Challenging pitfalls in frozen section pathology: a case of mandible ghost cell odontogenic carcinoma and the literature review.

BACKGROUND: Ghost cell odontogenic carcinoma (GCOC) is a rare malignancy characterized by the presence of ghost cells, preferably in the maxilla. Only slightly more than 50 case reports of GCOC have been documented to date. Due to the rarity of this tumor and its nonspecific clinical criteria, there is a heightened risk of misdiagnosis in clinical examination, imaging findings, and pathology interpretation. CASE PRESENTATION: A 50-year-old male patient presented to the hospital due to experiencing pain in his lower front teeth while eating for the past 2 months. Upon examination, a red, hard, painless mass was found in his left lower jaw, measuring approximately 4.0 cm × 3.5 cm. Based on the malignant histological morphology of the tumor and the abundant red-stained keratinized material, the preoperative frozen section pathology misdiagnosed it as squamous cell carcinoma (SCC). The surgical resection specimen pathology via paraffin section revealed that the tumor was characterized by round-like epithelial islands within the fibrous interstitium, accompanied by a large number of ghost cells and some dysplastic dentin with infiltrative growth. The malignant components displayed marked heterogeneity and mitotic activity. Additionally, a calcified cystic tumor component of odontogenic origin was observed. Hemorrhage, necrosis, and calcifications were present, with a foreign body reaction around ghost cells. Immunoreactivity for ß-catenin showed strong nuclear positivity in tumor cells, while immunostaining was completely negative for p53. The Ki67 proliferation index was approximately 30-40%. The tumor cells exhibited diffuse CK5/6, p63, and p40 immunoreactivity, with varying immunopositivity for EMA. Furthermore, no BRAFV600E mutation was identified by ARMS-PCR. The final pathology confirmed that the tumor was a mandible GCOC. CONCLUSION: We have reported and summarized for the first time the specific manifestations of GCOC in frozen section pathology and possible pitfalls in misdiagnosis. We also reviewed and summarized the etiology, pathological features, molecular characteristics, differential diagnosis, imaging features, and current main treatment options for GCOC. Due to its rarity, the diagnosis and treatment of this disease still face certain challenges. A correct understanding of the pathological morphology of GCOC, distinguishing the ghost cells and the secondary stromal reaction around them, is crucial for reducing misdiagnosis rates.

SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.

Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.

SEMA3B-AS1 suppresses colorectal carcinoma progression by inhibiting Semaphorin 3B-dependent VEGF signaling pathway activation.

Mounting evidence has demonstrated the considerable regulatory effects of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of various carcinomas. LncRNA Semaphorin 3B (SEMA3B) antisense RNA 1 (SEMA3B-AS1) has been found to be dysregulated in a few carcinomas recently. However, its potential function and mechanism in colorectal carcinoma (CRC) have not yet been examined. Here we show that SEMA3B-AS1 acts as a crucial regulator of CRC progression. We found that SEMA3B-AS1 expression was downregulated in CRC cell lines and tissues. Downregulation of SEMA3B-AS1 was significantly associated with poor survival in CRC patients. Overexpression of SEMA3B-AS1 reduced the cell growth and metastasis of CRC in vivo and in vitro. In addition, SEMA3B-AS1 promoted the expression of its sense-cognate gene SEMA3B, a member of the Semaphorin family (SEMAs), by recruiting EP300 to induce H3K9 acetylation at the SEMA3B promoter. Furthermore, we proved that SEMA3B-AS1 suppressed CRC angiogenesis by affecting the vascular endothelial growth factor signaling pathway activation which was regulated by the SEMA3B-NRP1 axis. Our work unravels a novel mechanism of SEMA3B-AS1 in the inhibition of CRC malignant progression and highlights its probability as a new promising diagnostic marker and therapeutic target for CRC interventions.

Warm acupuncture therapy alleviates neuronal apoptosis after spinal cord injury via inhibition of the ERK signaling pathway.

PURPOSE: Warm acupuncture (WA) therapy has been applied to treat spinal cord injury (SCI), but the underlying mechanism is unclear. The current study attempted to explore the WA therapy on neuronal apoptosis of SCI and the relationship with the extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: The rat SCI models were established by the impact method. SCI rat models were subjected to WA treatment at Dazhui (GV14) and Jiaji points (T10), Yaoyangguan (GV3), Zusanli (ST36), and Ciliao (BL32). The rat SCI models were established by the impact method. WA and U0126 treatments were performed on the SCI rats. Motor function and neuronal apoptosis were detected. The relative mRNA of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), the phosphorylation level of ERK 1/2 and levels of B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), and caspase-3 in spinal cord tissue were tested. RESULTS: After WA treatment, the Basso, Beattie & Bresnahan locomotor rating scale (BBB scale) of SCI rats in the WA treatment was significantly raised from 7 to 14 days after SCI. WA and U0126 treatment significantly diminished apoptotic cells and preserved the neurons in the injured spinal cord. WA and U0126 treatment alleviated the production of inflammatory cytokines in the spinal cord. The distinct increase of p-ERK 1/2 induced by SCI was reversed in WA and U0126 treatment groups. WA and U0126 treatment augmented the level of Bcl-2 and reversed the elevated cleaved caspase-3 protein level after SCI. CONCLUSION: Our study demonstrated that WA might be associated with the downregulation of the ERK signaling pathway. In summary, our findings indicated that WA promotes the recovery of SCI via the protection of nerve cells and the prevention of apoptosis. Meanwhile, the anti-apoptotic effect of WA might be associated with the downregulation of the ERK signaling pathway, which could be one of the mechanisms of WA in the treatment of SCI.

Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors.

SIRT1, a member of the sirtuin family, catalyzes the deacetylation of proteins with the transformation of NAD+ into nicotinamide and 2'-O-acetyl-ADP-ribose. Selective SIRT1/2 inhibitors have potential application in the chemotherapy of colorectal carcinoma, prostate cancer, and myelogenous leukemia. Here we identified novel SIRT1 inhibitors with the scaffold of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione. The most potent inhibitor 12n displayed an IC50 of 460 nM and a selectivity for SIRT1 over SIRT2, SIRT3, and SIRT5 of 113.5-, 254.3-, and 10.83-fold, respectively. It did not affect the activity of SIRT6. To elucidate the inhibitory mechanism, we determined the inhibition type of the inhibitor by enzyme kinetic analysis, showing that the inhibitor was competitive to the acetyl peptide and noncompetitive to NAD+. Further, the interaction of the inhibitor in SIRT1 was studied by using molecular docking, which was validated by the structure-activity relationship analysis of the inhibitors and the site-directed mutagenesis of SIRT1. Consistent with the in vitro assays, the inhibitors increased the acetylation level of p53 in a concentration-dependent manner in cells.

Extrapancreatic solid pseudopapillary neoplasm: report of a unique case of primary posterior mediastinum origin and review of the literature.

Solid pseudopapillary neoplasm (SPN) is a rare and low malignant potential neoplasm that traditionally occurs in pancreas. Herein, we report a mediastinal SPN in a 62-year-old woman. Clinically, the patient was asymptomatic. A mass in posterior mediastinum was detected by chest computerized tomographic (CT) scan during her annual checkup. The CT scan revealed a 30 mm solid nodule with well-defined outline in right posterior mediastinum. Histologically, the tumor was comprised of solid cellular nests as well as sheets of cells with an epithelioid appearance, and some pseudopapillary areas could also be identified. Immunohistochemically, the tumor cells were positive for ß-catenin (nuclear and cytoplasmic), cyclin D1, CD56, CD10, CD99 (paranuclear dot-like), SOX11 (weak) and TFE3, while negative for cytokeratin (AE1/AE3), E-cadherin, WT-1, synaptophysin, chromogranin and progesterone receptor. SPNs can occur in aberrant locations and this is the first one reported in mediastinum, pathologists should learn about the rare case for a better differential diagnosis. The patient underwent a video-assisted thoracoscope tumorectomy. She has been followed up for 5 months with no recurrence or metastasis.

Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin ß3 transcriptional activating and MAPK/AKT signalling.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been indicated to play critical roles in cancer development and progression. LncRNA HOXD cluster antisense RNA1 (HOXD-AS1) has recently been found to be dysregulated in several cancers. However, the expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown. METHODS: Real-time PCR and in situ hybridization were used to detect the expression of HOXD-AS1 in CRC tissue samples and cell lines. Gain- and loss-of-function experiments were performed to investigate the biological roles of HOXD-AS1 in CRC cell line. RNA pull down, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to investigate the mechanisms underlying the functions of HOXD-AS1 in CRC. RESULTS: We observed that HOXD-AS1 was located in the nucleus of CRC cells and that nuclear HOXD-AS1 was downregulated in most CRC specimens and cell lines. Lower levels of nuclear HOXD-AS1 expression were associated with poor outcomes of CRC patients. HOXD-AS1 downregulation enhanced proliferation and migration of CRC cells in vitro and facilitated CRC tumourigenesis and metastasis in vivo. Mechanistic investigations revealed that HOXD-AS1 could suppress HOXD3 transcription by recruiting PRC2 to induce the accumulation of the repressive marker H3K27me3 at the HOXD3 promoter. Subsequently, HOXD3, as a transcriptional activator, promoted Integrin ß3 transcription, thereby activating the MAPK/AKT signalling pathways. CONCLUSION: Our results reveal a previously unrecognized HOXD-AS1-HOXD3-Integrin ß3 regulatory axis involving in epigenetic and transcriptional regulation constitutes to CRC carcinogenesis and progression.

SATB2-AS1 Suppresses Colorectal Carcinoma Aggressiveness by Inhibiting SATB2-Dependent Snail Transcription and Epithelial-Mesenchymal Transition.

Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in colorectal carcinoma progression remains largely unknown, especially in colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in colorectal carcinoma. SATB2-AS1 suppressed colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of colorectal carcinoma. SIGNIFICANCE: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress colorectal cancer progression.See related commentary by Li, p. 3536.

[Expression of cAMP-dependent protein kinase inhibitor beta in colorectal carcinoma and its clinical significance].

OBJECTIVE: To investigate the expression of cAMP-dependent protein kinase inhibitor beta (PKIB) in colorectal carcinoma (CRC) and its association with the clinicopathological factors of the patients. METHODS: The expression of PKIB mRNA was detected with quantitative real-time PCR in 34 CRC tissues and paired adjacent tissues. Immunohistochemistry was used to detect the expression of PKIB protein in 72 CRC tissue specimens, and the relationship between PKIB protein expression and the clinicopathological features of the patients was analyzed. RESULTS: The expression of PKIB mRNA was significantly higher in CRC tissues than in the paired asjacent tissues (P<0.0001). The expression of PKIB protein in CRC patients was closely related with tumor infiltration (T stage) (P=0.038) but not with age, gender, tumor size, location, lymph node metastasis (N stage) or distant metastasis (M stage) (P>0.05). The survival time of patients with high PKIB expressions was significantly shorter than that of patients with low PKIB expressions (70.532∓6.190 vs 93.500∓5.847 months, P=0.023). CONCLUSION: A high expression of PKIB in CRC is positively correlated with tumor infiltration (T stage) and a poor prognosis, suggesting an important role of PKIB in the development of CRC and its value as an indicator for prognostic evaluation of CRC patients.

Drimane sesquiterpenoids from the Aspergillus oryzae QXPC-4.

Three new drimane sesquiterpenoids, astellolides C-E (1-3, resp.), four new drimane sesquiterpenoid p-hydroxybenzoates, astellolides F-I (4-7, resp.), together with two known compounds astellolides A and B (8 and 9, resp.), have been isolated from the liquid culture of Aspergillus oryzae (strain No. QXPC-4). Their structures were established by comprehensive analysis of spectroscopic data. The relative and absolute configurations were determined on the basis of NOESY and CD data, together with single-crystal X-ray diffraction analyses of compounds 1-3. The metabolites were evaluated for their cytotoxic activities, however, no compounds showed a significant cytotoxicity against the tested cell lines at a concentration of 20 µM.