Search Results (437)

Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor “N1” or protumor “N2” phenotypes, exerting diverse effects on tumor growth, metastasis, immune modulation, and treatment response. While previous studies have focused on the pathological roles of TANs in cancer, less attention has been given to how cancer therapies themselves influence the behavior of TANs. This review provides a comprehensive synthesis of current knowledge regarding the dynamics of TANs in response to major cancer treatment modalities, including chemotherapy, radiotherapy, cell-based immunotherapies, and oncolytic viral and bacterial therapies. We discuss how these therapies influence TAN recruitment, polarization, and effector functions within the TME, and highlight key molecular regulators involved. By consolidating mechanistic and translational insights, this review emphasizes the potential to therapeutically reprogram TANs to enhance treatment efficacy. A deeper understanding of context-dependent TAN roles will be essential for developing more effective, neutrophil-informed cancer therapies. Full article

Alagille syndrome (ALGS) is a multisystem disorder characterized by a paucity of intrahepatic bile ducts and cholestasis, often requiring liver transplantation before adulthood. Due to the lack of genotype–phenotype correlation, case series are essential to understand disease presentation and prognosis. Data on Mexican ALGS patients are limited. Therefore, we aimed to characterize a large series of Mexican patients by consolidating cases from major institutions and independent geneticists, with the goal of generating one of the most comprehensive cohorts in Latin America. We retrospectively analyzed clinical records of pediatric ALGS patients, focusing on demographics, clinical features, laboratory and imaging results, biopsy findings, and transplant status. Genetic testing was performed for all cases without prior molecular confirmation. We identified 52 ALGS cases over 13 years; 22 had available clinical records. Of these, only 6 had molecular confirmation at study onset, prompting genetic testing in the remaining 16. We identified six novel JAG1 variants and several previously unreported phenotypic features. A liver transplantation rate of 13% was observed in the cohort. This study represents the largest molecularly confirmed ALGS cohort in Mexico to date. Novel genetic and clinical findings expand the known spectrum of ALGS and emphasize the need for improved therapies, such as IBAT inhibitors, which may alleviate symptoms and reduce the need for transplantation. Full article

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

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial–mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022–2024) and highlights isorhamnetin’s roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin’s delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies. Full article

Precision neurosurgery is rapidly evolving as a medical specialty by merging genomic medicine, multi-omics technologies, and artificial intelligence (AI) technology, while at the same time, society is shifting away from the traditional, anatomic model of care to consider a more precise, molecular model of care. The general purpose of this review is to contemporaneously reflect on how these advances will impact neurosurgical care by providing us with more precise diagnostic and treatment pathways. We hope to provide a relevant review of the recent advances in genomics and multi-omics in the context of clinical practice and highlight their transformational opportunities in the existing models of care, where improved molecular insights can support improvements in clinical care. More specifically, we will highlight how genomic profiling, CRISPR-Cas9, and multi-omics platforms (genomics, transcriptomics, proteomics, and metabolomics) are increasing our understanding of central nervous system (CNS) disorders. Achievements obtained with transformational technologies such as single-cell RNA sequencing and intraoperative mass spectrometry are exemplary of the molecular diagnostic possibilities in real-time molecular diagnostics to enable a more directed approach in surgical options. We will also explore how identifying specific biomarkers (e.g., IDH mutations and MGMT promoter methylation) became a tipping point in the care of glioblastoma and allowed for the establishment of a new taxonomy of tumors that became applicable for surgeons, where a change in practice enjoined a different surgical resection approach and subsequently stratified the adjuvant therapies undertaken after surgery. Furthermore, we reflect on how the novel genomic characterization of mutations like DEPDC5 and SCN1A transformed the pre-surgery selection of surgical candidates for refractory epilepsy when conventional imaging did not define an epileptogenic zone, thus reducing resective surgery occurring in clinical practice. While we are atop the crest of an exciting wave of advances, we recognize that we also must be diligent about the challenges we must navigate to implement genomic medicine in neurosurgery—including ethical and technical challenges that could arise when genomic mutation-based therapies require the concurrent application of multi-omics data collection to be realized in practice for the benefit of patients, as well as the constraints from the blood–brain barrier. The primary challenges also relate to the possible gene privacy implications around genomic medicine and equitable access to technology-based alternative practice disrupting interventions. We hope the contribution from this review will not just be situational consolidation and integration of knowledge but also a stimulus for new lines of research and clinical practice. We also hope to stimulate mindful discussions about future possibilities for conscientious and sustainable progress in our evolution toward a genomic model of precision neurosurgery. In the spirit of providing a critical perspective, we hope that we are also adding to the larger opportunity to embed molecular precision into neuroscience care, striving to promote better practice and better outcomes for patients in a global sense. Full article

We present a 48-year-old female with a past medical history of endometrioid adenocarcinoma who presented with symptoms of spontaneous gum bleeding, post-coital bleeding, and upper extremities–lower extremities-abdomen ecchymosis. Initial laboratory findings were significant for cytopenia and disseminated intravascular coagulation (DIC). Due to a suspected case of acute promyelocytic leukemia (APL), conventional karyotyping and fluorescence in situ hybridization (FISH) were performed. FISH analysis confirmed an unusual chromosome rearrangement that affected chromosomes 3, 15, and 17. This t(3;15;17)(q29;q24;q21) was characterized by the presence of PML::RARA fusion on the derivative chromosome 15. Treatment at the hospital with standard APL therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) was complicated by the development of differentiation syndrome, which necessitated the temporary stoppage of ATO. However, complete remission was achieved despite complications after starting consolidation treatment. Full article

Background: Consolidation therapy with durvalumab after definitive chemoradiotherapy (CRT) has become the standard care for patients with stage III non-small-cell lung cancer (NSCLC) following the PACIFIC trial. However, real-world data evaluating outcomes under routine clinical conditions remain limited, particularly in European cohorts. Methods: In this retrospective single-center study, we analyzed clinical data from 72 patients with stage III NSCLC treated with definitive CRT between 2017 and 2022. The patients were stratified by receipt of durvalumab consolidation. Univariable and multivariable Cox regression models were used to assess overall survival (OS) and progression-free survival (PFS). Stepwise variable selection based on the Akaike Information Criterion (AIC) was used to construct an optimized multivariable model. A sensitivity analysis with adjustment for treatment period (2017–2018 vs. 2019–2022) was conducted to account for the introduction of durvalumab into routine clinical practice. Results: Among 72 patients, 35 received durvalumab and 37 did not. The median OS was 2.08 years; the 3- and 5-year OS rates were 38.6% and 30.3%, respectively. Multivariable regression revealed significantly improved OS associated with Karnofsky performance status (KPS) > 80% (HR 0.29, p = 0.003), Charlson Comorbidity Index (CCI) ≤ 2 (HR 0.39, p = 0.009), and durvalumab treatment (HR 3.99, p = 0.008). PD-L1 expression ≥ 1% showed a trend toward improved OS (HR 3.72, p = 0.063). The median progression-free survival (PFS) for the total cohort was 1.17 years. The estimated 3- and 5-year PFS rates were 31.1% and 26.3%, respectively. Patients treated with durvalumab had a longer median PFS (20.5 months) compared to those without durvalumab (12.0 months). In the multivariable analysis, KPS > 80% (HR 0.29, p < 0.001), CCI ≤ 2 (HR 0.53, p = 0.048), and durvalumab treatment (HR 2.81, p = 0.023) were significantly associated with improved PFS. A sensitivity analysis adjusting for treatment period—reflecting the introduction of durvalumab into routine clinical practice from 2019—confirmed the robustness of these findings. Conclusions: Our findings support the clinical benefit of durvalumab consolidation following CRT in a real-world population, especially in patients with good performance status and low comorbidity burden. These results confirm and extend the PACIFIC trial findings into routine clinical practice, highlighting the prognostic value of functional status and comorbidity alongside PD-L1 expression. Full article

Extracorporeal cardiopulmonary resuscitation (ECPR) is an established intervention for select patients experiencing refractory cardiac arrest. Among modifiable predictors of survival and neurologic recovery during ECPR implementation, timely restoration of circulation remains critical in the setting of refractory cardiac arrest (CA). The in-hospital cardiac arrest (IHCA) setting is particularly amenable to reducing the low-flow interval through structured system-based design and implementation. Despite increasing utilization of ECPR, the literature remains limited regarding operational standards, quality improvement metrics, and performance evaluation. Establishing operational standards and performance metrics is a critical first step toward systematically reducing low-flow interval duration. In support of this aim, we conducted a comprehensive literature review structured around the Extracorporeal Life Support Organization (ELSO) framework for ECPR implementation. At each step, we synthesized evidence-based best practices and identified operational factors that directly influence time-to-circulation. Our goal is to provide a stepwise evaluation of ECPR initiation to consolidate existing best practices and highlight process components with potential for further study and standardization. We further evaluated the literature surrounding key technical components of ECPR, including cannula selection, placement technique, and positioning. Ongoing research is needed to refine and standardize each stage of the ECPR workflow. Developing optimized, protocol-driven approaches to ensure rapid, high-quality deployment will be essential for improving outcomes with this lifesaving but resource-intensive therapy. Full article

Breast cancer remains one of the most prevalent malignancies worldwide, and radiation therapy is a central component of its management. However, intrinsic or acquired resistance to radiation significantly compromises therapeutic efficacy. This systematic review aimed to identify and evaluate molecular mechanisms and interventions that influence radiation sensitivity in breast cancer models. A comprehensive PubMed search was conducted using the terms “breast cancer” and “radiation resistance” for studies published between 2002 and 2024. Seventy-nine eligible studies were included. The most frequently investigated mechanisms included the dysregulation of the PI3K/AKT/mTOR and MAPK signaling pathways, enhanced DNA damage repair via non-homologous end joining (NHEJ), and the overexpression of cancer stem cell markers such as CD44⁺/CD24⁻/low and ALDH1. Several studies highlighted the role of non-coding RNAs, particularly the lncRNA DUXAP8 and microRNAs such as miR-21, miR-144, miR-33a, and miR-634, in modulating radiation response. Components of the tumor microenvironment, including cancer-associated fibroblasts and immune regulators, also contributed to radiation resistance. By synthesizing current evidence, this review provides a consolidated resource to guide future mechanistic studies and therapeutic development. This review highlights promising molecular targets and emerging strategies to enhance radiosensitivity and offers a foundation for translational research aimed at improving outcomes in radiation-refractory breast cancer. Full article

Pruritus is a common and distressing symptom in palliative care, often resulting from complex underlying conditions such as cancer, chronic kidney disease, and liver failure. Conventional pharmacological treatments frequently offer limited relief and may produce undesirable side effects in this medically fragile population. Despite the high prevalence and impact of pruritus in palliative care, there is a lack of consolidated evidence on integrative non-pharmacological approaches. This narrative review explores the potential role of essential oils as a complementary approach to managing pruritus in palliative settings. A review of the literature was conducted to examine the mechanisms of action, safety considerations, and clinical outcomes associated with the use of essential oils, with a particular focus on their anti-inflammatory, neuromodulatory, and soothing properties. Evidence suggests that essential oils may provide symptom relief and enhance quality of life when integrated into multidisciplinary care; however, small sample sizes, heterogeneity, and methodological weaknesses often limit the findings of these studies. Furthermore, the long-term safety and antigenotoxic potential of essential oils remain underexplored. This narrative review concludes that while essential oils appear promising as adjunct therapies for pruritus, further rigorous research, particularly well-designed clinical trials and toxicological assessments, is needed to support their safe and effective use in palliative care. Full article

Magnetotactic bacteria (MTB), a unique group of Gram-negative prokaryotes, have the remarkable ability to biomineralize magnetic nanoparticles (MNPs) intracellularly, making them promising candidates for various biomedical applications such as biosensors, drug delivery, imaging contrast agents, and cancer-targeted therapies. To fully exploit the potential of MTB, a precise understanding of the structural, surface, and functional properties of these biologically produced nanoparticles is required. Given these concerns, this review provides a focused synthesis of the most widely used microscopic and spectroscopic methods applied in the characterization of MTB and their associated MNPs, covering the latest research from January 2022 to May 2025. Specifically, various optical microscopy techniques (e.g., transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM)) and spectroscopic approaches (e.g., localized surface plasmon resonance (LSPR), surface-enhanced Raman scattering (SERS), and X-ray photoelectron spectroscopy (XPS)) relevant to ultrasensitive MTB biosensor development are herein discussed and compared in term of their advantages and disadvantages. Overall, the novelty of this work lies in its clarity and structure, aiming to consolidate and simplify access to the most current and effective characterization techniques. Furthermore, several gaps in the characterization methods of MTB were identified, and new directions of methods that can be integrated into the study, analysis, and characterization of these bacteria are suggested in exhaustive manner. Finally, to the authors’ knowledge, this is the first comprehensive overview of characterization techniques that could serve as a practical resource for both younger and more experienced researchers seeking to optimize the use of MTB in the development of advanced biosensing systems and other biomedical tools. Full article

Background: Total neoadjuvant therapy (TNT) has emerged as a promising strategy for locally advanced rectal cancer (LARC). By administering both chemoradiotherapy (CRT) and systemic chemotherapy (CHT) pre-surgery, TNT is associated with improved disease-free survival (DFS), reduced distant metastases, and higher pathological complete response (pCR) rates. Materials and Methods: This study included patients with LARC who received various TNT schedules: induction chemotherapy (iCHT), consolidation chemotherapy (cCHT), or a combination of both (sandwichCHT). We analyzed treatment adherence, toxicity, and pathological response. Local and distant disease recurrence, as well as survival outcomes, were also evaluated. Results: Between May 2021 and January 2025, 70 patients received TNT. Treatment included iCHT (41%), sandwichCHT (49%), and cCHT (10%). Most patients (94%) received long-course radiotherapy (LCRT). Overall, TNT was well tolerated, with grade 2 gastrointestinal toxicity during CRT being the most common frequent adverse event (33%). Disease progression during TNT was noted in five patients (7%); three of these patients were receiving chemotherapy, while two underwent surgical resection of the primary tumor. A watch-and-wait strategy was adopted for five patients (7%) following TNT. Surgical procedures performed included anterior resection (92%), abdominoperineal resection (7%), and local excision (1%). Pathological assessment revealed an overall pCR rate of 30%. With a median follow-up of 17 months, no patients experienced local recurrence. Post-surgery, 10 patients (17%) developed disease progression. The median DFS was 14.7 months. Five patients (7%) died during the follow-up period, with only one death attributed to causes other than disease progression. Conclusions: In this cohort of LARC patients, TNT demonstrated favorable tolerability and encouraging short-term efficacy. Full article

Osteoporosis is a chronic disease associated with significant morbidity and mortality and requires long-term therapy. Efficacious and well-tolerated treatments are available, but their effect is either short-lived or lost following their discontinuation. The exception is bisphosphonates that reduce bone resorption and turnover, can be administered in regimens ranging from once-daily to once-yearly, and have been shown in randomized clinical trials to reduce the incidence of all osteoporotic fractures, but their effect persists following their discontinuation. This is due to their property of being taken-up selectively by the skeleton and being slowly released following treatment arrest. This property allows the discontinuation of bisphosphonate treatment for different periods of time, the so-called drug holiday, which reduces the risk of rare adverse events while maintaining the effect; an action particularly important for patients at very high risk of fractures for whom sequential therapy with different agents is currently advised. Thus, bisphosphonates, apart from being the treatment of choice for certain groups of patients, are also indispensable for the consolidation and maintenance of the gains of all other treatments, providing, in addition, the opportunity of temporary treatment arrest. Most patients with postmenopausal osteoporosis will, therefore, receive bisphosphonate at some stage during therapy of their disease, regardless of their initial fracture risk. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Background: The accurate prediction of pathological complete response (pCR) following total neoadjuvant therapy (TNT) is crucial for optimising treatment protocols in locally advanced rectal cancer (LARC). Although conventional imaging techniques such as MRI show limitations in assessing treatment response, metabolic imaging utilising 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) provides distinctive information by quantifying tumour glycolytic activity. This study investigates the predictive value of sequential 18F-FDG PET-CT parameters, focusing on Total Lesion Glycolysis (TLG), in predicting pCR after TNT. Methods: We conducted a retrospective analysis of 33 LARC patients (T3–4/N0–1) treated with TNT (neoadjuvant-chemoradiation followed by consolidation FOLFOX chemotherapy). Sequential PET-CT scans were performed at baseline, interim (after 4 cycles of FOLFOX), and post-TNT. Metabolic parameters, including maximum standardised uptake value (SUVmax) and TLG, were measured. Receiver operating characteristic (ROC) analysis assessed the predictive performance of these parameters for pCR. Results: The pCR rate was 21.2% (7/33). Post-TNT TLG ≤ 10 demonstrated excellent predictive accuracy for pCR (AUC 0.887, 92.3% sensitivity, 85.7% specificity, and 96.0% PPV), outperforming SUVmax (AUC 0.843). Interim TLG ≤ 10 also showed a strong predictive value (AUC 0.824, 100% sensitivity, and 71.4% specificity). Conclusions: TLG may serve as a reliable metabolic biomarker for predicting pathologic complete response (pCR) after total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC). Its inclusion in clinical decision-making could improve patient selection for organ preservation strategies, thereby reducing the need for unnecessary surgeries in the future. However, given that the study is based on a small retrospective design, the findings should be interpreted with caution and used alongside other decision-making tools until more comprehensive data are collected from larger studies. Full article