Search Results (1,077)

Having appropriate and meaningful diagnostic procedures is crucial in the approach to patients with chronic spontaneous urticaria (CSU), so we wanted to investigate relationships between CSU patients’ common serum factors and clinical CSU features, and their temporal trends during antihistamine treatment. In this exploratory hypothesis-based study, we assessed disease severity and quality of life (QoL) in, initially, 41 CSU patients using UAS7, daily UAS, UCT, DLQI, and CU-Q2oL. Concurrently, we measured serum complete blood count (CBC), total IgE, thyroid antibodies and hormones, ANA, D-dimer, vitamin D, and the inflammatory molecules CRP, ESR and IL-6. We compared initial (T1) and follow-up findings (T2) (after 3 months of antihistamine therapy). Basophil concentration was the only examined serum factor useful in assessing current CSU severity/daily UAS (sensitivity 78.6%; specificity 63%; p = 0.028). Basopenia was more frequent in patients with moderate/severe CSU than in those with mild disease or remission, as measured by daily UAS (79% vs. 37%; p = 0.020). T4 values showed a significant dependence on CSU duration (r = −0.328; p = 0.036). ESR was the only examined serum factor significantly associated with weekly CSU severity (UAS7) (p = 0.038). Antihistamine treatment significantly reduced CSU activity (recorded by daily UAS and UAS7) and improved QoL (DLQI) (p = 0.006) and disease control/UCT (p = 0.005). After three months of treatment, only the CRP value correlated with CSU control/UCT (p = 0.014). We encourage the use of diagnostics employing basophil counts and clinical indices UAS7, daily UAS, UCT and DLQI for insight into a patient’s CSU clinical condition. Serum factor values did not change during the 3-month treatment period, so it is not useful to measure them repeatedly. Although this study involved a small cohort and has many limitations, these promising results highlight the need for replication with a greater number of CSU patients. Full article

Background: Proton beam therapy (PBT) is a valuable alternative to photon radiotherapy of CNS tumors in children and adolescents. While most recent studies deal with the outcome or long-term side effects of PBT, the aim of this study was to investigate the feasibility of PBT with a particular focus on the acute toxicity of a simultaneous radiochemotherapy (sPBCT). Patients and methods: We enrolled 199 children [median age 7.4 years (range, 0.9–17.9)], who received altogether 200 courses of PBT/sPBCT at initial diagnosis (n = 121) or at relapse (n = 79) with sPBCT in 52 (26%) courses. Data collection to PBT/sPBCT was based on the medical records and the KiProReg (Registry study of Standard Proton Therapy in Children at West German Proton Therapy Center) with a primarily descriptive-statistical and logistic regression analysis. Results: During PBT/sPBCT a total of n = 704 adverse events (AEs, mean 3.4 per course) were observed. Eighty-seven of them were graded as high-grade adverse events (HGAEs, Common Terminology Criteria for Adverse Eventº ≥3 (CTCAE)) which occurred in 67 (33.5%) PBT/sPBCT courses. HGAEs were in particular hematotoxicity (n = 43; 64.1%) and infections (n = 18; 26.8%). A significantly higher rate of HGAEs was documented in patients treated with sPBCT (n = 33/52; 63.5%) compared to those with PBT only (n = 34/148; 23.0%) (p = 0.001). In children with sPBCT, 15 (28.8%) patients could not receive the recommended dose or schedule of the planned chemotherapy (CTx) due to HGAEs, with the rate of planned CTx courses performed being significantly lower in patients receiving intensive intravenous CTx (p < 0.001). Interruptions of PBT and of simultaneous CTx were both significantly associated with the occurrence of infections [Odds ratios 3.002 (95% CI 1.005–8.971, p = 0.049) and 3.905 (95% CI 1.005–15.174, p = 0.049)]. Total discontinuation of treatment did not occur. Conclusions: Concurrent CTx during proton therapy is associated with a significant increased risk for HGAE occurrence and therapy interruptions requiring individual dose and schedule adjustments dependent on CTx intensity, very experienced interdisciplinary teams as well as intensive care and in-/out-patient oncology facilities on site. Full article

Left-ventricular non-compaction (LVNC) is a recently classified cardiomyopathy that involves abnormal trabeculations inside the left ventricle, most commonly located in the ventricular apex. There are 9 distinct types of non-compaction cardiomyopathy that can impact both the left and right ventricles with subtypes involving mostly pediatric patients with concurrent congenital heart disease (CHD), to individuals in late adult-staged ages. LVNC affects the population with an estimated range of incidence from 0.014% to 1.3% and the disease can be diagnosed with the utilization of imaging studies such as transthoracic echocardiography (TTE). LVNC can also impact and lead patients to develop heart failure with estimated prevalence that can reach to 3–4% during their lifetime. LVNC often leads to complications such as heart failure, arrhythmias, and thromboembolic events and without adequate medical management and pharmacological therapies this can progress and lead to worsening cardiac function, sudden cardiac arrest, and even death. There are no strict guidelines organized for screening and monitoring for LVNC in patients except with the inclusion of having a high suspicion in patients without other cardiac abnormalities. Thus, more advanced clinical research and the establishment of diagnostic protocols needs to be standardized in order to further investigate the causes, prognostic factors and therapeutic modalities of patients with LVNC. The field of LVNC cardiomyopathy is expanding but better understanding of the pathophysiology and genetic influence of this cardiac disease is vital for the precision treatment and personalized care of LVNC. Full article

Eating disorders (EDs) remain challenging to treat, with high dropout and low remission rates in cognitive-behavioral therapy for EDs (CBT-ED). Psilocybin treatment (PT) demonstrates therapeutic potential to enhance CBT-ED by exerting several neurobiological, psychological, and experiential effects (e.g., antidepressant, neuroplasticity, emotional openness) that are hypothesized to increase psychotherapeutic engagement, reduce dropout, and improve clinical outcomes. This narrative review provides the first consolidation of theoretical evidence for PT/CBT-ED, proposes considerations for a concurrent intervention protocol, and presents clinical and research considerations to empirically test its feasibility, safety, and efficacy. This line of inquiry is expected to advance the development of approaches that improve ED treatment outcomes and, more broadly, advance the study of psychedelics as tools to enhance evidence-based psychotherapy models. Full article

The Ralstonia solanacearum species complex (RSSC) is a globally significant plant pathogenic bacterium. Given the lack of effective chemical controls, phage therapy has emerged as a promising biocontrol alternative. While combining phages with antibiotics can counteract phage resistance, RSSC may still evolve concurrent resistance to both agents. However, the fitness consequences and underlying mechanisms of such resistance remain unclear. In this study, a novel RSSC phage was isolated to experimentally investigate the trade-offs between resistance and virulence in evolved strains. Compared to the wild-type, phage-resistant, antibiotic-resistant, and dual-resistant mutants showed no significant differences in growth rate, exopolysaccharide and lipopolysaccharide production. However, their motility, soil survival, and biofilm formation were significantly impaired, with the most severe decline observed in the dual-resistant mutants. Furthermore, phage-resistant strains exhibited enhanced antibiotic resistance, while antibiotic-resistant strains displayed cross-resistance. The antibiotic resistance gene bla_OXA-249 was upregulated only in antibiotic-resistant strains. In phage-resistant bacteria, the abortive infection system was activated. A reduction in bacterial cell numbers post-infection indicated that phage resistance limits phage propagation via a “suicidal” mechanism. These findings reveal that resistance evolution in RSSC carries substantial fitness costs and highlight phage steering as a novel strategy for designing phage agents. Full article

Background: Total neoadjuvant therapy (TNT) is increasingly administered in rectal cancer, but compared with concurrent chemoradiotherapy (CRT), data regarding the gastrointestinal (GI) toxicity profile and clinical predictors remain limited. Objectives: To evaluate GI toxicity associated with TNT compared with CRT and to explore clinical predictors of these adverse events (AEs). Methods: This retrospective study included 201 patients with rectal cancer treated with TNT (n = 157) and CRT (n = 44). GI AEs (nausea, vomiting, diarrhea) were graded according to CTCAE v5.0. In the analysis of factors associated with GI AEs, multiple clinical and pathological variables were included using multivariable logistic regression. Results: The composite endpoint “any GI AEs grade ≥ 1” was more frequent in the TNT group compared with the CRT group (33.1% vs. 15.9%; RR = 2.08; 95% CI 1.02–4.25; p = 0.038). Nausea was significantly more frequent in the TNT group (28.7% vs. 9.1%; RR = 3.15; 95% CI 1.20–8.30; p = 0.012), whereas vomiting (9.6% vs. 2.3%; p = 0.203) and diarrhea (17.8% vs. 9.1%; p = 0.242) did not reach statistical significance. In multivariable logistic regression, TNT (OR = 2.65; 95% CI 1.08–6.53; p = 0.032) and female sex (OR = 2.03; 95% CI 1.05–3.77; p = 0.033) were identified as independent predictors of grade ≥ 1 GI AEs. For nausea, TNT remained significant (OR = 4.37; 95% CI 1.45–13.20; p = 0.0089). Upper rectal tumor location was significantly associated with vomiting (p = 0.0054). No grade 3–4 GI AEs were observed in either treatment group. Conclusions: TNT was associated with a higher incidence of mild GI AEs, predominantly driven by nausea, without an increase in severe toxicities. TNT and female sex were identified as independent clinical predictors of an increased risk of GI AEs, while tumor location in the upper third of the rectum was associated with a higher occurrence of vomiting. Full article

Background/Objectives: Type 2 diabetes (T2DM) and hypothyroidism often coexist, worsening cardiometabolic risk. Oral semaglutide and levothyroxine each improve metabolic parameters, but the effect of combined therapy is understudied. This study aimed to evaluate whether oral semaglutide administered concomitant with levothyroxine provides additive benefits on lipid profile, glycemic control, and body weight in patients with both conditions. Methods: This prospective comparative observational study assessed a total of 210 patients who were enrolled (70 per group) with a 6-month follow-up. Group A (T2DM and hypothyroidism) received semaglutide and levothyroxine, group B (hypothyroidism only) received levothyroxine, and group C (T2DM only) received oral semaglutide. Lipid profile, glycemic profile (HbA1c), thyroid profile, and anthropometric parameters were comparable across groups at baseline and after 6 months. Results: Group A demonstrated significant improvements in lipid parameters: LDL-cholesterol decreased by 12.7%, HDL increased by 9.0%, and triglycerides decreased by 6.7% (all comparisons p < 0.001 unless otherwise specified). In contrast, group B experienced worsening lipid profiles (LDL increased by 11.0%, HDL decreased by 0.5%, and triglycerides increased by 9.1%), while group C showed modest changes (LDL increased by 4.5%). Glycemic control improved among diabetic patients, with HbA1c declining by 7.7% in group A and 12.6% in group C. Body mass index (BMI) decreased in groups A (4.9%) and C (6.0%). Conclusions: The concurrent administration of oral semaglutide and levothyroxine produces additive cardiometabolic advantages in individuals with T2DM and hypothyroidism. These findings suggest that combined treatment may optimize metabolic outcomes in this particularly high-risk population. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer, and its main treatments include chemotherapy with genotoxic drugs and immunotherapy. Central to the cellular response to genotoxic stress is the DNA damage response (DDR) network, regulated by key kinases such as ataxia-telangiectasia mutated and Rad3-related (ATR). Herein, we tested the hypothesis that inhibition of ATR enhances the cytotoxicity of genotoxic agents and the antitumor immune response. Methods: DDR-related parameters and redox status, expressed as GSH/GSSG ratio, and apurinic/apyrimidinic lesions, were evaluated in human (A549, H1299) and murine (LLC) NSCLC cell lines after co-exposure to ATR inhibitor (AZD6738) and ultraviolet C (UVC) irradiation or cisplatin. Using a syngeneic LLC model, treatments of AZD6738 alone or in combination with cisplatin and/or anti-programmed cell death 1 antibody (anti-PD1) were examined. Results: In all cell lines, combined treatment with AZD6738 and cisplatin or UVC irradiation markedly decreased cell viability, DNA repair efficiency, and GSH/GSSG ratios; increased drug-induced DNA damage; and augmented apurinic/apyrimidinic lesions. In vivo, following treatment with AZD6738 and cisplatin, flow cytometry analysis performed in tumor cells revealed an increased infiltration of CD3⁺ and CD8⁺ T cells, with the triple combination of AZD6738, cisplatin, and anti-PD1 achieving the strongest antitumor effect. The CD3⁺CD4⁻CD8⁻ double-negative (DN) T cell population in tumor samples also emerged as a contributing factor in this context. Conclusions: These results demonstrate that ATR blockade concurrently enhances the efficacy of genotoxic agents and immune checkpoint inhibitors, thus paving the way for combination therapies in NSCLC. Full article

Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and its derivative lyso-Gb3 within lysosomes. Beyond substrate storage, FD involves a complex interplay of molecular, metabolic, and inflammatory disturbances that collectively drive multisystemic damage. It seems that Gb3 accumulation impairs autophagic flux, promotes mitochondrial dysfunction, and triggers endoplasmic reticulum stress, leading to oxidative imbalance and bioenergetic failure. Concurrently, activation of innate immune pathways, particularly the TLR4/NF-κB axis, induces pro-inflammatory cytokine release and endothelial dysfunction, while complement activation and adaptive immune responses contribute to chronic inflammation and fibrosis. These mechanisms define a sustained state of “metaflammation,” linking lysosomal dysfunction to systemic inflammation. Understanding this molecular cross-talk provides a rationale for identifying novel biomarkers and designing therapies that go beyond enzymatic correction, including chaperone therapy, substrate reduction, and gene-based or anti-inflammatory approaches. A deeper comprehension of these interconnected patterns may guide the development of precision medicine strategies aimed at improving long-term outcomes in Fabry disease. Full article

Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system (CNS) and is characterized by poor prognosis and significant resistance to available treatments. Surgery, radiation therapy, and chemotherapy are the standard treatments; however, their efficacy is often limited by resistance. Resveratrol (RES), a naturally occurring polyphenol with antioxidant properties, has shown significant anticancer effects through inhibition of multiple cellular pathways. However, our earlier research revealed that the LN428 cell exhibited resistance, while the U251 cell showed sensitivity to RES monotherapy. Hence, RES and AG490, a JAK2 inhibitor, were used to overcome GBM cell resistance, which might enhance therapeutic efficacy. Methods: Human GBM cell lines LN428 and U251 were used. CCK-8, H&E staining, transwell, wound healing, calcein AM/PI, and flow cytometry assays were performed to evaluate cell proliferation, migration, and apoptosis. Molecular docking was performed to analyze the binding energy. Western blot, immunocytochemistry (ICC), and immunofluorescence (IF) were used to assess protein expression following treatment with RES, AG490, and their combination. Results: The results revealed that U251 cells were more sensitive to RES, AG490, and RES + AG490 than LN428 cells. Additionally, the combination of both compounds significantly reduced cell viability, proliferation, and migration, while increasing apoptosis in the LN428 and U251 cell lines. Moreover, the combination of RES and AG490 led to increased BAX protein expression while decreasing BCL-2 expression in LN428 and U251 cell lines. Notably, the monotherapy administration of RES did not significantly inhibit STAT3 or pSTAT3 protein expression in LN428 cells, while combination therapy significantly inhibited the expression of these proteins in LN428 and U251 cell lines. Conclusions: The concurrent administration of RES and AG490 effectively inhibited the JAK2/STAT3 signalling pathway and enhanced antitumor effects in GBM cells, indicating their potential as a therapeutic strategy. Full article

Background and Clinical Significance: Plasmablastic lymphoma (PBL) is a rare and highly aggressive B-cell neoplasm most often associated with immunodeficiency. Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into PBL is exceptionally uncommon, particularly in immunocompetent individuals. This paper describes a rare synchronous SLL-to-PBL transformation and summarizes current knowledge on synchronous and metachronous cases reported in the literature. Case Presentation A midle-aged immunocompetent patent presented with generalized lymphadenopathy and lumbar pain. Concurrent biopsies of an axillary lymph node and a retroperitoneal mass were obtained. Diagnostic evaluation included immunohistochemistry; fluorescent in situ hybridization (FISH); PCR-based assessment of IGH, IGK, and IGL loci; and next-generation sequencing (NGS) of IGHV to assess clonal relatedness. The patient was treated with six cycles of Dara-CHOP, followed by autologous stem cell transplantation and maintenance therapy with daratumumab and ibrutinib. The axillary node showed SLL (CD20+, CD5+, CD23+), while the retroperitoneal mass demonstrated classic features of PBL (CD138+, MUM1+, MYC+, Ki-67 ~100%, CD20−). FISH detected MYC rearrangement in the PBL component. PCR and NGS confirmed identical IGHV1-69 rearrangements, establishing clonal relatedness and Richter transformation. A review of published cases shows that both synchronous and metachronous CLL/SLL-to-PBL transformations are exceedingly rare. The patient achieved partial metabolic remission after treatment and remains in sustained metabolic response 24 months after diagnosis. Conclusions: This case highlights a rare example of synchronous CLL/SLL-to-PBL transformation in an immunocompetent patient. Integration of detailed molecular diagnostics enabled early recognition and guided a personalized treatment approach incorporating CD38-targeted therapy and BTK inhibition, resulting in an excellent long-term clinical outcome. Full article

Skin aging, photoaging, and chronic wounds are increasingly recognized to be driven by mitochondria-centered mechanisms characterized by oxidative stress, defective mitophagy, and impaired bioenergetics in cutaneous cells. Autologous biologics, including platelet-rich plasma, stromal vascular fraction, bone marrow aspirate concentrate, and mesenchymal stromal/stem cell–derived products, are widely used for skin rejuvenation and wound repair. Recent studies have suggested that many of these effects are mediated by mitochondrial mechanisms, including metabolic reprogramming, redox modulation, and intercellular mitochondrial transfer. Concurrently, biophysical modalities such as red/near-infrared photobiomodulation (PBM), low-intensity pulsed ultrasound, mechanical stimulation, and nanoengineered cues can modulate mitochondrial function in skin-relevant cells. In this review, we integrate these lines of evidence to introduce the concept of mitochondria-targeted biophysical priming of autologous biologics for dermatological applications. We summarize the mitochondrial biology in skin pathology, evaluate these biologics as mitochondria-active therapies, and outline ex vivo priming implementation using PBM, ultrasound, or mechanical stimulation. Finally, we discuss key regulatory considerations that support clinical translation. Full article

Cancer immunotherapy has revolutionized the treatment of cancer by harnessing the immune system to recognize and destroy malignant cells. However, a substantial proportion of patients exhibit primary or acquired resistance to these therapies, underscoring the urgent need to identify novel molecular targets to enhance therapeutic efficacy. Autophagy, an evolutionarily conserved cellular process of degradation and recycling, has emerged as a critical modulator of tumor immunity and the function of immune cells. In cancer cells, autophagy modulates antigen presentation, immunogenic cell death, metabolic reprogramming, and resistance to immune-mediated cell death. Concurrently, autophagy rigorously governs the viability, differentiation, and functional capacity of immune cells, including T cells, dendritic cells, macrophages, and natural killer (NK) cells. Dysfunctional autophagic flux in the tumor microenvironment can enhance immune evasion and limit the efficacy of immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. In this review, we provide an in-depth analysis of emerging molecular targets involved in the regulation of autophagy relevant to cancer immunotherapy. This includes key signaling pathways such as PI3K/AKT/mTOR, AMPK, Beclin-1 complexes, ULK1, and lysosomal regulators. Additionally, we explore the rational integration of the pharmacological modulation of autophagy, including small molecules, natural compounds, and nanoparticle-based drug delivery systems, with immunotherapeutic approaches. We highlight the importance of rational drug selection and combination therapies to overcome resistance to immunotherapy and minimize toxicity. Understanding the context-dependent role of autophagy will be essential for the development of next-generation, precision-targeted cancer immunotherapies. Therefore, a comprehensive understanding of the context-specific functions of autophagy in tumor and immune cells is crucial for devising precision-targeted combination methods that overcome immunotherapy resistance and produce more sustainable cancer treatment outcomes. Full article

Older patients with unresectable locally advanced non-small-cell lung cancer (NSCLC) frequently receive concurrent chemoradiotherapy (CCRT) with daily low-dose carboplatin; however, real-world data on its efficacy, safety, and prognostic factors remain limited. We aimed to retrospectively evaluate the clinical outcomes of this regimen and examined whether systemic inflammation-based indices predict prognosis in this setting. We reviewed 52 consecutive patients with locally advanced NSCLC treated with first-line CCRT using daily low-dose carboplatin at three Japanese institutions between April 2007 and December 2019. The median progression-free survival (PFS) and overall survival (OS) were 11.5 and 40.1 months, respectively. Twenty patients received durvalumab as consolidation therapy. In the overall cohort, multivariate analysis identified the Glasgow Prognostic Score (GPS) as an independent predictor of PFS. A GPS of 0–1 was also associated with a significantly longer OS in univariate analysis. CCRT with daily low-dose carboplatin provided durable disease control with acceptable toxicity in older patients with unresectable stage II/III NSCLC. The GPS appears to be a simple marker for PFS in this population and may aid in pretreatment risk stratification alongside histology and consolidation strategies. Full article

Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor, necessitating innovative multi-target strategies. Natural compounds like the triterpenoid Alisol B from Alisma orientale hold promise due to their polypharmacological potential, yet their system-level mechanisms are unclear. Using an integrated multi-omics approach (transcriptomics, proteomics, lysine acetyl-proteomics) in resistant GBM cells and validating findings in vitro and in AB strain zebrafish (Danio rerio) xenografts, we found that Alisol B induces endoplasmic reticulum stress and G2/M arrest, initiated by extensive lysine acetylation reprogramming on histones and metabolic enzymes (e.g., FASN, FDFT1). This epigenetic rewiring leads to disrupted cholesterol biosynthesis, characterized by transcriptional activation of the mevalonate pathway alongside post-transcriptional suppression of terminal enzymes (DHCR7, CYP51A1), suggestive of toxic intermediate accumulation. Alisol B also downregulated the oncogenic axis (BIRC5-FOXM1-ITGA4) and SCD5. This study delineates Alisol B’s novel multi-mechanistic action through concurrent epigenetic rewiring, metabolic dysfunction induction, and survival network dismantling. Our work elucidates the molecular pharmacology of a natural compound and provides a framework for developing polypharmacological therapies against resistant cancers, exemplifying natural products as tools to reveal new therapeutic paradigms. Full article