Search Results (127)

The ataxia–telangiectasia-mutated (ATM) protein plays a crucial role in the DNA damage response, particularly in the homologous recombination (HR) pathway. This study aimed to assess the impact of deleterious ATM variants on homologous recombination deficiency (HRD) and response to PARP inhibitors (PARPi) in melanoma patients, using a cell line established from melanoma tissue of a patient carrying the c.5979_5983del germline ATM variant. Despite proven loss of heterozygosity, lack of ATM activation, and HRD, our model did not show sensitivity to PARPi. We assessed the potential contribution of the Schlafen family member 11 (SLFN11) helicase, whose expression is inversely correlated with PARPi sensitivity in other cancers, to the observed resistance. The ATM mutant cell line lacked SLFN11 expression and featured hypermethylation-mediated silencing of the SLFN11 promoter. While sensitive to the ATR inhibitor (ATRi), the addition of ATRi to PARPi was unable to overcome the resistance. Our findings suggest that ATM mutational status and HRD alone do not adequately account for variations in sensitivity to PARPi in our model. A comprehensive approach is essential for optimizing the exploitation of DNA repair defects and ultimately improving clinical outcomes for melanoma patients. Full article

Objective: Craniopharyngioma recurrence risk studies comparing gross total resection (GTR) vs. subtotal resection (STR) with radiotherapy (XRT) provide inconclusive or contradictory results. This may be an effect of the small group sizes and diversity in the approaches used. Currently, the endoscopic endonasal approach (EEA) is preferred in craniopharyngioma management. Here, we aimed to perform a meta-analysis comparing recurrence risk after GTR vs. STR plus XRT in patients treated with the EEA regimen. Methods: We performed a systematic literature search of original English language papers on craniopharyngioma management published in the PubMed, Web of Science, and Scopus databases up to 18 October 2023. Eleven articles included data on recurrence rate after EEA: GTR vs. STR with XRT. We extracted the year of publication, number of patients, surgical approach, extent of resection, and follow-up duration. We used meta-analysis for the odds ratio (OR) in fixed and random effects models and Egger’s and Begg’s tests to assess heterogeneity and publication bias. Follow-up duration and time to recurrence were additionally included in Kaplan–Meier curves with log-rank test analysis. Results: We observed a lower recurrence rate in patients after GTR (10%) as compared to STR with XRT (30%), OR = 0.299, p < 0.001. To increase data reliability, we limited our analysis to studies with at least five patients in each subgroup and also observed lower recurrence in patients after GTR (12%) as compared to STR with XRT (27%), OR = 0.376, p = 0.011. Survival analysis confirmed significant differences in recurrence-free survival percentages between these groups (p = 0.008). Conclusions: To date, this is the largest meta-analysis evaluating the recurrence risk in patients undergoing EEA for craniopharyngioma resection, comparing outcomes between those treated with GTR and those treated with STR plus XRT. The results suggest that GTR significantly reduces recurrence risk. Full article

The Spanish Group for Cancer Immuno-Biotherapies (GÉTICA) held the X Forum on Translational Immunology and Cancer Immunotherapy (FIT Cancer 10) from 14 to 16 March 2024, in Seville (Spain). FIT Cancer is the largest meeting uniquely focused on cancer immunotherapy in Spain and brings together clinicians and researchers, with expertise in the field of cancer immunology and immunotherapy. Here, we present abstracts submitted by GÉTICA’s members to the X Forum on Translational Immunology and Cancer Immunotherapy, which were divided into three topics: cell-based immunotherapies, novel therapeutic targets and strategies and clinical scenarios and potential biomarkers. Full article

Lymphotoxin-alpha (LTα3) is a soluble cytokine of the TNF superfamily. Its role in inflammation and arthritis is not well known. Macrophages are important in K/BxN Serum-Transfer Arthritis (STA) and rheumatoid arthritis (RA). Anti-TNF monoclonal antibodies as well as etanercept (ETA), a soluble TNF receptor II that also neutralizes LTα3, are efficient in the treatment of RA. Objectives: To evaluate the role of LTα3 in macrophage phenotypes and in arthritis. Methods: Macrophages were cultured in the presence of recombinant LTα3, and their phenotypes were studied. The clinical effect of blocking LTα3 in STA was evaluated, as well as the effect of switching from anti-TNF monoclonal antibodies to etanercept in the “ROC” register of RA patients. Results: We showed that recombinant LTα3 was capable of directing mouse and human macrophages towards a pro-inflammatory “M1” phenotype. In K/BxN STA, ETA decreased clinical score and joint swelling. Anti-LTα3 reduced arthritis only in TNF-KO mice, indicating that the effect of LTα3 was visible in the absence of TNF. The “ROC” register indicated that switching anti-TNF mAb to ETA did not induce clinical and biological improvement in RA. Conclusion: We show a pro-inflammatory role for LTα3 in murine and human macrophages. The neutralization of both TNF and LTα3 is not beneficial in the treatment of RA. Full article

Autologous skin substitutes represent a promising advancement in the treatment of burn injuries, offering personalized solutions for patients with extensive skin loss. This white paper synthesizes the current knowledge on laboratory-generated autologous skin substitutes in Europe, incorporating expert opinions and legal considerations. The white paper examines the scientific principles underlying autologous skin substitute development, including cell sourcing, bioengineering techniques, and clinical applications. The regulatory framework governing the production and use of these advanced therapies in Europe is also examined, highlighting challenges in standardization, safety, and approval pathways. The text features expert insights that offer a real-world perspective on the clinical viability and translational hurdles of autologous skin substitutes. The findings highlight the potential of autologous skin substitutes to improve burn treatment outcomes while emphasizing the need for harmonized regulations to facilitate clinical implementation. Despite technological advancements, significant challenges persist, including production costs, scalability, and long-term efficacy. Another focus of this white paper are the legal changes, which have significantly impacted the production and availability of these technologies. The review concludes that while autologous skin substitutes hold great promise, further research, regulatory refinement, and interdisciplinary collaboration are essential to optimize their integration into clinical practice. Full article

Extracellular vesicles (EVs) are lipid bilayer-enclosed particles secreted by cells and ubiquitously present in various biofluids. They not only mediate intercellular communication but also serve as promising drug carriers that are capable of delivering therapeutic agents to target cells through their inherent physicochemical properties. In this review, we summarized the recent advances in EV isolation techniques and innovative drug-loading strategies. Furthermore, we emphasized the distinct advantages and therapeutic applications of EVs derived from different cellular sources in cancer treatment. Finally, we critically evaluated the ongoing clinical trials utilizing EVs for drug delivery and systematically assessed both the opportunities and challenges associated with implementing EV-based drug delivery systems in cancer therapy. Full article

Apical periodontitis may be associated with odontogenic sinusitis in cases where the apex of the root is close to, or even within, the maxillary sinus. This study investigated the anatomical relationship between the cortical sinus floor and the root apices of maxillary molars in relation to age and gender. Two hundred cone-beam computed tomography exams (FOV 5 × 5 cm or 8 × 8 cm) were evaluated to determine the proximity of the roots of the molars to the maxillary sinus, according to age group and gender. The maxillary second molar is the tooth with the closest contact with the maxillary sinus, mainly the mesial–buccal root. In maxillary first molars, the palatal root is the nearest one and sometimes lies inside the sinus. Considering the age factor, in the elderly group, lower distances were found for all roots for the male group. In the elderly group, the only difference was found in the female distobuccal root of tooth 16, which was found to be shorter than the males (p < 0.05). In conclusion, the distance between the cortical bone of the maxillary sinus and the root apices varies considerably, and smaller distances were found in older females and for the upper second molar, especially the mesial–buccal root. Full article

(1) Background: TNF inhibitors (TNFis) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30–40% of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFis have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor Nrf2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of six genes induced by Nrf2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3% accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine. Full article

Pheochromocytomas and paragangliomas (PPGLs) are infrequent neuroendocrine hypervascular neoplasms arising within different sites of the paraganglion system. They are divided into sympathetic (including pheochromocytomas and extraadrenal paragangliomas) and parasympathetic extraadrenal tumors. These tumors are usually not malignant and grow slowly; about 90% of them are found in the adrenal paraganglia (pheochromocytomas). Extraadrenal tumors are most frequently located in the abdominal cavity (85%), followed by the thoracic cavity (12%), and head and neck (3%). About 25% of PPGLs are related to germline mutations, which are risk factors for multifocal and metastatic disease. In PPGL diagnostics, laboratory, biochemical, and imaging (anatomical and functional) examinations are used. Surgery is the standard management choice for locoregional disease. For patients who are not candidates for surgery and who have stable, not-growing, or slow-growing tumors, active observation or other less invasive techniques (i.e., stereotactic surgery, hypofractionated stereotactic radiotherapy) are considered. In metastatic disease, systemic therapies (tyrosine kinase inhibitors [TKIs], mTORC1 inhibitor everolimus, immunotherapy, cold somatostatin analogs [biotherapy], and radioligand therapy) are used. The prognosis for PPGLs is quite good, and the 5-year survival rate is >90%. The goal of this paper is to review knowledge on the etiopathogenesis, current diagnostics, and therapy for PPGL patients. Our paper is particularly focused on the current management of PPGLs. Full article

Chemotherapy and radiotherapy, among other gonadotoxic treatments, can significantly affect ovarian reserve and function, potentially leading to premature ovarian insufficiency (POI) and sterility. With the increasing survival rates among young female cancer patients, fertility preservation (FP) has become an essential aspect of cancer care. The decision to pursue FP depends on various factors, including patient age, ovarian reserve, the type of treatment, and its gonadotoxic potential. Several FP strategies are available, including oocyte, embryo, and ovarian tissue cryopreservation. While oocyte and embryo cryopreservation are the gold standard techniques, ovarian tissue cryopreservation and in vitro maturation (IVM) present viable alternatives for patients who cannot undergo ovarian stimulation or for whom stimulation is contraindicated. Despite significant advances within the FP practice, challenges remain in ensuring timely FP counseling, equitable access to services, and optimizing long-term reproductive outcomes. Continued research is needed to refine existing FP techniques, explore innovative approaches, and address ethical considerations in FP decision-making. This review explores current FP options, their clinical applications, and future directions to improve reproductive outcomes in young women undergoing gonadotoxic treatments. Full article

Cancer is a major global health problem that poses significant challenges. Conventional cancer therapies often have severe side effects, necessitating the development of novel therapeutic approaches that are more effective and less toxic. The utilization of plant viral nanoparticles is one of the more promising strategies for cancer biotherapy. Plant viral nanoparticles exhibit advantageous properties, including safety, high stability, rapid production and scalability, biocompatibility and biodegradability, structural uniformity, inherent immunogenicity, ease of modification and high update efficacy as well as lower cost implications, making them attractive vehicles for health applications. Various studies have demonstrated the efficacy of plant viral nanoparticles in targeted therapeutic drug/molecule delivery, tumor imaging and immunotherapy, highlighting their potential as a versatile platform for cancer biotherapy. The drawbacks of plant viral nanoparticles include their perceived ability to induce a hypersensitive/allergic immune response, non-well-defined regulatory approval processes as well as the reluctance of pharmaceutical companies to adapt their manufacturing processes to facilitate plant-based expression. This review discusses applications of plant virus-derived nanoparticles in cancer therapeutics and prospects for translating these findings into clinical practice. Full article

Therapeutic education (TE) plays a central role in the management of chronic inflammatory rheumatic diseases and inflammatory bowel disease. The BIOSECURE questionnaire was developed and validated in 2012 to assess self-management and patient safety, initially in rheumatology. Objectives: The aim of our study was to assess the knowledge of patients followed in both rheumatology and gastroenterology regarding their treatment through the BIOSECURE questionnaire. The secondary objective was to identify factors associated with a low level of knowledge according to the BIOSECURE questionnaire. Methods: This was a descriptive observational study, conducted in a single center at the Reims University Hospital between January 2023 and April 2024. The population was divided into quartiles. Participation in therapeutic education (TE) included receiving brochures about their disease or treatment and/or participation in group or individual TE sessions. We compared the patients with the lowest scores to those with the highest scores. Results: The study population consisted of 312 patients, including 32.05% with rheumatoid arthritis (RA) and 29.81% with Crohn’s disease. In our population, 82.03% had participated in therapeutic education, which included a TE session and/or the distribution of brochures about their disease and/or treatment. The median [IQR] BIOSECURE score was 71.04/100 [IQR 61.77–81.9]. When comparing patients with a low BIOSECURE score (<61.77) to those with a high score (>81.9), univariate factors associated with a low score were older age (p = 0.02), less participation in therapeutic education (p = 0.01), shorter duration of targeted therapy (p = 0.01), and lower level of education (p < 0.05). Conversely, patients who had received therapeutic education had a higher BIOSECURE score (p = 0.01). There was no difference in BIOSECURE scores based on place of residence, location of patient follow-up, route of administration, or type of inflammatory disease. In a multivariate analysis with a model including age, TE participation, and duration of targeted therapy, the results remained significant (p < 0.05). Discussion: We were able to compare the results of our study with two other French studies previously conducted on the same population of 677 patients undergoing biotherapy for chronic inflammatory rheumatism. The median BIOSECURE score in those studies was 73/100. In the study by Rat AC, published in 2017, the population was divided based on their BIOSECURE questionnaire results into three groups; they compared high and low response levels. Similarly to our study, a lower educational level and unemployment were associated with a lower rate of correct responses. The same was true for the absence of therapeutic education (TE) or distribution of brochures. Conclusions: The analysis of the BIOSECURE questionnaire in our population provides a practical message: factors associated with a low BIOSECURE score include older age, lower educational level, recent initiation of targeted therapy, and lack of participation in therapeutic education. This population could be a priority target for TE in order to ensure treatment safety for these patients. Full article

Purpose: Currently, there is no clinical data reported on the therapy of dual biological agents in pediatric-onset inflammatory bowel disease (PIBD) patients in China. The purpose of this study was to evaluate the efficacy and safety of dual biologic therapy or biologics combined with small molecule drugs in refractory PIBD patients in China. Methods: Clinical, laboratory, endoscopic, and ultrasound data of PIBD patients from the Department of Gastroenterology of Beijing Children’s Hospital between January 2021 and October 2024 were retrospectively analyzed. PIBD patients who received dual biologic treatment or a combination of biologic and small molecule therapy were included in this study. Steroid-free clinical remission and adverse events were recorded. Results: In this retrospective study, out of 520 children with IBD, twelve children (2.3%) were diagnosed with refractory PIBD and met the criteria for dual biotherapy, including four with UC (33%) and eight with CD (67%). The median age of patients was 13.64 (range, 1.2–17.1) years at eligibility for dual biologic therapy. There are eight (67%) patients treated with infliximab/ustekinumab (IFX + UST), three (25%) patients with upadacitinib/ustekinumab (UPA + UST), one (8%) patient with infliximab/vedolizumab (IFX + VDZ). At 3, 6, and 12 months of dual biological treatment, 91.2% (11/12), 100% (12/12), and 100% (12/12) patients showed steroid-free clinical remission, respectively. The median fecal calprotectin decreased significantly from 1852.5 µg/g (IQR, 762.5–1988.25) at baseline to 359.0 (IQR, 217.5–730.25) μg/g at 3 months, 113 (IQR, 73.7–256) μg/g at 6 months, and 82.5 (IQR, 40.25–122.25) μg/g at 12 months. Only one CD patient with IFX + UST reported mild elevation of aminotransferase, who recovered after symptomatic treatment. Conclusions: Dual biologic or small molecule therapy may be effective and safe for children with refractory PIBD in China. Full article

(1) Background: Inflammatory bowel diseases (IBDs) are characterized by chronic and complex inflammatory processes of the digestive tract that evolve with frequent relapses and manifest at any age; they predominantly affect young individuals. Diet plays a direct role in maintaining the gut mucosal integrity and immune function. Regarding the diet, the administration of probiotics stands out. The use of probiotics for IBD treatment has shown promising effects on consumers’ quality of life. (2) Methods: This study aimed to conduct a literature review on the effects of probiotic and smart probiotic ingestion on IBD and analyze the available literature based on the searched keywords using boxplot diagrams to search for scientific data in the online literature published up to October 2024. (3) Results: Google Scholar (containing ~6 × 10⁶ articles) and Science Direct (containing ~5 × 10⁶ articles) were the databases with the highest number of articles for the keywords used in the study. When analyzing the content of the articles, although probiotic microorganisms are currently not part of the standard treatment protocol for IBD, these live biotherapeutics have proven to be an effective treatment option, considering the adverse effects of conventional therapies. Furthermore, the development of genetically engineered probiotics or smart probiotics is a promising treatment for IBD. (4) Conclusions: Probiotics and smart probiotics could represent the future of nutritional medicine in IBD care, allowing patients to be treated in a more natural, safe, effective, and nutritious way. However, although many studies have demonstrated the potential of this biotherapy, clinical trials standardizing dosage and strains are still necessary. Full article

To analyze the role of disulfidptosis in ulcerative colitis (UC), large-scale datasets combined with weighted gene co-expression network analysis (WGCNA) and machine learning were utilized and analyzed. When the hub genes that are associated with UC disease phenotypes and have predictive performance were identified, immune cell infiltration and the CeRNA network were constructed, the role of hub genes in UC pathogenies and biotherapy were investigated, and molecular docking studies and mice-verified tests were carried out to further explore the potential core genes and potential target. Finally, we found 21 DRGs involved in UC pathogenesis, including SLC3A2, FLNA, CAPZB, TLN1, RPN1, etc. Moreover, SLC3A2, TLN1, and RPN1 show a notable correlation with UC inflammatory state, and the expression of DRGs is closely related to the response to UC biotherapy. Our study suggests that disulfidptosis plays a crucial role in the pathogenesis and disease progression of UC. Higher expression of DRGs is commonly observed in moderate to severe UC patients, which may also affect their response to biologic therapies. Among the identified genes, SLC3A2 stands out, providing new insights into the underlying mechanisms of UC and potentially serving as a novel therapeutic target for the treatment of UC. Full article