Recognition of cyclic-di-GMP by a riboswitch conducts translational repression through masking the ribosome-binding site distant from the aptamer domain.

The riboswitch is a class of RNA-based gene regulatory machinery that is dependent on recognition of its target ligand by RNA tertiary structures. Ligand recognition is achieved by the aptamer domain, and ligand-dependent structural changes of the expression platform then usually mediate termination of transcription or translational initiation. Ligand-dependent structural changes of the aptamer domain and expression platform have been reported for several riboswitches with short (<40 nucleotides) expression platforms. In this study, we characterized structural changes of the Vc2 c-di-GMP riboswitch that represses translation of downstream open reading frames in a ligand-dependent manner. The Vc2 riboswitch has a long (97 nucleotides) expression platform, but its structure and function are largely unknown. Through mutational analysis and chemical probing, we identified its secondary structures that are possibly responsible for switch-OFF and switch-ON states of translational initiation.

Vocal cord inflammatory myofibroblastic tumor with mucoid deposits harboring TIMP3-ALK fusion: A potential diagnostic pitfall.

A 35-year-old Japanese man who had experienced hoarseness for 10 years presented with a vocal cord lesion. A gross examination revealed a left vocal cord polyp occupying two-thirds of the vocal space. The endoscopically resected lesion contained scattered atypical fibroblastic, stellate, or ganglion-like cells with mucoid stroma. Vacuolated cells were also seen. Lymphoplasmacytic infiltrate was largely undetectable. A vocal cord polyp was first suspected, but well-differentiated liposarcoma and inflammatory myofibroblastic tumor (IMT) were included in the differential diagnoses. The tumor cells were positive for anaplastic lymphoma kinase (ALK), calponin, and vimentin, and negative for other smooth muscle markers by immunohistochemistry. Structures resembling myofibroblasts were not observed by electron microscopy, which confirmed abundant rough endoplasmic reticulum in the tumor cells and accumulated lipid droplets in some tumor cells. ALK gene rearrangement was detected by fluorescence in situ hybridization, and TIMP3-ALK fusion was confirmed by 5' rapid amplification of cDNA ends. We diagnosed the lesion as an IMT, and an ALK-rearranged stellate cell tumor may be postulated. This is the first report of a fusion partner gene of ALK in a case of laryngeal IMT.

Macrocystic and non-necrotic salivary duct carcinoma of the submandibular gland: A case report.

Salivary duct carcinoma (SDC) is a major malignant salivary gland tumor that usually forms a solid tumor. Non-necrotic macrocystic SDCs have rarely been reported among salivary gland tumors. A 78-year-old Japanese man with a submandibular gland tumor was evaluated radiologically, pathologically, and immunohistochemically. A multilocular lesion with a maximum size of 6 cm was radiologically observed in the left submandibular region. It had been noticed 20 years earlier. Malignant cytological result was obtained, and surgical resection was performed. Pathological examination revealed a non-necrotic, macrocystic submandibular gland tumor lined with glandular, cribriform, or papillary forms of atypical cuboidal cells. Frankly invasive components were observed in intercystic areas. Intraductal, mucoepidermoid, and secretory carcinomas were identified as pathological differential diagnoses because of their macrocystic morphology. We diagnosed SDC because there was no intraductal growth based on the lack of myoepithelial markers, diffuse immunoreactivity to gross cystic disease fluid protein15, androgen receptor, and mammaglobin and immunonegativity to S100 and p63. Postoperative positron emission tomography revealed the absence of lymph node and distant metastases. The patient was disease-free 9 months after surgery. Salivary duct carcinoma can be included in the differential diagnoses of cystic salivary gland tumors.

Pairwise Engineering of Tandemly Aligned Self-Splicing Group I Introns for Analysis and Control of Their Alternative Splicing.

Alternative splicing is an important mechanism in the process of eukaryotic nuclear mRNA precursors producing multiple protein products from a single gene. Although group I self-splicing introns usually perform regular splicing, limited examples of alternative splicing have also been reported. The exon-skipping type of splicing has been observed in genes containing two group I introns. To characterize splicing patterns (exon-skipping/exon-inclusion) of tandemly aligned group I introns, we constructed a reporter gene containing two Tetrahymena introns flanking a short exon. To control splicing patterns, we engineered the two introns in a pairwise manner to design pairs of introns that selectively perform either exon-skipping or exon-inclusion splicing. Through pairwise engineering and biochemical characterization, the structural elements important for the induction of exon-skipping splicing were elucidated.

Diagnostic utility of fine-needle aspiration cytology in syphilitic lymphadenitis: A case report.

Syphilis is a sexually transmitted infection that causes serious health problems without treatment. Detection of syphilis is necessary to stop the spread of the infection. Cytological screeners and pathologists may experience fine-needle aspiration cytology (FNAC) for syphilitic lymphadenitis; however, its characteristic cytological features are rarely reported. We present FNAC cytological features of syphilitic lymphadenitis in a case of a 21-year-old man. He presented with a sore throat and painful neck lymphadenopathy. His swollen and painful neck persisted even with antibiotic treatment. Necrotizing lymphadenitis and lymphoma were clinically suspected. FNAC was taken from the swollen lymph node. Cytologic findings of the specimen showed various inflammatory cells with small-sized vessels arranged in a branching/arborizing fashion. The vessels were surrounded by inflammatory cells, including plasma cells, neutrophils, and macrophages. Perivascular plasma cell cuffing was focally seen along with inconspicuous granulomas. Neutrophils appeared to involve the vascular wall. The cytological findings suggested syphilitic lymphadenitis, and clinical findings and serological tests confirmed primary syphilis with concomitant human immunodeficiency virus infection. Branching/arborizing vessels associated with many plasma cells, vascular involvement of neutrophils, and granulomas may suggest syphilitic infection if the specimen is obtained via FNAC. (189 words).

Hybrid peripheral nerve sheath tumor of the nasal cavity showing schwannomatous, neurofibromatous, and perineuriomatous areas.

Soft tissue hybrid peripheral nerve sheath tumors (PNST), including schwannoma-perineurioma or neurofibroma-perineurioma, have recently been described. However, there are no reports on hybrid PNST arising in the nasopharyngeal area. In this article, we report such a case. A 58-year-old Japanese man presented with nasal obstruction and was found to have bilateral polypoid lesions in the middle meatus of the nose. Subsequently, nasal polypectomy was performed. Histologically, the tumor consisted of three components including schwannoma, neurofibroma, and perineurioma. Immunohistochemically, schwannoma, neurofibroma, and perineurioma components were positive for S-100 protein, CD34, and epithelial membrane antigen, respectively. In conclusion, this is the first case of hybrid PNST reported to occur in the nasopharyngeal area. Pathologists should be aware of the possibility that hybrid PNST may present outside soft tissue.

Chronic sclerosing pyelitis with an increased number of IgG4-positive plasma cells.

IgG4-related disease has been recently described. This disease occurs in various anatomic locations including pancreas, biliary tract, liver, retroperitoneum, kidney, breast, lung, thyroid gland, prostate, salivary gland, lacrimal gland, and lymph node. In this article, we report the first case of IgG4-related disease arising in the renal pelvis. A 49-year-old Japanese woman was found to show left hydronephrosis by a medical checkup. Histological examination of the renal pelvic tumor showed IgG4-related disease. Her postoperative serum IgG4 was elevated, and this was compatible with IgG4-related disease. Systemic examination showed swelling of major and minor salivary glands and the lacrimal glands, and biopsy of the minor salivary gland revealed the finding of IgG4-related disease. Finally, pathologists and clinicians should be aware of the possibility that the renal pelvis may be involved in IgG4-related systemic disease.

Lymphoid Papillary Hyperplasia Arising from the Upper Portion of the Left Palatine Tonsil: A Case Report and Literature Review.

Lymphoid papillary hyperplasia of the tonsils is a rare, benign lesion and is characterized by a papillomatous appearance with reactive follicular hyperplasia. Our case was unique because the lesion involved the unilateral and focal palatine tonsil, as the lesion usually involves the bilateral and entire palatine tonsils.

Infarcted Warthin tumor with mucoepidermoid carcinoma-like metaplasia: a case report and review of the literature.

BACKGROUND: Warthin tumor is a common, benign, painless salivary gland neoplasm. Rarely, Warthin tumors show large areas of squamous metaplasia; such Warthin tumors are called metaplastic or infarcted Warthin tumors because they are occasionally accompanied with tumor necrosis. The histological distinction between mucoepidermoid carcinomas and the metaplastic portions of Warthin tumors can be challenging; without a genetic study, mucoepidermoid carcinomas can be misdiagnosed as metaplastic Warthin tumors. We report a case of infarcted Warthin tumor partly showing mucoepidermoid carcinoma-like epithelial metaplasia. Only two cases of infarcted Warthin tumor similar to our case have been reported. CASE PRESENTATION: A 69-year-old Japanese man presented with a right parotid tumor. He had noticed the swelling on his right buccal region 1 year previously; the lesion had rapidly enlarged, with associated pain, 1 month previously. A radiological examination revealed a mass in the tail of the right parotid gland. Superficial parotidectomy was performed. On histological examination, the mass showed typical focal features of Warthin tumor; other areas showed coagulation necrosis of the tumor. These areas were surrounded by non-oncocytic epithelium comprising squamous and mucinous epithelial cells. Although cellular atypia of the non-oncocytic epithelium was not observed, a mixture of squamous and mucinous cells and lack of abundant lymphoid tissue mimicked low-grade mucoepidermoid carcinoma. Based on the results of fluorescence in situ hybridization, MAML2 gene rearrangement was not present in the typical portions of Warthin tumor and the mucoepidermoid carcinoma-like lesion. Therefore, a metaplastic or infarcted Warthin tumor was diagnosed. Our patient was disease-free 8 months after surgery. CONCLUSIONS: Clinicians need to know that pain is a clinical symptom of infarcted/metaplastic Warthin tumor. Pathologists should be aware that a metaplastic Warthin tumor can mimic a low-grade mucoepidermoid carcinoma. Our case showed a mucoepidermoid carcinoma-like lesion that was confined near the area of tumor necrosis, and neither cytological atypia nor apparent invasive growth was present. These findings appeared to be histological clues of a metaplastic Warthin tumor rather than a mucoepidermoid carcinoma. Careful clinicopathological evaluation as well as genetic studies are needed to clarify the distinction between mucoepidermoid carcinoma and metaplastic portions of Warthin tumors.

Efficacy of proton pump inhibitor in combination with rikkunshito in patients complaining of globus pharyngeus.

OBJECTIVE: Globus pharyngeus (GP) is a common symptom of laryngopharyngeal reflux disease (LPRD), and proton pump inhibitor (PPI) and rikkunshito, a traditional Japanese medicine having prokinetic effect improve LPRD symptoms. In the present study, we examined the efficacy of high-dose PPI in combination with rikkunshito in patients complaining of GP. METHODS: 106 patients complaining of GP without any organic endoscopic findings were enrolled. RESULTS: Patients were first administrated with high-dose PPI alone for 4 to 8 weeks and the symptom was improved in 65 patients. Among 41 patients with PPI-refractory GP, 22 patients were administrated with high-dose PPI in combination with rikkunshito, and the symptom was improved in 14 of 22 patients 4 weeks later. The average value of a modified reflux symptom index of the responders was similar to that of non-responders. Only a few patients had positive values in reflux finding scores in both groups. CONCLUSION: The present findings suggest the existence of a high prevalence of LPRD in patients complaining of GP. The data also suggest that gastroesophageal dysmotility is involved in GP, in addition to excessive acid reflux. The pre-therapeutic laryngopharyngeal symptoms and endoscopic findings could not predict the efficacy of the treatment for GP. J. Med. Invest. 63: 227-229, August, 2016.

Analysis of in vivo role of alpha-fodrin autoantigen in primary Sjogren's syndrome.

The alpha-fodrin N-terminal portion (AFN) autoantigen mediates in vivo immunoregulation of autoimmune responses in primary Sjögren's syndrome (SS). We further examined this process and found that cleavage products of AFN were frequently detected in the salivary gland duct cells of SS patients. In in vitro studies using human salivary gland HSY cells, anti-Fas-induced apoptosis resulted in specific cleavage of alpha-fodrin into the 120-kd fragment, in association of alpha-fodrin with mu-calpain, and activation of caspase 3. Significant proliferative responses against AlphaFN autoantigen were observed in the peripheral blood mononuclear cells (PBMCs) from SS patients with higher pathological score (grade 4) and with short duration from onset (within 5 years). In vivo roles of AFN peptides were investigated using PBMCs from patients with SS, systemic lupus erythematosus, and rheumatoid arthritis. Significant proliferative T-cell responses of PBMCs to AFN peptide were detected in SS but not in systemic lupus erythematosus or rheumatoid arthritis. AFN peptide induced Th1-immune responses and accelerated down-regulation of Fas-mediated T-cell apoptosis in SS. Our data further elucidate the in vivo role of AFN autoantigen on the development of SS and suggest that the AFN autoantigen is a novel participant in peripheral tolerance.

Development of autoimmune exocrinopathy resembling Sjögren's syndrome in estrogen-deficient mice of healthy background.

Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear. We speculate that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens. Previously, we have identified 120-kd alpha-fodrin as an important autoantigen in Sjögren's syndrome (SS). When healthy C57BL/6 (B6) mice were treated with an ovariectomy (Ovx), we found a significant increase in TUNEL(+)-apoptotic epithelial cells in the salivary gland cells associated with alpha-fodrin cleavage during 2 and 3 weeks after Ovx. By contrast, no apoptotic cells were found in estrogen receptor-alpha knockout mice. In in vitro studies using primary cultured mouse salivary gland cells and human salivary gland cells, we found a cleavage product of 120-kd alpha-fodrin in cells that had undergone tamoxifen (Tam)-induced apoptosis through caspase activation, especially caspase-1. Adoptive transfer of alpha-fodrin-reactive T cells into Ovx-B6 and -SCID mice resulted in the development of autoimmune exocrinopathy quite similar to SS. These results suggest that estrogen deficiency exerts a crucial influence on autoantigen cleavage, and may cause, in part, autoimmune exocrinopathy in postmenopausal women.