Search Results (331)

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article

Background and Clinical Significance: Hereditary Fibrinogen Disorders (HFDs) are a group of rare, inherited coagulation disorders with a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe bleeding or thrombotic events. Among these, hereditary hypofibrinogenemia (HH) poses particular challenges in obstetric care due to its unpredictable course and limited evidence-based guidelines. Case Presentation: This case report describes the novel obstetrical management of a 37 years old multiparous woman with severe HH (SHH) guided not only by fibrinogen levels but also by rotational thromboelastometry (ROTEM^®), a global test of hemostasis using specific parameters such as FIBTEM^® and NATEM^® assays. Despite persistent low fibrinogen levels during labor and peripartum (<100 mg/dL), favorable maternal and neonatal outcomes were achieved by relying on ROTEM^®-based parameters to guide clinical decisions. Conclusions: Current recommendations for managing pregnancies in women with HFDs are largely based on expert consensus and exclusively use fibrinogen levels. This case supports the use of specific assays (FIBTEM^® and NATEM^®) of the ROTEM^® global test of hemostasis as valuable tools in the obstetric management of women with HH. The use of FIBTEM^® and NATEM^® assays could provide individualized perinatal care, avoiding unnecessary therapeutic interventions and aiming for optimal perinatal outcomes. Full article

Odontogenesis, the development of teeth, is a complex, multistage process that unfolds from early embryogenesis through tooth eruption and maturation. It serves as a classical model of organogenesis due to the intricate reciprocal interactions between cranial neural crest-derived mesenchyme and oral epithelium. This narrative review synthesizes current scientific knowledge on human tooth development, tracing the journey from the embryological origins in the first branchial arch to the formation of a fully functional tooth and its supporting structures. Key morphogenetic stages—bud, cap, bell, apposition, and root formation—are described in detail, highlighting the cellular events and histological features characterizing each stage. We discuss the molecular and cellular regulatory networks that orchestrate odontogenesis, including the conserved signaling pathways (Wnt, BMP, FGF, SHH, EDA) and transcription factors (e.g., PAX9, MSX1/2, PITX2) that drive tissue patterning and cell differentiation. The coordinated development of supporting periodontal tissues (cementum, periodontal ligament, alveolar bone, gingiva) is also examined as an integral part of tooth organogenesis. Finally, developmental anomalies (such as variations in tooth number, size, and form) and the fate of residual embryonic epithelial cells are reviewed to underscore the clinical significance of developmental processes. Understanding the normal course of odontogenesis provides crucial insight into congenital dental disorders and lays a foundation for advances in regenerative dental medicine. Full article

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway’s genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation between the expression levels of selected genes of this pathway and the progression-free and overall survival of ovarian cancer patients. Using the database Kaplan–Meier plotter, which includes the gene expression and survival data of 1565 ovarian cancer patients, higher expression levels of the genes SHH, PTCH1, PTCH2, and GLI1 displayed better survival correlations, while GLI, GLI3, and SUFU correlated with adverse outcomes. Further dissection revealed a differential impact of the genes in specific clinical-histopathological categories. Notably, higher expression levels of SUFU were associated with a negative impact on ovarian cancer patients under many clinical–histopathological aspects. These results shed new light on the role of these genes in the chemoresponsiveness of ovarian cancer, especially SUFU, which could be considered a novel indicator for poor prognosis in epithelial ovarian cancer. Full article

Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3. It is defined by the inactivation of the SMARCB1 gene, leading to the loss of INI1, a protein essential for cell lineage determination and cell differentiation. Current standard of care treatment requires aggressive multimodal therapy with maximal safe resection, high-dose chemotherapy with autologous stem cell rescue, and radiation, yet overall survival remains < 50%. These intensive regimens have improved overall survival but are associated with significant morbidity and long-term effects. Molecular profiling has significantly advanced the understanding of ATRTs, revealing four molecular subgroups, ATRT-TYR, ATRT-MYC, ATRT-SHH, and ATRT-SMARCA4, each with distinct clinical presentations, oncogenic pathways, and prognoses. Molecular characterization enables better prognostic stratification, guiding treatment decisions and allowing for more personalized therapeutic approaches. Targeted therapies based on these molecular insights remain experimental, and continued exploration of molecular mechanisms and how they differ amongst subgroups is pivotal for the development of less toxic, more effective targeted treatments. Full article

Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment. There is significant treatment-related morbidity associated with MB, and overall prognosis varies between the subgroups of the disease. These tumors were previously risk-stratified based solely on histopathological features. However, advancements in oncologic molecular research have led to novel changes to MB tumor classification, which also affects the prognosis and treatment strategies for individual patients. The WHO CNS5 now recognizes four main molecular subgroups of MB. Each subgroup contains its own genomic heterogeneity that correlates with a unique way to risk stratify patients, determine overall prognosis, and inform treatment. These discoveries have already impacted the implications and outcomes of current treatments based on the subgroup of patients. Ongoing research to better understand this classification system has paved the way for the development of molecular targeted therapy. Full article

Malignant Triton Tumors (MTTs) are rare, high-grade malignant peripheral nerve sheath tumors (MPNSTs) frequently associated with Type 1 Neurofibromatosis (NF1). NF1, an autosomal dominant disorder, predisposes approximately 10% of affected individuals to developing MPNSTs, with 50% of these tumors occurring in NF1 patients, while others arise sporadically or in association with radiation exposure. MTTs predominantly affect anatomical regions rich in large nerves, such as the limbs, spinal root, and cranial nerves. Mediastinal presentations are exceedingly rare, posing significant diagnostic and therapeutic challenges. Current treatment strategies include surgical resection, chemotherapy, radiotherapy, and lung-sparing procedures for metastatic disease. Molecular studies of MPNSTs have revealed that NF1 mutations lead to dysregulation of the RAS signalling pathway, while epigenetic alterations (e.g., SUZ12/EED mutations) further contribute to tumor progression. Dysregulated phylogenetically conserved pathways, including Wnt/beta-catenin and non-canonical SHH signalling, play a role in sarcoma progression and Schwann cell transformation. Recent advances in miRNA research highlight their involvement in tumor invasion and progression, with dysregulated miRNA expression and chromatin remodeling contributing to the pathogenesis of these neoplasms. However, the distinct molecular profiles for MTTs remain incompletely understood. Further investigation of the genetic and epigenetic landscape is essential for improving our understanding and identifying potential therapies. Herein, we present a single-center retrospective case series of three patients with an intrathoracic triton tumor treated at our University Hospital between 2000 and 2024, serving as a starting point for future insights into MPNST pathobiology. Full article

Background: Medulloblastoma is the most common malignant brain tumor in children, classified into four primary molecular subgroups: WNT, SHH, Group 3, and Group 4, each exhibiting significant molecular heterogeneity and varied survival outcomes. Accurate classification of these subgroups is crucial for optimizing treatments and improving patient outcomes. DNA methylation profiling is a promising approach for subgroup classification; however, its application is still evolving, with ongoing efforts to improve accessibility and develop more accurate classification methods. Objectives: This study aims to develop a supervised machine learning-based framework using Illumina 450K methylation data to classify medulloblastoma into seven molecular subgroups: WNT, SHH-Infant, SHH-Child, Group3-LowRisk, Group3-HighRisk, Group4-LowRisk, and Group4-HighRisk, incorporating age and risk factors for enhanced subgroup differentiation. Methods: The proposed model leverages six metagenes, capturing the underlying patterns of the top 10,000 probes with the highest variances from Illumina 450K data, thus enhancing methylation data representation while reducing computational demands. Results: Among the models evaluated, the SVM achieved the highest performance, with a mean balanced accuracy 98% and a macro-averaged AUC of 0.99 in an independent validation. This suggests that the model effectively captures the relevant methylation patterns for medulloblastoma subgroup classification. Conclusions: The developed SVM-based model provides a robust framework for accurate classification of medulloblastoma subgroups using DNA methylation data. Integrating this model into clinical decision making could enhance subgroup-directed therapies and improve patient outcomes. Full article

Background/Objectives: The ineffective delivery of drugs into tumors and the existence of multidrug resistance (MDR) are the primary causes of chemotherapy failure. Downregulation of the Sonic Hedgehog (Shh) pathway has been shown to reduce P-glycoprotein (P-gp) expression on cell membranes and to resist MDR. Methods: In this study, we combine cyclopamine (CYP, a potent Shh antagonist) with paclitaxel (PTX, an antitumor drug that can produce MDR) in a nano-drug delivery system (CYP NP and PTX NP) for the treatment of drug-resistant breast cancer. Nanoparticles were characterized for size, zeta potential, and encapsulation efficiency. P-gp expression, nanoparticle accumulation, cytotoxicity, and apoptosis were evaluated in MCF-7 and MCF-7/Adr cells. Penetration ability was assessed using 3D multicellular tumor spheroids. Antitumor efficacy and nanoparticle biodistribution were validated in MCF-7/Adr-bearing nude mice models. Results: Our engineered CYP nanoparticles (~200 nm) demonstrated prolonged intratumoral retention, enabling sustained Shh pathway inhibition and P-gp functional suppression. This size-optimized formulation created a favorable tumor microenvironment for the smaller PTX nanoparticles (~30 nm), facilitating deeper tumor penetration and enhanced cellular uptake. Meanwhile, by down-regulating P-gp expression, CYP NPs could convert drug-resistant cells to PTX-sensitive cells in both cytotoxicity and apoptosis induction through the Shh pathway. The combination of CYP NP and PTX NP augmented the antitumor effects in MCF-7/Adr-bearing nude mice models. Conclusions: The CYP NP and PTX NP combination offers a new therapeutic strategy in cancer treatment. Full article

Objectives. The relationships among neuropathic pain, gut microbiota, microbiome-derived metabolites, and neuropathology have received increasing attention. This study examined the effects of two dosages of gingerol-enriched ginger (GEG) on mechanical hypersensitivity, anxiety-like behavior, gut microbiome composition and its metabolites, and neuropathology markers in female rats in the spinal nerve ligation (SNL) model of neuropathic pain. Methods. Forty female rats were assigned to 4 groups: sham-vehicle, SNL-vehicle, SNL+GEG at 200 mg/kg BW, and SNL+GEG at 600 mg/kg BW via oral gavage. All animals were given an AIN-93G diet for 5 weeks. Mechanical hypersensitivity was assessed by the von Frey test. Anxiety-like behavior was assessed by the open field test. Fecal microbiota composition and metabolites were determined using 16S rRNA gene sequencing and GC-MS, respectively. Neuropathology gene expression profiling of the amygdala was assessed by an nCounter^® Neuropathology pathway panel. Results. Both GEG-treated groups showed decreased mechanical hypersensitivity and anxiety-like behavior in the SNL model. Gut microbiome diversity in both GEG groups was decreased compared with untreated SNL rats. In the SNL model, phyla such as Bacteroidota, Proteobacteria and Verrucomicrobiota were decreased. Compared with the untreated SNL group, both GEG groups exhibited increased abundance of the phyla Bacteroidota (i.e., Rikenella, Alistipes, Muribaculaceae, Odoribacter), Firmicutes (i.e., UBA1819, Ruminococcaceae, Oscillospiraceae, Roseburia), and Verrucomicrobiota (i.e., Victivallis). GEG groups had higher levels of nine hydrophilic positive metabolites [val-glu, urocanic acid, oxazolidinone, L-threonine, L-norleucine, indole, imino-tryptophan, 2,3-octadiene-5,7-diyn-1-ol, and (2E)-3-(3-hydroxyphenyl) acrylaldehyde] and two hydrophilic negative metabolites [methylmalonic acid and metaphosphoric acid], as well as lower levels of five hydrophilic metabolites [xanthine, N-acetylmuramic acid, doxaprost, adenine, and 1-myristoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine]. Among the 770 neuropathology genes, 1 gene (PLA2G4A) was upregulated and 2 genes (CDK5R1 and SHH) were downregulated in SNL rats. GEG caused the upregulation of nine genes (APC, CCNH, EFNA5, GRN, HEXB, ITPR1, PCSK2, TAF9, and WFS1) and downregulation of three genes (AVP, C4A, and TSPO) in the amygdala. Conclusions. GEG supplementation mitigated pain-associated behaviors in female rats with neuropathic pain, in part by reversing the molecular neuropathology signature of the amygdala. This was associated with changes in the gut microbiome composition and fecal metabolites, which could play a role in mediating the effects of GEG on neuropathic pain. Full article

Cancer remains a leading cause of death globally, characterized by uncontrolled cell proliferation, tumor growth and metastasis. Bone morphogenetic proteins (BMPs) and their growth differentiation factor (GDF) relatives are crucial regulators of developmental processes such as limb, kidney and lung formation, cell fate determination, cell proliferation, and apoptosis. Cancer stem cells (CSCs) are a subpopulation of self-renewing cells within tumors that possess stemness properties and a tumor cell-forming capability. The presence of CSCs in a tumor is linked to growth, metastasis, treatment resistance and cancer recurrence. The tumor microenvironment in which CSCs exist also plays a critical role in the onset, progression and treatment resistance in many cancers. Growth factors such as BMPs and GDFs counterbalance transforming growth factor-beta (TGF-β) in the maintenance of CSC pluripotency and cancer cell differentiation. BMP signaling typically functions in a tumor suppressor role in various cancers by inducing CSC differentiation and suppressing stemness characteristics. This differentiation process is vital, as it curtails the self-renewal capacity that characterizes CSCs, thereby limiting their ability to sustain tumor growth. The interplay between BMPs and their secreted antagonists, such as GREM1, Noggin and Chordin, adds another layer of complexity to CSC regulation. Human cancers such as gastric, colorectal, glioblastoma, and breast cancer are characterized by GREMLIN1 (GREM1) overexpression, leading to inhibition of BMP signaling, facilitating the maintenance of pluripotency in CSCs, thus promoting tumorigenesis. GREM1 overexpression may also contribute to CSC immune evasion, further exacerbating patient prognoses. In addition to BMP inhibition, GREM1 has been implicated as a target of fibroblast growth factor (FGF) → Sonic hedgehog (Shh) signaling, as well as the Wnt/Frizzled pathway, both of which may contribute to the maintenance of CSC stemness. The complex role of BMPs and their antagonists in regulating CSC behavior underscores the importance of a balanced BMP signaling pathway. This article will summarize current knowledge of BMP and GREM1 regulation of CSC function, as well as conflicting data on the exact role of GREM1 in modulating CSC biology, tumor formation and cancer. Targeting this pathway by inhibiting GREM1 using neutralizing antibodies or small molecules may hold early-stage promise for novel therapeutic strategies aimed at reducing CSC burden in cancers and improving patient outcomes. Full article

Atypical teratoid rhabdoid tumors are rare embryonal tumors of the nervous system mainly seen in very young children with aggressive behavior and dismal prognosis when treated with conventional chemotherapy only. More recent multimodal strategies combining, variably, high dose chemotherapy, radiotherapy and or intrathecal chemotherapy have led to some stride in survival. We present the results of the most recent clinical trials and registry data for patients treated with these multimodal approaches with survival ranging from 37.1% to 88.9%. We review the current consensus of the molecular characterization of these tumors into 3 subgroups (ATRT-TYR, ATRT-SHH and ATRT-MYC) and discuss the potential clinical impact of molecular subgrouping on survival. We explore other therapeutic tools including intrathecal chemotherapy and maintenance and possible new targeted agents for patients failing multimodal strategies Full article

Background and Clinical Significance: Basal cell nevoid carcinoma syndrome, or Gorlin–Goltz Syndrome (GGS), is a genetic disease caused by germline mutations in genes involved in the Sonic HedgeHog (SHH) signaling pathway, mainly in the PTCH1 gene. PTCH1 is a receptor for SHH, and the activation of SHH signaling exerts a direct effect on the proliferation and maintenance of stem cells; alteration of its signaling could promote a favorable microenvironment for the maintenance of tumor viability. The main clinical manifestations of patients with GGS include multiple basal cell carcinomas, odontogenic keratocysts, calcification of the falx cerebri, palmoplantar fossae, hypertelorism, prognathism, fused or bifid ribs, and macrocephaly, which occur at different stages of life. Case Presentation: Here, the case of a 48-year-old woman is described, for whom a clinical and histopathological diagnosis of GGS was made due to the presence of two major criteria (multiple odontogenic keratocysts and calcification of the falx cerebri) and one minor criterion (congenital anomalies), according to Kimonis. Additionally, an end-point RT-PCR assay showed a decrease in PTCH1 gene expression. A conservative therapy was established, and satisfactory results were obtained in a follow-up period of 18 months. Conclusions: Kimonis' clinical criteria are important for establishing the diagnosis of Gorlin syndrome. Full article

Curcumin, a polyphenol found in turmeric, demonstrates multifaceted anti-cancer activity against glioblastoma. Its therapeutic potential stems from its ability to modulate various molecular pathways implicated in glioblastoma development and progression, enhance the effectiveness of radiation therapy, and induce cancer cell death through diverse mechanisms, including apoptosis, autophagy, and cell cycle arrest. These combined actions make curcumin a promising candidate for glioblastoma treatment, warranting further investigation into its clinical application. In this review, we summarize the latest research on curcumin and its analogs’ potential in glioblastoma therapy. Full article

Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Current therapy results in a poor prognosis for high-risk SHH/p53-mutated MB, emphasizing the importance of more effective therapeutic strategies. Here, we investigated the potential radiosensitizing effects of the checkpoint kinase inhibitors (Chk-is) prexasertib (Chk1/2) and SAR-020106 (Chk1) in human SHH/p53-mutated MB in vitro and in vivo. UW228 and DAOY cells were treated with Chk-is and irradiation (RT). Metabolic activity, proliferation, and apoptosis were determined at d3, and long-term clonogenicity was determined at d14. DNA damage was assessed after 1, 24, and 72 h. Patient-derived SHH/p53-mutated, luciferase-transfected MB cells were implanted orthotopically into NSG mice (d0). Fractionated therapy (daily, d7–11) was applied. Body weight (BW) was documented daily, tumor growth weekly, and proliferation at d42. In vitro, Chk-is exhibited a dose-dependent reduction in metabolic activity, proliferation, and clonogenicity and increased apoptosis. A combination of Chk-is with RT enhanced these antitumor effects, including proliferation, apoptosis, and clonogenicity, and increased residual DNA damage compared to RT alone. In vivo, tumor growth was delayed by Chk-is alone. Low-dose prexasertib enhanced RT-induced tumor growth inhibition. High-dose prexasertib and SAR-020106 showed opposite effects, at least at later time points (n = 3). BW assessments revealed that the treatment was well tolerated. Our data indicate a potential benefit of Chk-is in combination with RT in SHH/p53-mutated MB. However, high-dose Chk-is may compromise the RT effect, possibly through anti-proliferative activity. Furthermore, we demonstrate, for the first time, the intracranial antitumor activity of the Chk1-specific inhibitor SAR-020106. Full article