Search Results (1,468)

Background/Objectives: Breast cancer was the leading cause of malignant tumors among women in 2022. About two-thirds of breast cancer cases are hormone-receptor-positive. In these patients, aromatase inhibitors are a mainstay of treatment, but associated musculoskeletal symptoms can negatively affect patient compliance. Aromatase-inhibitor-induced carpal tunnel syndrome represents one of the main causes of aromatase inhibitor discontinuation, with a non-compliance rate of up to 67%, potentially leading to increased cancer mortality. This study investigates estrogen receptor expression in aromatase-inhibitor-induced carpal tunnel syndrome tissues, in order to better define its etiopathogenesis and derive preventive or therapeutic measures that can improve aromatase inhibitor patient compliance. To our knowledge, there is no study on this subject in the literature. Methods: Between 2023 and 2024, we recruited 14 patients at the Jewish Hospital of Rome, including seven patients with aromatase-inhibitor-induced carpal tunnel syndrome (study group) and seven with postmenopausal idiopathic carpal tunnel syndrome (control group). Each patient was evaluated based on a clinical visit, a questionnaire, instrumental exams, and serum hormone dosages and were treated with open carpal tunnel release surgery, during which transverse carpal ligament and flexor tenosynovium samples were collected. For immunohistochemical experiments, sections were treated with anti-estrogen receptor α and anti-estrogen receptor β antibodies. Results: The immunohistochemical features in the study and control groups were similar, demonstrating that tissues affected by aromatase-inhibitor-induced carpal tunnel syndrome are targets of direct estrogen action and that estrogen deprivation is correlated with disease etiogenesis. Surgery was effective in patient treatment. Conclusions: Aromatase-inhibitor-induced carpal tunnel syndrome represents a newly defined form of the disease. This syndrome represents one of the main causes of aromatase inhibitor discontinuation, due to its negative impact on the patient’s quality of life. The identification by clinicians of aromatase inhibitor use as a possible risk factor for carpal tunnel syndrome development is of essential importance, as early diagnosis and prompt management can improve patient compliance and overall breast cancer treatment outcomes. Full article

Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases DUOX1/DUOX2, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. Full article

Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for understanding these disparities. In LMICs, populations are disproportionately affected by air and water pollution, occupational hazards, and oncogenic infections, including human papillomavirus (HPV), hepatitis B virus (HBV), Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), and neglected tropical diseases, such as schistosomiasis. These infectious agents contribute to increased cancer susceptibility and poor outcomes, particularly in immunocompromised individuals. Moreover, climate change, food insecurity, and barriers to healthcare access exacerbate these risks. This review adopts a population-level exposome approach to explore how environmental and infectious exposures intersect with genetic, epigenetic, and immune mechanisms to influence cancer incidence and progression in LMICs. We highlight the critical pathways linking chronic exposure and inflammation to tumor development and evaluate strategies such as HPV and HBV vaccination, antiretroviral therapy, and environmental regulation. Special attention is given to tools such as exposome-wide association studies (ExWASs), which offer promise for exposure surveillance, early detection, and public health policy. By integrating exposomic insights into national health systems, especially in regions such as sub-Saharan Africa (SSA) and South Asia, LMICs can advance equitable cancer prevention and control strategies. A holistic, exposome-informed strategy is essential for reducing global cancer disparities and improving outcomes in vulnerable populations. Full article

Background and objectives: Trismus is a frequent and debilitating complication in people with head and neck cancer (HNC) which leads to significant functional limitations and reduced quality of life. Rehabilitation interventions are commonly recommended to manage or prevent trismus. However, in many randomized controlled trials (RCTs), the theoretical justification for these interventions is poorly articulated, and the underlying biological or physiological mechanisms are not described in detail, limiting our understanding of why certain treatments may (or may not) work. This review aimed to identify and analyze how RCTs report the rationale for rehabilitation interventions and the explanations used to manage this population. Materials and Methods: A scoping review was conducted in accordance with the PRISMA-ScR guidelines. Five databases (PubMed, PEDro, Web of Science, Scopus, and EMBASE) were searched up to May 2025 for RCTs evaluating rehabilitation interventions for the management or prevention of treatment-induced trismus in patients with HNC. Data were extracted and synthesized narratively, focusing on the type of intervention, the rationale for its use, and the proposed mechanisms of action. Results: Of 2215 records identified, 24 RCTs met the inclusion criteria. Thirteen studies focused on preventive interventions—primarily exercise therapy—while the remainder addressed established trismus using exercise, manual therapy, electrotherapy, or combined treatment modalities. The rationales provided for intervention selection were heterogeneous and often lacked depth, with most studies justifying interventions based on their potential to improve mouth opening or reduce fibrosis but rarely grounding these claims in detailed pathophysiological models. Only half of the studies provided any mechanistic explanation for the intervention’s effects, and these were typically generic or speculative. Conclusions: RCTs investigating rehabilitation interventions for treatment-induced trismus in patients with HNC frequently lack comprehensive rationales and mechanistic explanations for their interventions. This gap limits the ability to refine and optimize treatment approaches, as the underlying processes driving clinical improvements remain poorly understood. Future research should be guided by theoretical models and include objective outcomes to better elucidate the mechanisms of action of interventions to inform clinical practice. Full article

Obesity and metabolic dysfunction are established risk factors for luminal breast cancer, yet current preclinical models inadequately recapitulate the complex metabolic and immune interactions driving tumorigenesis. To develop and characterize an immunocompetent rat model of luminal breast cancer induced by chronic exposure to a cafeteria diet mimicking Western obesogenic nutrition, female rats were fed a cafeteria diet or standard chow from weaning. Metabolic parameters, plasma biomarkers (including leptin, insulin, IGF-1, adiponectin, and estrone), mammary gland histology, tumor incidence, and gene expression profiles were longitudinally evaluated. Gene expression was assessed by PCR arrays and qPCR. A subgroup underwent dietary reversal to assess the reversibility of molecular alterations. Cafeteria diet induced significant obesity (mean weight 426.76 g vs. 263.09 g controls, p < 0.001) and increased leptin levels without altering insulin, IGF-1, or inflammatory markers. Histological analysis showed increased ductal ectasia and benign lesions, with earlier fibroadenoma and luminal carcinoma development in diet-fed rats. Tumors exhibited luminal phenotype, low Ki67, and elevated PAI-1 expression. Gene expression alterations were time point specific and revealed early downregulation of ID1 and COX2, followed by upregulation of MMP2, THBS1, TWIST1, and PAI-1. Short-term dietary reversal normalized several gene expression changes. Overall tumor incidence was modest (~12%), reflecting early tumor-promoting microenvironmental changes rather than aggressive carcinogenesis. This immunocompetent cafeteria diet rat model recapitulates key metabolic, histological, and molecular features of obesity-associated luminal breast cancer and offers a valuable platform for studying early tumorigenic mechanisms and prevention strategies without carcinogen-induced confounders. Full article

Nonspecific toxicity to normal and malignant cells restricts the clinical utility of many anticancer drugs. In particular, anemia in cancer patients develops due to drug-induced toxicity to red blood cells (RBCs). The anticancer alkaloid, cepharanthine (CEP), elicits distinct forms of cell death including apoptosis and autophagy, but its cytotoxicity to RBCs has not been investigated. Colorimetric and fluorometric techniques were used to assess eryptosis and hemolysis in control and CEP-treated RBCs. Cells were labeled with Fluo4/AM and annexin-V-FITC to measure Ca²⁺ and phosphatidylserine (PS) exposure, respectively. Forward scatter (FSC) was detected to estimate cell size, and extracellular hemoglobin along with lactate dehydrogenase and aspartate transaminase activities were assayed to quantify hemolysis. Physiological manipulation of the extracellular milieu and various signaling inhibitors were tested to dissect the underlying mechanisms of CEP-induced RBC death. CEP increased PS exposure and hemolysis indices and decreased FSC in a concentration-dependent manner with prominent membrane blebbing. Although no Ca²⁺ elevation was detected, chelation of intracellular Ca²⁺ by BAPTA-AM reduced hemolysis. Whereas SB203580, D4476, acetylsalicylic acid, necrosulfonamide, and melatonin inhibited both PS exposure and hemolysis, staurosporin, L-NAME, ascorbate, caffeine, adenine, and guanosine only prevented hemolysis. Interestingly, sucrose had a unique dual effect by exacerbating PS exposure and reversing hemolysis. Of note, blocking KCl efflux augmented PS exposure while aggravating hemolysis only under Ca²⁺-depleted conditions. CEP activates Ca²⁺-independent pathways to promote eryptosis and hemolysis. The complex cytotoxic profile of CEP can be mitigated by targeting the identified modulatory pathways to potentiate its anticancer efficacy. Full article

Introduction: Breast cancer therapy is a common cause of lymphedema. The accumulation of protein-rich fluid in the affected extremity leads to a progressive path—swelling, inflammation, and fibrosis—namely, irreversible changes. Methods: A scientific literature analysis was performed on PubMed/Medline, Scopus, Web of Science (WoS), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Physiotherapy Evidence Database (PEDro) from inception until 30 June 2024. Results: Breast cancer-related lymphedema (BCRL) is indeed an important healthcare burden both due to the significant patient-related outcomes and the overall social impact of this condition. Even though lymphedema is not life-threatening, the literature underlined harmful consequences in terms of pain, infections, distress, and functional impairment with a subsequent and relevant decrease in quality of life. Currently, since there is no cure, the therapeutic approach to BCRL aims to slow disease progression and prevent related complications. A comprehensive overview of postmastectomy lymphedema is offered. First, the pathophysiology and risk factors associated with BCRL were detailed; then, diagnosis modalities were depicted highlighting the importance of early detection. According to non-negligible changes in patients’ everyday lives, novel criteria for patients’ functioning assessment are reported. Regarding the treatment modalities, a wide array of conservative and surgical methods both physiologic and ablative were analyzed with their own outcomes and downsides. Conclusions: Combined strategies and multidisciplinary protocols for BCRL, including specialized management by reconstructive surgeons and physiatrists, along with healthy lifestyle programs and personalized nutritional counseling, should be compulsory to address patients’ demands and optimize the treatment of this harmful and non-curable condition. The Lymphedema-specific ICF Core Sets should be included more often in the overall outcome evaluation with the aim of obtaining a comprehensive appraisal of the treatment strategies that take into account the patient’s subjective score. Full article

Migrastatic strategies are considered as candidate therapeutic approaches to suppress cancer invasion into local surrounding tissues and metastatic spread. The F-actin cytoskeleton is responsible for key properties regulating (cancer) cell migration. The cortical F-actin network controls cell stiffness, which, in turn, determines cell migration strategies and efficiency. Moreover, the dynamic remodeling of F-actin networks mediating filopodia, lamellipodia, and F-actin stress fibers is crucial for cell migration. Here, we have used a conditional knockout approach to delete cofilin, an F-actin-binding protein that controls severing. We find that the deletion of cofilin prevents the migration of cancer cells from tumoroids into the surrounding extracellular matrix without affecting their viability. This identifies cofilin as a candidate target to suppress metastatic spread. Pharmacological inhibitors interfering with F-actin dynamics have been developed but their effects are pleiotropic, including severe toxicity, and their impact on 3D tumor cell migration has not been tested or separated from this toxicity. Using concentration ranges of a panel of inhibitors, we select cytochalasins based on the suppression of 2D migration at non-toxic concentrations. We then show that these attenuate the escape of tumor cells from tumoroids and their migration into the surrounding extracellular matrix without toxicity in 3D cultures. This effect is accompanied by suppression of cell stiffness at such non-toxic concentrations, as measured by acoustic force spectroscopy. These findings identify cytochalasins B and D as candidate migrastatic drugs to suppress metastatic spread. Full article

Brain cancer is a heterogeneous collection of malignant neoplasms, such as glioblastoma multiforme (GBM), astrocytomas and medulloblastomas, with high morbidity and mortality. Its treatment is complicated by the tumor’s site, infiltrative growth mode and selective permeability of the blood–brain barrier (BBB). During tumor formation, the BBB dynamically remodels into the blood–brain tumor barrier (BBTB), disrupting homeostasis and preventing drug delivery. Furthermore, the TME (Tumor Micro Environment) supports drug resistance, immune evasion and treatment failure. This review points out the ways in which nanomedicine overcomes these obstacles with custom-designed delivery systems, sophisticated diagnostics and personalized therapies. Traditional treatments fail through a lack of BBB penetration, non-specific cytotoxicity and swift tumor adaptation. Nanomedicine provides greater drug solubility, protection against enzymatic degradation, target drug delivery and control over the release. Nanotheranostics’ confluence of therapeutic and diagnostic modalities allows for dynamic adjustment and real-time monitoring. Nanotechnology has paved the way for the initiation of a new era in precision neuro-oncology. Transcending the limitations of conventional therapy protocols, nanomedicine promises to deliver better outcomes by way of enhanced targeting, BBB penetration and real-time monitoring. Multidisciplinary collaboration, regulatory advancements and patient-centered therapy protocols customized to the individual patient’s tumor biology will be necessary to facilitate translation success in the future. Full article

Particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), and heavy metals (HMs) present in polluted air are strongly associated with an increased risk of respiratory diseases. In our study, we grouped cities based on their pollution levels using a method called Ward’s cluster analysis and looked at the increased cancer risk from PM₁₀-bound harmful substances for adult men and women living in Polish cities. The analysis was based on data from 8 monitoring stations where concentrations of PM₁₀, PAHs, and HMs were measured simultaneously between 2018 and 2022. The cluster analysis made it possible to distinguish three separate agglomeration clusters: cluster I (Upper Silesia, Wroclaw) with the highest concentrations of heavy metals and PAHs, with mean levels of lead 14.97 ± 7.27 ng·m⁻³, arsenic 1.73 ± 0.60 ng·m⁻³, nickel 1.77 ± 0.95 ng·m⁻³, cadmium 0.49 ± 0.28 ng·m⁻³, and ∑PAHs 15.53 ± 6.44 ng·m⁻³, cluster II (Warsaw, Łódź, Lublin, Cracow) with dominant road traffic emissions and low emissions, with average levels of lead 8.00 ± 3.14 ng·m⁻³, arsenic 0.70 ± 0.17 ng·m⁻³, nickel 1.64 ± 0.96 ng·m⁻³, and cadmium 0.49 ± 0.28 ng·m⁻³, and cluster III (Szczecin, Tricity) with the lowest concentration levels with favourable ventilation conditions. All calculated ILCR values were in the range of 1.20 × 10⁻⁶ to 1.11 × 10⁻⁵, indicating a potential cancer risk associated with long-term exposure. The highest ILCR values were reached in Upper Silesia and Wroclaw (cluster I), and the lowest in Tricity, which was classified in cluster III. Our findings suggest that there are continued preventive actions and stricter air quality control. The results confirm that PM₁₀ is a significant carrier of airborne carcinogens and should remain a priority in both environmental and public health policy. Full article

LC continues to be the leading cause of cancer mortality globally, among both males and females, representing a major public health challenge. The impact of mitochondria on human health and disease is a rapidly growing focus in scientific research, due to their critical roles in cellular survival and death. Mitochondria play an important role in controlling imperative cellular parameters, and alterations in mtDNAcn might be crucial for LC development. MtDNAcn has been studied as a possible marker for LC risk, but its role in prevention is still unclear. This review and meta-analysis aims to summarize the current evidence and provide an overall estimate of the relationship between the mtDNA copy number in human samples like blood and sputum. PubMed, Web of Science, and Scopus databases were used for studies published up to February 2024, following PRISMA and MOOSE guidelines. Studies were combined using a random-effects model, and we assessed the heterogeneity between studies with the chi-square-based Cochran’s Q statistic and the I² statistic. Publication bias was checked using Begg’s and Egger’s tests. Five studies, including a total of 3.748 participants, met the eligibility criteria. The MtDNA copy number was measured in blood or sputum samples and compared across different quantiles. The pooled analysis did not find a significant association between the mtDNA copy number and LC risk (OR = 0.94; 95% CI: 0.49–1.78). Moreover, when looking at different study designs, no significant results were found, due to the small number of studies available. No significant publication bias was detected. Further studies are needed to better understand the connection between the mtDNA copy number and LC risk and to better understand the role of potential confounders. Full article

Objectives: Persistent Human Papillomavirus (HPV) infection in the cervix and the preinvasive lesions it causes are significant risk factors for cervical cancer. Therefore, a treatment strategy is necessary to facilitate the clearance of HPV and prevent the progression of preinvasive lesions without causing cervical tissue destruction. This study aimed to evaluate the effectiveness of a vaginal adsorbent gel composed of a hydroxyethyl cellulose matrix formulation containing dispersed silicon dioxide, antioxidant sodium selenite, deflamin, and citric acid in patients with HPV infection. Methods: The study was designed as a retrospective cohort study and involved 449 women infected with HPV. For the purposes of the study, the patients were divided into two groups: the treatment group (TG) comprised 207 patients who used the vaginal gel daily for a period of three months, while the control group (CG), consisting of 242 patients, received no treatment under an “active surveillance” protocol. The study’s endpoints encompassed the domains of cytology, histology, and HPV clearance. Results: The regression rate of smear pathologies was 24.8% in the control group and 29.0% in the group using the vaginal adsorbent gel. In the first year, the histological regression rate in cervical biopsies was 49.3% in the treatment group and 19.4% in the control group, with a significant difference between groups (p < 0.001). Moreover, the clearance rate of HPV types was found to be significantly higher in the group using the vaginal adsorbent gel. Conclusions: The findings of this study suggest that the outpatient treatment approach can effectively prevent the oncogenic progression of cervical dysplasia. This alternative method has been shown to be efficacious in preventing the progression of cervical dysplasia and promoting regression. Furthermore, the efficacy of this gel in eradicating HPV has been demonstrated within a 12-month period. Full article

Breast cancer-related lymphedema (BCRL) is a debilitating complication in breast cancer survivors, with axillary lymph node dissection (ALND) as the greatest independent risk factor. Beyond non-surgical therapies such as complete decongestive and compression therapy, there has been increased interest in immediate microsurgical reconstruction via immediate lymphatic reconstruction (ILR) anastomosing transected lymphatic vessels to a local venous recipient at the time of ALND to mitigate the risks of BCRL. This work provides a scoping review of the landscape surrounding ILR, spanning the updated literature investigating patient outcomes, current accepted best practices, and critical components of surgical techniques for a successful multidisciplinary approach. While limited by heterogeneity in the methods of lymphedema detection, a growing body of work demonstrates the protective effects of ILR. From the pioneering work by Boccardo et al. in 2009 and his introduction of Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) using an intussusception-type end-to-end microanastmosis, to the first randomized control trial by Coriddi in 2023, which importantly employed relative upper extremity volume change as an outcome measure to circumvent the confounding effects of body size and BMI, the current literature supports ILR following ALND in the prevention of BCRL. Collaboration between the oncologic breast surgeon and reconstructive microsurgeon are central to the success of ILR. Critical components for operative success include preoperative and intraoperative lymphatic mapping, preservation of suitable venous targets, availability of supermicrosurgical instruments and sutures, as well as aptitude with a variety of microsurgical anastomotic techniques. Full article

Dual-drug delivery systems using hydrogel–nanoparticle composites have emerged as a versatile platform for achieving controlled, targeted, and efficient delivery of two distinct therapeutic agents. This approach combines the high loading capacity and tunable release properties of hydrogels with the enhanced stability and targeting ability of nanoparticles, providing synergistic benefits in various biomedical applications. While significant progress has been made, previous research has primarily focused on single-drug systems or simple co-delivery strategies, often lacking precise spatial and temporal control. This gap underscores the need for more sophisticated composite designs that enable programmable, multi-phase release. This review discusses representative fabrication methods, including physical embedding, covalent integration, and layer-by-layer assembly, to offer insights into practical implementation strategies. Also we present recent studies focusing on key applications—including wound healing, cancer therapy, infection prevention, transplant immunosuppression, and tissue regeneration—with an emphasis on composite design and formulation strategies, types of hydrogels and nanoparticles, and mechanisms of dual-drug release and evaluation. Recent advances in nanoparticle engineering and hydrogel formulation have enabled precise control over drug release and improved therapeutic outcomes. Dual-drug delivery systems using hydrogel–nanoparticle composites present a promising approach for overcoming the limitations of conventional monotherapy and achieving synergistic therapeutic effects. Ongoing research continues to optimize the design, efficacy, and safety of these systems, paving the way for their clinical translation. Full article

The global burden of respiratory viral infections is notable, which is attributed to their higher transmissibility compared to other viral diseases. Respiratory viruses are seen to have evolved resistance to available treatment options. Although vaccines and antiviral drugs control some respiratory viruses, this control is limited due to unexpected events, such as mutations and the development of antiviral resistance. The technology of proteolysis-targeting chimeras (PROTACs) has been emerging as a novel technology in viral therapeutics. These are small molecules that can selectively degrade target proteins via the ubiquitin–proteasome pathway. PROTACs as a therapy were initially developed against cancer, but they have recently shown promising results in their antiviral mechanisms by targeting viral and/or host proteins involved in the pathogenesis of viral infections. In this review, we elaborate on the antiviral potential of PROTACs as therapeutic agents and their potential as vaccine components against important respiratory viral pathogens, including influenza viruses, coronaviruses (SARS-CoV-2), and respiratory syncytial virus. Advanced applications of PROTAC antiviral strategies, such as hemagglutinin and neuraminidase degraders for influenza and spike proteins of SARS-CoV-2, are detailed in this review. Additionally, the role of PROTACs in targeting cellular mechanisms within the host, thereby preventing viral pathogenesis and eliciting an antiviral effect, is discussed. The potential of PROTACs as vaccines, utilizing proteasome-based virus attenuation to achieve a robust protective immune response, while ensuring safety and enhancing efficient production, is also presented. With the promises exhibited by PROTACs, this technology faces significant challenges, including the emergence of novel viral strains, tissue-specific expression of E3 ligases, and pharmacokinetic constraints. With advanced computational design in molecular platforms, PROTAC-based antiviral development offers an alternative, transformative path in tackling respiratory viruses. Full article