation.

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PURPOSE: Patients with metastatic castration-resistant prostate cancer (mCRPC) often undergo multiple treatments, making accurate response assessment vital. The conventional imaging-based PCWG3 criteria, incorporating the RECIST-1.1, have been the gold standard so far. Although 68Ga-PSMA-11-PET/CT has shown an incremental role in staging of prostate cancer, its utility in response evaluation lacks prospective validation. Here, we prospectively evaluate different 68Ga-PSMA-11-PET/CT-based response evaluation criteria, including RECIP-1.0, PPP, and aPERCIST, and compare these with the PCWG3 criteria. METHODS: mCRPC patients, initiating treatment with taxanes, androgen-receptor pathway inhibitors (ARPIs), or 177Lu-PSMA-617, underwent 68Ga-PSMA-11-PET/CT and conventional imaging (CECT and bone scintigraphy) at baseline, and every 12 weeks after treatment. RESULTS: Thirty-four mCRPC patients were included (median age: 68.5 y, median PSA: 61.9 ng/mL). Nonprogression rates at 12 weeks according to PCWG3, aPERCIST, PPP, and RECIP-1.0 were 23.5%, 8.8%, 17.6%, and 23.5%, respectively. The highest inter-reader agreement was observed with RECIP-1.0 (κ=0.84). The median OS was 16.5 months with nonprogression according to PCWG3 being associated with significantly better OS (P=0.02), and no significant associations were observed with the rest of the criteria. In surrogacy analysis of rPFS for OS in the overall cohort, the highest C-index was observed for PCWG3-rPFS (C=0.72), followed by RECIP-rPFS (C=0.71). In subgroup analyses, RECIP-rPFS had the highest C-index for non-ARPI patients (C=0.76), and PCWG3-rPFS for the ARPI patients (C=0.75). CONCLUSIONS: PCWG3 remains the most effective response criterion overall and for ARPI-treated patients, while RECIP-1.0 showed better prognostic value for non-ARPI patients. Larger studies are needed to validate these findings.

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The CD40 pathway has become one of the most promising immunologic axes in oncology. As a central intermediary between innate and adaptive immunity, CD40 activation engages dendritic cells (DCs), amplifies antigen presentation, and stimulates potent cytotoxic T-cell (CTL) activity. Therapeutic CD40 agonists have been studied in a broad range of cancers over the past decade to reconfigure the tumor's immune microenvironment (TIME) and overcome immune refractoriness to standard immunotherapies. Clinical development has been most significant in pancreatic cancer, an exemplar cold tumor resistant to immune checkpoint blockade. Here, CD40 agonists have demonstrated efficacy to repolarize immune-desert phenotypes to a more inflamed and treatable phenotype, particularly in combination with chemotherapy or programmed cell death protein 1 (PD-1) inhibitors. Clinical evidence has also been gained in melanoma and non-small cell lung cancer, where CD40-targeted strategies are examined in combination with current checkpoint inhibitors to accelerate T-cell priming. In hematologic malignancies and B-cell lymphomas, in particular, CD40 agonists exploit the natural activity of the B-cell activating receptor, providing a strong biological rationale for their clinical efficacy. Exploratory studies have gone on to extend into bladder, prostate, mesothelioma, and head and neck cancers, demonstrating the broad translational relevance of this pathway. Hopes fostered by preliminary signs of activity remain to be qualified in light of the difficulties. Systemic immune activation-associated toxicities, such as cytokine release syndrome, have justified cautious dosing schedules and exploration of local routes of drug administration. Additionally, heterogeneity between tumors in response underscores an urgent need for predictive biomarkers to enable the selection of patients and to tailor optimal clinical effects. In the future, drug development will be reliant on prudent combinations and novel delivery methods. Conjugation to vaccines, bispecific antibodies, radiotherapy, and oncolytic viruses is an attractive route to achieve their fullest immunostimulatory capabilities. Through a flexible approach to reeducate the immune microenvironment within tumors, CD40 agonist therapy can extend the use of immunotherapy to traditionally immune-refractory malignancies. This review intends to present a cross-cancer approach to CD40 agonist therapy, compiling existing clinical evidence while highlighting common issues and prospects for harnessing this pathway across various tumor settings.

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OBJECTIVES: Transcatheter aortic valve-in-valve is frequently performed in degenerated surgical valves. Notably, in small-sized surgical valves, bioprosthetic valve fracturing can improve the functional results of the transcatheter heart valve (THV). Therefore, this study aimed to investigate the impact of an expandable surgical valve on the functional improvement of 2 THV models. METHODS: An Inspiris Resilia (21 mm) and 2 different THV models-the self-expanding Evolut-PRO and the balloon-expandable SAPIEN 3 (each 23 and 26 mm)-were used for hydrodynamic testing at 4 different circulatory conditions in a pulse duplicator. Mean pressure gradient (MPG), effective orifice area (EOA), geometric orifice area (GOA), minimal internal diameter (MID), and pin-wheeling index (PWI) of the THVs were analysed before and after expansion of the Inspiris Resilia with a non-compliant balloon (6 atm). Leaflet kinematics were evaluated by high-speed video recording. The internal and external diameters of Inspiris Resilia were measured with a calliper gauge. Fluoroscopic images were recorded. RESULTS: The Inspiris Resilia showed 2 mm enlarged internal and external stent diameters after expansion, which are fluoroscopically visible. EOA and MPG of the THVs as valve-in-valve did not change significantly after the expansion of the Inspiris Resilia. However, the Inspiris Resilia expansion improved leaflet kinematics, resulting in an increased GOA and a decreased PWI of the THVs as valve-in-valve. CONCLUSIONS: The expansion of the Inspiris Resilia enlarged the stent diameter, resulting in improved leaflet kinematics of the THVs as valve-in-valve. These findings may be helpful for valve-in-valve interventions, especially in small-sized surgical valves.

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BACKGROUND: Medical image analysis has witnessed substantial advancements through recent deep learning (DL) algorithms development. Vision Transformers (ViTs) have emerged as a powerful alternative solution by leveraging self-attention to model both local and global interactions. Despite their promise, ViTs are data-intensive and lack inductive biases, limiting their utility in medical imaging. Conversely, radiomics offers domain-specific, interpretable descriptors of image heterogeneity but lacks scalability and integration with deep learning. This study proposes a unified Radiomics-Embedded Vision Transformer (RE-ViT) framework that combines handcrafted radiomic features and data-driven visual embeddings within a ViT architecture. PURPOSE: To develop and evaluate a RE-ViT framework that integrates radiomics and patch-wise ViT embeddings to improve feature representation for medical image classification across heterogeneous datasets. METHODS: Following the classic ViT design, the input image was first resampled into multiple image patches. For each image patch, handcrafted radiomic features, including intensity, texture, and spatial heterogeneity descriptors, were extracted. Simultaneously, standard patch embeddings were obtained via linear projection of pixel intensities. The two embeddings were averaged, normalized, and combined with positional encodings before being tokenized and processed by a ViT encoder. A learnable token aggregates patch-level information for final classification. The model was evaluated on three publicly available datasets, BUSI (lesion malignancy diagnosis through breast ultrasound), ChestXray2017 (lung pneumonitis diagnosis through chest x-ray), and Retinal OCT (retina disease diagnosis through retinal OCT), using 10-fold cross-validation. Performance metrics included accuracy, macro area under the ROC curve (AUC), sensitivity, and specificity. Ablation studies were implemented to assess the contribution of RE-ViT architectural components on these three clinical problems. Comparative analyses were also conducted against CNN (VGG-16, ResNet) and hybrid (TransMed) models. RESULTS: The proposed RE-ViT model demonstrated consistently robust classification performance across all three medical imaging datasets. In BUSI, RE-ViT achieved an accuracy of 0.848 ± 0.027, AUC of 0.950 ± 0.011, sensitivity of 0.796 ± 0.042, and specificity of 0.905 ± 0.020. In ChestXray2017, it yielded an accuracy of 0.950 ± 0.012, AUC of 0.989 ± 0.004, sensitivity of 0.953 ± 0.010, and specificity of 0.975 ± 0.005. In Retinal OCT, RE-ViT achieved an accuracy of 0.938 ± 0.001, AUC of 0.986 ± 0.001, sensitivity of 0.914 ± 0.023, and specificity of 0.969 ± 0.024. In the comparison studies, the RE-ViT matches or outperforms alternatives. Ablation revealed significant performance drops when removing either radiomics or projection-based embeddings. Attention map visualizations demonstrated imaging modality-specific utilization of radiomics and learned features, with improved localization of clinically relevant regions. CONCLUSIONS: The proposed radiomics-embedded vision transformer was developed for multiple image classification tasks. Current results underscore the potential of our approach to advance other transformer-based medical image classification tasks.

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Cervical cancer continues to pose significant health problems globally, often fueled by the persistent activity of KLF5, a prototypical oncogenic transcription factor responsible for enhanced cell proliferation, survival, and extensive tumor growth. Relaxin-2 (RLN2), which is part of the relaxin peptide hormone family, is known to exert a wide range of biological effects such as remodeling tissues and having anti-fibrotic effects. There is growing concern that RLN2 has anti-cancer activity; nevertheless, its function as well as the molecular mechanisms involved in cervical cancer is largely unknown. The goal of this research was to analyze the anti-tumor effect of RLN2 on cervical cancer and to determine its molecular mechanism, with particular emphasis on KLF5 and the cross-talks modulated by Hippo-YAP and JAK2/STAT3 signaling pathways. SiHa and C33A human cervical cancer cell lines were treated with recombinant RLN2 at different concentrations and times. The expression level of KLF5 along with the expression of constituent components of the cell cycle (Cyclin D1, PCNA, CDK4), apoptotic indicators (Bax, Bcl-2, cleaved caspase 3, PARP), and proteins of Hippo-YAP (YAP, pYAP, TEAD1/2) and JAK2/STAT3 (phospho-JAK2, phospho-STAT3) were evaluated by Western blotting. To validate KLF5's mediating role, analysis of proliferation and apoptosis-associated proteins was done after siRNA-induced silencing of KLF5. In addition, cell proliferation was further confirmed using the Sulforhodamine B (SRB) assay. Likewise, the wound healing assay was performed to evaluate the migratory potential in RLN2-treated SiHa cells compared to controls. The anti-tumor effect of RLN2 was assessed in vivo using a SiHa xenograft model in nude mice. The mice received intraperitoneal injections of RLN2 (20 µg/kg/day) for 21 days. Throughout the duration, tumor growth parameters were monitored, and upon excision, the tumors were subjected to immunohistochemical staining for Ki-67 (a proliferation marker). KLF5 protein expression was markedly reduced in both the cervical cancer cell lines following RLN2 treatment. This was coupled with a reduction of cell growth markers Cyclin D1, PCNA, and CDK4 which suggested G1 phase cell cycle arrest. There was a pronounced induction of apoptosis as indicated by increased Bax/Bcl-2 ratios along with greater amounts of cleaved caspase-3 and cleaved PARP 3. Consistent with these findings, the SRB assay confirmed a robust inhibition of cell proliferation, while the wound healing assay supported the strong anti-migratory potential of RLN2. In terms of mechanism, RLN2 blocked the Hippo-YAP pathway by promoting phosphorylation and sequestration of YAP into the cytoplasm, and downregulation of TEAD1/2 transcription factors. STAT3 and JAK2/2 signaling pathways were simultaneously inhibited as evidenced by decreased phosphorylation of JAK2 and STAT3, key oncogenic transcription drivers. KLF5 knockdown by siRNA showed effect opposite to RLN2 treatment which suggests KLF5 is indeed acting a mediator of these anti-tumor effects. In vivo, the addition of RLN2 resulted in substantial suppression of tumor volume and weight while causing no body weight changes. Examination of tumor tissue showed decreased Ki67 staining. This study makes it very clear that RLN2 has strong anti-cancer properties in cervical cancer by increasing the expression of the KLF5. The anti-proliferative and pro-apoptotic activities are achieved by the simultaneous inhibition of the Hippo-YAP and JAK2/STAT3 signaling pathways. These results underline the potential of RLN2 as a therapeutic target for treatment of advanced cervical cancer and necessitate further applied research to investigate its clinical use.

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BACKGROUND: Dynamic positron emission tomography (PET) is a powerful tool for clinical tumor diagnosis. However, the conventional dynamic scanning duration takes about 60 m i n $min$ , which is inconvenient for patients and limits the widespread application of this technology. PURPOSE: This study aims to develop an innovative method to achieve shortened high-quality K i $K_i$ parametric imaging based on the Patlak model. METHODS: We proposed a population-based input function integral estimation (PBIF-IE) method. The core of this method is to construct a linear regression model between the early-stage integral ( S e a r l y $S_{early}$ ) and the late-stage mean ( M l a t e $M_{late}$ ) of the image-derived input functions (IDIFs) in the training dataset. The goal is to estimate S e a r l y $S_{early}$ in the testing datasets using M l a t e $M_{late}$ and the linear regression model when only late-stage dynamic sequences are available. To verify the effectiveness and stability of the model, we set up three testing datasets, A, B, and C, each with different framing protocols for K i $K_i$ parametric imaging analysis. Furthermore, to explore the potential of our proposed method in shortening scan duration, we evaluated the K i $K_i$ parameter results obtained by our proposed method under three scan durations (30, 20, and 10 m i n $min$ ) using multiple quantitative metrics, including the peak signal-to-noise ratio (PSNR), the structural similarity index (SSIM), and the relative error (RE). RESULTS: Through multi-center data studies, we demonstrate the effectiveness of the PBIF-IE method. Extensive experimental results demonstrate that the PBIF-IE method outperforms other methods in both S e a r l y $S_{early}$ estimation and K i $K_i$ parametric imaging. The 30 m i n $min$ dynamic scanning protocol can obtain K i $K_i$ parameter images that are highly consistent with the 60 m i n $min$ scanning protocol, while the 20 m i n $min$ dynamic scanning protocol is sufficient for preliminary tumor localization. CONCLUSIONS: Based on the experimental results, the PBIF-IE method outperforms other existing methods for shortened K i $K_i$ parametric imaging. In future research, we plan to explore how the number of dynamic sequences used in the training dataset affects the model construction. This will help us further optimize the parametric imaging process.

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Lung adenocarcinoma (LUAD) is the predominant subtype of non-small cell lung cancer (NSCLC) with high mortality and treatment resistance. While the natural compound daucosterol (DS) shows anti-tumor potential, its role and mechanism in LUAD are unclear. Network pharmacology identified potential DS targets in LUAD, with binding affinity confirmed by molecular docking and dynamics simulations. In vitro, cell counting kit 8 (CCK-8), flow cytometry, and transwell assays were used to assess LUAD cell proliferation, apoptosis, migration, and invasion. Western blot and glycometabolism assays were employed to measure protein expression and glycolysis (glucose consumption and lactate production). In vivo anti-tumor efficacy of DS was validated in a xenograft mouse model using immunohistochemistry (IHC) and western blot. DS dose-dependently inhibited LUAD cell viability, migration, and invasion while inducing apoptosis. Network pharmacology identified Erb-B2 receptor tyrosine kinase 2 (ERBB2) as a key target for DS, supported by strong DS-ERBB2 binding affinity and complex stability. ERBB2 overexpression reversed DS-induced suppression of malignant phenotypes. Mechanistically, DS reduced ERBB2 expression to inhibit phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling, down-regulating hexokinase 2 (HK2) and lactate dehydrogenase (LDHA), and reducing glucose consumption and lactate production. In vivo, DS inhibited xenograft tumor growth and decreased Ki67, ERBB2, p-PI3K/PI3K, p-AKT/AKT, HK2, and LDHA expression in tumor tissues, which were reversible upon ERBB2 overexpression. DS exerts anti-tumor effects in LUAD by directly regulating ERBB2 expression, inhibiting PI3K/AKT signaling, and disrupting glycolysis. These findings support DS as a promising therapeutic candidate for LUAD.

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Reconstruction of pretibial defects remains challenging due to frequent bone exposure, lack of local flap options, and thin soft tissue coverage. These factors make achieving durable and aesthetically pleasing coverage difficult, often necessitating the use of free flaps to ensure successful reconstruction. This case report presents the case of a 68-year-old woman with a pretibial undifferentiated pleomorphic sarcoma treated with neoadjuvant radiotherapy and wide local excision, resulting in a 12 × 10 cm soft tissue defect with tibial bone exposure. Reconstruction was achieved using a combination of two perforator-based local flaps: A pedicled medial sural artery perforator (MSAP) flap for the medial aspect and a V-Y advancement flap based on an anterior tibial artery perforator for the lateral aspect. Postoperative recovery was uneventful. At one-year follow-up, the reconstruction showed stable coverage, satisfactory contour, and no signs of recurrence of the tumor or lymphedema. The combination of local perforator flaps offers a reliable and aesthetically favorable solution for complex pretibial defects. It allows surgeons to avoid microsurgical procedures, thereby reducing operative time, technical demands, and perioperative risks. This case highlights the potential of combining local flaps, preserving uninvolved donor sites, and minimizing overall morbidity. This solution represents a practical and effective alternative to free flap reconstruction and may contribute to expanding the reconstructive options available for managing complex lower limb defects.