Search Results (11,172)

Background: Due to the serious side effects and the resistant phenotype acquired by tumors, cisplatin has limited clinical efficacy. The current study aims to investigate the potential of disulfide-bridged phthalocyanines to make breast cancer cells (MCF-7) more sensitive to cisplatin. For this purpose, a novel disulfide-bridged dimeric phthalocyanine complex with a therapeutically active wavelength absorbance value that is activatable in cancer cells was synthesized and encapsulated in liposome nanoparticles. Methods: The synthesized phthalocyanine was characterized using FTIR, UV–visible, and MALDI-TOF-MS techniques; liposome nanoparticles containing the synthesized phthalocyanine were characterized using a particle size analyzer and were tested on MCF-7 breast cancer cell lines using MTT and flow cytometric assays. Results: The results have illustrated that GSH cleavages disulfide bonds of the synthesized disulfide-bridged dimeric phthalocyanine complex with quite favorable characteristics for photodynamic therapy, such as a therapeutically active wavelength absorbance value (685 nm), and disulfide-bridged phthalocyanine (ASG20)-containing liposome nanoparticles have quite favorable characteristics (average size of 167.6 nm and polydispersity index of 0.108) for biomedical applications. As evidenced by MTT and flow cytometric assays, by causing extra decreases in the viability of breast cancer cells (p < 0.01), pre-treatment of the breast cancer cells with photodynamic therapy using the activatable liposome nanoparticles significantly (p < 0.01) enhanced the anticancer activity of cisplatin in high and low doses. Conclusions: In conclusion, the activatable liposome nanoparticles containing disulfide-bridged dimeric phthalocyanine complexes can enable much more effective cisplatin-based therapies for breast cancer by overcoming the handicaps of cisplatin, drug resistance (by decreasing intracellular GSH levels), and serious side effects (by enabling the usage of lower doses of cisplatin in chemotherapy). Full article

Chronic wounds remain a major global health challenge despite substantial advances in biomaterials, regenerative medicine, and wound-care technologies. Current therapeutic strategies are largely based on the assumption that chronic wounds represent impaired or incomplete healing responses and therefore require augmentation of regenerative processes. This paradigm has driven the development of increasingly sophisticated wound dressings incorporating extracellular matrix analogs, growth factors, stem cells, extracellular vesicles, biosensors, and bioelectronic components. However, the clinical impact of these innovations has often fallen short of expectations. In this review, we propose a conceptual framework intended to generate experimentally testable hypotheses rather than provide a definitive mechanistic model. Persistent alterations in immune, stromal, vascular, extracellular matrix, metabolic, mechanical, and microbial networks create interconnected feedback systems that resist transition toward regeneration. From this perspective, successful therapy requires not only stimulation of repair mechanisms but also disruption of the processes that stabilize chronicity. We discuss how advances in systems biology, immunomodulatory biomaterials, bioelectronics, artificial intelligence, and precision medicine support the emergence of adaptive therapeutic interfaces capable of sensing, interpreting, and reprogramming pathological tissue behavior. Unlike previous reviews that primarily summarize emerging wound dressings or regenerative biomaterials, this Review proposes a systems-level conceptual framework in which chronic wounds are interpreted as stable pathological tissue states maintained by multiscale biological memory. This perspective integrates biomaterials, systems biology, artificial intelligence, and tissue-state dynamics into a unified translational model that has not previously been presented in the wound-healing literature. Previous reviews have predominantly focused on the design, biological activity, or clinical performance of individual biomaterials. In contrast, the present Review proposes a systems-level framework that integrates wound biology, biological memory, tissue-state dynamics, artificial intelligence, and adaptive biomaterials into a unified conceptual model for precision wound medicine. This state-based model reframes advanced wound dressings as tools for biological state engineering and provides a translational framework for the future of chronic wound management. Full article

Bladder cancer is the fifth most common cancer in the United States, causing approximately 17,000 deaths annually. Due to its vast genetic and molecular heterogeneity, presentation, prognosis, and therapeutic response vary greatly between individuals. To improve patient outcomes, there is a need for better drug-screening platforms. The genetic heterogeneity of bladder cancer often leads to chemotherapy resistance or low response rates. Moreover, chemotherapies are often contraindicated in patients with select comorbidities. Organoids offer a better option to replicate the tumor microenvironment than traditional 2D cell cultures, improving drug development and personalized therapy. In this study, we bioprinted gelatin-methacrylol (GelMA)-based organoids containing bladder cancer cell lines of different grades to model muscle-invasive bladder cancer. In the organoids, we observed distinct grade-dependent tumor proliferation and progression dynamics. Treatment with standard-of-care chemotherapies revealed a grade-dependent tumor response consistent with in vivo patient data, highlighting the suitability of these organoids for rapid, reliable drug testing. Lastly, we used the organoids to test LCI139, a novel small-molecule inhibitor of PI3K, CDK4/6, and CDK9 designed for the treatment of epithelial cancers, underscoring the potential of our model to evaluate the efficacy of newly developed drugs. The ability to quickly biofabricate reproducible bladder cancer organoids that are adaptable to different tumor grades represents a novel strategy to create an in vitro platform with strong potential to predict treatment outcomes of bladder cancer patients. Full article

Given the prevalence of chronic wounds and soft tissue defects, which are associated with major complications such as persistent inflammation, poor vascularization, infection risk, and delayed tissue remodeling, there is a need for new materials that can overcome these limitations. Fibrin-based materials have attracted researchers’ attention for their roles in hemostasis and wound healing, as well as their biocompatibility, biodegradability, and ability to mimic the extracellular matrix. Regarding the clinical applicability of fibrin-based materials, they are currently available on the market as fibrin sealants. However, efforts are underway to improve their properties by developing hydrogels, platelet-derived fibrin matrices, and composite scaffolds that enhance mechanical stability, bioactivity, and the controlled release of cells or therapeutic agents. In addition, the number of clinical studies and registered clinical trials reflects interest in the potential applicability of fibrin-based materials in medical applications. However, the available clinical evidence remains limited for many emerging systems, and further validation is required. Although significant limitations remain, including rapid degradation, variable mechanical strength, and the need for standardized manufacturing processes, recent advances in hybrid systems and biofabrication technologies suggest promising future potential for personalized regenerative therapies. Full article

Clostridioides difficile infection (CDI) is a leading healthcare-associated infection worldwide, causing significant morbidity, mortality, healthcare burden, and costs. Clinical manifestations range from mild, self-limiting diarrhea to severe, life-threatening complications such as toxic megacolon and septic shock. Early identification of patients at high risk of severe disease is essential to guide clinical decision-making and optimize therapy. This narrative review summarizes recent epidemiological data, current trends, and known risk factors as clinical context for severity prediction and then examines the utility and limitations of biomarkers that may predict CDI severity, including inflammatory, hematological, fecal, renal, and immune-response biomarkers. While some markers are already used in guideline-based assessment or routine clinical practice (e.g., C-reactive protein, white blood cell count, serum creatinine), they have limited specificity. Other markers emerging from CDI research, including procalcitonin, interleukins, and presepsin, may provide complementary prognostic information. The key challenge is not simply to identify additional biomarkers but to determine which biomarkers are clinically useful, at which stage of CDI progression, and in which patients they add value beyond conventional severity criteria. Validated predictive models integrating combinations of these biomarkers with clinical and microbiological data are needed to support early risk stratification and therapeutic decision-making at the time of diagnosis. Full article

Hypomethylating agents (HMAs) are the cornerstone in the treatment of higher-risk myelodysplastic syndromes (MDSs), particularly for patients who are not candidates for allogeneic hematopoietic cell transplant (allo-HCT). Despite demonstrated efficacy in improving hematologic outcomes, the clinical management of HMA-associated myelosuppression remains a challenge. This review discusses the use of azacitidine and oral decitabine-cedazuridine (DEC-C) for MDS management in the Canadian context, with a focus on optimizing therapy to mitigate myelosuppression and prevent early HMA discontinuation due to toxicity. Close monitoring of complete blood counts is critical to early detection of myelosuppression and management of treatment-related cytopenias. In the real-world setting, specific HMA dose adjustments are used based on patient risk factors for myelosuppression or treatment-related complications. Supportive care strategies, including the use of growth factors and antimicrobials, can complement monitoring and dose modifications for HMA-related myelosuppression management, although their use is variable. This review summarizes current evidence and real-world management approaches for HMA-induced myelosuppression, with the aim of improving outcomes for patients undergoing treatment for MDS. Full article

Background: Diabetic foot ulcers (DFUs) are a major cause of morbidity and lower extremity amputation. Numerous advanced wound therapies with various mechanisms of action have been developed to improve healing outcomes; however, the comparative certainty of evidence supporting these interventions remains unclear. This study evaluates randomized controlled trials (RCTs) of DFU therapies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Methods: A narrative synthesis of RCTs published between January 2016-January 2026 evaluating therapies for DFUs was performed. For studies that reported 12–week healing outcomes, risk of bias was assessed using the Cochrane Risk of Bias 2 tool and certainty of evidence for each therapy subgroup was evaluated using the GRADE framework. Results: A total of 143 RCTs were included with 45 RCTs undergoing GRADE assessment. The proportion of studies demonstrating statistically significant improvements in 12-week healing rates relative to controls varied and was not reflected in the GRADE assessment. Moderate-certainty evidence was assigned to the hyperbaric oxygen therapy subgroup. Low-certainty evidence was assigned to silver dressings, biosynthetic scaffolds, stem cell therapy, and negative pressure wound therapy. Very low-certainty evidence was assigned to topical oxygen, synthetic structural scaffolds, moisture-retaining dressings, local antimicrobial delivery, placental-derived skin substitutes, platelet-rich plasma, acellular dermal matrices, allografts/xenografts, and off-loading devices. No therapy subgroup was assigned high-certainty evidence. Conclusions: The certainty of evidence supporting DFU therapies varies substantially across intervention categories. These findings highlight the need for larger, methodologically rigorous comparative trials to clarify the effectiveness of DFU therapies and guide evidence-based wound care. Full article

Small cell lung cancer (SCLC) has historically been treated as a single, uniformly aggressive disease defined by neuroendocrine differentiation, near-universal loss of TP53 and RB1, and the absence of classical druggable oncogene addictions. Two converging lines of evidence are now reshaping that view. First, transcriptomic profiling has resolved SCLC into molecular subtypes—SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-I (inflamed)—with distinct immune microenvironments, surface-antigen expression patterns, and emerging therapeutic vulnerabilities, although intratumoral heterogeneity and phenotypic plasticity complicate clean subtype assignment. Second, the development of delta-like ligand 3 (DLL3)-directed therapies provides a natural experiment: the same validated surface antigen failed as an antibody–drug conjugate (rovalpituzumab tesirine, three negative randomized trials) yet succeeded as a bispecific T-cell engager (tarlatamab, which received FDA accelerated approval in 2024 and subsequent traditional FDA approval in 2025 following positive confirmatory phase 3 data). In this review, we integrate the current first-line standard of care—chemoimmunotherapy with atezolizumab- or durvalumab-based regimens followed by maintenance intensification with lurbinectedin–atezolizumab (IMforte)—with the molecular framework of subtypes and biomarkers, and we use DLL3 as a case study to propose that delivery modality is an important determinant of therapeutic success in SCLC and should be considered alongside target biology and tumor heterogeneity. Rapid proliferation, antigen heterogeneity, subtype plasticity, and a relatively less immunogenic microenvironment systematically penalize modalities dependent on payload accumulation and cell-cycle progression and reward modalities that recruit catalytic, cell-cycle-independent cytotoxic effectors. The emerging B7-H3 and SEZ6 programs—including ifinatamab deruxtecan and ABBV-706—are the next test of this framework. We discuss implications for biomarker development, trial design, and the operational challenges of subtype-guided precision oncology in a disease where tissue is scarce and biology shifts under therapy. Full article

In this article, we formulated a mathematical model to describe SARS-CoV-2 development in humans, accounting for the dynamics of susceptible and infected epithelial cells, viral particles, ACE2 receptors, cytotoxic T lymphocytes (CTLs), and antibodies. The basic reproduction number and equilibrium points are derived, with stability analysis showing that the disease-free equilibrium is maintained when ${\mathcal{R}}_0<1$, while an endemic equilibrium arises for ${\mathcal{R}}_0>1$. Additionally, Hopf bifurcating periodic solutions are observed under elevated viral replication and infection rates. To capture therapeutic intervention, an impulsive control framework based on antibody-mediated drug administration is introduced. The existence and stability of a disease-free periodic orbit are established through the impulsive reproduction number ${\mathcal{R}}_0^{imp}$, with stability ensured when ${\mathcal{R}}_0^{imp}<1$. The findings from numerical simulations support the analytical outcomes, proving the efficacy of impulsive control in suppressing viral persistence. The current research work offers important knowledge on the interaction between immune system and impulsive control mechanisms, which serves as a basis to develop therapies against SARS-CoV-2. Full article

Background Biological agents such as infliximab [IFX] and adalimumab [ADA] are employed in the treatment of severe Crohn’s disease [CD], especially in cases refractory to conventional therapies. This study assessed the predictive value of simple serum-based markers in terms of early response to anti-tumor necrosis factor [anti-TNF] biologics. Methods:A total of 55 adult patients who had undergone 57 individual courses of either IFX or ADA at the Department of Gastroenterology of the Medical University of Łódź were retrospectively evaluated: 33 males and 22 females, aged 18–70 years. Serum parameters were assessed upon initiation of biological therapy and at the 14th week treatment response assessment juncture. Results: A total of 50 of the 57 (87.7%) assessed courses presented with treatment response upon week 14. Intergroup comparison revealed a statistically significant discrepancy in albumin concentration between the responder and non-responder groups: 38.4 g/L (35–41) vs. 28.4 g/L (26.7–30.1) (p < 0.05). Similar results were observed upon division of the total group in regard to prior biological agent exposure—bionaïves and biopositives. Further receiver operating characteristic [ROC] analysis revealed either strong or excellent discriminatory performance in regard to early response in the total and biopositive groups of mean albumin concentration (AUC: 0.93, p < 0.05; 1.0, p < 0.05), CRP–albumin–lymphocyte [CALLY] (AUC: 0.81, p < 0.05; 0.88, p < 0.05), CRP/albumin ratio (AUC: 0.83, p < 0.05; 0.88, p < 0.05), and mean platelet volume [MPV] and red blood cell distribution width [RDW] in the bionaïve group (AUC: 0.87, p < 0.05) (AUC: 0.88, p < 0.05), respectively. Conclusions: Simple, readily available serum-derived markers appear promising in assessing the likelihood of early anti-TNF response in CD patients. Albumin and albumin-derived parameters especially demonstrated considerable potential in this regard. Full article

Leptomeningeal metastasis (LM) is a severe and increasingly recognized complication of advanced non-small-cell lung cancer (NSCLC), particularly in patients with actionable genomic alterations. Although LM has historically been associated with poor outcomes, molecularly targeted systemic therapies with improved central nervous system (CNS) activity are reshaping its therapeutic landscape. This review summarizes current concepts in the pathogenesis, diagnosis, and risk stratification of LM, focusing on systemic treatment strategies for NSCLC harboring actionable driver alterations. We highlight the rationale and emerging evidence for next-generation tyrosine kinase inhibitors targeting EGFR, ALK, and other oncogenic drivers, and discuss their role as the cornerstone of LM management. Intrathecal chemotherapy, immunotherapy, and radiotherapy are also reviewed within a risk-adapted treatment framework. An individualized approach integrating molecular profiling, neurological status, and disease distribution is essential to optimize outcomes. Prospective studies are needed to refine systemic treatment strategies and establish evidence-based algorithms for this high-risk population. Full article

Background: Vulvar cancer is a rare gynecologic malignancy comprising 1–3% of all cases. No established standard exists for advanced disease, and treatment is often extrapolated from cervical cancer. Although HER2 overexpression is well defined in breast cancer and recognized across multiple solid tumors, its prevalence and significance in vulvar cancer remain unclear. Recent activity of HER2-directed antibody–drug conjugate Trastuzumab deruxtecan in solid tumors with an objective response rate (ORR) of around 37% highlights the need to better characterize HER2 expression in vulvar cancer. Methods: We performed a systematic search of Medline, Embase, and the Cochrane Library up to May 2025. Eligible studies included ≥10 vulvar cancer cases, predominantly vulvar squamous cell carcinoma (VSCC), excluding vulvar Paget’s disease, with available HER2 assessment by immunohistochemistry and/or in situ hybridization. Two reviewers independently screened the studies. A random-effects model was used to estimate pooled HER2 positivity. Heterogeneity was assessed using Cochrane’s Q and Higgins’s I². Results: Of 506 records, nine retrospective studies including 769 patients with predominantly squamous cell carcinoma histology (98%, n = 752) met inclusion criteria. A total of 50 HER2-positive cases were observed. Median age at diagnosis of vulvar cancer was between 55 and 78, reported in three studies. Molecular profiling was limited. Among three studies with known TP53 status (n = 206), 59% of the tumors expressed TP53 (n = 122), and among two studies with known human papilloma virus (HPV) status (n = 128), 21% (n = 27) were HPV-positive. Six studies used American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines in breast cancer. Pooled HER2-positive expression across ASCO/CAP-based studies was 2% (95% CI: 1%, 3%) and for non-ASCO/CAP-based studies was 21% (95% CI: 2%, 52%). Exploratory pooled estimated proportion of HER2-positive expression was 5% (95% CI: 0.4%, 14%). There was substantial heterogeneity across studies, I² value of 91.1% [95% CI: 85.4%; 94.6%], and no significant publication bias was observed (Egger’s test p = 0.364). This study could not assess prognostic value of HER2 overexpression in VSCC. Conclusions: HER2 positivity in VSCC appears uncommon but it remains to be fully explored. Standardized assessment using contemporary ASCO/CAP breast, endometrial-specific and/or gastric criteria are needed to clarify the prevalence of HER2-positive versus HER2-low/ultralow disease to inform potential use of HER2-targeted therapy. Full article

Chronic heart failure [CHF] is a progressive clinical syndrome characterized by structural and functional impairment of the myocardium, in which energy metabolic remodeling plays a central role. Increasing evidence suggests that metabolic disturbances in CHF are not only a consequence of reduced cardiac output but also active regulators of epigenetic remodeling, thereby contributing to disease progression. Key metabolites, including α-ketoglutarate, acetyl-CoA, NAD⁺, S-adenosylmethionine, succinate, and 2-hydroxyglutarate, influence the activity of DNA methyltransferases, histone-modifying enzymes, and other chromatin regulators, thereby linking metabolic status to transcriptional control. Through these mechanisms, metabolic abnormalities promote persistent activation of pathological gene programs associated with cardiomyocyte hypertrophy, fibrosis, inflammation, apoptosis, and mitochondrial dysfunction, forming a self-reinforcing metabolic–epigenetic feedback loop in CHF. Although current guideline-directed medical therapies improve symptoms and clinical outcomes, they do not directly target this metabolic–epigenetic axis. Traditional Chinese medicine (TCM), including bioactive compounds, herbal formulas, patent medicines, and injections, has demonstrated potential in preclinical studies to modulate myocardial energy metabolism, improve mitochondrial function, and influence epigenetic regulators such as SIRT1, AMPK, and TET/JmjC-dependent pathways. However, most available evidence is derived from experimental models, and causal relationships between metabolite regulation, epigenetic remodeling, and cardiac functional improvement remain insufficiently validated. This review summarizes current knowledge on metabolite-driven epigenetic regulation in CHF and evaluates emerging evidence on the role of TCM in modulating this network. We also critically discuss key limitations, including reliance on non-clinical models, incomplete pharmacokinetic understanding, and insufficient causal validation. Finally, we propose future directions based on multi-omics integration, single-cell and spatial technologies, and systems biology approaches to facilitate mechanistic clarification and translational development of metabolism-targeted strategies for CHF. Full article

Pituitary adenoma is a clinically important brain tumor whose progression and therapeutic outcomes are influenced by intricate interactions between tumor development and the host immune response. Globally, pituitary adenomas account for approximately 15% of all intracranial tumors. This study aims to investigate clinical MRI data obtained from a patient who recovered from a pituitary adenoma. The collected data provide measurements of tumor volume (mm) at several time points throughout the treatment period. The patient received vaccine-based therapy accompanied by regular clinical assessments, and achieved recovery after nearly twenty-two months. Motivated by the clinical observations and the underlying treatment mechanism, a mathematical model describing tumor–immune–vaccine interactions is developed. The proposed ordinary differential equation (ODE) framework incorporates tumor cells, immune cells, and vaccine components to characterize the temporal evolution of tumor volume during treatment. Fundamental dynamical properties of the model, including positivity, boundedness, existence of solutions, and equilibrium stability, are established through analytical techniques. In addition, numerical simulations are performed using the fourth-order Runge–Kutta (RK4) method and validated against the available clinical measurements. The numerical results exhibit close agreement between the observed and simulated data, yielding a minimal root mean square error (RMSE). Furthermore, sensitivity analysis highlights the significant role of immune- and vaccine-related parameters in regulating tumor suppression. The findings suggest that a relatively simple mechanistic framework can effectively capture the reduction in pituitary adenoma under vaccine-based therapy. Full article

Background: Cardiac involvement in cryoglobulinemia (CG) is rare but potentially fatal, and its clinical spectrum remains poorly characterized. Methods: This retrospective study enrolled 11 patients with cardiac involvement among 885 patients with CG at Peking Union Medical College Hospital between January 2015 and March 2026. We analyzed its clinical characteristics, radiological features and management. Results: Among 885 CG patients, 11 (1.2%; 4 type I, 7 type II) had cardiac involvement. Cardiac symptoms included dyspnea (n = 6), chest tightness (n = 4), edema (n = 3), and orthopnea (n = 1). All patients had elevated N-terminal pro-B-type natriuretic peptide (median 29,799 pg/mL). Echocardiography, performed in all 11 patients, revealed left heart enlargement (n = 9), reduced left ventricular ejection fraction (n = 7), myocardial disease (n = 6), pericardial effusion (n = 4), and pulmonary hypertension (n = 3). Cardiac magnetic resonance in 5 of 11 patients showed non-ischemic late gadolinium enhancement in two cases. For first-line therapy, 6 of 11 patients received rituximab-based regimens, 3 of 11 received bortezomib-based regimens, and 1 of 11 received antiviral therapy with corticosteroids; 1 patient declined treatment. All 10 treated patients achieved initial cardiac improvement, with 5 relapsing and 2 dying during a median follow-up of 57 months (range 9–130 months). The estimated 4-year overall and progression-free survival rates were 77.9% (95% CI: 0.546–1.000) and 50.0% (95% CI: 0.269–0.929), respectively. Conclusions: Cardiac involvement in CG is rare and associated with diverse structural and functional abnormalities. Cardiac involvement should be considered in CG patients presenting with unexplained cardiac manifestations after excluding alternative causes. B-cell-targeted therapy induced an initial response, but relapse is common. Early intervention is essential given the substantial relapse burden and potential for severe morbidity. Full article