Clinical characteristics, proteins, and genes related to interstitial pneumonia-associated squamous cell carcinoma of the lungs.

Squamous cell carcinoma (SCC) is a common histological type of lung carcinoma that is associated with interstitial pneumonia (IP). We hypothesized that identifying specific genetic alterations or molecular markers of SCC with IP may aid the development of novel therapeutic strategies for the same. Therefore, in the present study, we aimed to identify tumorigenic genetic alterations and molecular markers in cases of SCC with IP. We included 28 lung SCC cases (14 cases with IP and 14 cases without IP). We performed immunohistochemistry for STAT3, STAT5, and TLE1, and next-generation sequencing was performed using an iSeq 100 system. The panel used in this study targeted 50 cancer-associated genes. Immunohistochemically, the rate of TLE1 positivity was higher in the SCC without IP group (93 %) than in the SCC with IP group (29 %), while that of STAT5 was higher in the SCC with IP group (79 %) than in the SCC without IP group (14 %). STAT3 expression was high in both the groups (SCC with IP, 64 %; SCC without IP, 71 %). Eighteen genes were mutated in more than six samples, and FBXW7 mutation was mainly observed in the SCC with IP group (p < 0.01). Mechanisms underlying tumorigenesis in SCC with IP included STAT5 activation via inflammation, while that in SCC without IP included squamous TLE1-mediated metaplasia. These findings are based on smoking-induced STAT3 activation; therefore, patients with IP who smoke are more likely to have progressive SCC. We also found that FBXW7 mutations may be associated with SCC with IP and keratinization. ERBB4 and KDR mutations were observed in both with or without IP, and these genes may be tumor-related genes in SCC. These molecular markers may help determine the prognoses of patients with SCC with IP and direct the development of treatment approaches.

Uncommon case of cytopathological features of sialadenoma papilliferum.

Sialadenoma papilliferum, a benign and rare salivary gland neoplasm, accounts for 0.4%-1.2% of all salivary gland tumors and occurs primarily in minor salivary glands of the oral cavity. Here, we report a case of sialadenoma papilliferum and its associated cytological findings. A papillary tumor was incidentally detected on the palate of an 86-year-old Japanese man. Conventional oral exfoliative cytology was performed; the cytology smear exhibited epithelial clusters composed of atypical epithelial cells with a high nuclear/cytoplasm ratio and arranged in sheet or small papillary-like projections. Cytoplasmic vacuoles were also observed in the papillae. It was difficult to make a definitive diagnosis due to the presence of uncommon cytological features. The excisional biopsy specimen revealed histological features characteristic of sialadenoma papilliferum. Mutational analysis detected BRAFV600E mutation, which confirmed the diagnosis of sialadenoma papilliferum. To the best of our knowledge, no prior cytomorphological evaluations of sialadenoma papilliferum have been reported in detail. Oral exfoliative cytology specimens from salivary gland tumors can demonstrate uncommon cytomorphological features. A differential diagnosis of sialadenoma papilliferum can be based on the observation of mildly atypical epithelial cells that form small papillary-like structures.

CD8/PD-L1 immunohistochemical reactivity and gene alterations in cutaneous squamous cell carcinoma.

In recent years, several immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) or PD-1 have been developed for cancer therapy. The genetic background of tumors and factors that influence PD-L1 expression in tumor tissues are not yet elucidated in cutaneous squamous cell carcinoma (cSCC). CD8-positive tumor-infiltrating lymphocytes (TILs) are known to be related to tumor immunity. Here, we aimed to study the relationship between CD8/PD-L1 immunohistochemical reactivity and gene alterations in cSCC. Tumorigenic genes were examined to identify gene alterations using next-generation sequencing (NGS). We collected 27 cSCC tissue samples (from 13 metastatic and 14 non-metastatic patients at primary diagnosis). We performed immunohistochemical staining for CD8 and PD-L1, and NGS using a commercially available sequencing panel (Illumina Cancer Hotspot Panel V2) that targets 50 cancer-associated genes. Immunohistochemically, CD8-positive TILs showed a high positive score in cSCC without metastasis; in these cases, cSCC occurred predominantly in sun-exposed areas, the tumor size was smaller, and the total gene variation numbers were notably low. The tumor depth, PD-L1 positivity, and gene variation number with or without tumor metastasis were not related, but the gene variation number tended to be higher in cSCCs arising in non-sun-exposed areas. Tumor metastasis was more common in cSCC arising in non-sun-exposed areas, which decreased the number of TILs or CD8-positive cells. From a genetic perspective, the total gene alterations were higher in cSCC with metastasis. Among them, ERBB4 and NPM1 are presumably involved in cSCC tumorigenesis; in addition, GNAQ, GNAS, JAK2, NRAS, IDH2, and CTNNB1 may be related to tumor metastasis. These results provide information on potential genes that can be targeted for cSCC therapy and on immune checkpoint inhibitors that may be used for cSCC therapy.

Micronodular Thymic Carcinoma with Lymphoid Stroma: A Case Report.

Background. Micronodular thymic carcinoma (MTC) with lymphoid hyperplasia is believed to be the malignant counterpart of micronodular thymoma (MT) with lymphoid hyperplasia. Since MT and MTC share a similar morphology, MTC is considered a malignant form of MT; there have been a few malignant transformations from MT to MTC. We report a case of MTC with lymphoid hyperplasia. Case presentation. A 53-year-old woman presented with an incidental tumor on a chest X-ray. The resected tumor consisted of nodular epithelial nests and lymphoid tissue within a surrounding germinal center. Some epithelial nests showed apparent malignant morphology. Atypical epithelial cells with large vesicular nuclei formed nests, some of which showed comedo necrosis. These cells showed transition continuously to low-grade type B thymoma-like cells, demonstrating cord-like arrangements. Carcinomatous elements, expressed GLUT1, CD5, KIT, and BCL2; conversely, low-grade nests displayed attenuated expression of these markers. GTF2I point mutation and Langerhans/dendritic cells, which are indicators of favorable thymoma prognosis, were not detected. Due to pleural metastasis, the patient was treated with lenvatinib 27 months postoperatively. Conclusions. This is the first report of a partially low-grade, GTF2I-negative MTC. Histological and genetic findings might be predictive of tumor prognosis.

Immunohistochemical Reactivity of Prostate-Specific Membrane Antigen in Salivary Gland Tumors.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in the prostate gland and prostate cancer. PSMA has been recently used in positron emission tomography/computed tomography (PET/CT) imaging and targeted alpha-radiation therapy (TAT) for prostate cancer. Recently, the tubarial gland, a type of minor salivary gland that is described as a new organ situated in the pharynx, is reported to express PMSA. Here, we studied the expression of PSMA in common benign and malignant salivary gland tumors. We performed immunohistochemistry for PSMA in 55 salivary gland tumors comprising 10 pleomorphic adenomas, 10 Warthin tumors, 9 basal cell adenomas, 9 adenoid cystic carcinomas, 9 mucoepidermoid carcinomas, and 8 salivary duct carcinomas. PSMA was expressed in 97% of benign tumors and 77% of malignant tumors. Moreover, PSMA was expressed in 59% of normal salivary glands adjacent to the tumor. PSMA is relatively expressed in salivary gland tumors and salivary glands. Therefore, salivary gland neoplasm, and normal salivary gland, possibly demonstrate the accumulation of PSMA in PET/CT. Thus, we need to monitor the side effects in the salivary glands during TAT for prostate cancer.

Pulmonary wedge aspiration cytology for the rapid diagnosis of pulmonary tumor thrombotic microangiopathy: A case report.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a cancer-related pulmonary complication characterized by rapid progression of dyspnea and pulmonary hypertension, occasionally causing sudden death. Given the condition of patients with dyspnea, lung biopsies are limited because of their invasiveness. A 72-year-old man presented with chronic atrial fibrillation and a high right heart load, as determined using ultrasonography. He had previously undergone resection of the left axillary skin secondary to extramammary Paget's disease (EMPD). Clinically, PTTM was suspected and pulmonary wedge aspiration cytology, collected from the pulmonary artery during catherization, was performed. Cytologically, the tumor demonstrated three-dimensional cell clusters with good cohesion and molding by the blood vessel lumen. Additionally, endothelial-like cells were observed at the periphery of the tumor clusters; fibrin was evident in the clusters. The tumor cells were large, round, and had high nuclear/cytoplasmic ratios. The nuclei demonstrated a variety of sizes and were irregularly shaped, with prominent nucleoli; cells undergoing mitosis were evident. The tumor cells were suspected of being poorly differentiated adenocarcinoma cells, consistent with PTTM. Two days after the aspiration cytology, the patient died and a pathological autopsy was performed. Histologically, the PTTM was determined to have caused the pulmonary hypertension and the primary PTTM site was apparently derived from the EMPD. For rapid diagnoses, an understanding of the tumor's cytological features is important and should contribute to early treatment intervention. Aspiration cytology, using pulmonary artery blood samples, during catherization is a useful tool for diagnosing PTTM.

An Autopsy Case of Acute Pancreatitis Caused by Cholesterol Crystal Embolization.

Cholesterol crystal embolization (CCE) shows a poor prognosis and it can cause ischemic organ damage due to a cholesterol embolism from atherosclerotic lesions in large blood vessels. Such an embolism mainly affects the kidneys and skin, although cases involving digestive organs have also been reported. We encountered an autopsy case of CCE with damage mainly to the digestive organs, including the pancreas. The patient had non-specific abdominal symptoms or image findings. Symptomatic therapy failed to save him. CCE can involve the digestive organs, and so must be differentiated from abdominal pathologies. Moreover, conventional treatments may be ineffective, and new treatments might thus be necessary.

Pulmonary tumor thrombotic microangiopathy associated with extramammary Paget's disease: An autopsy case report.

Pulmonary tumor thrombotic microangiopathy (PTTM) is histologically characterized by micro tumor cell embolism and intimal fibrocellular proliferation of pulmonary arteries or arterioles. We report a secondary case of PTTM associated with extramammary Paget's disease (EMPD). The patient was a 72-year-old man with exertional dyspnea. Clinical examinations found he had pulmonary hypertension and multiple osteolytic lesions of vertebra. Cytological analysis of pulmonary wedge artery sample detected malignant cells and he was dead before treatment was started. Multiple tumor embolisms (>17) were identified in pulmonary arteries or arterioles at autopsy, consistent with PTTM. Metastatic nodules were found in liver and lymph node. Furthermore, disseminated carcinomatosis of the bone marrow (DCBM) was seen. Immunostaining results pointed out that tumor cells possessed mammary gland phenotype. He had 4-years history of EMPD in the left axilla without recurrence, and immunohistochemistry results were the same as the autopsy specimen. Thus, we diagnosed the primary site of PTTM to be EMPD. Our case highlights the usefulness of the recent proposed classification of PTTM, potential association between PTTM and DCBM, and the necessity for long-term follow-up in EMPD. EMPD can rarely cause PTTM to manifest as a paraneoplastic syndrome.

Dynamic X-ray diffraction observation of shocked solid iron up to 170 GPa.

Investigation of the iron phase diagram under high pressure and temperature is crucial for the determination of the composition of the cores of rocky planets and for better understanding the generation of planetary magnetic fields. Here we present X-ray diffraction results from laser-driven shock-compressed single-crystal and polycrystalline iron, indicating the presence of solid hexagonal close-packed iron up to pressure of at least 170 GPa along the principal Hugoniot, corresponding to a temperature of 4,150 K. This is confirmed by the agreement between the pressure obtained from the measurement of the iron volume in the sample and the inferred shock strength from velocimetry deductions. Results presented in this study are of the first importance regarding pure Fe phase diagram probed under dynamic compression and can be applied to study conditions that are relevant to Earth and super-Earth cores.

Cadmium-coordinated supramolecule suppresses tumor growth of T-cell leukemia in mice.

Cadmium is a toxic pollutant with occupational and environmental significance, due to its diverse toxic effects. Supramolecules that conjugate and decontaminate toxic metals have potential for use in treatment of cadmium intoxication. In addition, metal-coordinating ability has been postulated to contribute to the cytotoxic effects of anti-tumor agents such as cisplatin or bleomycin. Thiacalixarenes, cyclic oligomers of p-alkylphenol bridged by sulfur atoms, are supramolecules known to have potent coordinating ability to metal ions. In this study, we show that cadmium-coordinated thiacalix[4]arene tetrasulfate (TC4ATS-Cd) exhibits an anti-proliferative effect against T-cell leukemia cells. Cadmium exhibited cytotoxicity with IC50 values ranging from 36 to 129 µM against epithelia-derived cancer cell lines, while TC4ATS-Cd elicited no significant cytotoxicity (IC50 > 947 µM). However, a number of T-cell leukemia cell lines exhibited marked sensitivity to TC4ATS-Cd. In Jurkat cells, toxicity of TC4ATS-Cd occurred with an IC50 of 6.9 µM, which is comparable to that of 6.5 µM observed for cadmium alone. TC4ATS-Cd induced apoptotic cell death through activation of caspase-3 in Jurkat cells. In a xenograft model, TC4ATS-Cd (13 mg/kg) treatment significantly suppressed the tumor growth of Jurkat cells in mice. In addition, TC4ATS-Cd-treated mice exhibited significantly less cadmium accumulation in liver and kidney compared to equimolar cadmium-treated mice. These results suggest that cadmium-coordinated supramolecules may have therapeutic potential for treatment of T-cell leukemia.

Cyclic sulfoxides-garlicnins K1, K2, and H1-extracted from Allium sativum.

Newly identified cyclic sulfoxides-garlicnins K1 (1), K2 (2), and H1 (3)-were isolated from the acetone extracts of the bulbs of garlic, Allium sativum. Garlicnin H1 (3) demonstrated potential to suppress tumor cell proliferation by regulating macrophage activation. The structures of garlicnins K1 and K2, 3,4-dimethyl-5-allyl-tetrahydrothiophen-2-one-S-oxides, and the structure of garlicnin H1, 3-carboxy-3-hydroxy-4-methyl-5-allylsulfoxide-tetrahydrothiophen-2-(ethane-1,2-diol)-S-oxide were characterized by spectroscopic analysis.

Double stranded DNA discrimination by di-pyrene modified gamma-cyclodextrin.

Neutral fluorescent active di-pyrene modified gamma-cyclodextrin (1) was synthesized in order to discriminate with single and double strand DNA (ssDNA and dsDNA, respectively) with high selectivity. The binding and selectivity of 1 for dsDNA was indicated by increase of the fluorescent intensity in an addition of dsDNA. On the other hand, an increase of fluorescent intensity of 1 was not recognized in an addition of ssDNA.

Rechargeable batteries driven by redox reactions of Mn12 clusters with structural changes: XAFS analyses of the charging/discharging processes in molecular cluster batteries.

Molecular clusters such as the Mn12 cluster (Mn12) can be used as a cathode-active material in Li batteries. X-ray absorption fine structure studies on the cathode materials in Mn12 molecular cluster batteries demonstrated that the charging/discharging processes include four-electron-redox reaction of Mn12 with a significant change in its molecular structure.

A highly sensitive probe detecting low pH area of HeLa cells based on rhodamine B modified beta-cyclodextrins.

Two kinds of rhodamine modified beta-cyclodextrins (R-1 and R-2), which are coupled up ethylene diamine (EDA) and tetraethylene pentamine (TEPA) between Rh B and beta-cyclodextrin, respectively, have been synthesized. R-1 and 2 work as a new fluorogenic probe for monitoring pH of Hela cells, and MTT of assay R-1, R-2, and rhodamine B indicate that less a cytotoxicity of those R-1 and R-2 than that of rhodamine B, where R-1 has much less one than that of R-2. The fluorogenetic probe capability of R-2 was recognized in an area of acidic area in living cell, which is lysosome.

Preparation, photocatalytic activities, and dye-sensitized solar-cell performance of submicron-scale TiO2 hollow spheres.

We prepared submicron-scale spherical hollow particles of anatase TiO2 by using a polystyrene-bead template. The obtained particles were very uniform in size, with a diameter of 490 nm and a shell thickness of 30 nm. The Brunauer-Emmett-Teller surface area measurements revealed a large value of 70 m2/g. The photocatalytic property was investigated by the complete decomposition of gaseous isopropyl alcohol under UV irradiation. It was indicated that the activity of the hollow spheres was 1.8 times higher than that of the conventional P25 TiO2 nanoparticles with a diameter of 30 nm. Furthermore, we fabricated a dye-sensitized solar cell (DSC) using an electrode of the TiO2 hollow spheres, and examined the photovoltaic performance under simulated sunlight. Although the per-area efficiency was rather low (1.26%) because of a low area density of TiO2 on the electrode, the per-weight efficiency was 2.5 times higher than those of the conventional DSCs of TiO2.

HSP90-like artificial chaperone activity based on indole beta-cyclodextrin.

Indole beta-cyclodextrin (beta-1) was found to be able to prevent aggregation of citrate synthase (CS) on heating condition. As a result, beta-1 showed anti-CS aggregation in this system by regulating in early stage. The depression mechanism of beta-1 for aggregation of CS is as follows: the beta-1 formed a complex with hydrophobic parts of the beta-sheet structure of CS. From CD spectra, CS was changed own conformation was changed by beta-1 addition. So, it was concluded that beta-1 works as beta-sheet inducer in thermal condition. On the other hand, native beta-cyclodextrin (beta-CyD) shows small suppression capability for CS aggregation.

Synthesis of adenophostin A analogues conjugating an aromatic group at the 5'-position as potent IP3 receptor ligands.

Previous structure-activity relationship studies of adenophostin A, a potent IP(3) receptor agonist, led us to design the novel adenophostin A analogues 5a-c, conjugating an aromatic group at the 5'-position to develop useful IP(3) receptor ligands. The common key intermediate, a D-ribosyl alpha-D-glucoside 10alpha, was stereoselectively synthesized by a glycosidation with the 1-sulfinylglucoside donor 11, which was conformationally restricted by a 3,4-O-cyclic diketal protecting group. After introduction of an aromatic group at the 5-position of the ribose moiety, an adenine base was stereoselectively introduced at the anomeric beta-position to form 7a-c, where the tetra-O-i-butyryl donors 9a-c were significantly more effective than the corresponding O-acetyl donor. Thus, the target compounds 5a-c were synthesized via phosphorylation of the 2', 3' ', and 4' '-hydroxyls. The potencies of compounds 5a-c for Ca(2+) release were shown to be indistinguishable from that of adenophostin A, indicating that bulky substitutions at the 5'-position of adenophostin A are well-tolerated in the receptor binding. This biological activity of 5a-c can be rationalized by molecular modeling using the ligand binding domain of the IP(3) receptor.

Design and synthesis of 5'-deoxy-5'-phenyladenophostin A, a highly potent IP3 receptor ligand.

[structure: see text] 5'-Deoxy-5'-phenyladenophostin A (5), designed as a useful IP(3) receptor ligand based on the previous structure-activity relationship studies, was successfully synthesized via two key stereoselective glycosidation steps. This compound proved to be a highly potent IP(3) receptor agonist.