Search Results (23,158)

Although oxidants are known to be deleterious for cellular homeostasis by oxidizing macromolecules like DNA or proteins, they are also involved in signaling processes essential for cellular proliferation and survival. Here, we investigated the role of superoxide anion (O₂⁻) and hydrogen peroxide (H₂O₂) homeostasis for the proliferation and survival of classical Hodgkin’s lymphoma (cHL) cell lines. Inhibition of NADPH oxidases (NOX) using apocynin (Apo) and diphenylene iodonium (DPI), or treatment with the antioxidant butylated hydroxyanisole (BHA), significantly reduced proliferation and induced apoptosis in HL cell lines. These effects correlated with transcriptomic alterations involving redox regulation, immune signaling, and cell cycle control. Interestingly, treatment with DPI or antioxidants attenuated constitutive Signal Transducer and Activator of Transcription (STAT) activity, as seen by decreased phospho-STAT6 levels and reduced STAT6 DNA binding. This suggests a sensitivity of the Janus kinase (JAK)/STAT pathway in cHL cell lines to O₂⁻ and H₂O₂ depletion. Functional assays confirmed this by demonstrating partial restoration of proliferation or apoptosis in L428 cells that expressed constitutively active STAT6 or were transfected with small interfering RNAs (siRNAs) that targeted STAT regulators. These findings highlight that oxidants, particularly H₂O₂, act as both general oxidative stressors and essential modulators of oncogenic signaling pathways. Specifically, maintenance of oxidant homeostasis is critical for sustaining JAK/STAT-mediated growth and survival programs in cHL cells. Targeting redox homeostasis might offer a promising therapeutic strategy to impair JAK/STAT-driven proliferation and survival in cHL. Full article

Objective: The role of adjuvant chemoradiotherapy (CRT) following curative gastrectomy remains controversial, especially in the context of D2 dissection. This research evaluated survival indicators through an analysis of previous observational studies and it evaluated treatment outcomes between patients who underwent CRT and those who received CT as their sole therapy. Methods: The researchers performed a non-randomized retrospective cohort study which analyzed 206 patients who underwent R0–R1 resection for gastric adenocarcinoma and received either adjuvant CRT (n = 107) or CT alone (n = 99). A Kaplan–Meier analysis together with Cox regression methods were used to evaluate survival outcomes of patients. Inverse probability of treatment weighting (IPTW) was applied to adjust for baseline differences between groups at the beginning of the study. The median follow-up was 52.0 months. Results: The baseline characteristics differed markedly between groups, with CRT patients showing higher rates of T4 tumors (34.6% vs. 22.2%), N3 disease (47.7% vs. 26.3%), vascular invasion (72.9% vs. 50.5%), and R1 resection (10.3% vs. 1.0%). Unadjusted survival favored CT alone (median DFS 81.7 vs. 103.9 months; median OS 86.2 months vs. not reached). These differences lost significance after IPTW adjustment (DFS: HR 1.18, p = 0.428; OS: HR 1.24, p = 0.336). T3–T4 stage, N2–N3 nodal status, vascular invasion, and positive margins emerged as independent prognostic factors. Subgroup analyses revealed no treatment interactions (all p > 0.05). Conclusions: The research used a retrospective study design which showed substantial differences between treatment groups at the beginning of the study. The survival results that showed better outcomes for CT alone became attenuated after the researchers applied propensity score adjustment to adjust for confounding from treatment selection. The study established that advanced T–N stage, vascular invasion, and positive margins were identified as independent prognostic factors. The research results are hypothesis-generating and require randomized controlled trials to establish the exact difference in effectiveness between different treatments. Full article

Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma (DMG) and low-grade glioma (LGG). The most common mutations that can be targeted for treatment are the KIAA1549-BRAF fusion; BRAF V600E mutation; EGFR, FGFR, PDGFR, NTRK, and CDK4/6 mutations; other MAP kinase pathway alterations; and PI3K/AKT/mTOR activation. The bithalamic high-grade glioma especially demonstrates EGFR mutations which makes it a distinct entity. Targeted therapy, including tyrosine kinas inhibitors has been shown to improve the overall survival compared to conventional therapy in certain situations. Demonstrating the mutation carried by the tumor is very critical in this regard. The purpose of this article is to focus on the treatment of thalamic glioma in pediatric patients in light of molecular information. Full article

Background: Site-specific long-term outcomes, including neurofibromatosis type 1 (NF1), Ki-67 prognostic value, and very late recurrences of small bowel gastrointestinal stromal tumors (GISTs), remain inadequately defined. Methods: This retrospective cohort study investigated the clinical characteristics, diagnostic challenges, and long-term outcomes of patients with small bowel GISTs. This retrospective, single-center study (2008–2024) analyzed 27 consecutive patients (average age: 62.2 years) with jejunal/ileal GISTs. Clinicopathologic features, diagnostic yield of balloon-assisted enteroscopy (BAE), treatments, and outcomes were evaluated during a 10.2-year median follow-up period. Recurrence-free survival (RFS) and overall survival (OS) were estimated by Kaplan–Meier with log-rank testing. Ki-67 was assessed using MIB-1; a prespecified 5% cut-off was chosen based on prior evidence. Results: Tumor (mean size, 62.4 mm) sites included the jejunum (74.1%) and ileum (25.9%). NF1 was present in 3/27 (11.1%) patients, all with multiple jejunal tumors. Among the 14 patients who underwent BAE, biopsy was attempted in six and yielded a histological diagnosis in one (16.7%). Six patients had recurrence; two died from disease >10 years postoperatively. Five-year OS and RFS were 91.3% and 68.7%, respectively. Adverse RFS was associated with ileal location (p = 0.03), size ≥ 10 cm (p < 0.001), mitoses > 5/50 high-power fields (p = 0.002), and Ki-67 ≥ 5% (p < 0.001). One patient labeled low risk by conventional models had recurrence with Ki-67 = 10%. Another classified as low risk by conventional models experienced recurrence >10 years after surgery, with a Ki-67 index of 10%. Conclusions: Extended, risk-adapted surveillance may be reasonable for small-bowel GISTs, and it may be beneficial to incorporate Ki-67 (≥5%) into site-based risk stratification. These observations remain hypothesis-generating and require validation in larger, multicenter cohorts and prospective studies. Full article

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy caused by persistent infection with human T-cell leukemia virus type 1 (HTLV-1). ATLL remains difficult to treat despite intensive chemotherapy, antiviral therapy, and hematopoietic stem cell transplantation. The limited durability of current treatment strategies highlights the need for mechanism-based therapeutic approaches. Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates transcription, RNA splicing, DNA damage responses, and immune signaling through symmetric dimethylation of histone and non-histone substrates. PRMT5 is frequently overexpressed across hematologic and solid tumors. Preclinical studies indicate that PRMT5 expression is elevated during HTLV-1-mediated T-cell transformation and that pharmacologic inhibition of PRMT5 selectively impairs the survival and transformation of infected T cells in vitro and in vivo. In this review, we highlight the current understanding of PRMT5 biology in cancer, summarize preclinical studies supporting PRMT5 as a therapeutic target in ATLL, and discuss key challenges to future clinical translation. We also discuss emerging approaches such as rational combination therapies and tumor-selective PRMT5 inhibitors as potential paths toward treatment for ATLL. Full article

This systematic review investigates the impact of chronic stress on treatment outcomes among cancer patients with divergent survival rates, focusing on breast, prostate, pancreatic, and ovarian cancers. The analysis explores how chronic stress influences molecular pathways and tumor progression while comparing cancers with five-year survival rates above and below 50%. A comprehensive literature search was conducted in PubMed and Scopus for studies published between 2014 and 2025 using combinations of keywords related to “chronic stress,” “psychological stress,” “psychotherapy,” and selected cancer types. All studies met the inclusion criteria according to the PRISMA 2020 guidelines. Evidence suggests that chronic stress is associated with the activation of neuroendocrine and immune mechanisms, including β-adrenergic and glucocorticoid signaling. These multifactorial processes are associated with disease progression and survival, particularly in pancreatic and ovarian cancers; however, these links remain primarily associative rather than causative. Conversely, psychotherapeutic interventions alleviate stress-related biological responses, improve quality of life, and may indirectly enhance therapeutic efficacy. By structuring the evidence around cancers with higher versus lower five-year survival, our review provides a survival informed synthesis of cancer type specific stress biology and stress-mitigating interventions, highlighting potentially targetable pathways and clear evidence gaps for future trials. The findings underscore the need to integrate psychological care into oncological practice to improve overall outcomes. Full article

Invasive Candida infections in the neonatal intensive care unit (NICU) are associated with significant morbidity and mortality, particularly among extremely preterm neonates. Early treatment with antifungals is critical to improve survival rates and avoid long-term adverse outcomes. Prevention with antifungal prophylaxis in high-risk neonates has been shown to reduce the prevalence of invasive Candida infections effectively. However, the irrational and/or inappropriate use of antifungals has been documented. This narrative review aims to provide an overview of the rationales for the inappropriate use of antifungals in the NICU, the consequences that ensue, and the promising strategy of antifungal stewardship programs to optimize antifungal use. The nonspecific clinical presentation of systemic Candida infections and the lack of rapid, accurate diagnostic techniques for Candida identification and specification in most settings lead to a high rate of empirical treatment in neonates without a proven infection. Moreover, evidence on the optimal dosing of antifungal agents and the treatment duration in the neonatal population is lacking, which may result in excessive or subtherapeutic drug exposure. Antifungal misuse is associated with microbiological consequences, including the emergence of antifungal-resistant Candida strains, and clinical consequences, such as drug toxicities and alterations in the intestinal mycobiome. It is therefore imperative to optimize antifungal use in the NICU. The implementation of antifungal stewardship programs, which, through a multidisciplinary approach, aim to improve diagnosis and guide clinicians on antifungal selection, dosing, and duration for both prevention and treatment according to the local epidemiology, represents a promising strategy for antifungal optimization in the NICU. Full article

Background/objectives: Improvements in esophageal adenocarcinoma (EAC) treatment have reduced mortality. While chemoradiation before surgery was previously a standard of care, updated guidelines recommend peri-operative chemotherapy without chemoradiation. Continued investigation into optimal non-operative treatment paradigms for patients who defer surgery or are not candidates for surgery and certain chemotherapy regimens is needed. The impact of induction chemotherapy prior to chemoradiation on survival and surgical outcomes remains unclear. This study assessed survival and surgical outcomes in a real-world cohort of EAC patients receiving induction chemotherapy before chemoradiation. Methods: This single-institution, IRB-approved, retrospective cohort study included patients with newly diagnosed stage II-IVb (oligometastatic for IVb) EAC who received definitive chemoradiation (radiation ≥ 40 Gy and two cycles of chemotherapy) +/− esophagectomy from 2007 to 2022. Patients receiving induction chemotherapy were compared to those who did not. Endpoints included survival and surgical outcomes. Results: A total of 141 EAC patients received definitive chemoradiation; 83 received induction chemotherapy before chemoradiation. Patients receiving induction chemotherapy were younger (p < 0.01) with slightly lower performance status (p = 0.27) and presented at a more advanced stage (p < 0.001). Median OS was 3.5 years in the induction chemotherapy group compared to 2.2 years (p = 0.10). There was no difference in pathologic complete response (p = 0.81), esophagectomy frequency (p = 0.87), or surgical downstaging between treatment groups (p = 0.84). Conclusions: In this real-world, single-institutional patient cohort investigating induction chemotherapy prior to chemoradiation in EAC, patients receiving induction chemotherapy did well but did not have a statistically significant improvement in survival outcomes or surgical outcomes. This study showed that significant numbers of real-world patients may not receive esophagectomy. Thus, prospective, randomized clinical trials are warranted to better delineate the efficacy and selection of patients for induction chemotherapy when non-operative approaches are favored. Full article

Background: Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is associated with poor prognosis and recurrence despite standard of care and newer immunotherapies. This warrants exploration of synergistic approaches such as combination immunotherapy for improved tumor control. Methods: We initiated a systematic review of articles from 2015–2025 in PubMed, Embase, Scopus, Cochrane, and Web of Science if they assessed immunotherapy for GBM. Results: We included 49 studies (n = 3002 patients) with no significant demographic differences across publications. Combination immunotherapy regimens demonstrated higher pooled ORRs in limited comparative analyses, though findings were driven by a small number of studies. Single-arm analysis for overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs), and ORR showed no significant differences among the groups. However, treatment–control arm analysis showed pooled ORs of 9.51 for combination immunotherapies and 0.44 in the control group. Conclusions: Combining immunotherapeutics across mechanisms may potentiate immune response effectiveness against GBM. Full article

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC—an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities. Full article

S. suis is a prominent zoonotic pathogen responsible for diseases such as arthritis in piglets, swine septicemia, and meningitis. The emergence of multi-drug resistance (MDR) underscores the urgent need for the development of novel antibacterial strategies. In this context, a systematic evaluation of the antibacterial potential of the bacteriophage lytic enzyme Ply900 was conducted in this study, along with an analysis of its domain functions and an in vivo study of its therapeutic dynamics. Ply900 exhibits potent in vitro lytic activity against multiple bacteria, including Streptococcus suis, Streptococcus agalactiae, and Staphylococcus aureus. Notably, it possesses broad biochemical stability, with tolerance to diverse environmental conditions. In a mouse model of S. suis serotype 2 SC19 infection, both the direct Ply900 treatment group and the triple therapy group achieved effective eradication of S. suis, with markedly improved survival rates. The remaining bacteria remained susceptible to Ply900, with no evidence of induced resistance development. Mechanistic analysis revealed that the SH3B domain of Ply900 enhances targeted cleavage efficiency by binding synergistically to peptidoglycan with the CHAP domain, with CYS-34, HIS-59, and ASP-28 serving as key amino acid sites for Ply900’s cleavage activity. Collectively, these findings lay the foundation for the potential dual applications of the lysin Ply900, both in the clinical treatment of S. suis infections and in the prevention and control of these pathogenic bacteria in livestock farming. Full article

While research on high-incidence tumors such as breast, prostate, and lung cancer has led to significant increases in patient survival in recent years, this has not been the case for low-incidence tumors such as high-grade gliomas, the most common and lethal brain tumors, for which the last significant therapeutic advance dates back to 2005. The high infiltration capacity of these tumors into normal brain tissue essential for both vegetative and relational life, the tumor microenvironment, with poor immunological activity, the multiple resistance mechanisms, and the unattractiveness of research investments due to the limited number of patients have made, and continue to make, the path to achieving significant improvements in the survival of patients with high-grade gliomas long and arduous. The objective of this article is to update the slow but continuous radiotherapeutic progress for adult and pediatric high-grade gliomas to the second half of 2023. We analyzed the progress of preclinical and clinical research on both adult and pediatric high-grade gliomas, with a particular focus on improvements in radiotherapy. Interactions between non-radiant new therapies and radiotherapy were also covered. A literature search was conducted in PubMed using the terms (“glioma* and radio*”) and the time limit of 1 July 2023 to 31 December 2023. The inclusion and exclusion criteria for the review were relevance to advances in radiotherapy for high-grade gliomas in adults and children. Treating patients with advanced disease progression only, using “historical” data as controls, as well as repurposing drugs developed for purposes completely different from their intended use, were the major (but not the only) methods to assess risk of bias in the included studies. The effect measures used in the synthesis or presentation of the results were tabulated and/or displayed in figures. A total of 100 relevant references were reviewed. Advances in preclinical studies and in clinical radiotherapy treatment planning, innovative fractionation, use of radioisotopes/radiopharmaceuticals, radiosensitization procedures, and radiation-induced damage were focused on. While this analysis may be limited by the relatively short publication period, high-grade glioma research remains impacted, especially at the clinical level, by potential issues with trial design, such as treating patients with advanced disease progression, using “historical” data as controls, and repurposing drugs developed for completely different purposes than intended. Addressing these aspects of high-grade glioma research could improve its efficacy, which often remains low despite the associated costs. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Background: Acinetobacter baumannii (AB), particularly carbapenem-resistant strains (CRAB), is a major cause of difficult-to-treat infections associated with substantial mortality. Contemporary data from Central and Eastern Europe remain scarce. We aimed to characterize the epidemiology, clinical features, and survival of patients with AB bloodstream infection in a multicenter Polish cohort. Methods: We conducted a retrospective multicenter study including consecutive adults with microbiologically confirmed AB bloodstream infection. Clinical and demographic data, comorbidities, infection origin, and antimicrobial treatments were collected. Outcomes included all-cause in-hospital mortality and infection-attributed mortality. Survival was assessed using Kaplan–Meier curves and log-rank tests, while factors associated with death were examined with univariable and multivariable Cox regression. Results: Among 245 patients with CRAB bloodstream infection, overall mortality was 69.4%, and infection-attributed mortality reached 51.8%. Most infections (75.1%) were hospital-acquired. In univariable analyses, male sex (HR = 0.66; p = 0.008) and colistin-based therapy (HR = 0.71; p = 0.037) were associated with improved survival. Conversely, hospital-acquired infection (HR = 0.43; p < 0.001) and acute kidney injury (HR = 1.40; p = 0.038) were linked to higher mortality. In the multivariable model, male sex remained protective (HR = 0.61; p = 0.006), while hospital-acquired infection (HR = 0.35; p < 0.001) and COVID-19 (HR = 1.64; p = 0.049) independently predicted death. After adjustment, no other comorbidities or antimicrobial regimens showed significant associations. Conclusions: In this multicenter cohort of patients with CRAB bloodstream infection, mortality remained extremely high. Hospital-acquired infection, acute kidney injury, and COVID-19 were strong independent predictors of poor outcomes, whereas male sex was associated with better survival. Although colistin-containing therapy appeared beneficial in univariable analysis, this effect did not persist after adjustment, underscoring potential confounding. These findings highlight the urgent need for early recognition, optimized antimicrobial strategies, and prevention of healthcare-associated spread to improve outcomes in CRAB bacteremia. Full article

Background. Acute radiation injury to the small-intestinal mucosa and the hematopoietic system is a key determinant of early mortality after high-dose total-body irradiation. ε-Aminocaproic acid (EACA), a lysine analogue with antifibrinolytic properties, has been proposed as a potential radioprotective agent, but its effects on intestinal and hematologic injury remain insufficiently characterized. Methods. In this experimental study, 240 male Wistar rats were subjected to single-dose total-body γ-irradiation at 10.6 Gy and randomized into six groups: two non-irradiated controls (CG-1, CG-2), an irradiated control without treatment (CG-3), and three experimental groups receiving EACA (EG-1: 3 h before irradiation; EG-2: 3 h after irradiation; EG-3: both 3 h before and 3 h after irradiation). Pain behavior was assessed using the Rat Grimace Scale. Intestinal damage was evaluated by a modified Radiation Injury Intestinal Mucosal Damage Score (RIIMS_sum), villus and crypt morphometry, and qualitative histology of the ileum. Hemoglobin, leukocytes, and platelets were measured serially, and 30-day survival was analyzed using Kaplan–Meier curves with log-rank tests. Results. Across all EACA regimens, the odds of being in a higher Rat Grimace Scale pain category were reduced compared with CG-3, with the strongest effect in EG-3 (OR 0.42; 95% CI 0.31–0.58). At 72 h after irradiation, the cumulative RIIMS score was lower in EACA-treated groups by approximately 17–36% versus CG-3, with the lowest injury in EG-3 (18.5 vs. 29.0 points). EACA attenuated shortening and blunting of villi, preserved crypt architecture, and mitigated anemia, leukopenia, and thrombocytopenia. Thirty-day survival was 20% in CG-3 and 60%, 65%, and 80% in EG-1, EG-2, and EG-3, respectively (all p < 0.05 vs. CG-3). Conclusions. ε-Aminocaproic acid exerts a pronounced, timing-dependent radioprotective effect in a rat model of acute total-body γ-irradiation, concurrently reducing the severity of radiation enteritis, hematologic toxicity, and early mortality. These findings support further investigation of EACA as a candidate adjunct in the prevention of acute radiation injury. Full article