Search Results (7,050)

The Constrained Disorder Principle (CDP) characterizes systems by their inherent variability, which is regulated within dynamic boundaries to ensure optimal function and adaptability. In biological systems, this variability, or “noise”, is crucial for resilience and flexibility at various scales, ranging from genes and cells to more complex organ systems. Disruption of the boundaries that control this noise—whether through amplification or suppression—can lead to malfunctions and result in pathological conditions. White noise (WN), defined by equal intensity across all audible frequencies, is an exemplary clinical application of the CDP. It has been shown to stabilize disrupted processes and restore functional states by utilizing its stochastic properties within the auditory system. This paper explores WN-based therapies, specifically for the masking, habituation, and alleviation of tinnitus, a subjective perception of sound. It describes the potential to improve WN-based therapies’ effectiveness by applying the CDP and CDP-based second-generation artificial intelligence systems. Understanding the characteristics and limitations of these approaches is essential for their effective implementation across various fields. Full article

Anxiety and depression are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), which can contribute to increased morbidity, reduced quality of life, and worse clinical outcomes. Nevertheless, these psychological conditions remain largely overlooked. This narrative review includes studies published between 1983 and 2025 to synthesise the current evidence on the risk factors, clinical impacts, and therapeutic strategies for these comorbidities. While the exact mechanisms leading to their increased prevalence are not fully understood, growing evidence implicates a combination of biological (e.g., systemic inflammation), social (e.g., isolation and stigma), and behavioural (e.g., smoking and inactivity) factors. Despite current guidelines recommending the identification and management of these comorbidities in COPD, they are not currently included in COPD assessments. Undetected and unmanaged anxiety and depression have serious consequences, including poor self-management, non-adherence to medications, increased risk of exacerbation and hospitalisations, and even mortality; thus, there is a need to incorporate screening as part of COPD assessments. There is robust evidence showing that pulmonary rehabilitation, a core non-pharmacological intervention, can improve mood symptoms, enhance functional capacity, and foster psychosocial resilience. Psychological therapies such as cognitive behavioural therapy (CBT), mindfulness-based approaches, and supportive counselling have also demonstrated value in reducing emotional distress and improving coping mechanisms. Pharmacological therapies, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed in moderate to severe cases or when non-pharmacological approaches prove inadequate. However, the evidence for their efficacy in COPD populations is mixed, with concerns about adverse respiratory outcomes and high discontinuation rates due to side effects. There are also barriers to optimal care, including underdiagnosis, a lack of screening protocols, limited provider training, stigma, and fragmented multidisciplinary coordination. A multidisciplinary, biopsychosocial approach is essential to ensure early identification, integrated care, and improved outcomes for patients with COPD. Full article

Background: Small airway dysfunction (SAD) plays a critical role in the management of severe asthma, particularly in patients at risk of requiring biological therapies (BTs). Short-term studies have shown that switching to single-inhaler triple therapy (SITT) with extrafine beclomethasone–formoterol–glycopyrronium improves outcomes and helps achieve quiet asthma, a state marked by symptom control, no exacerbations or oral steroids, reduced inflammation, and better small airway function. This study investigated whether, over one year, patients could maintain this state as Steady Quiet Asthma (SQA) and whether baseline measures could predict this sustained response. Methods: Twenty-six patients with severe asthma and SAD were transitioned from open triple-inhaler therapy to a closed, single-inhaler triple therapy containing extrafine beclomethasone–formoterol–glycopyrronium. Assessments at baseline (T0) and at one-year follow-up (T12) included clinical evaluations, spirometry, and impulse oscillometry, with a focus on Fres as a predictor for the need for BT. When prescribed, biologic therapies included mepolizumab, benralizumab, and dupilumab. Results: Of the 26 patients, 9 (34.6%) achieved SQA and did not require biologic therapy at the one-year follow-up, while 17 patients (65.4%) initiated biologic treatment. At T0, patients who required biologics had significantly higher median Fres (21 (19.47; 24.58) vs. 17.61 (15.82; 20.63); p = 0.049) compared to those who remained biologic-free. They also exhibited higher residual volume to total lung capacity ratio (%RV/TLC) values and lower forced expiratory volume in one second/forced vital capacity ratios (FEV₁/FVC). At T12, patients spared from BT showed significant reductions in Fres (p = 0.014) and improvements in small airway function (difference in airway resistance between 5 Hz and 20 Hz (R5–20), forced expiratory flow between 25% and 75% of FVC (%FEF25–75), and better asthma control (ACT). In contrast, patients on BT demonstrated less favorable changes in these parameters. Conclusions: Baseline Fres, FEV1/FVC ratio, and %FEV25–75 are valuable predictors of achieving Steady Quiet Asthma (SQA) and sparing biologic therapy. These findings support the use of SITT in severe asthma and highlight the importance of early functional assessments to guide personalized management. Full article

Background/Objectives: Acute severe ulcerative colitis (ASUC) is often managed by tacrolimus induction therapy followed by maintenance therapy. We compared the effectiveness of ustekinumab versus vedolizumab as maintenance therapies after tacrolimus induced improvement in patients with ASUC. Methods: This single-center retrospective cohort study included patients with ASUC who received tacrolimus induction therapy followed by ustekinumab or vedolizumab between January 2018 and November 2024. The primary outcome was clinical remission at week 16. Secondary and exploratory outcomes included clinical remission at week 8, biologic persistence, and relapse risk. An inverse probability of treatment weighting (IPTW) analysis was performed using the following covariates: male sex, prior biologics or JAK inhibitors, partial Mayo score, CRP, and albumin. Results: Among 235 tacrolimus-treated patients, 29 received ustekinumab and 22 received vedolizumab. After IPTW adjustment, the clinical remission rates were significantly higher in the ustekinumab group at both week 8 (82.1% vs. 51.8%, p = 0.02) and week 16 (85.4% vs. 36.8%, p = 0.02). Biologic persistence was significantly higher in the ustekinumab group (p = 0.004), and ustekinumab significantly reduced the hazard of relapse in multivariable analyses (HR 0.42 [95% CI: 0.20–0.88], p = 0.02). Conclusions: Ustekinumab showed greater effectiveness than vedolizumab in terms of achieving remission at 16 weeks after tacrolimus induction therapy in patients with ASUC. Full article

Background and Aim: Long-term treatment with biologic therapy alongside immunomAfodulators in patients with inflammatory bowel disease (IBD) can be associated with severe side effects. The objective of this study was to determine whether discontinuing anti-TNF treatment after two years in patients who have achieved mucosal healing is associated with lower relapse rates. Materials and Methods: A total of 67 patients with IBD from a single tertiary IBD Center who had achieved mucosal healing were enrolled in this retrospective study. In this single-center retrospective study (January 2014–December 2022), we screened 67 IBD patients in deep remission (endoscopic mucosal healing after ≥2 years of anti-TNF therapy). After excluding three patients without histologic data, 64 patients (25 ulcerative colitis, 39 Crohn’s disease) were analyzed. Mayo endoscopic sub-score and SES-CD were used to evaluate endoscopic activity after two years of anti-TNF therapy. Histological activity was assessed using the GHAS (for CD) and Nancy index (for UC). Results: A total of 67 patients were screened, of whom 3 were excluded due to a lack of biopsies. Of the 64 included patients, 39.06% (25/64) had UC and 60.9% (39/64) had CD, with a mean disease duration of 11.6 ± 8.0 years. All patients were in endoscopic remission at the time of therapy de-escalation, and 60.9% (39/64) also achieved histological remission (“deep remission”). In the follow-up of 38.6 months (IQR 30–48) after biologic therapy was stopped, 57.8% (37/64) relapsed with a median time to relapse of 13.5 months (IQR 8–24) off anti-TNF—a total of 34 patients required a restarting of biologic therapy. Using Spearman’s correlation, a moderate connection was observed between histological activity at withdrawal and subsequent relapse (rho = 0.467, p < 0.001). The probability of relapsing within 4 years after anti-TNF cessation was significantly higher (OR 2.72) in patients with histologically active disease at the time of de-escalation. Conclusions: Achieving ‘deep remission’ (clinical, endoscopic, and histological healing) may be a suitable parameter for making decisions on when to de-escalate therapy; however, given that over half of patients in endoscopic remission relapse after discontinuation, any de-escalation should be approached with caution and individualized patient assessment. Full article

Sjögren’s Disease (SjD) is an autoimmune disorder characterized by sicca symptoms arising from impaired salivary and lacrimal gland function and accompanying extraglandular involvement. SjD is recognized as an illness of female dominance for which the 2002 American–European Consensus Group Classification Criteria and the American College of Rheumatology/European Alliance of Associations for Rheumatology 2016 classification criteria are utilized for inclusion in clinical trials, and treatment recommendations from countries belonging to the American College of Rheumatology or the European Alliance of Associations for Rheumatology are globally recognized. It is presumed that there are geographical differences among female sufferers, and unique diagnostic criteria and recommendations are used in clinical practice in Japan. In addition to the items included in the classification criteria, several methods to measure saliva secretion, serum biomarkers, and artificial intelligence tools have recently been reported to be useful for the assessment of SjD. While symptomatic therapies including tear drops, artificial saliva, and muscarinic agonists are still the mainstay for treating SjD, several kinds of molecular targeted drugs, such as biological drugs and Janus kinase inhibitors, that are expected to improve the prognosis of SjD have been tested in recent clinical trials. Full article

Obesity, a multifactorial metabolic syndrome driven by genetic–epigenetic crosstalk and environmental determinants, manifests through pathological adipocyte hyperplasia and ectopic lipid deposition. With the limitations of conventional anti-obesity therapies, which are characterized by transient efficacy and adverse pharmacological profiles, the scientific community has intensified efforts to develop plant and fungal polysaccharide therapeutic alternatives. These polysaccharide macromolecules have emerged as promising candidates because of their diverse biological activities and often act as natural prebiotics, exerting beneficial effects through multiple pathways. Plant and fungal polysaccharides can reduce blood glucose levels, alleviate inflammation and oxidative stress, modulate metabolic signaling pathways, inhibit nutrient absorption, and reshape gut microbial composition. These effects have been shown in cellular and animal models and are associated with mechanisms underlying obesity and related metabolic disorders. This review discusses the complexity of obesity and multifaceted role of plant and fungal polysaccharides in alleviating its symptoms and complications. Current knowledge on the anti-obesity properties of plant and fungal polysaccharides is also summarized. We highlight their regulatory effects, potential intervention pathways, and structure–function relationships, thereby providing novel insights into polysaccharide-based strategies for obesity management. Full article

Rheumatoid arthritis (RA) is a chronic inflammatory disease frequently associated with alterations in body composition, including reduced lean mass and increased fat mass. These alterations are thought to be driven by persistent systemic inflammation, which may be influenced by inflammatory activity and by therapeutic interventions. Objectives: This pilot study aimed to provide preliminary data on changes in body composition and inflammatory activity in biologic-naive patients with active RA during the initial 6 months of TNF inhibitor treatment, and to compare baseline body composition with healthy controls. We conducted a single-center, observational, 24-week pilot study of 70 biologic-naive RA patients with moderate-to-severe disease activity and 70 matched healthy controls. Lean mass, fat mass, and lean mass index (LMI) were measured using dual-energy X-ray absorptiometry at baseline for both groups, and after 6 months only in the RA group. Clinical, laboratory, adipokines, and cytokine parameters were also recorded. At baseline, RA patients had lower lean mass and LMI than controls. Over 6 months, RA patients showed significant clinical and laboratory improvement, with a corresponding increase in lean mass and LMI. No statistically significant change was observed in fat mass. The increase in lean mass was paralleled by a reduction in inflammatory markers. The LMI was inversely associated with female sex (β = −0.562) and C-reactive protein (β = −0.432) and directly associated with body mass index (β = 0.570). Similar associations were observed for total lean mass and change in lean mass, as well as for DAS28 (β = −0.333). This pilot study provides preliminary evidence that TNF inhibitor therapy may be associated with increased lean mass and decreased inflammation in RA patients. Owing to the absence of a comparator RA group not receiving TNF inhibitors, these findings should be interpreted as hypothesis-generating. Full article

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article

Background: Behçet’s Disease (BD) was traditionally classified according to the International Study Group (ISG), where oral ulcers were mandatory. The International Team for the Revision of the International Criteria for BD (ICBD) introduced a scoring system instead. Our aim was to assess (a) sensitivity, (b) concordance between ISG and ICDB criteria in global and severe BD cases (ocular, vascular, and neurological), and (c) evaluate their clinical implications. Methods: Retrospective cohort study including 142 BD patients diagnosed in a well-defined population in Northern Spain, between January 1980 and November 2023. Both ISG and ICBD criteria were compared, sensitivity and concordance were assessed using Prevalence-Adjusted and Bias-Adjusted Kappa (PABAK) and the unadjusted Kappa. Results: A total of 142 BD patients diagnosed by expert rheumatologists (73 men; mean age of 36.4) were studied. Among them, 84 met ISG criteria, while 116 fulfilled ICBD criteria. Sensitivity of ISG and ICBD criteria in the overall cohort was (59.1% and 81.6%), respectively. Among patients with severe manifestations (ocular, vascular, or neurological), sensitivity increased to 71.2% for ISG and 92.5% for ICBD. Overall concordance was moderate (Kappa = 0.490), with 70.4% of patients classified identically. When adjusting prevalence and bias, concordance improved slightly (PABAK = 0.549). Of the 32 patients classified as BD exclusively by ICBD, 7 were receiving anti-TNF therapy, and 2 were receiving apremilast. Conclusions: The ICBD criteria demonstrated higher sensitivity than the traditional ISG criteria in classifying BD, particularly in severe cases. Classifying these additional patients under ICBD facilitated the initiation of on-label biologic treatments, potentially enhancing BD management, especially for severe cases. Full article

Bee products, in particular honey, propolis and bee venom, are of growing scientific interest due to their broad spectrum of antimicrobial activity. In the face of increasing antibiotic resistance and the limitations of conventional therapies, natural bee-derived substances offer a promising alternative or support for the treatment of infections. This paper summarizes the current state of knowledge on the chemical composition, biological properties and antimicrobial activity of key bee products. The main mechanisms of action of honey, propolis and bee venom are presented, and their potential applications in the prevention and treatment of bacterial, viral and fungal infections are discussed. Data on their synergy with conventional drugs and prospects for use in medicine and pharmacology are also included. The available findings suggest that, with appropriate standardization and further preclinical and clinical analyses, bee products could become an effective support for the treatment of infections, especially those caused by pathogens resistant to standard therapies. Full article

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy’s scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds. Full article

Platelet-rich plasma (PRP) is widely used in regenerative medicine, yet clinical outcomes remain inconsistent. While traditional strategies have focused on platelet concentration and activation methods, emerging evidence suggests that the biological age of platelets, especially platelet senescence, may be a critical but overlooked factor influencing therapeutic efficacy. Senescent platelets display reduced granule content, impaired responsiveness, and heightened pro-inflammatory behavior, all of which can compromise tissue repair and regeneration. This review explores the mechanisms underlying platelet aging, including oxidative stress, mitochondrial dysfunction, and systemic inflammation, and examines how these factors influence PRP performance across diverse clinical contexts. We discuss the functional consequences of platelet senescence, the impact of comorbidities and aging on PRP quality, and current tools to assess platelet functionality, such as HLA-I–based flow cytometry. In addition, we present strategies for pre-procedural optimization, advanced processing techniques, and adjunctive therapies aimed at enhancing platelet quality. Finally, we challenge the prevailing emphasis on high-volume blood collection, highlighting the limitations of quantity-focused protocols and advocating for a shift toward biologically precise, function-driven regenerative interventions. Recognizing and addressing platelet senescence is a key step toward unlocking the full therapeutic potential of PRP-based interventions. Full article

Traditional anti-inflammatory medications—such as corticosteroids, biological agents, and non-steroidal anti-inflammatory drugs—are commonly employed to mitigate inflammation, despite their potential for debilitating side effects. There is a growing need for alternative next-generation therapies for symptomatic, unchecked, and/or detrimental inflammation with more favorable adverse effect profiles. The long history of use of gold salts as anti-inflammatory agents and the more recent exploration of gold nanoparticle (AuNP) formulations for clinical indications suggest that the targeted delivery of nanoparticles to inflammatory sites may be a promising approach worth investigating. Coupled with peptides that specifically target immune cells, AuNPs could potently counteract inflammation. Here, we provide an overview of the selective infiltration of AuNPs into immune cells and summarize their interactions with and impact on these cells. Additionally, we provide a comprehensive mechanistic summary of how AuNPs exert their anti-inflammatory effects. Full article

The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase (TPMT) was initially the primary focus, the discovery of nudix hydrolase 15 (NUDT15) appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of NUDT15 pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of NUDT15 in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated NUDT15 variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that NUDT15 genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines. Full article