Search Results (2,392)

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

Objective: The accurate visualization of root canal systems on periapical radiographs is critical for successful endodontic treatment. This study aimed to evaluate and compare the effectiveness of several image enhancement algorithms—including a novel Total Variation–Contrast-Limited Adaptive Histogram Equalization (TV-CLAHE) technique—in improving the detectability of root canal configurations in mandibular incisors, using cone-beam computed tomography (CBCT) as the gold standard. A null hypothesis was tested, assuming that enhancement methods would not significantly improve root canal detection compared to original radiographs. Method: A retrospective analysis was conducted on 60 periapical radiographs of mandibular incisors, resulting in 420 images after applying seven enhancement techniques: Histogram Equalization (HE), Contrast-Limited Adaptive Histogram Equalization (CLAHE), CLAHE optimized with Pelican Optimization Algorithm (CLAHE-POA), Global CLAHE (G-CLAHE), k-Caputo Fractional Differential Operator (KCFDO), and the proposed TV-CLAHE. Four experienced observers (two radiologists and two dentists) independently assessed root canal visibility. Subjective evaluation was performed using an own scale inspired by a 5-point Likert scale, and the detection accuracy was compared to the CBCT findings. Quantitative metrics including Peak Signal-to-Noise Ratio (PSNR), Signal-to-Noise Ratio (SNR), image entropy, and Structural Similarity Index Measure (SSIM) were calculated to objectively assess image quality. Results: Root canal detection accuracy improved across all enhancement methods, with the proposed TV-CLAHE algorithm achieving the highest performance (93–98% accuracy), closely approaching CBCT-level visualization. G-CLAHE also showed substantial improvement (up to 92%). Statistical analysis confirmed significant inter-method differences (p < 0.001). TV-CLAHE outperformed all other techniques in subjective quality ratings and yielded superior SNR and entropy values. Conclusions: Advanced image enhancement methods, particularly TV-CLAHE, significantly improve root canal visibility in 2D radiographs and offer a practical, low-cost alternative to CBCT in routine dental diagnostics. These findings support the integration of optimized contrast enhancement techniques into endodontic imaging workflows to reduce the risk of missed canals and improve treatment outcomes. Full article

This study presents and discusses evidence on the value of biomarker testing and precision medicine in Latin America through a health equity lens. It is essential to explore how to harness the benefits of precision medicine to narrow the health equity gap, ensuring all patients have access to the best cancer treatment. The methodology employed to develop this document consists of a non-systematic literature review, followed by a process of validation and feedback with a group of experts in relevant fields. Precision medicine could help reduce health inequities in Latin America by providing better diagnosis and treatment for everyone with cancer. However, its success in achieving this depends on the implementation of policies that promote equitable access. Findings indicate that the current policy landscape in the Latin American region is not conducive to improving access, reach, quality, or outcome-related problems in cancer care, nor to realizing the full potential of precision medicine. The study explores how precision medicine can advance health equity, concluding with an analysis of the challenges and recommendations for overcoming them. Full article

Chemotherapy remains a cornerstone in the treatment of esophageal cancer (EC), yet chemoresistance remains a critical challenge, leading to poor outcomes and limited therapeutic success. Mitochondrial DNA (mtDNA) has emerged as a pivotal player in mediating these responses, influencing cellular metabolism, oxidative stress regulation, and apoptotic pathways. This review provides a comprehensive overview of the mechanisms by which mtDNA alterations, including mutations and copy number variations, drive chemoresistance in EC. Specific focus is given to the role of mtDNA in metabolic reprogramming, including its contribution to the Warburg effect and lipid metabolism, as well as its impact on epithelial–mesenchymal transition (EMT) and mitochondrial bioenergetics. Recent advances in targeting mitochondrial pathways through novel therapeutic agents, such as metformin and mitoquinone, and innovative approaches like CRISPR/Cas9 gene editing, are also discussed. These interventions highlight the potential for overcoming chemoresistance and improving patient outcomes. By integrating mitochondrial diagnostics with personalized treatment strategies, we propose a roadmap for future research that bridges basic mitochondrial biology with translational applications in oncology. The insights offered in this review emphasize the critical need for continued exploration of mtDNA-targeted therapies to address the unmet needs in EC management and other diseases associated with mitochondria. Full article

Background/Objectives: Nowadays, intravascular lithotripsy (IVL) has emerged as a novel technique for treatment of vascular calcifications, first in coronary and then in peripheral arteries. In the current literature there is little evidence that describes IVL as an effective and safe solution in treating severe aortic and aorto-iliac calcifications. The aim of this study is to report current available data about the use of IVL in treating aortic and aorto-iliac calcified lesions and its application in facilitating other endovascular procedures. Methods: the present review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Guidelines. Preliminary searches were conducted on MEDLINE and Pubmed from January 2015 to February 2025. Studies were divided into 3 main categories depending on the location of calcifications and the type of treatment: IVL in visceral and infrarenal obstructive disease (group 1), IVL in aorto-iliac obstructive disease (group 2), IVL used to facilitate other endovascular procedures. Main primary outcomes in the perioperative period were technical and clinical successes and perioperative complications. Primary outcomes at 30 days and mid-term (2 years) were overall survival, limb salvage rate, primary patency, primary assisted patency, secondary patency, and residual stenosis. Results: Sixteen studies were identified for a total of 1674 patients. Technical and clinical successes were 100%, with low rates of perioperative complications. Dissection rate reaches up to 16.1% in some studies, without any differences compared to plain old balloon angioplasty (POBA) alone (22.8%; p = 0.47). At 30 days, limb salvage and survival rates were 100%. At 2 years, primary patency, assisted primary patency, and secondary patency were 95%, 98%, and 100%, respectively, with no difference compared to IVL + stenting. Conclusions: IVL has emerged as a novel approach to treat severe calcified lesions in visceral and aorto-iliac atherosclerotic disease and to facilitate other endovascular procedures. This technique seems to offer satisfactory early and mid-term outcomes in terms of primary, primary assisted patency, and secondary patency with low complication rates. Full article

Background/Objectives: The advent of tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), achieving survival rates near those of the general population. Despite this success, prolonged therapy presents challenges, including physical, emotional, and financial burdens. Treatment-free remission (TFR), defined as sustained deep molecular response (DMR) after discontinuing TKIs, has emerged as a viable clinical goal. This study evaluates real-world data from the Canary Islands Registry of CML (RCLMC) to explore outcomes, predictors, and the feasibility of TFR. Methods: This retrospective observational study included 393 patients diagnosed with CML-CP between 2007 and 2023. Molecular response was monitored according to international guidelines. Survival probabilities were estimated using the Kaplan–Meier method. Logistic regression analysis was performed to identify predictors of molecular relapses after TKI discontinuation. Results: Of the 383 patients who received TKI treatment, 58.3% achieved molecular response grade 2 (MR2) (BCR-ABL1 ≤ 1%), 95.05% achieved MR2, and 50.5% reached MR4 within the first year. Of the 107 patients attempting TFR, 73.2% maintained remission at 36 months. Relapses occurred in 24 patients, all regaining molecular response upon reintroduction of TKIs. No cases of disease progression were observed. Conclusions: Our findings support the feasibility and safety of TFR in a real-world clinical setting for well-selected patients, with outcomes consistent with international studies. The study underscores the importance of molecular monitoring and patient-specific strategies to optimize outcomes. Full article

Objective: Cervical pregnancy (CP) accounts for less than 1% of all ectopic pregnancies. The standard of management for CP is still under detailed investigation; however, among the known treatment methods, super-selective uterine artery embolization (UAE) and the use of methotrexate (MTX) have emerged as effective and minimally invasive options in recent years. Our aim is to present our center’s experience and provide available evidence evaluating the efficacy of UAE in the treatment of CP. Materials and Methods: This single-center and retrospective study evaluated the procedural and clinical outcomes of patients with CP who underwent endovascular uterine embolization with MTX between 2017 and 2024. Both procedural and clinical efficacy and safety, as well as the rate of complications and long-term outcomes, were noted. Results: A total of nine patients were diagnosed with CP (imaging examination included transvaginal ultrasound and/or magnetic resonance imaging) and referred for endovascular treatment. The mean age of the patients was 36.7 years, and the mean gestational age on admission was 9 weeks. In all cases, selective catheterization of supplying vessels and subsequent embolization with a mixture of methotrexate and gel sponge was carried out. The technical success rate was 100% with no complications. Follow-up ultrasound confirmed the disappearance of the flow signal around the intracervical gestational sac in all cases. Conclusions: In conclusion, this retrospective study demonstrated the procedural and clinical safety and efficacy of uterine artery embolization in patients with cervical pregnancy. This is why endovascular therapy should be proposed to these individuals and be included in treatment options discussed during multidisciplinary boards. Full article

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, largely due to its profound intratumoral heterogeneity and immunosuppressive microenvironment. Various classifications of GBM subtypes were created based on transcriptional and methylation profiles. This effort, followed by the development of new technology such as single-nuclei sequencing (snRNAseq) and spatial transcriptomics, led to a better understanding of the glioma cells’ plasticity and their ability to transition between diverse cellular states. GBM cells can mimic neurodevelopmental programs to resemble oligodendrocyte or neural progenitor behavior and hitchhike the local neuronal network to support their growth. The tumor microenvironment, especially under hypoxic conditions, drives the tumor cell clonal selection, which then reshapes the immune cells’ functions. These adaptations contribute to immune evasion by progressively disabling T cell and myeloid cell functions, ultimately establishing a highly immunosuppressive tumor milieu. This complex and metabolically constrained environment poses a major barrier to effective antitumor immunity and limits the success of conventional therapies. Understanding the dynamic interactions between glioma cells and their microenvironment is essential for the development of more effective immunotherapies and rational combination strategies aimed at overcoming resistance and improving patient outcomes. Full article

Background: Diabetes mellitus is associated with worse outcomes after cardiac arrest. Hyperglycemia, diabetes treatments and other long-term sequalae may contribute to this association. We sought to determine the acute effect of diabetes on the return of spontaneous circulation (ROSC) and post-arrest cardiac function in a rat cardiac arrest model. Methods: Eighteen male Wistar rats were utilized, and 12 underwent the induction of type II diabetes for 10 weeks through a high-fat diet and the injection of streptozotocin. The carotid artery flow and femoral arterial pressure were measured. Seven minutes of asphyxial cardiac arrest was induced. An external cardiac compression was performed via an automated piston. Post-ROSC, epinephrine was titrated to a mean arterial pressure (MAP) of 70 mmHg. Data was analyzed using the Mann–Whitney test. The significance was set at p ≤ 0.05. Results: The rate of the ROSC was significantly lower in animals with diabetes, 50% compared to 100% in non-diabetics. Additionally, it took significantly longer to achieve the ROSC in diabetics, p = 0.034. In animals who survived, the cardiac function was reduced, as indicated by an increased epinephrine requirement, p = 0.041, and a decreased cardiac output at the end of the experiment, p = 0.017. The lactate, venous and arterial pressures, heart rate and carotid flow did not differ between groups at 2 h. Conclusions: Diabetes negatively affects the survival from cardiac arrest. Here, the critical difference was the rate of the conversion to a life-sustaining rhythm and the achievement of the ROSC. The post-ROSC cardiac function was depressed in diabetic animals. Interventions targeted at improving defibrillation success may be important in diabetics. Full article

Resistance to cytarabine (Ara-C) remains a major obstacle to the successful treatment of acute myeloid leukemia (AML). Therefore, modulating Ara-C resistance is indispensable for improving clinical outcomes. We previously demonstrated that sodium caseinate (SC), a salt derived from casein, the principal milk protein, inhibits proliferation and modulates the expression of Ara-C resistance-related genes in chemoresistant cells. However, it remains unclear whether the combination of SC with antineoplastic agents enhances apoptosis, modulates chemoresistance-related genes, and prolongs the survival of tumor-bearing mice implanted with chemoresistant cells. Here, we investigated the effects of SC in combination with Ara-C or daunorubicin (DNR) on cell proliferation, apoptosis, the expression of chemoresistance-associated genes, and the survival of tumor-bearing mice. Crystal violet assays, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, flow cytometry, and Kaplan–Meier survival curves were used to evaluate the effects of combinations in chemoresistant cells. We demonstrate that the IC₂₅ concentration of SC, when combined with antileukemic agents, increases the sensitivity of chemoresistant WEHI-CR50 cells to Ara-C by downregulating SIRT1 and MDR1, upregulating the expression of ENT1 and dCK, enhancing apoptosis, and prolonging the survival of WEHI-CR50 tumor-bearing mice. Our data suggest that SC in combination with antileukemic agents could be an effective adjuvant for Ara-C-resistant AML. Full article

Background and Objectives: Depression is a leading cause of disability globally, with treatment challenges including limited access, stigma, and poor adherence. Gamification, which applies game elements such as points, levels, and storytelling into non-game contexts, offers a promising strategy to enhance engagement and augment traditional treatments. Our research is the first study designed to explore the implementation of gamification within the Malaysian context. The objective was to explore the feasibility of implementation of gamification as an adjunctive treatment for adults with depression. Materials and Methods: Focus group discussions were held with five mental health professionals and ten patients diagnosed with moderate depression. The qualitative component assessed perceptions of gamified interventions, while quantitative measures evaluated participants’ depressive and anxiety symptomatology. Results: Three key themes were identified: (1) understanding of gamification as a treatment option, (2) factors influencing its acceptance, and (3) characteristics of a practical and feasible intervention. Clinicians saw potential in gamification to boost motivation, support psychoeducation, and encourage self-paced learning, but they expressed concerns about possible addiction, stigma, and the complexity of gameplay for some patients. Patients spoke of gaming as a source of comfort, escapism, and social connection. Acceptance was shaped by engaging storylines, intuitive design, balanced difficulty, therapist guidance, and clear safety measures. Both groups agreed that gamification should be used in conjunction with standard treatments, be culturally sensitive, and be presented as a meaningful therapeutic approach rather than merely as entertainment. Conclusions: Gamification emerges as an acceptable and feasible supplementary approach for managing depression in Malaysia. Its success depends on culturally sensitive design, robust clinical oversight, and seamless integration with existing care pathways. Future studies should investigate long-term outcomes and establish guidelines for the safe and effective implementation of this approach. We recommend targeted investment into culturally adapted gamified tools, including training, policy development, and collaboration with key stakeholders to realistically implement gamification as a mental health intervention in Malaysia. Full article

Background/Objectives: Anterior dental trauma in adolescents presents complex restorative challenges due to ongoing craniofacial development and high aesthetic expectations. This study evaluated the long-term clinical performance of feldspathic ceramic veneers and lithium disilicate crowns used in the anterior region following dental trauma in adolescents. Methods: A total of 209 restorations were placed in 85 adolescents (50 females, 35 males), aged 11.1–17.9 years (mean age: 15.1 years). Of these, 144 were lithium disilicate crowns, and 65 were feldspathic ceramic veneers. All restorations were fabricated using minimally invasive protocols and followed up for periods ranging from 3 to 60 months. Outcomes were assessed based on standardized clinical criteria for success and failure. Results: Lithium disilicate crowns exhibited superior long-term performance, with the majority of failures occurring in feldspathic veneers (p < 0.001), primarily due to chipping or structural fracture. Age and gender had no statistically significant influence on failure rates. Conclusions: Both feldspathic and lithium disilicate ceramic restorations represent viable treatment options for anterior dental trauma in adolescents. However, lithium disilicate demonstrates greater mechanical reliability, particularly in teeth with significant hard tissue loss. These results support the use of durable ceramic materials in adolescent restorative protocols involving dental trauma. Full article

Background: Peripancreatic collections (PPCs) are a frequent and severe complication of acute and chronic pancreatitis, as well as pancreatic surgery, often requiring interventions to treat and prevent infection, gastric obstruction, and other complications. Endoscopic ultrasound (EUS)-guided drainage has emerged as a minimally invasive alternative to surgical and percutaneous approaches, offering reduced morbidity and shorter recovery times. However, the effectiveness of EUS-guided drainage in post-surgical PPCs remains underexplored. Methods: This retrospective, single-center study evaluated the technical and clinical outcomes of EUS-guided drainage in patients with PPCs between October 2021 and December 2024. Patients were categorized as having post-pancreatitis or post-surgical PPCs. Technical success, clinical success, complications, recurrence rates, and the need for reintervention were assessed. Results: A total of 50 patients underwent EUS-guided drainage, including 42 (84%) with post-pancreatitis PPCs and 8 (16%) with post-surgical PPCs. The overall technical success rate was 100%, with clinical success achieved in 96% of cases. Lumen-apposing metal stents (LAMSs) were used in 84% of patients, including 7.1% as a dual-gate salvage strategy after the failure of double-pigtail drainage. The complication rate was 24%, with infection being the most common (16%). The recurrence rate was 25%, with no significant difference between post-pancreatitis and post-surgical cases. Patients with walled-off necrosis had a significantly higher reintervention rate (35%) than those with pseudocysts (18%; p = 0.042). Conclusions: EUS-guided drainage is a highly effective and safe intervention for PPCs, including complex post-surgical cases. The 100% technical success rate reinforces its reliability, even in anatomically altered post-surgical collections. While recurrence rates remain a consideration, EUS-guided drainage offers a minimally invasive alternative to surgery, with comparable outcomes in both post-pancreatitis and post-surgical patients. Future multi-center studies should focus on optimizing treatment strategies and reducing recurrence in high-risk populations. Full article

During red wine production, managing the pomace cap is key for a successful fermentation, allowing the extraction of phenolics and other metabolites and providing the necessary oxygen for yeast activity. In recent years, automatic cap management systems based on the injection of gases have gained popularity, despite the limited scientific information regarding the outcomes of their use. This trial aimed to evaluate the composition of wine during industrial red wine fermentations using an automatic sequential air injection system (i.e., AirMixing MI^TM). Fourteen lots of Cabernet Sauvignon grapes were fermented using four air injection regimes, where the intensity and daily frequency of air injections were set to either low or high. As expected, the treatment combining high-intensity and high-frequency air injection produced the largest dissolved oxygen peaks reaching up to 1.9 mg L⁻¹ per cycle, compared to 0.1 mg L⁻¹ in the low-intensity and low-frequency treatment. Yet, in all cases, little to no accumulation of oxygen overtime was observed. Regarding phenolics, the highest intensity and frequency of air injections led to the fastest increase in total phenolics, anthocyanins, short polymeric pigments, and tannin concentration, although compositional differences among treatments equilibrate by the end of fermentation. The main differences in phenolic compounds observed during fermentation were mediated by temperature variation among wine tanks. Based on these findings, it is advisable to keep the characterizing kinetics of phenolic extraction and expand the study to the aroma evolution of wines fermented with this technology. Full article

Introduction: The World Health Organization has declared carbapenem-resistant organisms a research and development priority. Although ceftazidime–avibactam was approved around a decade ago, there is still a lack of prospective data on the treatment of resistant pathogens with this agent. Methods: We conducted a prospective, observational, single-center, investigator-initiated study of patients treated with ceftazidime–avibactam for infections caused by carbapenem-resistant organisms. The primary outcome was clinical cure 14 days after the initiation of ceftazidime-avibactam treatment. Secondary outcomes, which were assessed on day 30, included microbiological failure, development of resistance, all-cause mortality, and length of stay in the intensive care unit. Results: A total of 50 patients were included in the study. At baseline, the median Charlson Comorbidity Index and Sequential Organ Failure Assessment Score were 5.5 and 7. Approximately three-quarters of the patients were treated in an intensive care unit and had undergone mechanical ventilation within the previous 7 days prior to the commencement of ceftazidime–avibactam treatment. Half of the patients were diagnosed with nosocomial pneumonia. Most infections were caused by Pseudomonas aeruginosa (48%) and Klebsiella pneumonia (28%). Clinical cure at day 14 was achieved in 59% of patients. Four deaths (9%) and two cases of microbiological failure (4%) were observed. The median length of stay in the intensive care unit was 14 days. There was no emergence of resistance to ceftazidime–avibactam. Discussion: Our study contributes to the growing body of evidence supporting the effectiveness of ceftazidime–avibactam in treating infections caused by carbapenem-resistant organisms. In this cohort of critically ill patients, our results in terms of both clinical success and survival are in the upper range compared to those from mainly retrospective and some prospective studies. Although the benefits of ceftazidime–avibactam have been demonstrated in this and other studies, it must be prescribed cautiously to ensure it remains effective. Full article