Search Results (33,372)

Triple-negative breast cancer (TNBC) accounts for about 10–15% of all breast cancers and is an aggressive disease with a poor prognosis. There is currently no standard treatment regimen for TNBC patients; thus, chemotherapy remains the main treatment. Anthracycline- and taxane-based regimens are the most widely used in a clinical setting, either alone or in combination with other chemotherapeutic agents, including poly (ADP-ribose) polymerase (PARP) inhibitors and platinum drugs. Platinum drugs have been used particularly in patients with BRCA1-mutated TNBC. Preclinical and clinical trials revealed that the response to PARP inhibition was directly correlated to the sensitivity to platinum chemotherapies. Inhibition of PARP enzymes has been shown to specifically target BRCA1 dysfunctional cells. Therefore, targeting breast cancer cells that possess genetic alterations that are absent in normal cells could be attained by the exploitation of synthetic lethality for the discovery of other candidate metals, i.e., ruthenium-derived compounds, as next-generation drugs for the treatment of TNBC. This prospective approach provides new insight into alternative treatments for breast cancers with BRCA1-associated TNBC. Full article

The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a crucial role in regulating immune homeostasis, inflammatory responses, and intestinal barrier function. Indole compounds and their derivatives are ligands of AHR, which can activate the AHR signal transduction pathway and show significant regulatory potential in various inflammatory and immune diseases. Cystic fibrosis (CF) is a life-threatening autosomal recessive genetic disorder. Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction affects multiple systems throughout the body. The core of its pathological process is chronic infection, abnormal inflammation, and tissue damage caused by mucus accumulation. Exploring alternative or adjunctive therapeutic strategies targeting pathological pathways downstream of CFTR is of significant importance. The aim of the present study is to explore the multiple beneficial effects that indole compounds may exert in regulating pulmonary infection and inflammation, repairing intestinal barrier function, and regulating immune homeostasis in CF patients by activating the AHR signaling pathway. Additionally, this study discusses the risks and challenges associated with developing indole compounds as CF drugs, offering a novel research approach distinct from traditional CFTR modulators for creating new CF therapeutics. Full article

Breast cancer affects women at an increasingly younger age, with genetic predispositions and other factors contributing to its second-highest cancer mortality rate. The diversity of pharmacological treatment stems from its heterogeneity, which favors a more precise approach to each subtype. Despite the extensive advances in medicine in recent decades, the problem of treating cancer patients remains significant. The problem with modern therapeutic methods is low effectiveness, emerging side effects, difficulty in eliminating all cancer cells, and the quite common use of monotherapy and the associated drug resistance, which may lead to disease progression. The aim of this review is to present the latest therapeutic strategies (combination therapies) used in the treatment of breast cancer. PubMed databases and clinical data from ClinicalTrials.gov were used for this purpose. The review included characteristics of the latest clinical trials from the last year (2024–2025), which present currently recruiting studies of breast cancer treatment with immunotherapy. The review also presented characteristics of clinical trials from the last 5 years (2020–2025) using nanoparticles as an adjunct to breast cancer treatment. Articles published between 2016 and August 2025 (excluding articles that describe the first use of a given drug) were included in the review. The review analyzed drugs targeting molecular targets, including intracellular pathways responsible for cell cycle regulation, as well as new directions such as nanotechnology in treatment breast cancer. Full article

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual variability in drug response and safety remains a major challenge, particularly in elderly patients with comorbidities and polypharmacy. Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to variability in apixaban exposure and bleeding risk. This study aimed to evaluate the association of polymorphisms in ABCB1, CYP3A4, and CYP3A5 with steady-state plasma concentrations of apixaban (Cssmin) and hemorrhagic complications in elderly patients with NVAF. Methods: This cross-sectional study included 197 patients (mean age 83 ± 8 years; 67% women) with NVAF treated with apixaban (5 mg twice daily). Genotyping of ABCB1 (rs1045642, rs2032582, rs1128503), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) was performed using allele-specific real-time PCR. Cssmin of apixaban was determined by high-performance liquid chromatography coupled with tandem mass spectrometry. Associations with bleeding events were evaluated. Results: Bleeding events were recorded in 40 patients (20.3%). An association signal was observed for ABCB1 rs1045642, where carriers of the CC genotype had a higher risk of bleeding compared with alternative alleles (OR = 2.805; 95% CI: 1.326–5.935; p = 0.006). After correction for multiple testing, the association remained significant only under the log-additive model (OR = 1.93 per C allele; 95% CI: 1.17–3.20; q = 0.0275; p_adj = 0.044), while recessive and codominant effects did not withstand Bonferroni adjustment. No significant associations were observed for rs2032582, rs1128503, CYP3A4*22, or CYP3A5*3. None of the studied polymorphisms, including rs1045642, significantly affected Cssmin. Concomitant therapy, particularly with antiarrhythmic drugs and statins (rosuvastatin), also increased bleeding risk. Conclusions: The findings highlight the potential contribution of ABCB1 rs1045642 and specific drug–drug interactions to the risk of hemorrhagic complications in elderly NVAF patients receiving apixaban. Full article

Intestinal bacterial dysbiosis develops in a number of immune-mediated disorders. Fecal microbiota transfer (FMT) is considered a potentially efficient tool for restoration of the patient’s gut microbiota. The aim of our study was to trace the time course of dominant bacterial populations and some Enterobacteria phages in patients with GVHD and Crohn’s disease after FMT procedure. Patients and methods: We observed 12 patients with intestinal graft-versus-host disease (GVHD), and 15 persons with Crohn’s disease after massive anti-infectious treatment. FMT was performed by a standard protocol using oral capsules administered for 2 days. Fecal bacteriome was assessed by 16S rRNA sequencing. Viral sequences were identified by NGS with a customized primer set. Plasma citrulline levels were measured in order to assess enterocyte damage in the patients. Results: Complete clinical response to FMT was observed in 5 of 12 GVHD patients and 10 of 15 Crohn’s disease cases. Before FMT, most anaerobic Bacillota were exhausted in both Crohn’s disease patients and GVHD. Following FMT, Akkermansia ratios tended to decrease within 30 days in Crohn’s disease, along with higher Faecalibacteria, Romboutsia, and Dialister ratios than in GVHD, thus suggesting lesser damage to anaerobic microbiota in Crohn’s disease. Increased contents of facultative anaerobes (Enterococcus and E.coli) was detected in GVHD patients after FMT. Fecal virome changes in Crohn’s disease after FMT included early transient decrease in Caudoviricetes with a rise in Lederbergvirus and Eganvirus ratios at later terms. In GVHD patients, reverse correlations were revealed between E.coli and E.coli-hosted Eganvirus species. Intestinal damage assessed by low plasma citrulline levels was associated with fecal Klebsiella expansion, being more pronounced in GVHD than in Crohn’s disease. Clinical response to FMT in GVHD patients correlated with increased plasma citrulline and lower Eganvirus abundance. Future studies will concern specific relations between fecal bacteriome and virome reconstitution following FMT in gut GVHD and other immune-mediated intestinal disorders. Full article

Spatially fractionated radiotherapy (SFRT) is emerging as a powerful tool in cancer therapy for patients who are ineligible for treatment with clinically established irradiation techniques. Microbeam radiotherapy (MRT) is characterized by spatial dose fractionation in the micrometre range. This presents challenges in both treatment planning and dosimetry. While a dosimetry system with a spatial resolution of 10 µm and an option for real-time readout already exists, this system can only record dose in a very small volume. Thus, we are exploring dosimetry in an N-isopropylacrylamide (NIPAM) gel as an option for 3D dose visualization and, potentially, also three-dimensional dosimetry in larger volumes. In the current study, we have recorded the geometric patterns of single- and multiport irradiation with microbeam arrays in NIPAM gel. Data for 3D dose distribution was acquired in a 7T small animal MRI scanner. We found that the resolution of the gel is well suited for a detailed 3D visualization of microbeam patterns even in complex multiport geometries, similar to that of radiochromic film, which is well established for recording 2D dose distribution in MRT. The results suggest that a dose–response calibration is required for reliable quantitative dosimetry. Full article

YKL-40 is a glycoprotein that may be present at elevated levels in many cancers and neurodegenerative diseases. It has been investigated in numerous studies as a potential biomarker for several conditions, including Alzheimer’s Disease (AD). In this study, a biosensor with Surface Plasmon Resonance imaging (SPRi) detection, sensitive to YKL-40, was constructed for the detection of this analyte in the blood plasma of AD patients. Extensive validation of the biosensor was performed. This included the determination of analytical parameters such as the biosensor’s response characteristics, detection and quantification limits, precision, accuracy, repeatability, selectivity, stability, and performance in natural samples. Validation parameters were primarily tested using standard solutions, while natural samples were employed to evaluate repeatability, stability, and assay accuracy in three groups of samples from different patients. A YKL-40-specific antibody was used as the receptor layer, immobilized on a gold plate using the EDC/NHS protocol on thiol 11-MUA. The biosensor exhibited a wide operating range (1–200 ng/mL), a low detection limit (LOD) of 2 pg/mL, and a quantification limit (LOQ) of 7 pg/mL. High precision and accuracy were confirmed by the calculated standard deviations (SD) and coefficients of variation (CV), which ranged from 0.0009 to 7.02 ng/mL and from 0.12% to 9.24%, respectively. The sensor also demonstrated good repeatability (CV = 4.995%) and was capable of detecting the analyte of interest in complex biological matrices. Its applicability was confirmed in a study using plasma from AD patients and two selected control groups: plasma from smokers and patients with prostatitis. This allowed the assessment of YKL-40 levels across different groups. The results were consistent with literature values, and statistical analysis confirmed the significance of concentration differences between groups. Furthermore, ROC curve analysis confirmed the diagnostic usefulness of the constructed YKL-40 test in the context of Alzheimer’s disease. Full article

Pediatric-type diffuse high-grade gliomas (pHGGs) tend to have a dismal prognosis. Some of these gliomas feature alterations in genes such as ROS1, ALK, MET, and NTRK1–3. Despite development of targeted agents, the therapeutic application of these agents in pHGGs is still unclear. The aim of this retrospective case series is to report the outcome of two patients with pHGGs who were treated at Arkansas Children’s Hospital with targeted agents (Cabozantinib for a MET fusion in patient 1 and Lorlatinib for an ALK fusion in patient 2) with an initial, objective response followed by treatment resistance. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. In both cases, relapse occurred while on targeted inhibition. Recurrent tumor sequencing for patient 2 revealed a MET copy gain suggesting a mechanism of resistance in this patient. Pediatric high-grade gliomas with targetable alterations can show objective responses to pathway inhibition. Relapse after initial response may warrant additional surgical samples to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and earlier integration of these agents may be beneficial. Full article

Antimicrobial resistance (AMR) is a growing global threat, exacerbated by the adaptive mechanisms of Gram-negative ESKAPE pathogens, which include biofilm formation and outer membrane vesicle (OMV) production. Biofilms create robust protective barriers that shield bacterial communities from immune responses and antibiotic treatments, while OMVs contribute to both defense and offense by carrying antibiotic-degrading enzymes and delivering virulence factors to host cells. These mechanisms not only enhance bacterial survival but also increase the virulence and persistence of infections, making them a significant concern in clinical settings. This review explores the molecular processes that drive biofilm and OMV formation, emphasizing their critical roles in the development of AMR. By understanding these mechanisms, new therapeutic strategies can be developed to disrupt these defenses, potentially improving the efficacy of existing antibiotics and slowing the spread of resistance. Additionally, the use of OMVs in vaccine development and drug delivery offers promising avenues for future research. Addressing these challenges requires a comprehensive approach, combining advanced research with innovative therapies to combat the escalating threat of AMR and improve patient outcomes. Full article

Background: Parental cognitive characteristics may represent environmental risk factors in obsessive–compulsive disorder (OCD). This study compared obsessive beliefs, metacognitions, and ruminative thinking in parents of adolescents with OCD and healthy controls (HCs), and examined links with clinical features in patients. Methods: Participants were 45 adolescents with OCD, 45 HCs, and both their mothers and fathers. The Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) assessed symptom severity in adolescents. Parents completed the Obsessive Beliefs Questionnaire (OBQ), Ruminative Thought Style Questionnaire (RTSQ), 30-item Metacognitions Questionnaire (MCQ-30), and Patient Health Questionnaire-9 (PHQ-9). Data were analyzed using linear mixed-effects models, followed by correlation and regression analyses. Results: Parents of patients had higher scores on the importance/control of thoughts, the need to control thoughts, and cognitive self-consciousness (MCQ-CSC). Mothers of adolescents with OCD had the highest scores on inflated responsibility/threat estimation (OBQ-RTE), perfectionism/intolerance of uncertainty (OBQ-PIU), rumination, and cognitive confidence (MCQ-CC). Regression analyses showed that lower maternal MCQ-CC predicted earlier OCD onset, while higher rumination predicted later onset. Obsession severity in adolescents was linked to higher maternal MCQ-CSC, obsessive slowness to maternal OBQ-PIU, and pathological doubt to greater maternal rumination. Children’s indecisiveness correlated with paternal OBQ-RTE and OBQ-PIU. Conclusions: Our findings revealed elevated cognitive vulnerabilities for OCD in mothers of affected adolescents and identified specific associations between parental cognitive characteristics and their children’s symptom profiles. Future longitudinal studies using dyadic parental design with larger samples may further elucidate the role of parental cognitive patterns in the development and course of OCD. Full article

Atrial fibrillation (AF) is the supraventricular tachy-arrhythmia most commonly detected in the general population, with significant sex-related differences in epidemiology, pathophysiology, and treatment outcomes. Emerging evidence highlights the role of sex hormones—particularly estrogen and testosterone—in modulating left atrial electrophysiologic substrate, structural remodeling, inflammation, and thromboembolic risk. Hormonal fluctuations across different lifespan influence AF onset, progression, and therapeutic response, yet current management approaches largely overlook such determinants. This narrative review integrates data from basic, translational, and clinical research to examine hormonal effects on atrial substrate, disease progression, and differential results of treatments, including stroke prevention, pharmacological options, and transcatheter ablation. It also explores the potential of hormone-targeted interventions, antifibrotic therapies, and precision strategies tailored to hormonal status. Addressing these mechanisms could optimize patient-specific management, improve outcomes and guide future clinical practice recommendations. Advancing toward sex-specific, hormone-informed AF care requires further mechanistic studies, hormonal profiling, and sex-stratified clinical trials. Full article

Background/Objectives: High-frequency ultrasonography (HFUS) has gained increasing attention in dermatology as a non-invasive imaging technique capable of visualizing cutaneous structures with high resolution. In cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF)/Sézary syndrome (SS), HFUS may provide an objective method for assessing disease activity and monitoring treatment response. This study aimed to evaluate the clinical utility of HFUS in detecting therapy-induced changes in subepidermal low-echogenic band (SLEB) thickness. Methods: We conducted a prospective, single-center study between May 2021 and May 2025. Thirty-three patients with histologically confirmed MF (n = 31) or SS (n = 2) underwent HFUS at baseline and after 4–8 weeks of treatment. SLEB thickness was measured before (E1) and after early treatment (E2). Patients received systemic agents, phototherapy, or topical regimens. Statistical analysis included mixed-model ANOVA with repeated measures to assess SLEB changes, and post hoc tests were applied to explore the influence of therapy type, age, and gender. Results: Among 31 evaluable patients with MF, HFUS revealed a significant reduction in SLEB thickness after treatment (0.90 ± 1.10 mm vs. 0.69 ± 0.89 mm; F(1,29) = 8.88, p = 0.006, η² = 0.23). The type of early therapy (systemic vs. topical) did not significantly affect outcomes (p = 0.452). Age emerged as a relevant factor: patients ≥ 66 years exhibited higher baseline SLEB values and a significant reduction post-treatment (p < 0.001), whereas no comparable effect was observed in younger patients. Gender did not significantly influence SLEB changes. Conclusions: HFUS is a sensitive and clinically applicable imaging tool for monitoring treatment response in MF/SS. Reductions in SLEB thickness were observed across therapeutic modalities and aligned with early clinical improvement. HFUS may serve as a valuable adjunct to standard clinical and histopathological evaluation in the routine management of MF/SS. Full article

Neoadjuvant therapy has become the standard of care in early-stage triple-negative breast cancer (TNBC), providing both prognostic information and a platform for treatment individualization. The achievement of a pathological complete response (pCR) is strongly associated with excellent long-term outcomes, whereas the presence of residual disease (RD) indicates a markedly increased risk of recurrence. This dual prognostic value has established post-neoadjuvant treatment as a critical arena for risk-adapted strategies. In patients achieving pCR, de-escalation of adjuvant therapy is under active investigation, with several randomized trials assessing whether surveillance may safely replace prolonged immunotherapy. Conversely, the management of patients with RD has become increasingly complex, as clinicians must navigate between established options such as capecitabine, olaparib, and pembrolizumab, while antibody-drug conjugates are likely to emerge as future therapeutic options in this high-risk setting. In parallel, locoregional approaches are evolving, with trials evaluating axillary de-escalation and even the omission of surgery in highly selected cases. Looking forward, the integration of biomarkers such as circulating tumor DNA and tumor-infiltrating lymphocytes may help refine these strategies, paving the way toward truly personalized post-neoadjuvant care in TNBC. Full article

Background: hearing loss represents, today, one of the most significant health problems affecting the world’s population. This clinical condition, particularly manifest in adulthood, can arise or be aggravated by both the presence of specific pathologies and by taking multiple classes of drugs at the same time. Methods: to understand this relationship, the present non-interventional observational study aimed to investigate the relationship between worsening hearing abilities in 1651 patients aged between 18 and 99 years. In particular, the thorough history of patients allowed us to evaluate the pathological profiles, pharmacological profiles, and therapeutic regimens adopted. This allowed us to evaluate its association with self-reported hearing loss, assessed through the administration of the HHIE-S-It questionnaire. Furthermore, given the presence of multimorbidity, the possible correlation between self-reported hearing loss and the specific classes of drugs, categorized using the Anatomical Therapeutic Classification (ATC) system, was evaluated. Results: the results highlighted how patients taking drugs, both in mono- and polytherapy regimens, had higher hearing deficits than patients not taking drugs. Furthermore, an apparent dose–response effect, in which the risk of moderate to severe impairment progressively increased with the number of drugs taken, was also observed. Different classes of drugs, particularly those used for the treatment of diseases of the cardiovascular system, as well as drugs for acid-related disorders, were significantly linked to an increased risk of perceived hearing impairment. On the contrary, agents belonging to the antidiabetic category have proven to be drugs capable of offering a potential protective effect. Conclusion: this study highlighted how both the number of drugs taken and some specific categories of drugs can contribute to perceived hearing impairment. While this evidence highlights the importance of integrating audiological evaluation into the management of patients in polypharmacy, the cross-sectional nature of the design precludes the inference of causality. This evidence still favors safer and more personalized therapeutic strategies. Full article

Background: Medulloblastoma is the childhood tumor with the highest morbidity and mortality worldwide. This type of cancer is characterized by a high degree of heterogeneity that gives rise to different molecular groups with disparities in the clinical presentation and prognosis. Among the molecular differences, one of the most relevant factors is alternative splicing, as it is responsible for transcriptomic diversity. EZH2 is a gene processed by alternative splicing that functions as an epigenetic regulator. In cancer, certain EZH2 mRNA variants are associated with tumorigenesis; however, in medulloblastoma, the alternative splicing pattern of EZH2 has not been studied. Currently, the best tool for identifying alternative splicing variants is long-read sequencing. Methods: We amplified the most variable region of EZH2 alternative splicing and used nanopore sequencing to obtain the transcriptional profile of the gene in patients with medulloblastoma. We verified the variants identified with Sanger sequencing and digital RT–PCR. Finally, we studied the relationship between the expression levels and the clinical–biological characteristics of the patients. Results: We identified seven mRNA variants of EZH2 expressed in medulloblastoma patients, five of which had not been reported previously. In addition, high expression of the novel variant EZH2_RetI8 was associated with patient mortality (p < 0.05). Conclusions: This is the first evidence of the EZH2 mRNA variant profile in medulloblastoma, revealing seven alternative transcripts, one of which is associated with patient mortality. This is a clear example of the complexity of the transcriptome and how long-read sequencing can resolve alternative splicing patterns. Full article