Genes and Genetic Pathways Regarding the Etiology and Pathogenesis of Ameloblastoma.

FREQUENT COEXISTENCE OF GLI1 OVEREXPRESSION AND BRAF(V600E) MUTATION IN AMELOBLASTOMAS

Therapeutic Opportunities for Medulloblastoma Come of Age

This study aims to explore the plastic changes in cell lineages during the progression of osteoarthritis (OA) and their relationship with dysregulation of signaling pathways and provide new molecular targets for precise treatment. Single-cell RNA sequencing (scRNA-seq) technology was utilized to perform high-resolution cell lineage analysis of OA patients. The mappings of distinct cell subpopulations were systematically constructed and revealed the changes in key cell types and their transformation trajectories throughout the progression of OA. Furthermore, KEGG and GO enrichment and pseudotime trajectory analysis were applied to elucidate the functional reprogramming of different cell types and the dynamic imbalance of their signaling networks in OA. Additionally, in vitro experiments were conducted to validate the biological functions of candidate genes in OA. Articular cartilage showed a transcriptional cellular heterogeneity in OA by scRNA-seq analysis; the annotated PreFC, FC, and PreHTC subsets accounted for the main part of OA samples. PreFC cells revealed transcription, signaling, and metabolic reprogramming in OA; pseudotime trajectory found that PreFC transformed to FC cells under the condition of hypoxia and metabolic reprogramming, while fibrosis and ECM degradation pathways showed intense upregulation in preHTC evolved from PreFC cells. HIF1A and ANGPTL4 were identified as key molecular regulators of OA progression, contributing to ECM degradation, inflammation, and apoptosis in chondrocytes, as confirmed through functional validation. The cellular trajectories of OA show significant plasticity changes which are influenced by the dysregulation of multiple signaling pathways. This research provides new insights into the pathological process of OA and offers potential targets for therapeutic strategies targeting these abnormal mechanisms.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10238-025-01947-x.

Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through β-catenin signaling

Predictable and complete periodontal regeneration following periodontitis has been the ultimate goal of periodontal treatment. It has been recognized that Hertwig's epithelial root sheath (HERS) cells play a crucial role in cementogenesis and root formation. As the descendants of HERS and unique odontogenic epithelium in the adult periodontium, epithelial cell rests of Malassez (ERM) have long been considered as quiescent epithelial remnants devoid of structure and function. Here we will present an overview of our present understanding and putative functions of the ERM in the regeneration of periodontal tissues.

OBJECTIVE Meningiomas located in the skull base are surgically challenging. Recent genomic research has identified oncogenic SMO and AKT1 mutations in a small subset of meningiomas. METHODS The authors performed targeted sequencing in a large cohort of patients with anterior skull base meningiomas (n = 62) to better define the frequency of SMO and AKT1 mutations in these tumors. RESULTS The authors found SMO mutations in 7 of 62 (11%) and AKT1 mutations in 12 of 62 (19%) of their cohort. Of the 7 meningiomas with SMO mutations, 6 (86%) occurred in the olfactory groove. Meningiomas with an SMO mutation presented with significantly larger tumor volume (70.6 ± 36.3 cm3) compared with AKT1-mutated (18.2 ± 26.8 cm3) and wild-type (22.7 ± 23.9 cm3) meningiomas, respectively. CONCLUSIONS Combined, these data demonstrate clinically actionable mutations in 30% of anterior skull base meningiomas and suggest an association between SMO mutation status and tumor volume. Genotyping of SMO and AKT1 is likely to be high yield in anterior skull base meningiomas with available surgical tissue.

A dentigerous cyst (DC) is the most common developmental cystic lesion of the jaws. Histologically, these cysts derive from the odontogenic epithelium that includes the reduced enamel epithelium, epithelial cell rests of Serres, and epithelial cell rests of Malassez. Radiographically, DCs are usually presented as well-defined radiolucencies associated with the crown of an unerupted tooth at the level of the cementoenamel junction (CEJ). Glandular odontogenic cysts (GOCs) are classified under the same category as DCs. Radiographically, glandular odontogenic cysts (GOCs) may appear as unilocular or more commonly as multilocular radiolucencies with well-defined margins. It is evident that there is a significant overlap in the radiographic features of the two pathologies. This case report describes one of those cases.A 49-year-old male patient was referred for a cone beam computed tomography (CBCT) imaging series for the evaluation of possible pathology in areas #17-#19 and ramus to the Graduate Oral and Maxillofacial Radiology Clinic, Health Science Center, San Antonio, University of Texas. The radiographic interpretation revealed a well-defined corticated low-density lesion in the left mandibular molar-ramus region. The mandibular canal was intact and traceable but displaced buccally and inferiorly. The radiographic findings were suggestive of a slow-growing odontogenic process, most likely cystic. Marsupialization and incisional biopsy of the lesion were carried out, which was highly suggestive of GOC. Two months after the initial incisional biopsy, it was decided that enucleation and curettage, as well as extraction of #17, #18, and #19, should be carried out. The enucleated specimen was sent to the histopathology laboratory for evaluation. The second biopsy showed a dentigerous cyst associated with impacted #17. Histopathology continues to be, statistically, the most reliable method for diagnosing these types of abnormalities. However, in certain cases, such as this one, the accuracy of histopathological examination may falter due to overlapping characteristics and different histopathological features based on the location of acquisition of the specimen. The initial radiographic estimation included the differential diagnosis of a DC as a second differential and, although contradicted by the first biopsy result, was eventually supported by the second final biopsy of the entire specimen. Although DCs do not tend to recur, the need for regular follow-ups should not be underestimated, neither by the attending clinician nor by the patients themselves. In conclusion, the radiographically proven, uneventful wound healing constitutes the only reassurance for the patient's well-being.

Odontogenic epithelial stem cells: hidden sources

Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. SMO, a gene encodes Smoothened protein, which is an important signal converter in Sonic Hedgehog (SHH) signal pathway. Studies have shown that CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring SMO mutation, suggested that SMO may be related to immune microenvironment and tumor immunity, but the association between SMO mutation and TMB or survival in metastatic Colorectal Cancer(mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs were retrieved from publicly accessible data (Pancancer.Samstein2018.NGS.1661) and the association between SMO mutation overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. The association between SMO mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 149 patients with Rectum Adenocarcinoma (READ) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and SMO mutation status was further analyzed by CIBERSORT. Statistical significance was set at p=0.05. Results: 7.3% (8/109) patients in the clinical cohort harbored SMO mutation. Survival analysis in the public cohort demonstrated that SMO mutation resulted in significantly longer OS (10.5 vs 8 months; HR, 0; p=0.035) in mCRC patients treated with ICIs. Moreover, SMO mutation is associated with higher TMB in public cohort (p<0.0001). Furthermore, the correlation analysis between immune infiltration and SMO mutation status in mCRC which was analysed in TCGA shows that M1 macrophages, CD8 T cells, Gamma Delta T cells increased significantly (p=0.048, p=0.043, p=0.002). Conclusions: This study shows that SMO mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages, CD8 T cells, as well as the Gamma Delta T cells may be another potential mechanism for the better efficacy of ICIs in patients with SMO mutation. Citation Format: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang. SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5253.

Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base. This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

Sonic Hedgehog, a Novel Endogenous Damage Signal, Activates Multiple Beneficial Functions of Human Endometrial Stem Cells.

ABSTRACTLong-term use of cyclooxygenase (COX) inhibitors (NSAIDs) in humans leads to a 50% reduction in risk for colorectal cancer. However, prolonged use of COX-2 selective inhibitors (coxibs) increases cardiovascular toxicity in some individuals, which highlights the importance of identifying all of the molecular targets that drive progression of colorectal cancer. Colorectal cancer offers a unique model to study the synergistic induction of intestinal neoplasia via dysregulation of multiple signaling pathways. Emerging evidence demonstrates that the peroxisome proliferator-activated receptor δ (PPARδ) is a focal point of crosstalk between the signaling cascades involved in the progression of colorectal cancer. More importantly, activation of PPARδ can promote tumor growth by inhibiting epithelial tumor cell apoptosis by affecting a VEGF autocrine signaling loop. These findings may provide a rationale for the development of PPARδ antagonists for cancer prevention and/or treatment.

The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Bruton's tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex- and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)-responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.

Characterization of a New Syndrome That Associates Craniosynostosis, Delayed Fontanel Closure, Parietal Foramina, Imperforate Anus, and Skin Eruption: CDAGS

BackgroundLiposarcoma (LPS) is one of the most common soft tissue malignancies in adults, and it is characterized by dysregulation of multiple signaling pathways, including MDM2 proto‐oncogene (MDM2) amplification. MicroRNA (miRNA) regulates gene expression through incomplete complementary pairing with the 3' untranslated region of mRNAs involved in tumor progression.MethodsIn this study, bioinformatics analysis, RT‐qPCR, dual‐luciferase reporter gene, MTT, flow cytometry, cell scratches, chamber migration, colony formation, FISH, WB, and CCK8 were used.ResultsRT‐qPCR showed that the expression of MDM2 was increased when miR‐215‐5p was overexpressed compared with the control group. The dual‐luciferase reporter gene showed that the Renilla ratio firefly fluorescence intensity was decreased in the overexpression group compared with the control group. Cell phenotype experiments revealed that the overexpression group had increased cell proliferation rate, increased apoptosis rate, increased colony formation rate, increased cell healing area ratio, and increased number of cell invasions. FISH revealed increased MDM2 expression in the overexpression group. WB suggested decreased Bax expression, increased PCNA, Bcl‐2, and MDM2 expression, and decreased P53 and P21 expression in the overexpression group.ConclusionsIn this study, we suggest that miR‐215‐5p can target and promote MDM2 expression, promote the proliferation and invasion of LPS cells SW‐872, and inhibit apoptosis.Targeting miR‐215‐5p may be a novel therapeutic strategy for the treatment of LPS.