Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor.

We optimized the structure of an active metabolite (1) of WAY-123783, which was obtained from mouse urine after oral administration, to improve selectivity for SGLT2 and oral bioavailability. O-glucoside derivative 24 (remogliflozin etabonate) was subsequently identified as a potent, highly selective, and orally available SGLT2 inhibitor.

Direct and Indirect Bactericidal Effects of Cold Atmospheric-Pressure Microplasma and Plasma Jet.

The direct and indirect bactericidal effects of dielectric barrier discharge (DBD) cold atmospheric-pressure microplasma in an air and plasma jet generated in an argon-oxygen gas mixture was investigated on Staphylococcus aureus and Cutibacterium acnes. An AC power supply was used to generate plasma at relatively low discharge voltages (0.9-2.4 kV) and frequency (27-30 kHz). Cultured bacteria were cultivated at a serial dilution of 10-5, then exposed to direct microplasma treatment and indirect treatment through plasma-activated water (PAW). The obtained results revealed that these methods of bacterial inactivation showed a 2 and 1 log reduction in the number of survived CFU/mL with direct treatment being the most effective means of treatment at just 3 min using air. UV-Vis spectroscopy confirmed that an increase in treatment time at 1.2% O2, 98.8% Ar caused a decrease in O2 concentration in the water as well as a decrease in absorbance of the peaks at 210 nm, which are attributed NO2- and NO3- concentration in the water, termed denitratification and denitritification in the treated water, respectively.

Video-assisted neck surgery (VANS) using a gasless lifting procedure for thyroid and parathyroid diseases: "The VANS method from A to Z".

PURPOSE: To describe and evaluate our video-assisted neck surgery (VANS) method for thyroid and parathyroid diseases. METHODS: We describe in detail the VANS method for enucleation, lobectomy, total (nearly total) thyroidectomy, and lymph node dissection for malignancy and Graves' disease. In collaboration with the Japan Society of Endoscopic Surgery (JSES), we evaluated several aspects of this method. The JSES evaluated the method for working-space formation and surgical complications, whereas we examined the learning curve of the surgeons, and the cosmetic satisfaction of the patients and the degree of numbness and pain they experienced. We also asked patients who underwent conventional surgery whether they would have selected VANS had it been available. RESULTS: The working space for 81.5% of the procedures in Japan was created using the gasless lifting method. The learning curve, considering both blood loss and operating time, decreased after 30 cases. Both factors improved for tumors smaller than 5 cm in diameter. Over 60% of the patients who underwent conventional surgery stated that they would have selected VANS, had it been available. Postoperative pain was worse after conventional surgery than after VANS, but neck numbness after VANS was more frequent than expected. CONCLUSIONS: The VANS method is a feasible, safe, and cost-effective procedure with clear cosmetic advantages over conventional surgery.

Tyrosine-kinase inhibitors to treat radioiodine-refracted, metastatic, or recurred and progressive differentiated thyroid carcinoma [Review].

Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients' quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

Clinicopathologic features and outcomes in patients with diffuse sclerosing variant of papillary thyroid carcinoma.

BACKGROUND: Diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare variant more common among younger patients. MATERIALS AND METHODS: Excluding patients with microcarcinoma, 5848 patients with PTC underwent initial surgery between 1995 and 2011. Twenty-two patients (0.4 %) were histologically diagnosed with DSV, of whom 20 (91 %) were <45 years old. We compared clinicopathologic characteristics and outcomes between patients with DSV and those with classical PTC <45 years old. Univariate analysis by the Kaplan-Meier method in relation to cause-specific survival (CSS) and disease-free survival (DFS) rates was performed with regard to the following variables: sex; anti-thyroglobulin antibody (TgAb) positivity; presence of distant metastasis; pathological lymph node metastasis; extra-thyroidal invasion; and pathological variant (classical vs. DSV). RESULTS: The 20 patients with DSV <45 years old comprised 18 females and 2 males. Frequencies of TgAb, pN1b, and local recurrence were higher in the DSV group than in the classical PTC group. Ten-year CSS and DFS rates for PTC patients <45 years old were 99.7 and 88.6 % in the classical PTC group and 100 and 60.5 % in the DSV group. CSS rate did not differ between groups, but DFS rate was significantly lower in the DSV group than in the classical PTC group (p < 0.0001, log-rank test). Multivariate analysis identified DSV group and pN1b as prognostic factors for recurrence in young PTC patients. CONCLUSIONS: Most DSV patients were young and had a background of chronic thyroiditis. Outcomes for DSV were very good, but recurrence was more common than in classical PTC.

Radioactive iodine (RAI) therapy for distantly metastatic differentiated thyroid cancer (DTC) in juvenile versus adult patients.

In general, juvenile differentiated thyroid carcinoma (DTC) demonstrate indolent characteristics and favorable prognosis are observed in comparison with many other carcinomas. However, recurrence is frequent, necessitating additional treatment, including radioactive iodine (RAI) therapy. In this report, the probability of recurrence, prognostic factors, treatment, and outcomes in both juvenile- and adult-onset DTC were analyzed and compared. At our institution, a total of 1552 DTC patients underwent thyroidectomy and/or lymph node dissection. The patients included 23 in their teens, 118 in their twenties, and 1412 in their thirties or older. The risk factors for distant metastases for DTC were male gender, follicular carcinoma, size of the PTC primary tumor, cervical lymph node metastases from PTC, and the presence of more than two distant metastatic foci. Patients with the highest risk underwent RAI ablation in line with institutional guidelines. Although the overall outcome in our juvenile patients was excellent, during follow-up, 4 (17.4%) of the 23 patients developed recurrent disease: 91.3% achieved complete remission, 4.35% partial remission, and 4.35% stable disease, with no disease-related deaths. Among the 118 patients in their twenties to thirties, 1 (0.8%) experienced progressive disease and disease-related death. A younger age at diagnosis and less radical primary surgery without subsequent RAI ablation are factors strongly predictive of distant metastases in patients with juvenile-onset DTC. To reduce the rate of relapse and improve surveillance for recurrent disease, total thyroidectomy followed by RAI appears to be the most beneficial initial treatment for patients with high- and intermediate-risk juvenile DTC.

Effects of microplasma irradiation on human gingival fibroblasts.

The purpose of this research was to clarify the effects of microplasma irradiation on human gingival fibroblasts (HGF). Microplasma irradiation exposure for all HGF samples was limited to 30 s at an irradiation distance of 10 mm with a gas flow of 10 L/min. Three experimental groups were used: a 0 V control group (Control); a 650 V (low) microplasma irradiation group (LV); and a 975 V (high) irradiation group (HV). The following cellular characteristics were evaluated in order to analyze the effects of microplasma treatment; morphology, cell count, DNA content, metabolic activity, cell migration, fibroblast growth factor ß (FGF-2) production, type I collagen secretion, and cytotoxic analysis. Cell count, DNA content and FGF-2 production have all been linked to wound healing and, interestingly, both the LV and HV groups showed significant (P < 0.05) increases in these categories at 72 h after irradiation when compared to the control group. Cytotoxic effects were measured by determining the levels of lactate dehydrogenase, cell death, and DNA damage in HGF cells. In these analyses, the HV and LV groups were not statistically different when compared with the control group at 72 h post-irradiation. These findings suggest that microplasma irradiation activated HGF with no clear cell-damaging effects.

Design, synthesis, and structure-activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl ß-D-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1).

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl ß-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.

Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma.

OBJECTIVE: Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects. PATIENTS AND METHODS: For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls. RESULTS: Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation. CONCLUSION: This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1. DESIGN/PATIENTS: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed. MEASUREMENTS: Clinical and genetic features of Japanese patients with MEN1 were examined. RESULTS: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient. CONCLUSIONS: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl ß-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl ß-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).

Clinicopathological characteristics and prognosis of non-small cell lung cancer patients associated with a family history of lung cancer.

INTRODUCTION: Clinicopathological characteristics and prognosis of non-small cell lung cancer (NSCLC) patients with a family history of lung cancer (FHLC) have not been well established. METHODS: Clinical records of patients with NSCLC treated at our institute from 1982 to 2010 were reviewed with special reference to family history of lung cancer and clinicopathological factors including patient's outcome. Univariate analyses of the factors between the groups of FHLC and non-FHLC were performed using unpaired two-tailed t tests or the chi-square test. The Cox proportional hazards model was used to evaluate the hazard ratio of death. RESULTS: Of the 1013 NSCLC patients, 124 (12.2%) had a FHLC of whom 119 (96%) were the first-degree relatives. The frequency of early stages of lung cancer was high in both groups of FHLC and non-FHLC patients. Patients with FHLC had a significantly higher frequency of early pathological stages and a prepomderance of adenocarcinoma, and a hazard ratio of death of 0.870 (95% confidence interval: 0.599-1.263, p value: 0.465) compared with the non-FHLC patients. CONCLUSIONS: NSCLC patients with FHLC could be characterized by early pathological stages and preponderance of adenocarcinoma, however they were not at a decreased hazard ratio of death. These findings emphasize the importance of early detection of lung cancer and employment of less invasive therapeutic interventions.

Study on decomposition of indoor air contaminants by pulsed atmospheric microplasma.

Decomposition of formaldehyde (HCHO) by a microplasma reactor in order to improve Indoor Air Quality (IAQ) was achieved. HCHO was removed from air using one pass through reactor treatment (5 L/min). From an initial concentration of HCHO of 0.7 ppm about 96% was removed in one pass treatment using a discharge power of 0.3 W provided by a high voltage amplifier and a Marx Generator with MOSFET switches as pulsed power supplies. Moreover microplasma driven by the Marx Generator did not generate NOx as detected by a chemiluminescence NOx analyzer. In the case of large volume treatment the removal ratio of HCHO (initial concentration: 0.5 ppm) after 60 minutes was 51% at 1.2 kV when using HV amplifier considering also a 41% natural decay ratio of HCHO. The removal ratio was 54% at 1.2 kV when a Marx Generator energized the electrodes with a 44% natural decay ratio after 60 minutes of treatment.

Learning Curve for Endoscopic Thyroidectomy Using Video-Assisted Neck Surgery: Retrospective Analysis of a Surgeon's Experience with 100 Patients.

BACKGROUND: Endoscopic thyroidectomy offers excellent cosmetic outcomes but requires some time for surgeons to become proficient. We examined the learning curve for the first 100 patients treated by a single surgeon using a subclavian approach for video-assisted neck surgery (VANS). METHODS: We retrospectively studied the records of 100 patients (99 women, 1 man; mean age, 36.2 years) with either benign or malignant thyroid disease treated between 2016 and 2020. RESULTS: Preoperative diagnosis was papillary thyroid carcinoma (PTC) in 36 cases and other (non-PTC) in 64 cases. All patients underwent lobectomy, with additional unilateral central node dissection for patients with PTC. Mean operative time was 125 min for non-PTC cases and 129 min for PTC cases (p = 0.43); blood loss was 33.8 mL and 7.6 mL, respectively (p = 0.01). Recurrent laryngeal nerve paralysis (RNP) was observed in 12 patients (12%) and hemorrhage in 2 patients (2%). In a comparison of the first 30 cases and subsequent 70 cases, no significant differences in operative time or blood loss were evident, although tumor size was significantly greater among later non-PTC cases (32.4 mm vs. 39.5 mm, p = 0.039). RNP was significantly lower in later cases (26.7% vs. 5.7%, p = 0.003). Multivariate analysis revealed that tumor size was a significant risk factor for increased blood loss, and increased experience significantly correlated with a decrease in RNP. CONCLUSIONS: In VANS, satisfactory surgical proficiency was reached after treating 30 patients.

Melanin-producing medullary thyroid carcinoma with transformation to melanoma: A case report.

Only one case of melanoma arising from melanin-producing medullary thyroid carcinoma (MTC) has been reported previously. In the present study, a second such case was reported and compared with the previous one. The patient was an 86-year-old male who presented with a right anterior neck mass. Ultrasound revealed a nodule measuring 49x48x40 mm in the right lobe of the thyroid. The levels of serum calcitonin (2,298 pg/ml) and carcinoembryonic antigen (CEA; 27.0 ng/ml) were markedly elevated. Aspiration cytology revealed suspected malignant anaplastic thyroid carcinoma and total thyroidectomy without neck nodal dissection was performed. On gross observation, the nodule was well encapsulated, soft, solid and black. Light microscopy indicated that the nodule was composed mainly of large, occasionally huge, pleomorphic cells with a solid or alveolar growth pattern. On immunohistochemistry, these cells were positive for melan-A and S-100 protein, and negative for thyroid transcription factor 1, calcitonin, chromogranin A and CEA. In the subcapsular area, melanin-producing MTC was intimately intermingled with the pleomorphic cells. No primary site of the melanoma was detectable in other organs. At three years after surgery, the patient died due to metastasis of the melanoma to the brain. The previously reported case had no detectable recurrence or distant metastasis up to 11 years after surgery. In comparison with that case, the present case had a similar morphology but the outcome was poorer. Thus, the prognosis of melanoma that transforms from MTC appears to remain uncertain.

Case Report: A Case of Moyamoya Syndrome Associated With Multiple Endocrine Neoplasia Type 2A.

To the best of our knowledge, we report a case of MEN2A complicated by moyamoya syndrome. A 52-year-old woman presented with vertigo. Magnetic resonance angiography (MRA) revealed bilateral supraclinoid stenosis of the internal carotid artery and abnormal moyamoya-like vessels around the basal ganglia. She had a heterozygous variant of RNF213, which is the susceptibility gene for moyamoya disease. She had also previously received diagnoses of medullary thyroid carcinoma (MTC) at age 23 and left-sided pheochromocytoma (PHEO) at age 41. Genetic testing revealed heterozygosity for a mutation at codon 634 in exon 11 (TGC-TTC mutation; p.Cys634Phe) of the Ret gene. Intracranial vascular stenosis may have been caused by a genetic mutation of RNF213 and hypersecretion of catecholamines by MEN2A. Physicians should recognize that MEN2A can be present with moyamoya syndrome.

Prognostic impact of extrathyroid extension and clinical lymph node metastasis in papillary thyroid carcinoma depend on carcinoma size.

BACKGROUND: Although papillary thyroid carcinoma (PTC) generally has an indolent nature, massive extrathyroid extension (Ex) and clinical lateral node metastasis (N1b) are prominent predictors of a dire prognosis. However, it remains unknown whether these factors affect patient prognosis with uniformity. In this study, we investigated the relationships between the prognostic impact of these factors and carcinoma size. METHODS: A total of 5,917 patients who underwent initial and curative surgery for PTC between 1987 and 1995 were enrolled in this study. After dividing these patients into four subsets based on tumor size--≦1.0 cm, 1.1-2.0 cm, 2.1-3.0 cm, and >3.0 cm--we investigated the prognostic impacts of Ex and N1b in each subset. RESULTS: Relative risk (RR) of disease-free survival (DFS) of N1b was the highest in the subset ≦1.0 cm and decreased with tumor size. RR of Ex was smaller in carcinoma ≦3.0 cm but larger in carcinoma >3.0 cm compared with that of N1b in the respective subsets. On multivariate analysis, N1b was a more important prognostic factor than Ex in carcinoma ≦3.0 cm, but the prognostic impacts of these two factors were reversed in carcinoma >3.0 cm. Similar findings were obtained in analyses for cause-specific survival (CSS) and prognostic value of N1b was more significant in carcinoma ≦3.0 cm but less significant in carcinoma >3.0 cm than that of Ex. CONCLUSIONS: The prognostic values of Ex and N1b vary with tumor size in PTC. It is important for physicians to pay attention to tumor size when evaluating the prognostic impact of these two prominent factors.

Molecular size of collagen peptide reverses the permeability of Caco-2 cells.

Intestinal permeability to size-classified fish collagen peptides (FCPs) was examined using Caco-2 monolayers. Minimum-sized FCPs were most efficiently transported across the Caco-2 monolayers. Permeability depended on peptide size. It was independent of the H(+)-coupled peptide transport system but was associated with tight junction permeability, suggesting that the paracellular pathway is responsible for transepithelial transport of collagen peptides.

Utilization of three-dimensional computed tomography for papillary thyroid carcinoma arising in the thyroglossal duct remnant: report of a case.

This report presents a rare and interesting case of papillary thyroid carcinoma arising in a thyroglossal duct remnant (TDR) that was diagnosed by three-dimensional computed tomography (3DCT). The patient, a 61-year-old woman, presented with a painless mass in the anterior suprahyoid region that had gradually enlarged over a 2-year period. Three-dimensional CT successfully revealed the thyroglossal duct (TD) descending from the tumor to the isthmus of the thyroid. An ultrasonography-guided fine-needle aspiration biopsy of the tumor was positive for carcinoma. A total thyroidectomy was performed in addition to the Sistrunk procedure. The histological findings indicated papillary thyroid carcinoma arising in the TDR and thyroid papillary microcarcinoma in the left thyroid lobe. The patient underwent radioactive iodine ablation and thyroid suppression therapy. This is apparently the first reported case of papillary thyroid carcinoma arising in a TDR evaluated using 3DCT. Three-dimensional CT was able to clarify the relative locations of the tumor, TD, and thyroid in the present case, and visualization of the TD allowed a definitive preoperative diagnosis that would not otherwise have been possible using conventional imaging techniques. This case suggests that 3DCT may therefore play an important role in providing definitive information on patients with anterior neck masses that are difficult to diagnose.

Venous hemangioma of the anterior mediastinum.

We report a rare case of venous hemangioma (VH) of the anterior mediastinum in a 56-year-old man admitted to our hospital because of hematemesis. Systemic examinations were performed and chest computer tomography (CT) revealed a 1.5-cm sized small nodule with contrast enhancement in the thymus. Both CT and magnetic resonance imaging (MRI) suggested a solid tumor such as a thymoma or neurogenic tumor rather than a vascular neoplasm. A partial thymectomy including this nodule by video-assisted thoracic surgery (VATS) was performed. Histological examination showed VH. There was no recurrence with no further treatment.