Significant Side Effects Research Articles (Page 1)

Radiotherapy (RT) is a commonly employed treatment in oncological setting. Unfortunately, the therapeutic dose required for tumor control often induces significant side effects in normal tissues, leading to suboptimal outcomes and reduced patient quality of life. FLASH radiotherapy (FLASH-RT) is distinguished by its exceptionally high dose rates, surpassing 40 Gy/s. This advancement has emerged as a promising innovation in the field of cancer treatment. Indeed, FLASH-RT may reduce normal tissue toxicity compared to conventional radiotherapy (CONV-RT) while maintaining tumor control. Here, FLASH-RT and CONV-RT have been compared in an alternative embryonic model of pancreatic carcinoma, a cancer type with poor prognosis and limited therapeutic options. The chorioallantoic membrane models (CAMs) have been employed to assess the tumor control and the treatment toxicity by analyzing the embryo survival. FLASH-RT exhibited significantly reduced off-target toxicity on the embryos, as evidenced by the embryonic growth analysis and histopathological analysis. The tumor control outcomes were comparable between FLASH-RT and CONV-RT, confirming the iso-efficacy between the two strategies. These findings confirm the paradigm-shifting potential of FLASH-RT to enhance the therapeutic ratio, particularly in anatomically complex and radioresistant tumors such as pancreatic carcinoma, warranting further investigation in clinical settings. Additionally, a solid embryonic in vivo model has been introduced for comprehensive investigations on emerging radio-treatment approaches. While further investigations are necessary to optimize dose delivery and evaluate long-term outcomes, this research underscores the transformative promise of FLASH-RT in redefining radiotherapy standards for challenging malignancies.

The purpose of this study is to estimate the prevalence and factors associated with fear of cancer recurrence (FCR) in post-menopausal women 5years after the diagnosis of breast cancer (BC). Using data from the VICAN-5 survey, we included women with non-metastatic BC, aged 55years or more at diagnosis, who had not experienced disease progression in the 5years post-diagnosis. Multinomial logistic regression was used to identify factors associated with FCR, characterized using a three-level indicator: no, mild, and moderate/severe FCR derived from a single item. Among the 382 women included, the mean age was 66years at diagnosis. Five years later, 38% of women were still receiving adjuvant endocrine therapy (AET), and 27% were no longer on AET. Overall, 34.8% reported mild FCR, and 14.2% reported moderate/severe FCR. Cancer-related sequelae, anxiety, and a decrease in physical activity were associated with mild or moderate/severe FCR. Moderate/severe FCR was also more often reported by women still on AET experiencing significant side effects and those who had never taken AET. Mild FCR was more frequent in the two-thirds of women consulting a GP for the management of their cancer. Moderate/severe FCR affected one out of seven post-menopausal BC survivors 5years after diagnosis, particularly those with anxiety, cancer sequelae, physical limitations, significant side effects of AET, but also among those who had never taken AET. BC survivors should be informed of long-term side effects of treatments, in particular AET, to help them cope with ongoing symptoms and related FCR.

Background: Primary headaches are common in pediatric age and can significantly impact children's quality of life especially when they have a high frequency. Best practices in headache management involve a multidisciplinary approach combining pharmacological and non-pharmacological strategies. Among the latter, psychological interventions targeting cognitive, behavioral, and emotional factors have shown efficacy in reducing migraine-related pain, distress, and disability. Mindfulness is a recent behavioral approach that offers an effective option for adolescents with headache, helping reduce pain and disability by increasing awareness and teaching techniques alternative to medications. Methods: This is a prospective study involving patients aged 11–18 years, referred to four juvenile headache centers and meeting defined inclusion and exclusion criteria. Selected patients participated in eight weekly online 1-hour sessions of guided mindfulness-based meditation combined with education on healthy lifestyle habits to prevent or reduce the impact of headache. Follow-up assessments are scheduled at 3, 6 and 12 months, including clinical evaluations and standardized questionnaires completed by both patients and parents. Results: Twenty-eight adolescents with frequent primary headaches (migraine or tension-type headache) were enrolled. The intervention demonstrated good feasibility with high participation and adherence rates to the weekly sessions. Only 3 participants have dropped out, with an overall adherence rate of 89.3%. No significant side effects were reported; in one case, dropout was due to increased anxiety. In preliminary analysis, patients reported a subjective impression of global improvement. We expect positive changes in standardized tests at 3, 6 and 12-months follow up. Conclusion: This study investigated a well-tolerated, promising and feasible behavioral intervention for adolescents with high-frequency primary headaches. Our preliminary results showed high compliance and favorable disease progression in our population, demonstrating that mindfulness (made online in small groups) is a valuable and safe approach in adjunct to preventive drugs.

Parkinson's disease remains a progressive and debilitating neurodegenerative disorder with limited therapeutic options that can modify disease progression. While conventional treatments like levodopa alleviate motor symptoms, they often fall short in addressing long-term neurodegeneration and may lead to significant side effects. Recent advances in regenerative medicine have highlighted the potential of combining stem cell therapy with Brain-Derived Neurotrophic Factor (BDNF) enhancement as a synergistic approach to restore dopaminergic function and promote neuronal survival. Stem cells not only offer the capacity to replace lost neurons but can also serve as delivery vectors for sustained BDNF expression, amplifying neuroprotective effects through Tropomyosin receptor kinase B-mediated signaling pathways. Preclinical studies in animal models demonstrate that this combined strategy enhances motor recovery, reduces neuroinflammation, and promotes neural circuit integration. As the field progresses, this dual therapy holds great promise for transforming the future management of Parkinson's disease by offering both symptomatic relief and disease modification.

Essential tremor (ET) is a common movement disorder, characterized by bilateral postural or kinetic tremor and associated non-motor symptoms including anxiety and cognitive impairment. Current treatments offer limited efficacy and significant side effects, highlighting the need for novel therapeutic approaches. This study investigated the therapeutic potential of memantine and vitamin D3 (vitD3) combination therapy in a harmaline-induced mouse model of essential tremor. Adult male Swiss mice were divided into eight groups (n = 8/group): control, sham, harmaline-induced ET (10mg/kg, i.p. on days 1, 3, and 5), memantine (5mg/kg, i.p. for 7days), vitD3 (0.1µg/kg, i.p. for 7days), and combination treatment groups. Tremor severity, footprint analysis, rotarod, and wire grip tests were conducted to assess motor function. Moreover, anxiety-like behavior, depressive-like behavior, and cognitive function were examined. Expression of leucine-rich repeat and immunoglobulin domain-containing protein 1 (Lingo-1) and NMDA receptor expression in cerebellar tissue was evaluated using quantitative real-time PCR. Histological evaluation of Purkinje cell morphology was performed using hematoxylin-eosin staining. Harmaline administration induced significant tremor, motor coordination deficits, anxiety-like behaviors, and cognitive impairments. Treatment with memantine and/or vitD3 significantly reduced tremor scores on days 3 and 5 compared to harmaline alone. Combination therapy restored locomotor activity. Both individual and combination treatments demonstrated significant anxiolytic effects. VitD3 alleviated depressive-like behavior. Moreover, cognitive assessment revealed that combination therapy significantly improved passive avoidance learning and memory retention. Harmaline dramatically upregulated Lingo-1 and NMDA receptor expression, which was effectively normalized by memantine and/or vitD3 treatment. Histological examination demonstrated that vitD3 and combination therapy significantly reduced harmaline-induced Purkinje cell degeneration. Memantine and vitD3 combination therapy ameliorates both motor and non-motor symptoms in a mouse model of ET through modulation of Lingo-1 and NMDA receptor expression pathways. These findings suggest that this combination approach represents a therapeutic strategy that addresses the complex pathophysiology of ET while providing neuroprotective benefits.

Iron-deficiency anemia (IDA) is a prevalent global health concern, with nonheme iron salts being the most commonly used iron supplementation therapies. However, these therapies are associated with significant side effects and poor efficacy due to interactions with dietary components. Heme iron, which is less susceptible to such interactions, holds promise as an alternative, but suffers from high individual variability in clinical efficacy. This study systematically investigates the biopharmaceutical properties of hemin and identifies its poor solubility and permeability, classifying it as a Class IV drug with low oral bioavailability, which may explain its suboptimal clinical performance. To overcome this limitation, we developed a hemin-loaded nanoparticle formulation (HNP) to enhance the oral bioavailability and therapeutic efficacy of hemin. The formulation is simple to produce, with a high drug loading capacity (30%), and significantly improves the solubility and permeability of hemin. In rats, the HNP increased the relative bioavailability of hemin by 6.5 times. In vivo studies in an IDA mouse model demonstrated that HNP effectively improved anemia-related indicators, such as the red blood cell count, hemoglobin levels, and hematocrit while also alleviating gastrointestinal inflammation. Additionally, HNP administration restored the diversity and abundance of gut microbiota, which is often impaired in IDA. With excellent safety and biocompatibility, HNP represents a promising oral formulation for the treatment of IDA, offering a potential strategy to enhance heme iron bioavailability and reduce individual variability in therapeutic outcomes.

Introduction: SGLT-2 inhibitors, initially intended to treat diabetes, have had efficacy in adult trials to reduce mortality and morbidity with heart failure (HF). This mediations were recently added to GDMT guidelines for adults with HF in 2022. FDA has approved SGLT 2 inhibitors in children aged 10 years and older with type 2 diabetes. In pediatric congenital heart disease (CHD) patients with HF, there is a scarcity of data for the safety and efficacy of SGLT-2 inhibitors, as well as adults with CHD (ACHD) who have developed HF. The purpose of this systematic review is to understand if SGLT-2 inhibitors have the appropriate safety, tolerability, and efficacy in these specific patient populations. Methods: The articles selected for this review were case series, case-control studies, prospective&retrospective cohort reviews, and randomized controlled trials. Articles that were selected had study populations of either pediatric patients (ages 0-18) in heart failure and/or congenital heart disease, or adult patients, older than 18 years with congenital heart disease (ACHD). The articles were searched in all the major search engines, PubMed, Web of Science, Embase, and the Cochrane Library using designated key words. Results: A total of 632 articles were found from databases. From this initial number, 21 specific articles fit the eligibility criteria and were included in the systematic review from 2022-2024. In total, SGLT2 inhibitors was used in 157 pediatric and 433 adult patients with CHD based on published literature. 30% (n=47) of pediatric patients had side effects (SE) related to SGLT-2i, whereas 6% (n=26) of adults in studies had the side effects. The most common documented side effects were glycosuria, UTI’s, and abdominal pain. None of the patient developed DKA or hypoglycemia. No deaths were reported and no significant changes were seen in renal funtion and GFR. Efficacy data is available in only 48 patients so far and 29 patients had significant symptomatic improvement, 3 patients had significant improvement in systemic ventricular ejection fraction, and 18 had significant drop in BNP levels. Conclusion: This is the first systematic review of SGLT2 inhibitors in pediatric patients with heart failure and adults with congenital heart disease. SGLT-2 inhibitors appear to be safe, and efficacious so far with no significant side effect profile in pediatric patients with CHD associated heart failure and adult patients with ACHD.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, predominantly affecting the elderly. Current treatments rely mainly on corticosteroids and immunosuppressive agents but are often limited by significant side effects. Omalizumab, an anti-IgE monoclonal antibody, has emerged as a promising off-label therapy for BP, but predictive markers for treatment response remain poorly understood. This study evaluates the efficacy and safety of omalizumab in BP and explores potential predictors of response, with a focus on tissue eosinophil counts. A retrospective analysis of 27 patients with severe BP treated with omalizumab was conducted. Complete remission (CR) was achieved in 63% of patients, partial remission (PR) in 18.5%, and no response/flare-up in 18.5%. The median total number of omalizumab doses was six (range 6-12), and 70.4% of patients received biweekly dosing. Notably, responders had significantly higher median tissue eosinophil counts (p = 0.040) than non-responders. No significant correlation was observed between treatment response and variables such as age, gender, disease duration, or blood eosinophil counts. Our findings suggest that tissue eosinophil levels may serve as a reliable predictor of omalizumab response in BP (Z = -2.034, p = 0.040). Omalizumab demonstrated significant efficacy with minimal adverse effects, as only one patient reported a mild side effect (tickling sensation in the throat). While the study's single-center design and small sample size limit generalizability, it provides valuable insights into potential predictive markers and supports omalizumab as a safe and effective treatment option for BP.

Curvilinear sprint acceleration-speed profile in youth soccer players is constrained by tighter radii and sprinting side dominance.

Pulmonary delivery of small circular RNA vaccines for influenza prevention.

Lactate-mediated immune suppression and MDSC expansion in endometriosis: Mechanisms and nanoparticle-targeted therapies.

Multifunctional hydrogel for the treatment of atopic dermatitis: current advances and translational challenges.

Combined nanodiamond-mediated drug delivery and upconversion phototherapy for enhanced liver cancer treatment.

Light-responsive coumarin-functionalised nanogels for metformin delivery.

Nanozyme-synbiotics to improve iron-deficiency anemia.

As the threat of multidrug-resistant Klebsiella pneumoniae strains rises, the potential of phages as promising alternatives to antibiotics is increasingly being demonstrated. In this study, we isolated and characterized phiK2044, a highly specific and efficient lytic phage targeting the model strain K. pneumoniae NTUH-K2044. Demonstrating wide host compatibility, potent lytic activity, and robust environmental adaptability, phiK2044 exhibited exceptional efficacy against hypervirulent subtypes, including hypervirulent K. pneumoniae (45.2%), sequence type 23 (87.5%), and capsular K1 (92.3%). In the mouse model, phiK2044 effectively cleared bacteria without significant side effects, highlighting its therapeutic potential. Mechanistically, we identified wcaJ, a gene encoding a glycosyltransferase essential for capsular synthesis, as the critical determinant of the binding of phiK2044 to the host. Beyond its clinical utility, phiK2044 represents a model for studying phage ecology, host-microbe interactions, and capsule-dependent tropism. Collectively, phiK2044 represents a valuable tool against ST23/K1 K. pneumoniae infections, such as liver abscesses and bacteremia.IMPORTANCEThe rise of multidrug-resistant Klebsiella pneumoniae demands innovative therapies. This study identifies phiK2044, a lytic phage with high specificity and efficacy against hypervirulent subtypes. It safely clears infections in mice and reveals wcaJ-dependent capsule synthesis as the key host interaction mechanism. Beyond its therapeutic promise, phiK2044 serves as a critical tool for studying phage-host dynamics and capsule-mediated tropism, bridging clinical solutions and fundamental research in combating antimicrobial resistance.

Background: Immunosuppressive drugs are critical for managing organ transplantation and autoimmune diseases by targeting aberrant T lymphocyte activation and immune responses. However, existing therapies often cause significant side effects, driving the urgent need for safer alternatives. Natural products, particularly from marine-derived sources like mangrove endophytic fungi, have emerged as promising candidates due to their bioactive diversity and minimal toxicity profiles. Methods: To explore this potential, this study investigated pestalotiopyrone M (PyM), a new pyrone derivative obtained from the endophytic fungus Pestalotiopsis sp. HHL101, which was isolated from the Chinese mangrove plant Rhizophora stylosa. Its immunosuppressive activity targeting calcineurin (CN) was evaluated, and spleen cell viability was tested by CCK-8. The effects of PyM on T cell proliferation were assessed using Con A-induced splenocyte proliferation and unidirectional mixed lymphocyte response (MLR) models. Cell cycle and apoptosis analysis were performed to determine potential cytostatic effects. Additionally, the impact of PyM on NFAT1 dephosphorylation, translocation, and subsequent cytokines secretion (IL-2, IL-4, TNF-α, and IFN-γ) was examined in ConA-stimulated cells. Results: We verified that PyM obviously inhibited Con A-induced splenocyte proliferation and unidirectional MLR. Crucially, it demonstrated markedly reduced cytotoxicity, exhibiting approximately 38-fold lower cytotoxic effects compared to the clinically used drug CsA. It arrested the cell cycle from G1-phase to S-phase and G2-phase. Furthermore, we confirmed that PyM suppressed ConA-stimulated activation of NFAT1 dephosphorylation and blocked NFAT1 translocation in vitro, subsequently inhibiting the transcription and expression of IL-2, IL-4, TNF-α, and IFN-γ. Conclusions: These results indicate that PyM is an efficient inhibitor of the CN/NFAT signaling pathway. It shows promising immunosuppressive activity by targeting T cell activation and proliferation, indicating its potential as a candidate for development into an immunosuppressive agent for treating adverse immune responses.

Metabolic reprogramming is a hallmark of cancer, essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes and inhibiting this pathway has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable due to significant side effects. Thus, repurposing safe FDA-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles predicting treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in ROS levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, co-treatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, while iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

Bladder cancer is a common malignancy with high rates of recurrence and progression. Chemotherapy is employed at various stages of treatment to improve patient outcomes and survival; however, it is sometimes ineffective and often associated with significant side effects. Moreover, growing evidence suggests that chemotherapy may paradoxically enhance tumor invasiveness and metastatic potential in certain cancer types. These concerns underscore the need to better understand the impact of chemotherapy and to develop personalized prognostic strategies for managing bladder cancer. Here, we present an organoid biosensing platform designed to evaluate chemotherapy-induced effects in a patient-specific manner. Freshly isolated tumor organoids and self-assembled microtumors derived from transurethral resection of bladder tumors are cultured within a tumor-on-gel biomimetic microenvironment. By integrating live single cell nanobiosensors with 3D time-lapse microscopy, the platform enables real-time detection of molecular biomarkers and rapid assessment of tumor invasiveness. We demonstrate the platform's capability to evaluate cisplatin-induced invasion in bladder cancer organoids at the individual patient level. These findings highlight the potential of this organoid biosensing system to investigate patient-specific risks of chemotherapy-induced invasion and to guide more personalized approaches to bladder cancer treatment.

Natural products in the treatment of autoimmune hepatitis: A comprehensive review of therapeutic potential and mechanisms.