Search

Adrenomedullin (AM) is a peptide with pleiotropic physiological functions that attenuates intestinal mucosal inflammation. However, the mechanism underpinning mucosal protection by AM is not fully understood, and its effect on intestinal epithelial cells remains unclear. Here, we investigated the effects of AM on junctional molecules in primary‐cultured murine intestinal epithelial cells and discovered that AM upregulates claudin‐4 expression. In a mouse model of dextran sulfate sodium‐induced colitis, AM administration also enhanced claudin‐4 expression and accelerated mucosal regeneration. Furthermore, AM reversed TNFα‐mediated downregulation of claudin‐4 and loss of cell–cell adhesion of the HCT116 human intestinal epithelial cell line in vitro. These results indicate that AM may enhance intestinal epithelial integrity by upregulating claudin‐4 expression.

Abstract Background Hyalinizing trabecular tumor is a rare follicular cell-derived thyroid neoplasm that is considered to be a borderline tumor with malignant potential rather than a benign tumor. The detection of RET/PTC rearrangements and nuclear cytologic features suggests a relationship between hyalinizing trabecular tumor and papillary thyroid carcinoma. Some recent observations of pathogenic genetic alterations in hyalinizing trabecular tumor have indicated that hyalinizing trabecular tumor is not related to papillary thyroid carcinoma, and should be considered an independent entity. Here we present a case of papillary thyroid carcinoma with hyalinizing trabecular tumor-like features and discuss its interesting aspects and diagnostic issues from a histopathological perspective. Case presentation A 19-year-old Japanese woman with an enlarged thyroid gland was admitted to our hospital. Based on fine-needle aspiration cytology, the enlarged nodule was suspected to be a follicular lesion or follicular tumor. A nodular lesion approximately 3 cm in diameter was detected in the left lobe of the thyroid gland. Histological analysis revealed that the tumor cells were mainly arranged in follicles. Solid nests with occasional trabecular arrangements and papillary structures were intermingled, and the tumor cells showed ground-glass nuclei and occasional nuclear grooving. Petaloid and block-like periodic-acid-Schiff and periodic-acid-methenamine-positive basement membrane components were observed in the interstitium of the solid portions of the tumor. Incomplete membranous immunoreactivity of MIB-1 (Ki-67 (cell prolferation marker)) was also observed in the cells within the solid areas. Moreover, this tumor displayed extracapsular invasion and metastasis to the perithyroidal lymph nodes, suggesting that it may be a malignant tumor. However, BRAF V600E mutation, RET/PTC rearrangements, and PAX8/GLIS 1 and PAX8/GLIS 3 rearrangements were not detected. Conclusion We diagnosed the tumor as a papillary thyroid carcinoma with characteristic features of hyalinizing trabecular tumor. Importantly, this case may indicate a possible relationship between papillary thyroid carcinoma and hyalinizing trabecular tumor, although specific genetic alterations could not be detected. We also discuss the preoperative diagnostic difficulties with fine-needle aspiration cytology and the unusual pathological findings in this case.

Abstract Background Dura-attached supratentorial extra-axial ependymoma is a very rare type of tumor, with only nine reported cases. Preoperative diagnosis of dura-attached supratentorial extra-axial ependymoma is difficult and often radiologically misdiagnosed as a meningioma. We report a case of dura-attached supratentorial extra-axial ependymoma that was misdiagnosed using intraoperative histological and cytological examinations. Case presentation A 26-year-old Japanese man with headache and nausea was referred to our medical facility. Magnetic resonance imaging revealed a cystic mass of 70 × 53 × 57 mm in the left temporoparietal lobe. A peritumoral band with hyperintensity on T2-weighted imaging was observed at the periphery of the lesion, suggesting an extra-axial lesion with no apparent connection to the ventricle. A dural tail sign was also noted on the gadolinium-enhanced T1-weighted image. Preoperative clinical diagnosis was meningioma. Proliferated tumor cells in sheets with intermingled branching vessels were observed in the frozen tissue. Perivascular rosettes were inconspicuous, and the tumor cells had rhabdoid cytoplasm. The tumor was intraoperatively diagnosed as a meningioma, suspected to be a rhabdoid meningioma. Perivascular rosettes were evident in the formalin-fixed paraffin-embedded tissues, suggesting ependymoma. The tumor cells had eosinophilic cytoplasm without a rhabdoid appearance. Anaplastic features, such as high tumor cellularity, increased mitotic activity, microvascular proliferation, and necrosis, were observed. Ependymal differentiation was confirmed on the basis of ultrastructural analysis. Molecular analysis detected C11orf95-RELA fusion gene. The final diagnosis was RELA fusion-positive ependymoma, World Health Organization grade III. Conclusion Owing to its unusual location, dura-attached supratentorial extra-axial ependymomas are frequently misdiagnosed as meningiomas. Neuropathologists should take great precaution in intraoperatively diagnosing this rare subtype of ependymoma to avoid misdiagnosis of the lesion as other common dura-attached tumors.

Abstract Background Adult cases of retroperitoneal isolated enteric duplication cyst (IEDC) are rare, with only 17 case reports in the relevant literature. We herein present a case, which was characterized by changes in intra-cystic density on computed tomography (CT), which was safely resected by laparoscopic surgery. Case presentation The patient was a 60-year-old male who received abdominal CT to investigate the cause of increased serum CA19-9 levels. CT revealed a unilocular cystic mass located in the lower right retroperitoneum. The size increased from 5 to 10 cm in three and a half years and the CT value decreased from 101 Hounsfield Units (HU) to 20 HU. We performed laparoscopic surgical resection, because the possibility that the enlargement of the lesion represented malignant transformation could not be denied. The large cystic mass firmly adhered to the appendix and its mesentery via the retroperitoneum, the appendix was resected en bloc with the cystic lesion. Microscopically, it had no communication with the appendix, and had an intestinal wall structure of muscularis mucosae and muscularis propria. The final pathological diagnosis was IEDC in the retroperitoneal space. There was no histological evidence of malignancy. Conclusion When we encounter a retroperitoneal cystic lesion, we should consider the possibility of malignancy to determine the treatment strategy and perform a careful operation without breaking the cyst wall, irrespective of the preoperative diagnosis.

Abstract Background Spontaneous common bile duct (CBD) perforation is an extremely rare disease in adults. We report an adult case of CBD perforation due to choledocolithiasis accompanied with pancreaticobiliary maljunction, which is, to our knowledge, the first such case report based on a search using PubMed. Case presentation A 71-year-old woman with consciousness disorder was transported to the emergency department of another hospital. She was diagnosed as having severe peritonitis with septic shock and transferred to our hospital for emergency surgery. Enhanced computed tomography (CT) revealed supraduodenal CBD dilation similar to a diverticulum and a defect of bile duct wall continuity. Furthermore, CT showed a long common channel of the pancreaticobiliary duct, so she was diagnosed as having spontaneous CBD perforation with pancreaticobiliary maljunction. Emergency surgery was performed that revealed a necrotic diverticulum-like change on the supraduodenal part, and a 2.5 × 1 cm perforation was found on the anterolateral wall of the CBD. Peritoneal lavage was performed, and CBD perforation was resolved with a T-tube. The patient suffered refractory intra-abdominal and retroperitoneal abscess formation and bleeding from the abdominal wall, which required a long period of postoperative management. The T-tube was removed on day 136, and the patient was transferred on day 153. Conclusion The cause of CBD perforation is commonly considered to be increased intraductal pressure or weakness of the bile duct wall. In this case, pancreaticobiliary maljunction may have significantly influenced onset and the postoperative course. This case suggests that early surgical intervention and appropriate drainage are important to ensure survival.

Abstract Background Rhabdomyomas comprise the majority of cardiac tumors in fetuses and are found in association with tuberous sclerosis complex. More than 90% of fetuses and neonates with multiple cardiac rhabdomyomas have signs of tuberous sclerosis complex. However, solitary cardiac rhabdomyoma cases are largely unrelated to tuberous sclerosis complex. Here, we report a case involving multiple cardiac rhabdomyomas not associated with tuberous sclerosis complex in a dizygotic twin. Case presentation A 36-year-old Japanese woman was diagnosed with a dizygotic twin pregnancy in the first trimester. Consistent with dizygosity, the fetal sex was discordant (male and female). At 27 weeks of gestation, hydrops and multiple echogenic cardiac masses were noted in the male baby, with the largest mass measuring 34 × 30 mm. The female fetus appeared normal. The cardiac masses enlarged gradually with the progression of the hydrops. At 32 weeks of gestation, intrauterine death of the male fetus was confirmed. The next day, autopsy of the male fetus was performed after cesarean section. Three well-demarcated white-tan-colored nodules were formed in the ventricular walls and interventricular septum, with the largest nodule (40 × 30 mm) in the left ventricular wall. Histologically, these lesions were diagnosed as rhabdomyomas. Conclusions We encountered a case involving multiple cardiac rhabdomyomas arising in one of dizygotic twin fetuses. Unlike most reported cases of multiple cardiac rhabdomyomas, this case was not accompanied by tuberous sclerosis complex. To the best of our knowledge, this is the first case report of multiple cardiac rhabdomyomas that developed in only one of dizygotic twins in the English literature.

Abstract Aims/Introduction Diabetic polyneuropathy (DPN) is a factor that reduces lower extremity muscle strength (LEMS) in older type 2 diabetes patients. This relationship remains unclear in longitudinal studies. Therefore, we longitudinally investigated the apparent effects of DPN on changes in LEMS. Furthermore, we cross‐sectionally examined relationships among DPN, LEMS, mobility and health‐related quality of life. Materials and Methods Bodyweight‐normalized (relative) knee extension force (KEF) was examined in 51 DPN and 54 non‐DPN patients (68.9 ± 5.6 and 70.2 ± 5.9 years, respectively) at baseline and follow up at 3.6 ± 0.6 years. At follow up, mobility was measured using a 25‐question geriatric locomotive function scale. Health‐related quality of life was assessed using the five‐dimensions of EuroQol for quality‐adjusted life years calculation. Results Relative KEF in the DPN group was significantly lower at follow up (1.22 ± 0.47 Nm/kg) than at baseline (1.31 ± 0.47 Nm/kg; P

Abstract Background Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1. The clinical course of ATLL is very heterogeneous, and many organs, including the gastrointestinal (GI) tract, can be involved. However, there are few detailed reports on ATLL infiltration in the GI tract. We investigated the clinical characteristics of ATLL infiltration in the GI tract. Methods This retrospective observational single-center study included 40 consecutive ATLL patients who underwent GI endoscopy. The patients’ demographic and clinical characteristics and endoscopic findings were analyzed retrospectively. Patients with ATLL who were diagnosed by histological examination were divided into two groups based on GI tract infiltration. Results Multivariate analysis revealed that the absence of skin lesions was significantly associated with GI infiltration (P

A recent trend in Japan is the increasing number of older patients with diabetes. Treatment for diabetes mellitus in older patients involves a wide variety of strategies, not only for better glycemic control, but also for the prevention and improvement of locomotive syndrome, sarcopenia, and frailty. Previous studies have shown that tele-guidance treatment interventions are effective for weight loss and increase in physical activity, but their effects on locomotive syndrome, sarcopenia, and glycemic control have not been examined. The objective of this study is to assess the efficacy of tele-guidance for intensive therapeutic interventions for diabetes mellitus in older patients, carried out by a qualified physical therapist with diabetes-specific qualifications and knowledge. This multi-center study, including 6 hospitals in Japan, is a prospective, parallel-group, single-blinded, randomized controlled trial. A total of 78 patients will be registered based on our preliminary studies. Patients aged 65–89 years with type 2 diabetes mellitus will be assigned randomly to intensive intervention and control groups. The effectiveness of 6 months of intervention will be verified by a physical therapist. The primary outcome measure will be the change in isometric knee extension force (KEF), whereas the secondary outcomes will be changes in skeletal muscle mass, motor function, glycemic control, and satisfaction with the treatment. When prescribing exercise therapy to older patients with diabetes mellitus, the various risks associated with exercise should be taken into consideration. Therefore, this study has been designed to establish the efficacy of intensive physiotherapy programs in older patients with diabetes mellitus. Provided that this study shows the effectiveness of tele-guidance in improving physical function and glycemic control, it can be a new intervention strategy for exercise therapy in older diabetes patients.

Abstract Background The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. Methods We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. Results Sixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. Conclusions All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

Abstract Background True thymic hyperplasia is a rare condition characterized by enlargement of the thymus while its normal structure is retained. True thymic hyperplasia is known to accompany Graves’ disease, but no association between true thymic hyperplasia and thyroid follicular tumor has been reported so far. We report a case of true thymic hyperplasia in a patient with a thyroid follicular tumor. Case presentation A 52-year-old Japanese man was referred to our hospital for evaluation of a thyroid mass and a mediastinal mass. His serum thyroglobulin level was high, and hemithyroidectomy was performed to remove the thyroid mass. The resected mass was diagnosed as a follicular tumor of uncertain malignant potential. After resection of the thyroid lesion, the patient’s serum thyroglobulin levels were markedly decreased. Seven months later, the patient underwent resection of the mediastinal mass. On pathological examination, the mass was found to consist of lobules, which formed a corticomedullary structure with Hassall’s bodies, indicating a normal thymic mass with hyperplastic thymic tissue, less organized cellular cords, and intermingled adipose tissue. Immunostaining for cytokeratin 19 and cytokeratin 7 indicated that the lesion was consistent with thymic tissue. The lesion was diagnosed as true thymic hyperplasia, and the histological findings suggested that secondary atrophy had occurred. No evidence of recurrence was observed at 24 months after surgery. Conclusions We present a case of a combination of true thymic hyperplasia and thyroidal follicular tumors that, to our knowledge, has not been reported previously. High serum thyroglobulin levels might play a role in hyperplasia of the thymus. Although true thymic hyperplasia is a rare disorder, it should be included in the differential diagnosis of a mediastinal mass in patients with thyroid disease.

Resistance training is effective in chronic hemodialysis patients with type 2 diabetes mellitus, but its effect on toe pinch force (TPF) is unknown. This study was a randomized controlled trial conducted at three hospitals to investigate the effect of short-term toe resistance training on TPF in chronic hemodialysis patients with type 2 diabetes. The patients were randomly allocated to intervention (performed aerobic exercise and four toe resistance training exercises) and control (performed aerobic exercise only) groups. After 2 weeks of exercise intervention program, evaluations of TPF and clinical parameters were performed. In addition, the rate of retention of exercise therapy was assessed 6 months after the exercise intervention program was completed. After the exercise intervention program, TPF was significantly higher in the intervention group than in the control group. The intervention group had a significantly higher rate of continuation of exercise therapy. Two weeks of toe resistance training significantly increased the TPF in chronic hemodialysis patients with type 2 diabetes. Toe resistance training was shown to be an effective training method for continuing exercise therapy. Toe resistance training is recommended in clinical practice for chronic hemodialysis patients with type 2 diabetes.

Abstract Objective We previously reported the identification of monocarboxylate transporter 4 (MCT4) and glypican-3 (GPC3) as prognostic factors for hepatocellular carcinoma (HCC), which are now considered significant poor prognostic factors for the disease. This study aimed to clarify the detailed interaction of these two factors in HCC to improve our understanding of aggressive HCC phenotypes. A total of 225 Japanese patients with HCC from our previous study were subjected to immunohistochemical analyses. Results The number of MCT4-positive (MCT4+) HCC cases was 47 (21%), and most MCT4+ HCC showed high GPC3 expression (94%, 44/47 cases). In 44 MCT4+/GPC3+ HCC cases, intratumoral heterogeneity of GPC3 or MCT4 expression was further evaluated. We observed reciprocal (inverse), synergistic, mixed reciprocal and synergistic, or irrelevant interaction of MCT4 and GPC3 expression in 29 (66%), 5 (11%), 1 (2%), and 9 cases (21%), respectively. The cases exhibiting reciprocal expression of both markers tended to have cirrhosis without a history of neoadjuvant therapy. In summary, although MCT4+ HCC cases are mostly GPC3+, intratumoral expression patterns of MCT4 and GPC3 are frequently reciprocal each other, suggesting that dual targeting of MCT4 and GPC3 may achieve a better antitumor effect for MCT4+ HCC cases.

Abstract We presented a difficult‐to‐diagnose case of cardiac angiosarcoma. The patient presented pericardial effusion, but cytology of the effusion was negative. Because cytological detection of angiosarcoma cells is difficult, a possibility of malignancy should not be excluded with negative cytological examination. Biopsy of cardiac mass is the best way for diagnosis.

Abstract In multinodular lesions or tumors with mixed benign and malignant components, malignant elements may be undetectable using fine‐needle aspiration biopsy/cytology in preoperative pathological diagnosis of some cases, because of sampling error.

Few studies have examined the effects of different aerobic-exercise intensities on intraocular-pressure (IOP) changes. This may be important for eye diseases that are impacted by IOP or its fluctuation, including glaucoma, and diabetes that is complicated by diabetic retinopathy. We investigated the effects of low-, moderate-, and high-intensity exercise on IOP in healthy subjects. A submaximal cardiopulmonary exercise test was performed in 18 healthy male subjects, and the maximal oxygen uptake was calculated. The subjects then exercised for 20 min at 30%, 50%, and 70% ·VO2 of maximal oxygen uptake, and their IOP was measured at rest and every 5 min during exercise. Oxygen uptake was monitored using an expiratory gas analyzer during exercise to maintain accurate exercise intensity and adjust exercise load. Oxygen uptake during exercise was significantly higher at all intensities from 5 to 20 min than at rest. IOP was significantly lower at 70% exercise intensity from 5 to 20 min than at rest. A negative correlation existed between IOP and ·VO2. IOP remained unchanged during low- and moderate-intensity exercise but significantly declined during high-intensity exercise compared with that at rest. Although various factors, such as β-blockers, are involved in IOP decline at rest, a different mechanism is involved in IOP decline during exercise.

Colorectal cancer is one of the most important malignancies worldwide, with high incidence and mortality rates. Several studies have been conducted using two-dimensional cultured cell lines; however, these cells do not represent a study model of patient tumors very well. In recent years, advancements in three-dimensional culture methods have facilitated the establishment of patient-derived organoids, which have become indispensable for molecular biology-related studies of colorectal cancer. Patient-derived organoids are useful in both basic science and clinical practice; they can help predict the sensitivity of patients with cancer to chemotherapy and radiotherapy and provide the right treatment to the right patient. Regarding precision medicine, combining gene panel testing and organoid-based screening can increase the effectiveness of medical care. In this study, we review the development of three-dimensional culture methods and present the most recent information on the clinical application of patient-derived organoids. Moreover, we discuss the problems and future prospects of organoid-based personalized medicine.

Abstract The increase in the proportion of elderly people in the population is one of the most remarkable sociodemographic phenomena of the twenty-first century. The number of patients with diabetes is also increasing worldwide with this demographic change. Given these facts, consideration of the problems the general elderly population is facing in the management of diabetes is essential. In this review article, we focus on sarcopenia, which is the decrease in lower extremity muscle mass and muscle strength accompanying aging, describe the relationship between sarcopenia and diabetes, and highlight the specific factors through which diabetes contributes to loss of muscle strength. The quantitative methods for evaluating lower extremity muscle strength will also be described. These methods hold the key to assessing the effectiveness of exercise therapy and optimizing the assessment of the degree of autonomy in the activities of daily living. Exercise is one of the basic treatments for type 2 diabetes and may also prevent and improve sarcopenia. This review discusses the aspects common to the two health conditions and elucidates the effectiveness and necessity of exercise as a preventive measure against diabetes among the elderly.

The purpose of this cross-sectional study was to investigate the effect of chronic hemodialysis on toe pinch force (TPF). A total of 37 chronic hemodialysis patients without type 2 diabetes mellitus (T2DM) (age: 69.4 ± 11.8 years, duration of hemodialysis: 3.5 ± 3.4 years) were enrolled in this study. The TPF in chronic hemodialysis patients without T2DM was compared with that in 34 apparently healthy participants and 37 chronic hemodialysis patients with T2DM. There was no significant difference in clinical profiles between healthy participants and chronic hemodialysis patients with and without T2DM. The TPF in chronic hemodialysis patients without T2DM was lower compared with that in healthy participants (2.70 ± 1.05 kg vs. 3.34 ± 0.99 kg, p = 0.025). In addition, the TPF in patients with T2DM was even lower compared with that in patients without T2DM (2.12 ± 1.01 kg vs. 2.70 ± 1.05 kg, p = 0.042). This study showed a dramatic reduction in TPF in chronic hemodialysis patients, especially in those with T2DM.

Abstract Objective Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor that is expressed on the surface of epithelial cells. Evidence has suggested that decreased cell surface HAI-1 in carcinoma cells results in enhanced invasiveness. However, little is known regarding the expression of HAI-1 in pancreatic ductal adenocarcinoma (PDAC). This study aimed to analyze HAI-1 expression in PDAC and its impact on patient prognosis. Results HAI-1 immunohistochemistry was performed on samples from 67 PDAC cases. HAI-1 expression was increased in intraepithelial neoplasia compared to the adjacent non-neoplastic ductal epithelium. Of the 67 samples tested, 58% (39/67) of PDAC cases showed diffuse (> 75%) immunoreactivity in PDAC cells. The remaining cases showed reduced HAI-1 immunoreactivity in a substantial number of cancer cells. Although there was no correlation between HAI-1 status and tumor size, histologic grade or lymph node metastasis, diffuse HAI-1 positive cases showed longer disease-free survival (DFS; p = 0.006, log-rank test). In conclusion, HAI-1 is upregulated in pancreatic intraepithelial neoplasia and broadly expressed in PDAC cells. However, PDAC cases having areas of reduced HAI-1 immunoreactivity may show shorter DFS.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease in China, Korea, and Japan caused by the SFTS virus (SFTSV). SFTS has a high mortality rate due to multiorgan failure. Recently, there are several reports on SFTS patients with mycosis. Here, we report a middle-aged Japanese SFTS patient with invasive pulmonary aspergillosis (IPA) revealed by an autopsy. A 61-year-old man with hypertension working in forestry was bitten by a tick and developed fever, diarrhea, and anorexia in 2 days. On day 4, consciousness disorder was appearing, and the patient was transferred to the University of Miyazaki Hospital. A blood test showed leukocytopenia, thrombocytopenia, as well as elevated levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase. The SFTSV gene was detected in serum using a reverse-transcription polymerase chain reaction. On day 5, respiratory failure appeared and progressed rapidly, and on day 7, the patient died. An autopsy was performed that revealed hemophagocytosis in the bone marrow and bleeding of several organs. IPA was observed in lung specimens. SFTSV infection may be a risk factor for developing IPA. Early diagnosis and treatment of IPA may be important in patients with SFTS.

The number of patients with diabetes was approximately 463 million worldwide in 2019, with almost 57.6% of this population concentrated in Asia. Asians often develop type 2 diabetes (T2D), even if they are underweight and consume a smaller amount of food. Soft drinks contain large amounts of sweeteners, such as high-fructose corn syrup (HFCS). Excessive intake of HFCS drinks is considered to be one of the causes of T2D. In the present study, we investigated the effect of excessive consumption of HFCS–water on glucose tolerance and obesity under conditions of controlled caloric intake using a mouse model. Three-week-old male ICR mice were divided into two groups and given free access to 10% HFCS–water or deionized water. The caloric intake was adjusted to be the same in both groups using a standard rodent diet. The excess HFCS–water intake did not lead to obesity, but led to impaired glucose tolerance (IGT) due to insulin-secretion defect. It affected glucose and fructose metabolism; for example, it decreased the expression of glucokinases, ketohexokinase, and glucose transporter 2 in the pancreas. These results suggest that excessive consumption of HFCS drinks, such as soft drinks, without a proper diet, induces nonobese IGT due to insulin-secretion defect.

Extranodal Rosai-Dorfman disease (RDD) of the kidney is rare, with unknown etiology. We present a case of extranodal RDD of the kidney. Imaging revealed a nodular lesion in the right renal pelvis, with accompanying pelvic dilation and parenchymal atrophy, reminiscent of immunoglobulin G4 (IgG4)-related disease. With the clinical diagnosis of suspected renal pelvic cancer, laparoscopic right nephrectomy was performed. Macroscopic findings showed a mass with a white-tan cut surface. Histological examination revealed histiocytes with emperipolesis and patchy infiltration of plasma cells, lymphocytes and foamy macrophages in a fibrocollagenous stroma. Immunohistochemically, the histiocytes were positive for S100, CD68 and CD163, but negative for CD1a, p80/ALK and phospho-p44/42 MARK (Thr202/Tyr204). IgG4-positive plasma cells were not evident.These findings indicated that the lesion represented extranodal RDD of the kidney. No mutations of the K- and N-RAS genes could be identified in this case. Although rare, extranodal RDD should be included in the differential diagnosis of a renal pelvic mass. Keywords: Rosai-Dorfman disease, Sinus histiocytosis with massive lymphadenopathy, Kidney

Objective: The proportion of elderly individuals (≥65 years old) in Japan has markedly increased. However, the definition of senility in Japan is controversial. The aim of the present study was to investigate changes and variations in the number of deaths due to senility in Japan. Methods: Information on the number of deaths due to senility between 1995 and 2018 as well as other major causes of death was obtained from the Statistics Bureau of Japan official website. Changes and variations in the number of deaths due to senility were compared with other major causes of death in Japan. The relationships between the number of deaths due to senility and socioeconomic factors were also examined in an ecological study. Results: The number of deaths due to senility was 35.7 ± 23.2/one hundred thousand people/year during the observation period and has continued to increase. A change point was identified in 2004 by a Jointpoint regression analysis. Variations in the number of deaths due to senility, which were evaluated by a coefficient of variation, were significantly greater than those due to other major causes of death, i.e., malignant neoplasm, heart diseases, cerebrovascular diseases, and pneumonia. The number of elderly individuals (≥65 years old) (%) and medical bills per elderly subject (≥75 years old) correlated with the number of deaths due to senility. Conclusion: The number of deaths due to senility has been increasing, particularly since 2004. However, variations in the number of deaths due to senility were observed among all prefectures in Japan.

Objective: The purpose of this study was to investigate the risk factors linked to patient dropout from continuous positive airway pressure (CPAP) therapy for the treatment of obstructive sleep apnea syndrome (OSAS). Methods: This study included 1191 patients with OSAS at baseline assessment, who were followed for 3 years. We evaluated clinical parameters, indicators related to OSAS treatment, exercise habits and the presence of locomotive syndrome (LS). LS was evaluated by a ‘loco-check’, as established by the Japanese Orthopedic Association. The OSAS patients were categorized at baseline as belonging to an ‘LS group’ or a ‘non-LS group’, and clinical parameters were compared. Results: Eighty-six patients (7.2%) dropped out of CPAP therapy during the 3 year follow-up period. The dropout rate of the LS group was significantly higher than that of the non-LS group. Using a Cox-proportional hazard model, the LS, old age and poor compliance were determined to be significant risk factors for dropping out of CPAP therapy. The hazard ratios (95% CI) of LS, elderly people and poor CPAP compliance were 2.11 (1.31–3.48), 1.80 (1.11–2.94) and 1.61 (1.04–2.47), respectively. Conclusion: LS may be the critical risk factor for dropping out of CPAP therapy among patients with OSAS.

Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

Objective: It is well known that air temperature is closely related to health outcomes. We investigated the relationship between air temperature parameters and the number of deaths stratified by cause in Gifu prefecture, Japan. Methods: The number of deaths stratified by cause in Gifu prefecture Japan between January 2007 and December 2016 was obtained from the official homepage of Gifu prefecture, Japan. Air temperature parameters (℃), i.e., the mean air temperature, mean of the highest air temperature, mean of the lowest air temperature, the highest air temperature, and the lowest air temperature during the same period in Gifu city were also obtained from the Japan Meteorological Agency official home page. The relationship between air temperature parameters and the number of deaths was evaluated in an ecological study. Results: The number of deaths due to heart disease, cerebrovascular disease, pneumonia, accidents, or renal failure in January (coldest winter season in Japan) was the highest among the months. Simple correlation analysis also demonstrated a significant and negative relationship between air temperature parameters and the number of deaths due to heart disease, cerebrovascular disease, senility, pneumonia, accidents, and renal failure. Conclusion: Lower air temperature may be associated with a higher number of deaths due to diseases in Gifu prefecture, Japan.

Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. Given the mildly acidic extracellular environment of solid tumors, matriptase activation may, thus, be accelerated in the tumor microenvironment. HGFA and matriptase activities are regulated by HGFA inhibitor (HAI)-1 (HAI-1) and/or HAI-2 in the pericellular microenvironment. HAIs may have an important role in cancer cell biology by regulating HGF/SF-activating proteases.

Glypican-3 (GPC3) is an oncofetal glycoprotein attached to the cell membrane by a glycophosphatidylinositol anchor. GPC3 is overexpressed in some kinds of tumors, particularly hepatocellular carcinoma (HCC). The prognostic significance of serum GPC3 levels and GPC3 immunoreactivity in tumor cells has been defined in patients with HCC. In addition to its usefulness as a biomarker, GPC3 has attracted attention as a novel therapeutic target molecule, and clinical trials targeting GPC3 are in progress. The major mechanism of anti-GPC3 antibody (GPC3Ab) against cancer cells is antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity. Since GPC3Ab is associated with immune responses, a combination of protocols with immune checkpoint inhibitors has also been investigated. Moreover, some innovative approaches for GPC3-targeting therapy have emerged in recent years. This review introduces the results of recent clinical trials targeting GPC3 in HCC and summarizes the latest knowledge regarding the role of GPC3 in HCC progression and clinical application targeting GPC3.

In our previous report, an 80% ethanol bitter gourd seed extract (BGSE) was found to suppress proliferation of adult T-cell leukemia (ATL) cell lines. The present study aimed to identify the bioactive compounds from BGSE specific against ATL. From the result of an HPLC-MS analysis, α-eleostearic acid (α-ESA) was present in BGSE at 0.68% ± 0.0022% (±SD, n = 5). In the cell proliferation test, α-ESA potently suppressed proliferation of two ATL cell lines (ED and Su9T01; IC50 = 8.9 and 29.3 µM, respectively) more than several other octadecanoic acids. However, α-ESA moderately inhibited phytohemagglutinin-activated human peripheral blood mononuclear cells (PBMC; IC50 = 31.0 µM). These results suggest that BGSE-derived α-ESA has potential as a functional food constituent because of its activity against ATL, particularly against ED cells. Moreover, α-ESA might be effective for the prevention of moderate adverse effects of ATL on normal T cells.

Hepatocyte growth factor (HGF) plays an important role in cancer progression via phosphorylation of MET (c-met proto-oncogene product, receptor of HGF). HGF-zymogen (pro-HGF) must be processed for activation by HGF activators including matriptase, which is a type II transmembrane serine protease and the most efficient activator. The enzymatic activity is tightly regulated by HGF activator inhibitors (HAIs). Dysregulated pro-HGF activation (with upregulated MET phosphorylation) is reported to promote cancer progression in various cancers. We retrospectively analyzed the expression of matriptase, phosphorylated-MET (phospho-MET) and HAI-1 in tumor specimens obtained from patients with invasive bladder cancer by immunohistochemistry. High expression of phospho-MET and increased expression of matriptase were significantly associated with poor prognosis, and high matriptase/low HAI-1 expression showed poorer prognosis. Furthermore, high expression of matriptase tended to correlate with phosphorylation of MET. Increased expression of matriptase may induce the ligand-dependent activation of MET, which leads to poor prognosis in patients with invasive bladder cancer.

Hepatocyte growth factor (HGF) promotes pleiotropic signaling through its specific receptor tyrosine kinase, MET. As such, it has important roles in the regeneration of injured tissues. Since HGF is produced mainly by mesenchymal cells and MET is expressed in most epithelial, endothelial and somatic stem cells, HGF functions as a typical paracrine growth factor. HGF is secreted as an inactive precursor (proHGF) and requires proteolytic activation to initiate HGF-induced MET signaling. HGF activator (HGFAC) is a serum activator of proHGF and produces robust HGF activities in injured tissues. HGFAC is a coagulation factor XII-like serine endopeptidase that circulates in the plasma as a zymogen (proHGFAC). Thrombin, kallikrein-related peptidase (KLK)-4 or KLK-5 efficiently activates proHGFAC. The activated HGFAC cleaves proHGF at Arg494-Val495, resulting in the formation of the active disulfide-linked heterodimer HGF. Macrophage stimulating protein, a ligand of RON, is also activated by HGFAC in vivo. Although HGFAC functions primarily at the site of damaged tissue, a recent report has suggested that activated HGFAC relays a signal to stem cells in non-injured tissues via proHGF activation in the stem cell niche. This review focuses on current knowledge regarding HGFAC-mediated proHGF activation and its roles in tissue regeneration and repair.

MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. Based on the results, we produced HAI-2 stable knockdown 786-O cells, and analyzed invasiveness and motility. Expression of HGF and matriptase was increased in bone metastasis compared with the control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system.

BACKGROUND: Neural progenitor cells (NPCs) in the developing neuroepithelium are regulated by intrinsic and extrinsic factors. There is evidence that NPCs form a self-supporting niche for cell maintenance and proliferation. However, molecular interactions and cell-cell contacts and the microenvironment within the neuroepithelium are largely unknown. We hypothesized that cellular proteases especially those associated with the cell surface of NPCs play a role in regulation of progenitor cells in the brain. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we show that NPCs, isolated from striatal anlage of developing rat brain, express hepatocyte growth factor activator inhibitor-1 and -2 (HAI-1 and HAI-2) that are cell surface-linked serine protease inhibitors. In addition, radial glia cells derived from mouse embryonic stem cells also express HAI-1 and HAI-2. To study the functional significance of HAI-1 and HAI-2 in progenitor cells, we modulated their levels using expression plasmids or silencing RNA (siRNA) transfected into the NPCs. Data showed that overexpression of HAI-1 or HAI-2 decreased cell proliferation of cultured NPCs, whilst their siRNAs had opposite effects. HAI-1 also influenced NPC differentiation by increasing the number of glial fibrillary acidic protein (GFAP) expressing cells in the culture. Expression of HAI-1 in vivo decreased cell proliferation in developing neuroepithelium in E15 old animals and promoted astrocyte cell differentiation in neonatal animals. Studying the regulation of HAI-1, we observed that Bone morphogenetic protein-2 (BMP-2) and BMP-4 increased HAI-1 levels in the NPCs. Experiments using HAI-1-siRNA showed that these BMPs act on the NPCs partly in a HAI-1-dependent manner. CONCLUSIONS: This study shows that the cell-surface serine protease inhibitors, HAI-1 and HAI-2 influence proliferation and cell fate of NPCs and their expression levels are linked to BMP signaling. Modulation of the levels and actions of HAI-1 in NPCs may be of a potential value in stem cell therapies in various brain diseases.

Matriptase, a membrane-associated serine protease, plays an essential role in epidermal barrier function through activation of the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin. The matriptase-prostasin proteolytic cascade is tightly regulated by hepatocyte growth factor activator inhibitor (HAI)-1 such that matriptase autoactivation and prostasin activation occur simultaneously and are followed immediately by the inhibition of both enzymes by HAI-1. However, the mechanisms whereby matriptase acts on extracellular substrates remain elusive. Here we report that some active matriptase can escape HAI-1 inhibition by being rapidly shed from the cell surface. In the pericellular environment, shed active matriptase is able to activate hepatocyte growth factor (HGF), accelerate plasminogen activation, and shed syndecan 1. The amount of active matriptase shed is inversely correlated with the amount of antithrombin (AT) bound to the surface of the keratinocytes. Binding of AT to the surface of keratinocytes is dependent on a functional heparin binding site, Lys-125, and that the N-glycosylation site Asn-135 be unglycosylated. This suggests that β-AT, and not α-AT, is responsible for regulation of pericellular matriptase activity in keratinocytes. Keratinocytes appear to rely on AT to regulate the level of pericellular active matriptase much more than breast and prostate epithelial cells in which AT regulation of matriptase activity occurs at much lower levels than keratinocytes. These results suggest that keratinocytes employ two distinct serine protease inhibitors to control the activation and processing of two different sets of matriptase substrates leading to different biological events: 1) HAI-1 for prostasin activation/inhibition, and 2) AT for the pericellular proteolysis involved in HGF activation, accelerating plasminogen activation, and shedding of syndecans.

Background/Aim: The global prevalence of type 2 diabetes (T2D) continues to increase, necessitating the need for understanding the causes of its development. The widespread use of high-fructose corn syrup (HFCS) in drinks and diets is suspected to play a role in metabolic disorders. Although many studies have reported on the effects of excessive HFCS and excessive energy intakes in middle-aged individuals, few have focused on energy restriction. This study aimed to investigate the effects of excessive HFCS drink intake under energy restriction on developing T2D in early middle-aged mice. Materials and Methods: Early middle-aged mice were divided in HFCS and control groups; they were provided either 10% HFCS water or deionized water ad libitum for 12 weeks, respectively. Total energy intake was controlled using a standard rodent diet. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), tissue weight measurements, serum parameter analyses, and mRNA expression assessments were performed. Results: No increase in body and adipose tissue weight was observed with excessive HFCS intake under energy restriction. Moreover, serum lipid parameters did not differ from those of controls. However, in the OGTT and ITT, the HFCS group showed higher blood glucose levels than the control group. Moreover, the pancreatic weight and insulin II mRNA expression were reduced. Conclusion: The excessive HFCS drink intake under energy restriction did not induce obesity; however, it induced impaired glucose tolerance, indicating its negative effects on the pancreas in early middle-aged mice. When translated in human physiology, our results show that even if one does not become obese, excessive HFCS may affect the overall metabolic mechanism; these effects may vary depending on age. [ABSTRACT FROM AUTHOR]