Medical Molecular Morphology最新文献

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a major adverse effect of bisphosphonates, yet its underlying pathogenesis remains poorly understood. Bone metabolism and remodeling relies on the interaction between osteoblasts (OBs) and osteoclasts (OCs). Sphingosine 1-phosphate (S1P), a bioactive sphingolipid metabolite, is an important mediator of OC-OB communication. In this study, we aimed to investigate the role of the S1P/S1P receptor (S1PR) axis in the development of BRONJ. A co-culture system was used to examine the interaction between OCs and OBs. Western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression of related proteins and messenger ribonucleic acids (mRNAs). Finally, an in vivo BRONJ mouse model was used to validate the role of S1P/S1PR axis in disease progression. In our study, we showed that zoledronate (ZOL) promoted S1P secretion from OCs and enhanced the migration of osteoclast precursor cells (OCPs) through S1PR signaling. In addition, OCs promoted the excessive osteogenic differentiation and migration of OBs via S1P/S1PR axis. Importantly, pharmacological inhibition of S1PR facilitated the recovery of BRONJ-like lesions in vivo. In conclusion, these findings indicate that the S1P/S1PR axis plays an important role in the pathogenesis of BRONJ and may represent a potential therapeutic target for its treatment.

We describe a rare and aggressive case of multiple myeloma (MM) characterized by extensive lymph node involvement, loss of CD138 expression, and adipophilin (ADP)-positive cytoplasmic vacuolization, highlighting the role of lipid metabolism in disease aggressiveness. An 83-year-old woman presented with painless cervical lymphadenopathy and widespread osteolytic lesions. Bone marrow examination confirmed MM, while lymph node biopsy showed diffuse infiltration of atypical lymphoid cells with numerous tingible body macrophages, initially mimicking a high-grade lymphoma. Immunophenotyping showed CD3/CD5/CD20/CD23 negativity, focal CD138/CD79a positivity, diffuse MUM1 and κ-light chain positivity, and a high Ki-67 index. Compared with bone marrow plasma cells, lymph node MM cells exhibited prominent cytoplasmic vacuoles and nuclear enlargement. Immunohistochemistry demonstrated ADP positivity in lymph node lesions but not in bone marrow MM cells, suggesting metabolic reprogramming toward lipid utilization. Despite anti-myeloma therapy, the disease rapidly progressed, and the patient died within two months. This case underscores the clinical significance of CD138 down-regulation as a marker of dedifferentiation and poor prognosis, and suggests that altered lipid metabolism may contribute to the aggressiveness of metastatic MM. To the best of our knowledge, this is the first MM case with lymph node involvement showing CD138 down-regulation and ADP positivity.

We have previously isolated the epithelial rests of Malassez (ERM) clone cells with strong Amelx expression, named as ERM-2, from the crude ERM cells. In the present study, we examined whether conditioned medium (CM) derived from cultured ERM-2 promotes the crystallization of immature enamel in tooth germs. Tooth germs from postnatal day 3 mice were incubated with ERM-2 conditional medium (CM). ERM-2 cells were transfected with si-RNA targeting specific enamel matrix proteins (EMPs). After 2 days of incubation, each CM was collected and employed to culture the tooth germs. The surface layers of the enamel structure were examined with a scanning electron microscope (SEM). Tooth germs cultured with ERM-2 CM on days 3 and 7 showed elongation and densification of the columnar structures in SEM analysis. The columnar structures became denser and aggregated forming a HAP-like hexagonal columnar structure 14 days after culture in ERM-2 CM. In contrast, no clear columnar structures were observed in ERM-2 CM with si-RNA of each EMPs. In conclusion, the present study demonstrated that CM derived from ERM-2 could form enamel-like structures on the surface of the tooth germ. ERM-2 may provide the possibility for the clinical use of enamel regeneration.

This study aimed to investigate carcinogenesis-related fibrosis patterns in liver biopsy tissues from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) by comprehensively measuring and quantifying various fibrosis patterns using artificial intelligence. Liver biopsy tissues from 13 patients with advanced fibrosis at MASLD diagnosis were subjected to collagen quantification and morphological and structural fiber characteristic evaluation using FibroNest (PharmaNest, Princeton, NJ, USA), which was described using up to seven quantitative fibrosis parameters (qFPs). The collagen-fibrosis composite score (FCS), morphometric-FCS, architecture-FCS, and phenotypic-FCS (Ph-FCS) were compared between patients with and without hepatocellular carcinoma (HCC). The collagen quantification alone could not discriminate between HCC and non-HCC cases. Regarding the individual qFPs of morphological fiber characteristics, the kurtosis and skewness of fiber twists were significantly lower in HCC cases than in non-HCC cases. In HCC cases, fiber width and density kurtosis tended to be larger, whereas fiber length kurtosis tended to be smaller than those in non-HCC cases. Ph-FCS could discriminate HCC from non-HCC at a threshold of 4.2, with 85% sensitivity and 100% specificity. A combination of fiber morphology and structural characteristics predicted HCC development with higher accuracy and might help define carcinogenic risk groups among patients with MASLD.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most well-known cancer types, with a persistently poor 5-year survival rate. We previously reported MCM4 as a molecule associated with cancer stem cells; however, its role in PDAC has not been reported. Therefore, in this study, we aimed to fill this gap in the literature. We analyzed MCM4 expression in 81 PDAC samples using immunohistochemistry (IHC). The functional role of MCM4 in PDAC was investigated using RNA interference in PDAC cell lines. Additionally, a single-cell analysis was conducted by downloading data from six PDAC cases. On IHC, high MCM4 expression was observed in 42 out of 81 (51.9%) PDAC cases. MCM4-positive PDAC was significantly associated with a higher pN grade. Furthermore, high MCM4 expression was linked to a significantly poorer prognosis and was identified as an independent prognostic factor in multivariate analysis. In PDAC cell lines, MCM4 knockdown impairs cell growth and spheroid formation. Single-cell analysis also revealed that MCM4-expressing cells were located upstream of the trajectory, with a cluster showing a correlation with KIFC1, which has been reported to be associated with cancer stemness. These results indicated the significance of MCM4 expression in PDAC and its association with cancer stemness.

Soft tissue sarcomas are heterogenous groups of tumors that show variable morphology as well as clinical behavior. Morphological features do not always directly reflect clinical behavior. Certain mesenchymal tumors exhibit an indolent clinical course. Among them are superficial CD34-positive fibroblastic tumors characterized by PRDM10 fusion. In our study, we aimed to detect PRDM10 gene rearrangement in superficial CD34-positive fibroblastic tumors and other pleomorphic sarcomas included in its differential diagnosis by immunohistochemistry and Fluorescence in situ hybridization. Totally, 33 cases were enrolled into this study. The results showed that two cases diagnosed as superficial CD34-positive fibroblastic tumor and two cases diagnosed as undifferentiated pleomorphic sarcoma have PRDM10 gene rearrangement. Immunohistochemically, not all rearranged tumors showed PRDM10 staining that suggests a low sensitivity of PRDM10 antibody. In conclusion, we suggested that PRDM10 gene rearrangement is not limited to superficial CD34-positive fibroblastic tumors; undifferentiated pleomorphic sarcomas may exhibit this molecular alteration and immunohistochemistry has lower sensitivity than fluorescence in situ hybridization.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive neoplasm with no effective treatment options. ATC with osteoclast-like giant cells (OGCs; ATC/OGC) is a rare variant of ATC, and no detailed pathological examination has been reported to date. A 59-year-old woman presented with sudden neck swelling. Computed tomography revealed a 5 cm tumor in the thyroid gland, which was surgically resected. Pathological examination revealed a diagnosis of ATC/OGC. The patient succumbed to progressive lung metastases within four months despite postoperative lenvatinib therapy. Immunohistochemical (IHC) examination indicated absence of PD-L1 expression in the OGCs, which comprised the majority of the tumor, with only sparse T cell infiltration in the area occupied by OGCs. Increased TGF-β expression was observed in the area containing OGCs, and both OGCs and infiltrating myeloid cells, including CD1a/CD11c-positive dendritic cells and CD68/CD163/CD204-positive macrophages, appeared to produce TGF-β. Pathological analysis of this case suggests that OGCs might be involved in immune suppression by secreting TGF-β, potentially serving as a critical cytokine in the immunosuppressive microenvironment of ATC/OGC. TGF-β-targeted therapy might be useful in the treatment of this very rare subtype of ATC.