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Shibagaki, Kotaro; Kushima, Ryoji; Mishiro, Tsuyoshi; Araki, Asuka; Niino, Daisuke; Ishimura, Norihisa; Ishihara, Shunji
doi: 10.1111/pin.13456pmid: 38837872
Reports of Helicobacter pylori (Hp)‐naïve gastric neoplasm (HpNGN) cases have been rapidly increasing due to the recent increase in the Hp‐naïve population in Japan. Most HpNGNs exhibit the gastric immunophenotype and a low malignant potential regardless of histological type. Especially, foveolar‐type gastric adenoma (FGA) and intestinal‐type gastric dysplasia (IGD) rarely progress to invasive carcinoma. FGA is a foveolar epithelial neoplasm that occurs in the fundic gland (oxyntic gland) mucosa and is classified as the flat type or raspberry type (FGA‐RA). The flat type is a large, whitish flatly elevated lesion while FGA‐RA is a small reddish polyp. Genomically, the flat type is characterized by APC and KRAS gene mutations and FGA‐RA by a common single nucleotide variant in the KLF4 gene. This KLF4 single‐nucleotide variant reportedly induces gastric foveolar epithelial tumorigenesis and activates both cell proliferation and apoptosis, leading to its slow‐growing nature. IGD consists of an intestinalized epithelial dysplasia that develops in the pyloric gland mucosa, characterized as a superficial depressed lesion surrounded by raised mucosa showing a gastritis‐like appearance. Immunohistochemically, it exhibits an intestinal or gastrointestinal phenotype and, frequently, p53 overexpression. Thus, IGD shows unique characteristics in HpNGNs and a potential multistep tumorigenic process.
doi: 10.1111/pin.13458pmid: 38888200
Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto‐Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated.
Yamato, Mariko; Dai, Tomoko; Murata, Yoshihiko; Nakagawa, Tomoki; Kikuchi, Shinji; Matsubara, Daisuke; Noguchi, Masayuki
doi: 10.1111/pin.13457pmid: 38874190
Eukaryotic elongation factor 1 alpha 2 (eEF1A2) encodes an isoform of the alpha subunit of the elongation factor 1 complex and is responsible for the enzymatic delivery of aminoacyl tRNA to the ribosome. Our proteomic analysis has identified eEF1A2 as one of the proteins expressed during malignant progression from adenocarcinoma in situ (AIS) to early invasive lung adenocarcinoma. The expression level of eEF1A2 in 175 lung adenocarcinomas was examined by immunohistochemical staining in relation to patient prognosis and clinicopathological factors. Quantitative PCR analysis and fluorescence in situ hybridization (FISH) were performed to evaluate the amplification of the eEF1A2 gene. Relatively high expression of eEF1A2 was observed in invasive adenocarcinoma (39/144 cases) relative to minimally invasive adenocarcinoma (1/10 cases) or AIS (0/21 cases). Among invasive adenocarcinomas, solid‐type adenocarcinoma (15/32 cases, 47%) showed higher expression than other histological subtypes (23/92, 25%). Patients with eEF1A2‐positive tumors had a significantly poorer prognosis than those with eEF1A2‐negative tumors. Of the five tumors that were eEF1A2‐positive, two cases showed amplified genomic eEF1A2 DNA, which was confirmed by both qPCR and FISH. These findings indicate that eEF1A2 overexpression occurs in the course of malignant transformation of lung adenocarcinomas and is partly due to eEF1A2 gene amplification.
Huang, Min; Li, Shuang; Zeng, Hai; Zhu, Yan; Zhang, Fan; Cai, Jun
doi: 10.1111/pin.13459pmid: 38940569
Exosomes from cancer cells function as carriers to spread or transport specific microRNAs (miRNAs) to distant sites to exert their effects, but the mechanism of exosomal miRNA action in esophageal squamous cell carcinoma (ESCC) has not been fully explained. Therefore, in this study, we were interested in the impact of exosomal miR‐196a‐5p in ESCC progression. We found that miR‐196a‐5p was expressed enriched in clinical tissues, ESCC cells, and exosomes. Functionally, depletion of miR‐196a‐5p impeded ESCC cell growth, migration, and invasion, whereas overexpression of miR‐196a‐5p produced the opposite results. Moreover, enhancement of exosomal miR‐196a‐5p in recipient ESCC cells triggered more intense proliferation and migration. Mechanistically, we identified integral membrane protein 2B (ITM2B) as a direct target of miR‐196a‐5p. Silencing of ITM2B partially counteracted the inhibitory effect of miR‐196a‐5p inhibitors on the malignant phenotype of ESCC. Furthermore, in vivo, lower miR‐196a‐5p levels triggered by the introduction of antagomiR‐196a‐5p resulted in the generation of smaller volume and weight xenograft tumors. Thus, our results demonstrated novel mechanisms of exosomal and intracellular miR‐196a‐5p‐mediated ESCC growth and migration and identify the interaction of miR‐196a‐5p with ITM2B. These works might provide new targets and basis for the development of clinical treatment options for ESCC.
Matsunaga, Ayano; Saito, Mariko; Ijiri, Kaya; Tsuchiya, Motohiro; Yasuda, Akimasa; Kitamura, Kazuya; Ogata, Sho; Chiba, Kazuhiro; Matsukuma, Susumu
doi: 10.1111/pin.13465pmid: 38994749
“Cysts of the ligamentum flavum (cysts‐LF)” is the term for non‐neoplastic cystic lesion involving LF. The aim of the present study was to elucidate the histopathological characteristics and pathogenesis of “cysts‐LF”. Herein, we defined cysts‐LF as spinal cysts containing degenerative LF components. From archival cases, we investigated 18 symptomatic cysts‐LF surgically removed from 18 patients (13 males and five females; median age 68.5 years [range, 42–86 years]). The elastic fibers of LF components in the wall were separated and/or torn, and cyst walls were accompanied by chondroid metaplasia (17 cases), myxoid changes (13 cases), ossification (11 cases), amyloid deposits (14 cases), hemosiderosis (six cases), granular/smudgy calcification (four cases), synovial cell linings (three cases), and severe inflammatory infiltrates (one case). These histologic features of our cysts‐LF were shared by previously reported “cysts‐LF.” Fourteen cysts‐LF demonstrated vascular stenosis/occlusion, and eight showed thick hyalinized vessels, suggesting local circulatory insufficiency. Eight cases (44%) exhibited lipomembranous fat necrosis, accompanied by hyalinized vascular changes (p = 0.003). Ischemic conditions were observed in nearly half of the present cysts‐LF, and may be one of the main contributing factors for the formation of cysts‐LF, via degeneration and cystic changes in the LF.
doi: 10.1111/pin.13455pmid: 38818886
Clear cell hidradenoma is a rare benign tumor of the breast, its origin and pathogenesis are controversial. We have experienced a case of breast clear cell hidradenoma with mastermind like transcriptional coactivator 2 (MAML2) gene rearrangement. The patient found a painless mass with a hard texture in the left breast areola without nipple discharge. Microscopically, the tumor was cystic and solid, locally arranged in a glandular structure, covered by single cuboidal cells; it was composed of clear cells, epidermoid cells, and basaloid cells; there were no necrosis or mitotic figures. Immunohistochemical staining showed that the tumor cells positively expressed low‐molecular cytokeratin 7, low‐molecular cytokeratins (Cam5.2), high‐molecular cytokeratin 5/6, cytokeratin 14, CD117, and p63; and did not express calponin, and smooth muscle myosin heavy chain. The cuboidal cells were positive for SOX10 but negative for p63. Additionally, periodic acid‐Schiff reaction showed purple‐red granules in the tumor cytoplasm, but Alcian blue staining showed no blue mucus in the cytoplasm. The split signals of MAML2 gene were detected by fluorescence in situ hybridization. Subtle histological and immunophenotypical differences may help to distinguish breast clear cell hidradenoma from common breast tumors. Furthermore, the MAML2 gene rearrangement may be a molecular genetic characteristic of breast clear cell hidradenoma.
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