Someya M, Tsuchiya T, Fukushima Y
… +13 more, Hasegawa T, Hori M, Kitagawa M, Gocho T, Mafune S, Ikeuchi Y, Hirohashi Y, Torigoe T, Iwasaki M, Matsuura M, Saito T, Matsumoto Y, Sakata KI
To supplement clinical decision-making in the management of cervical cancer, various prognostic factors, including tumor immune microenvironments, were examined in patients with cervical cancer treated with definitive ch...To supplement clinical decision-making in the management of cervical cancer, various prognostic factors, including tumor immune microenvironments, were examined in patients with cervical cancer treated with definitive chemoradiotherapy. We retrospectively analyzed the expression of CD8, FoxP3, HLA-1, PD-L1, and XRCC4 in 100 cases of cervical cancer. The observed tumor immune microenvironments were also classified into three types: inflamed, excluded, and cold type. Less FoxP3+ T cells and cold-type tumor were found to be poor prognostic factors in addition to non-SCC, large pre-treatment tumor volume, and three or less cycles of concurrent chemotherapy based on multivariate analysis. Cold-type tumors had significantly worse prognoses than the other two types, whereas inflamed- and excluded-type tumors showed similar 5-year disease-specific survival (P < 0.001; 0% vs. 60.3% vs. 72.3%). Radiotherapy could overcome the inhibitory immune microenvironment that occurs in excluded type. Individualized combination therapy adapted to pre-treatment tumor immunity may be necessary to improve radiotherapy outcomes in cervical cancer.
A previous retrospective study of a neuroendocrine carcinoma of the endometrium including 42 cases employed a central pathologic review to ensure the reliability of the findings. However, the pathological processes were...A previous retrospective study of a neuroendocrine carcinoma of the endometrium including 42 cases employed a central pathologic review to ensure the reliability of the findings. However, the pathological processes were not described in detail. In this study, we further analyzed these processes and the results of pretreatment endometrial cytology of neuroendocrine carcinoma. Of the 65 patients from 18 institutions registered in the study, 42 (64.6%) were diagnosed with neuroendocrine carcinoma of the endometrium based on the central pathological review. Thirteen of the 23 excluded cases conflicted from their original diagnoses: 5 (38.5%) were diagnosed with endometrioid adenocarcinoma, 5 (38.5%) with undifferentiated carcinoma, and 3 (23.1%) with carcinosarcoma. Immunohistochemical staining led to a change in diagnosis for 8 (61.5%) of the 13 cases. Pretreatment endometrial cytology was examined in 38 (90.5%) cases; 34 (89.5%) of these 38 cases were found, or suspected, to be positive. To ensure the selection of appropriate therapy and keeping patients correctly informed, it is important to distinguish neuroendocrine carcinoma from other similar histologic types. Endometrial cytology may help in the early detection of this disease.
We prepared a polyclonal antibody against a teicoplanin (TEIC)-bovine serum albumin conjugate that was specific to both conjugated and free forms of TEIC. We demonstrated that this antibody could be used to detect the ti...We prepared a polyclonal antibody against a teicoplanin (TEIC)-bovine serum albumin conjugate that was specific to both conjugated and free forms of TEIC. We demonstrated that this antibody could be used to detect the time-dependent localization of TEIC in rat kidneys. Immunohistochemistry revealed immunoreactivity specifically in the microvilli and apical cytoplasm of epithelial cells in proximal tubule segments S1 and S2, 1 h after intravenous TEIC injection, with higher staining intensity in the S2 segments. The epithelial cells of S3 segments showed moderate immunostaining with a few cells exhibiting nuclear staining. Furthermore, we found that the distal tubules and collecting ducts contained both TEIC-positive and -negative cells. TEIC immunoreactivity decreased rapidly over time; only weak staining remained in the S3 segments, distal tubules, and collecting ducts 24 h after administration. No staining was detected 7 days after injection. These results were significantly different from those of our previous study obtained using vancomycin, which showed moderate staining in the proximal tubule segments S1 and S2, distal tubules, and the collecting ducts 8 days after administration. The lower TEIC accumulation in tissues may account for a lower risk of adverse events compared to that using vancomycin.
Sclerosing mucoepidermoid carcinoma (SMC) is described as a "sclerosing variant" of mucoepidermoid carcinoma, and it is characterized by dense fibrosis and sclerosis of the stroma. SMC with eosinophilia (SMCE) is another...Sclerosing mucoepidermoid carcinoma (SMC) is described as a "sclerosing variant" of mucoepidermoid carcinoma, and it is characterized by dense fibrosis and sclerosis of the stroma. SMC with eosinophilia (SMCE) is another and more rare subtype characterized by eosinophilia in addition to the sclerotic stroma common to SMC. However, unlike SMC, SMCE is not listed in the current 4th edition of WHO classification. Here, we describe three cases: one SMC in the parotid gland, one SMCE in the submandibular gland and one SMCE in the minor salivary gland of the oral cavity. The patients included a 71-year-old Japanese male, a 74-year-old Japanese female, and an 81-year-old Japanese female. They each complained of mass formation and underwent surgical resection. Histologically, the tumors mainly consisted of squamous cells with scarce keratinization that formed irregular large and small nests along with cystic structures containing mucous cells against the background of sclerotic stroma. One oral SMCE showed fine nesting and trabecular invasion. The two SMCEs included dense aggregates of eosinophils as well as more prominent lymphoid infiltration. Fluorescence in situ hybridization for MAML2 confirmed split signals in SMC, but not in SMCE.
A 16-year-old Japanese man was admitted to our hospital because of syncope during exercise. His father and his younger brother had permanent pacemaker implantation because of sick sinus syndrome. Several examinations rev...A 16-year-old Japanese man was admitted to our hospital because of syncope during exercise. His father and his younger brother had permanent pacemaker implantation because of sick sinus syndrome. Several examinations revealed first-degree atrioventricular block, complete right bundle branch block, sick sinus syndrome, and ventricular tachycardia with normal cardiac function. As no abnormalities were evident on coronary angiography, right ventricular endomyocardial biopsy was performed. It showed myocardial disarrangement and lipofuscin accumulation in hypertrophic myocytes. Moreover, electron microscopy showed a few degenerative myocytes, Z-band streaming, disarrangement, increased small capillaries with Weibel-Palade bodies in endothelial cells, and endothelial proliferations. Genetic analysis of the proband, his father, and his younger brother revealed a missense mutation, D1275N, in SCN5A, a gene which encodes sodium ion channel protein, are related to cardiomyopathy and arrhythmia. The proband was diagnosed with a cardiac conduction defect (CCD) and underwent permanent pacemaker implantation. These pathological findings suggest various myocardial changes presented in CCD patients with a missense mutation, D1275N, in SCN5A.
Recent studies have found that microRNAs (miRNAs) are present in body fluids, including blood, cerebrospinal fluid, tears, saliva, breast milk, and urine in a stable form, and are called circulating miRNAs. Although thei...Recent studies have found that microRNAs (miRNAs) are present in body fluids, including blood, cerebrospinal fluid, tears, saliva, breast milk, and urine in a stable form, and are called circulating miRNAs. Although their biological roles remain to be determined, circulating miRNAs are considered as mediators of intercellular communication like hormones and cytokines. Because circulating miRNAs can be collected in a non-invasive manner called as "liquid biopsy", they have also been studied as potential biomarkers for early detection, evaluation of therapeutic effects, and prediction of prognosis in various diseases, including cancers. In this review, we focus on the studies on circulating microRNA-92a-3p (miR-92a-3p) in colorectal cancer (CRC), considering their existence form, isolation methods, potential as biomarkers, and roles in CRC development and progression.
Oike T, Uchihara Y, Permata TBM
… +3 more, Gondhowiardjo S, Ohno T, Shibata A
Med Mol Morphol
· 2021 Jun · PMID 33501611
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To obtain quantitative volumetric data for the Golgi apparatus after ionizing radiation (IR) using super-resolution three-dimensional structured illumination (3D-SIM) microscopy. Normal human retinal pigment epithelial (...To obtain quantitative volumetric data for the Golgi apparatus after ionizing radiation (IR) using super-resolution three-dimensional structured illumination (3D-SIM) microscopy. Normal human retinal pigment epithelial (RPE) cells were irradiated with X-rays (10 Gy), followed by immunofluorescence staining of the Golgi marker RCAS1. 3D-SIM imaging was performed using DeltaVision OMX version 4 and SoftWoRx 6.1. Polygon rendering and spot signal identification were performed using Imaris 8.1.2. Differences between groups were assessed by Welch's t test. RCAS1 signals in untreated cells were located adjacent to nuclei and showed a reticular morphology. Upon IR, the area of RCAS1 signals expanded while retaining the reticular morphology. Polygon rendering imaging revealed that the volume of RCAS1 at 48 h post-IR was greater than that for unirradiated cells (93.7 ± 19.0 μm vs. 33.0 ± 4.2 μm, respectively; P < 0.001): a 2.8-fold increase. Spot signal imaging showed that the number of RCAS1 spot signals post-IR was greater than that for unirradiated cells [3.4 ± 0.8 (× 10) versus 1.3 ± 0.2 (× 10), respectively; P < 0.001]: a 2.7-fold increase. This is the first study to report quantitative volumetric data of the Golgi apparatus in response to IR using super-resolution 3D-SIM microscopy.
Nishikawa M, Ito H, Noda M
… +3 more, Hamada N, Tabata H, Nagata KI
Med Mol Morphol
· 2021 Jun · PMID 33492483
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Abnormalities of PLEKHG2 gene, encoding a Rho family-specific guanine nucleotide exchange factor, are involved in microcephaly with intellectual disability. However, not only the role of PLEKHG2 in the developmental proc...Abnormalities of PLEKHG2 gene, encoding a Rho family-specific guanine nucleotide exchange factor, are involved in microcephaly with intellectual disability. However, not only the role of PLEKHG2 in the developmental process but also its expression profile is unknown. In this study, we prepared a specific antibody against PLEKHG2 and carried out expression analyses with mouse tissues. In western blotting, PLEKHG2 exhibited a tissue-dependent expression profile in adult mouse and was expressed in a developmental stage-dependent manner in brain. Then, in immunohistochemical analyses, while PLEKHG2 was observed in the cortical plate and ventricular zone surface of the cerebral cortex at embryonic day 14, it came to be distributed throughout the cerebral cortex in layer II/III and V during corticogenesis. PLEKHG2 was also detected mainly in the nucleus of neurons in the hippocampal CA regions and dentate gyrus at P7. Notably, the nuclear accumulation disappeared at P30 and PLEKHG2 came to be located at the axons and/or dendrites at this time point. Moreover, in vitro immunofluorescence revealed that PLEKHG2 was at least partially localized at both excitatory and inhibitory synapses in primary cultured hippocampal neurons. These results suggest roles of PLEKHG2 in the development of the central nervous tissue and synaptic function.
Adenomatous polyposis coli (APC), a well-known anti-oncogene, is considered to have multiple functions through its several binding domains. We have continuingly studied APC mice (APC1638T mice) to elucidate the functions...Adenomatous polyposis coli (APC), a well-known anti-oncogene, is considered to have multiple functions through its several binding domains. We have continuingly studied APC mice (APC1638T mice) to elucidate the functions of APC other than tumor suppression. A distinctive feature of the APC1638T mice is they are tumor free and live as long as APC mice (WT mice). Previously, we found the length of crypt-villus axis in the jejunum was significantly elongated in APC1638T mice compared with that of WT mice. The populations of goblet cells, Paneth cells, and enteroendocrine cells were also disordered in APC1638T mice. Here, we further analyzed the intestinal dyshomeostasis in APC1638T mice, focusing on the proliferation and differentiation of intestinal stem cell (ISC) lineages, and apoptotic cell shedding at the villus tips. We found that the proliferation of ISC lineages was normally controlled; however, the shedding process of apoptosis cells was significantly delayed in the APC1638T mouse jejunum. Furthermore, the number of microfold cells (M cells) was significantly increased in the APC1638T mouse jejunum. Our data suggested both differentiation process of ISCs and turnover process of intestinal epithelia were disturbed in APC1638T mice, and that contributed to the villus elongation in the APC1638T mouse jejunum.
The incidence rate of post-cataract surgery posterior capsule opacification (PCO) and lens turbidity is about 20% in 5 years. Soemmering's ring, which is a type of PCO also called a regenerated lens with similar tissue s...The incidence rate of post-cataract surgery posterior capsule opacification (PCO) and lens turbidity is about 20% in 5 years. Soemmering's ring, which is a type of PCO also called a regenerated lens with similar tissue structure to that of a human lens, is an important proxy for elucidating the mechanism of lens regeneration and maintenance of transparency. The authors created new human immortalized crystalline lens epithelial cells (iHLEC-NY1s) with excellent differentiation potential, and as a result of culturing the cells by static and rotation-floating methods, succeeded in producing a three-dimensional cell structure model (3D-iHLEC-NY1s) which is similar to Soemmering's ring in tissue structure and expression characteristics of αA-crystalline, βB2-crystalline, vimentin proteins. 3D-iHLEC-NY1s is expected to be a proxy in vitro experimental model of Soemmering's ring to enable evaluation of drug effects on suppression of cell aggregate formation and transparency. By further improving the culture conditions, we aim to control the cell sequence and elucidate the mechanism underlying the maintenance of lens transparency.
Secretory carcinoma of the salivary glands is a relatively new disease concept, and is characterized by "morphological resemblance to mammary secretory carcinoma and ETV6-NTRK3 gene fusion." Herein we describe a confusin...Secretory carcinoma of the salivary glands is a relatively new disease concept, and is characterized by "morphological resemblance to mammary secretory carcinoma and ETV6-NTRK3 gene fusion." Herein we describe a confusing case and briefly discuss practical diagnostic problems. The patient was a 71-year-old Japanese man who had a tumor consistent with secretory carcinoma at the microscopic and immunohistochemical levels. Immunohistochemically, EMA and S100 protein were noted to be positive along with various cytokeratins as well as mammaglobin and pSTAT5. Moreover, vimentin was focally positive. Smooth muscle actin, p63, p40, and androgen receptor were negative. However, a search using fluorescence in situ hybridization did not reveal a definite split signal for the ETV6 gene. It is presumed that confirming the diagnosis of secretory carcinoma without genetic retrieval will be accepted as a diagnostic method, and we hope that worldwide general recognition may earlier reach "gradual acceptance."
A Japanese male aged 61 presented with persistent pain in the left posterior area of the mandible for several weeks. A panoramic X-ray revealed a unilocular lesion showing characteristics of a dentigerous cyst associated...A Japanese male aged 61 presented with persistent pain in the left posterior area of the mandible for several weeks. A panoramic X-ray revealed a unilocular lesion showing characteristics of a dentigerous cyst associated with an impacted third molar. A cystectomy was performed and histopathological examination revealed a cystic lesion with a fibrous wall. The lumen was covered with non-keratinizing squamous cells with obvious intercellular bridges, which were intermingled with partially ciliated goblet-cell-type mucous and columnar cells. Such cystic lesions should be carefully examined to distinguish them from the glandular odontogenic cyst and central mucoepidermoid carcinoma of the jawbone.
Monsur M, Yamaguchi M, Tashiro H
… +8 more, Yoshinobu K, Saito F, Erdenebaatar C, Li C, Iwagoi Y, Ohba T, Iyama KI, Katabuchi H
Med Mol Morphol
· 2021 Jun · PMID 33399963
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POLE-mutated endometrial cancer (EC) frequently shows high-grade endometrioid histology, which represents heterogeneity in the dualistic classification of EC. This study aimed to assess the clinicopathology and pathogene...POLE-mutated endometrial cancer (EC) frequently shows high-grade endometrioid histology, which represents heterogeneity in the dualistic classification of EC. This study aimed to assess the clinicopathology and pathogenesis of POLE-mutated EC due to the scarcity of related information for Asian women. POLE variants were sequenced in tissues of Japanese women with EC. The tumor mutation burden (TMB) was assessed in tissues with a POLE variant of unknown significance. In the POLE-mutated EC tissues, the immunostaining expression of CD8, hormonal receptors, and p53 was evaluated, and the POLE variants in cancer and atypical endometrial hyperplasia (AEH) lesions were assessed by laser-capture microdissection. POLE variants were identified in five patients (3.9%) with high-grade endometrioid carcinoma among 127 patients with EC (S459F in two tissues and P441P in three tissues with a high TMB). The five cancer tissues coexisted with normal endometrium and/or AEH. Both AEH and cancer cells showed hormonal receptor positivity and harbored the same POLE mutation. Two patients showed a subclonal overexpression pattern of p53 in cancer and AEH lesions. In conclusion, POLE-mutated EC progresses through the type I pathway, even though it frequently shows high-grade endometrioid morphology. The common POLE mutation sites in EC might vary among races.
Kusunoki M, Fujiwara Y, Komohara Y
… +4 more, Imamura Y, Honda R, Ohba T, Katabuchi H
Med Mol Morphol
· 2021 Jun · PMID 33392726
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Endometriosis is a chronic inflammatory disease. Endometriotic cysts contain hemoglobin (Hb) and infiltrated macrophages, indicating that the metabolism of Hb by macrophages may play an important role in the inflammation...Endometriosis is a chronic inflammatory disease. Endometriotic cysts contain hemoglobin (Hb) and infiltrated macrophages, indicating that the metabolism of Hb by macrophages may play an important role in the inflammation of endometriotic cysts. In this study, we investigated the distribution of immune cells and CD163 (Hb receptor)-positive cells in the endometriotic cyst wall using immunohistochemistry. We also examined the role of macrophage activation by Hb on the pathogenesis of endometriotic cysts by measuring the cytokine concentration in the cystic fluids and macrophage-culture supernatant using ELISA. Macrophages were the most prominent immune cells observed in the endometriotic cysts and were differentially distributed in the different histological areas of the cyst wall. The localization of CD163-positive macrophages was restricted to the hemorrhagic and outer areas in the cyst wall. High concentrations of IL-6 and CCL2 were found in the cystic fluids, and inflammatory cytokines (IL-6, TNF-α, and CCL2) were secreted from macrophages on stimulation by Hb. IL-6 is a promotional factor for endometriotic stromal cells and ovarian clear cell carcinoma, the most common histological subtype of endometriosis-related ovarian cancer, hence, the continuous activation of macrophages by Hb could be a potential mechanism underlying endometriosis development and carcinogenesis.
Honma Y, Miyagawa K, Hara Y
… +8 more, Hayashi T, Kusanaga M, Ogino N, Minami S, Oe S, Ikeda M, Hino K, Harada M
Med Mol Morphol
· 2021 Jun · PMID 33386512
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Hepatitis C virus (HCV) infection has been known to use autophagy for its replication. However, the mechanisms by which HCV modulates autophagy remain controversial. We used HCV-Japanese fulminant hepatitis-1-infected Hu...Hepatitis C virus (HCV) infection has been known to use autophagy for its replication. However, the mechanisms by which HCV modulates autophagy remain controversial. We used HCV-Japanese fulminant hepatitis-1-infected Huh7 cells. HCV infection induced the accumulation of autophagosomes. Morphological analyses of monomeric red fluorescent protein (mRFP)-green fluorescent protein (GFP) tandem fluorescent-tagged LC3 transfection showed HCV infection impaired autophagic flux. Autophagosome-lysosome fusion assessed by transfection of mRFP- or GFP-LC3 and immunostaining of lysosomal-associated membrane protein 1 was inhibited by HCV infection. Decrease of HCV-induced endoplasmic reticulum (ER) stress by 4-phenylbutyric acid, a chemical chaperone, improved the HCV-mediated autophagic flux impairment. HCV infection-induced oxidative stress and subsequently DNA damage, but not apoptosis. Furthermore, HCV induced cytoprotective effects against the cellular stress by facilitating the formation of cytoplasmic inclusion bodies as shown by p62 expression and by modulating keratin protein expression and activated nuclear factor erythroid 2-related factor 2. HCV eradication by direct-acting antivirals improved autophagic flux, but DNA damage persisted. In conclusion, HCV-induced ER stress correlates with autophagic flux impairment. Decrease of ER stress is considered to be a promising therapeutic strategy for HCV-related chronic liver diseases. However, we should be aware that the risk of hepatocarcinogenesis remains even after HCV eradication.
Rico SD, Höflmayer D, Büscheck F
… +31 more, Dum D, Luebke AM, Kluth M, Hube-Magg C, Hinsch A, Möller-Koop C, Perez D, Izbicki JR, Neipp M, Mofid H, Lárusson H, Daniels T, Isbert C, Coerper S, Ditterich D, Rupprecht H, Goetz A, Fraune C, Möller K, Menz A, Bernreuther C, Clauditz TS, Sauter G, Uhlig R, Wilczak W, Simon R, Steurer S, Lebok P, Burandt E, Krech T, Marx AH
Med Mol Morphol
· 2021 Jun · PMID 33373033
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Mucin 5AC (MUC5AC) is a secreted gel-forming mucin expressed by several epithelia. In the colon, MUC5AC is expressed in scattered normal epithelial cells but can be abundant in colorectal cancers. To clarify the relation...Mucin 5AC (MUC5AC) is a secreted gel-forming mucin expressed by several epithelia. In the colon, MUC5AC is expressed in scattered normal epithelial cells but can be abundant in colorectal cancers. To clarify the relationship of MUC5AC expression with parameters of tumor aggressiveness and mismatch repair deficiency (dMMR) in colorectal cancer, a tissue microarray containing 1812 colorectal cancers was analyzed by immunohistochemistry. MUC5AC expression was found in 261 (15.7%) of 1,667 analyzable colorectal cancers. MUC5AC expression strongly depended on the tumor location and gradually decreased from proximal (27.4% of cecum cancers) to distal (10.6% of rectal cancers; p < 0.0001). MUC5AC expression was also strongly linked to dMMR. dMMR was found in 21.3% of 169 cancers with MUC5AC positivity but in only 4.6% of 1051 cancers without detectable MUC5AC expression (p < 0.0001). A multivariate analysis showed that dMMR status and tumor localization predicted MUC5AC expression independently (p < 0.0001 each). MUC5AC expression was unrelated to pT and pN status. This also applied to the subgroups of 1136 proficient MMR (pMMR) and of 84 dMMR cancers. The results of our study show a strong association of MUC5AC expression with proximal and dMMR colorectal cancers. However, MUC5AC expression is unrelated to colon cancer aggressiveness.
Akisada N, Nishimoto K, Takao S
… +12 more, Gion Y, Marunaka H, Tachibana T, Makino T, Miki K, Akagi Y, Tsumura M, Toji T, Yoshino T, Nishizaki K, Orita Y, Sato Y
Med Mol Morphol
· 2021 Mar · PMID 33315143
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Lenci N, Francesco P, Scarciglia E
… +6 more, Fiorentino V, Schino M, Palermo G, Racioppi M, Bassi P, Martini M
Med Mol Morphol
· 2021 Jun · PMID 33175195
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Metanephric adenoma (MA) is an uncommon benign renal tumor whose histomorphological aspect resembles that of Wilms' tumor and papillary renal cell carcinoma. From a diagnostic and therapeutic perspective, recognition of...Metanephric adenoma (MA) is an uncommon benign renal tumor whose histomorphological aspect resembles that of Wilms' tumor and papillary renal cell carcinoma. From a diagnostic and therapeutic perspective, recognition of this entity is important as it has a more favorable clinical outcome compared with Wilms' tumor and papillary renal cell carcinoma. MA should not be treated with nephrectomy if the tumor size is small, opting for a conservative treatment. However, the preoperative diagnosis of this disease is extremely challenging. The present study describes a case of this rare disease, showing an ambiguous radiological imaging and that only after a percutaneous biopsy, was defined as a MA and treated with partial nephrectomy. Moreover, the histological diagnosis of this case was partially complicated by the equivocal immunohistochemical analysis showing negativity for BRAF VE1 staining. Only the mutational analysis demonstrated the presence of the BRAF V600K mutation (for the first time described in a case of metanephric adenoma), highlighting the necessity of sequencing in case of MA with negativity for BRAF VE1 clone.