Dietary soyasaponin attenuates 2,4-dinitrofluorobenzene-induced contact hypersensitivity via gut microbiota in mice.

Soyasaponins (SSs) are abundant in soybeans and display inhibitory activity against contact hypersensitivity (CHS), which is often used as a mouse model for allergic contact dermatitis (ACD); however, their therapeutic mechanisms remain unknown. Here, we attempted to clarify the role of gut microbiota in the inhibition of CHS by dietary soyasaponins. For antibiotic treatment, mice were administered a mixture of ciprofloxacin and metronidazole or vancomycin. These antibiotics and SSs were given to mice via drinking water 3-weeks prior to CHS induction with 2,4-dinitrofluorobenzene, and the mice were analysed for ear swelling, tissue oedema, infiltration of Gr-1-positive immune cells, the composition of faecal microbiota and regulatory T (Treg ) cells. The soyasaponin diets attenuated ear swelling and tissue oedema, and reduced the number of Gr-1-positive cells infiltrating ear tissues. CHS caused changes in the structure of the gut microbiota, but dietary SSs blocked the changes in the microbiota composition. Ciprofloxacin and metronidazole treatments significantly enhanced the severity of CHS symptoms, whereas vancomycin treatment blocked the suppressive effect of dietary SSs on CHS. These antibiotic treatments differed in their effects on the gut microbiota composition. Treg cells in auricular lymph node and spleen increased under SS-enriched diets, but this increase was blocked by vancomycin treatment. These results suggest that dietary SSs exert their inhibitory activity on CHS via the gut microbiota in mice, suggesting that dietary supplementation with SSs may have beneficial effects on ACD patients, but that the gut microbiota is a critical determinant of the therapeutic value of dietary SSs.

Adenosarcoma of the uterine body initially presenting as an interstitial small tumor of the uterus: a case report.

Adenosarcoma of the uterine body is a rare mixed tumor in which a benign epithelial component is mixed with a malignant stromal element. It has been considered that this tumor originates from the endometrium and its most common finding of imaging is a polypoid tumor occupying the uterine cavity. The authors herein present a case of 37-year-old female with a complaint of abnormal vaginal bleeding. At the first visit, transvaginal ultrasound and magnetic resonance imaging (MRI) showed a round mass with a diameter of one cm in the uterine wall. No malignant pathological finding was detected. The patient visited the authors again one year later, because of continuous bleeding. At that time, they found a polypoid tumor in the uterine cavity, which turned out to be adenosarcoma with sarcomatous overgrowth. The round mass in the uterus detected at first time seems to have been incipience of adenosarcoma. Prodromal sign of adenosarcoma has not been reported previously.

Biochemical and hematologic effects of polyvinylpyrrolidone-wrapped fullerene C60 after oral administration.

The fullerene C60 is used in consumer products such as cosmetics owing to its antioxidative effects and is being developed for nanomedical applications. However, knowledge regarding the safety of fullerene C60, especially after oral administration, is sparse. Here, we examined the safety of fullerene C60 in mice after 7 d of exposure to orally administered polyvinylpyrrolidone (PVP)-wrapped fullerene C60 (PVP-fullerene C60). Mice treated with PVP-fullerene C60 showed few changes in the plasma levels of various markers of kidney and liver injury and experienced no significant hematologic effects. Furthermore, the histology of the colon of PVP-fullerene C60-treated mice was indistinguishable from that of control mice. These results suggest that PVP-fullerene C60 lacks toxicity after high-dose oral administration and indicate that PVP-fullerene C60 can be considered safe for oral medication. These data provide basic information that likely will facilitate the production of safe and effective forms of fullerene C60.

Laminar-type gratings overcoated with carbon-based materials to enhance analytical sensitivity of flat-field emission spectrograph in the VUV region.

Laminar-type spherical diffraction gratings overcoated with carbon-based materials were designed, fabricated, and evaluated for the purpose of enhancing the analytical sensitivity of the flat-field spectrograph in a vacuum ultraviolet region of 35-110 eV. As the design benchmark for numerical calculations, diffraction efficiency (DE) and spectral flux, which are defined by the product of the DE and numerical aperture and correlate with the analytical sensitivity of the spectrograph, were used. To simplify the feasibility study on the overcoating effects, we assumed a laminar-type grating having a grating constant of 1/1000 mm and coated with a Au layer of 30.0 nm thickness and an incidence angle of 84.0°. The optimized groove depth and duty ratio were 30.0 nm and 0.3, respectively. In addition, the optimum thicknesses of the overcoating layer were 44, 46, 24, and 30 nm for B4C, C, diamond-like-carbon, and SiC, respectively. Based on these results, we have fabricated a varied-line-spacing holographic grating overcoated with B4C with a thickness of 47 nm. For the experimental evaluation, we used the light source of Mg-L and Al-L emissions excited by the electron beam generated from an electron microscope, an objective flat-field spectrograph, and a CCD imaging detector. The experimental results showed that the spectrograph employing a new grating overcoated with the B4C layer indicated almost the same spectral resolution and 2.9-4.2 times higher analytical sensitivity compared with those obtained with a previously designed Au-coated grating having a grating constant of 1/1200 mm and used at an incidence of 86.0°.

Reflux esophagitis after esophagectomy: impact of duodenogastroesophageal reflux.

Reflux esophagitis (RE) is a known complication disturbing patients' quality of life after esophageal resection. It is generally recognized that bile reflux as well as acid reflux cause RE. However, the clinical influence of acid and bile reflux, and Helicobacter pylori (H. pylori) infection on RE in the cervical esophagus after esophagectomy is not yet clarified. Sixty patients who underwent cervical esophagogastrostomy following esophagectomy were enrolled in this study. They underwent examination for H. pylori infection, endoscopic examination, and continuous 24-hour pH and bilirubin monitoring, at 1 month after surgery. The influence of acid and/or bile reflux, H. pylori infection, and others on the development of RE were investigated. RE was observed in 19 patients (32%) at 1 month after esophagogastrostomy, mild RE in 16 (27%), and severe RE in 3 (5%). The percentage of time duration of both acid and bile reflux into the cervical esophagus was higher in patients with RE than in those without (P = 0.027, P < 0.001). A significant difference in %time pH < 4 acid reflux was found between mild RE and severe RE (P = 0.014), and a statistical difference in %time abs. > 0.14 between non-RE and mild RE (P = 0.017). Acid and/or bile reflux was observed in 31 patients (52%), acid-only reflux in 6 (10%), bile-only reflux in 15 (25%), and acid-and-bile reflux in 10 (17%). Severe RE was observed only in patients having acid-and-bile reflux. On the univariate analysis, no infection of H. pylori, acid reflux, and bile reflux were determined to be the influencing factors to RE among the clinical factors including age, gender, route of esophageal reconstruction, H. pylori infection, and acid-and-bile reflux. In the subanalysis using the logistic model, there were significant correlations between bile reflux and RE irrespective of the presence of H. pylori infection (P = 0.016, P = 0.007). On the other hand, there was a significant correlation between acid reflux and RE only in patients without H. pylori infection (P = 0.039). In the early period after esophagogastrostomy, bile reflux could cause RE irrespective of H. pylori infection, while acid reflex could cause RE only in patients without H. pylori infection. There is a possibility that bile reflux plays an important role in the development of RE after esophagectomy.

Applying very high resolution microfocus X-ray CT and 3-D reconstruction to the human auditory apparatus.

Conventional high-resolution X-ray computed tomography (XCT) is an important medical technique because it provides sectional images (tomograms) of internal structures without destroying the specimen. However, it is difficult to observe and to analyze fine structures less than a few cubic millimeters in size because of its low spatial resolution of 0.4 mm. Overcoming this problem would not only enable visualization of human anatomical structures in living subjects by means of computer images but would make it possible to obtain the equivalent of microscopic images by XCT without making microscopic sections of biopsy material, which would allow the examination of the entire body and detection of focal lesions at an early stage. Bonse et al. and Kinney et al. studied absorption contrast microtomography by using synchrotron radiation and achieved 8-microns spatial resolution in human cancellous bone. Recently, Momose et al. reported examining the soft tissue of cancerous rabbit liver by a modification of the phase-contrast technique using synchrotron radiation with a spatial resolution of 30 microns (ref. 4). However, the equipment for synchrotron radiation requires a great deal of space and is very expensive. Aoki et al., on a different tack, reported microtomography of frog embryos by using a conventional laboratory microfocus X-ray source with a spot size of about 2 microns (ref. 5). As no human tomographic studies by superresolution microfocus XCT (MFXCT) using a normal open-type X-ray source have been reported, we tried using MFXCT with a maximum experimental spatial resolution of 2.5 microns, especially designed for industrial use, on the auditory ossicles of a human fetus, the smallest and lightest bones in the skeletal system. No XCT studies of fetal auditory ossicles have been reported to date. The fine tomograms with three-dimensional reconstructions obtained showed the existence of an apparently previously undescribed joint between the tympanic ring and the anterior process of the malleus. We hope the early development of this MFXCT for clinical use will make a great contribution to medicine.

Thoracic endovascular aortic repair for aortic complications after esophagectomy for cancer: report of three cases.

Aortic complications after esophageal cancer surgery are rare and usually fatal. Here, we report three patients who underwent thoracic endovascular aortic repair (TEVAR) for aortic complications after esophagectomy for cancer. In the first case, aortic rupture was caused by pyothorax due to residual tumor after esophagectomy. In the second case, aortic rupture was caused by pyothorax due to anastomotic leakage. In the third case, a pseudoaneurysm was caused by surgical injury during esophagectomy. TEVAR was safe and effective for severe aortic complications when graft infection was avoided. The first case died of sepsis on the 84th postoperative day, and the other two cases have survived 4 years and 2 years to date.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Cytodifferentiation activity of synthetic human enamel sheath protein peptides.

BACKGROUND AND OBJECTIVE: Enamel sheath protein (ESP) is involved in the construction of the enamel sheath during tooth development. The 17 kDa ESP is a one-step cleavage product processed by proteolysis from the N-terminal side of sheathlin (ameloblastin/amelin), one of the porcine enamel matrix proteins. Enamel sheath protein exhibits periodontal ligament and cementum regeneration activity in a buccal dehiscence model in dogs, and promotes the cytodifferentiation of cultured human periodontal ligament (HPDL) cells. The aim of this study was to determine the peptide segment on the C-terminal side sequence of the human ESP that possesses a cytodifferentiation activity on cultured HPDL cells. MATERIAL AND METHODS: The peptides synthesized on the basis of human ESP C-terminal side sequence were tested for their ability to increase the alkaline phosphatase (ALP) and mineralization activity of cultured HPDL cells. The expressions of osteocalcin, osteopontin and bone sialoprotein were measured by semi-quantitative PCR and therefore were determined to be specific indicators of mineralized tissue differentiation. RESULTS: Multiple synthetic peptides from the human ESP increased the ALP activity and stimulated matrix mineralization in long-term cultures of HPDL cells. Semi-quantitative PCR demonstrated the osteocalcin, osteopontin and bone sialoprotein expressions to increase relative to the control values. The peptide SDKPPKPELPGVDF had the strongest cytodifferentiation activity among all the synthetic peptides tested. CONCLUSION: A specific peptide sequence derived from the C-terminal side of the human ESP promotes the cytodifferentiation and mineralization activity of HPDL cells in a cell culture system.

Surgical management for small cell carcinoma of the esophagus.

Esophageal small cell carcinoma (SmCC) has been regarded as a rare and aggressive tumor with early metastasis. The optimal treatment has not yet been established, and the role of surgery has remained controversial. In this retrospective study, we report seven cases studies of SmCC of the esophagus and analyze the clinical outcomes after surgery. Between 1986 and 2007, there were seven patients with esophageal SmCC treated surgically in our institution. All the patients with clinically limited disease underwent transthoracic esophagectomy with lymphadenectomy. Lymph node involvement was found in all cases irrespective of the depth of tumor invasion. Three of the seven patients were diagnosed as having an extensive disease on pathological examination after esophagectomy. Five patients received postoperative chemotherapy. Two patients are alive with no recurrence at 16 months and at 45 months after surgery. Another one without chemotherapy survived 93 months and died of another disease. The remaining four patients died of recurrent disease or another disease. The median overall survival to date of these patients was 16 months (range 12-93 months). Esophagectomy with lymphadenectomy resulted in a relatively better survival in some patients with esophageal SmCC. We concluded that surgery may be helpful as part of multimodality treatment in selected patients with esophageal SmCC.

Pharyngolaryngeal reflux in patients who underwent cervical esophago-gastrostomy following esophagectomy.

Pharyngolaryngeal reflux has been generally accepted as a cause for pharyngolaryngitis, hoarseness, aspiration pneumonia, chronic cough, and nocturnal asthma. Although patients who have undergone gastric conduit reconstruction after esophagectomy are at a high risk to pharyngolaryngeal reflux disease (PLRD), PLRD after esophagectomy is still unknown. The aim of this study is to investigate the correlation between reflux pharyngolaryngitis and acid reflux into the hypopharynx and into the cervical esophagus in patients who have undergone cervical esophagogastrostomy. We enrolled 62 patients who received follow-up endoscopy and 24-h pH monitoring after cervical esophagogastrostomy. These included 26 at 1 month after surgery and 36 at 1 year or more after surgery. We investigated: (i) the correlation between the extent of reflux pharyngolaryngitis and that of reflux esophagitis based on endoscopic findings; and (ii) the correlation between the extent of reflux pharyngolaryngitis and that of acid exposure -'% time pH < 4' measured by 24-h pH monitoring - in the hypopharynx and in the cervical esophagus, and of acidity in the gastric conduit. There was no difference in acid exposure between the hypopharynx and the cervical esophagus according to time after surgery. However, the acidity in the gastric conduit was significantly more at one year or more after surgery compared with acidity at 1 month after surgery (P= 0.001). There was a significant correlation between acid exposure in the hypopharynx and that in the cervical esophagus (P < 0.001), although acid exposure in the hypopharynx was significantly less than that in the cervical esophagus (P < 0.001). A significant correlation between reflux pharyngolaryngitis and reflux esophagitis was observed (P < 0.001). There was a significant correlation between reflux pharyngolaryngitis and acid exposure in the hypopharynx (P= 0.021), and also that in the proximal esophagus (P= 0.001). The correlation between the extent of reflux pharyngolaryngitis and the acidity in the gastric conduit was not observed. These findings are consistent with pharyngolaryngitis being caused by gastro-esophago-pharyngolaryngeal reflux in patients after cervical esophagogastrostomy, despite the upper esophageal sphincter strongly preventing acid reflux from the cervical esophagus into the hypopharynx.

Outcomes of multimodality therapy for stage IVB esophageal cancer with distant organ metastasis (M1-Org).

Esophageal cancer patients with distant organ metastasis have usually been treated only to palliate symptoms without multimodality therapy. The current study evaluates the role of multimodality therapy in esophageal squamous cell cancer patients with distant organ metastasis. Between February 1988 and January 2007, 80 esophageal squamous cell cancer patients with distant organ metastases were treated at our institution. Multimodality therapy was performed in 58 patients: 43 patients received chemoradiotherapy, 13 underwent surgery followed by chemotherapy and/or radiation therapy, and two received chemotherapy or chemoradiotherapy followed by surgery. Thirteen patients received single-modality therapy; chemotherapy, radiotherapy, or surgery alone. The remaining nine patients received best supportive care alone. The metastatic organ was the liver (n= 40), the lungs (n= 33), bone (n= 10), and other (n= 6). Nine patients had metastasis in two organs. There was no difference in the median survival among the sites of organ metastasis, lung, liver, or bone (P= 0.8786). The survival of patients treated with multimodality therapy was significantly better than that of the patients who received single-modality therapy or best supportive care alone (P < 0.0001). In patients treated with multimodallity therapy, there was no difference in survival for patients treated with surgery compared with patients treated without surgery (P= 0.1291). This retrospective study involves an inevitable issue of patient selection bias. However, these results suggested that multimodality therapy could improve survival of the esophageal squamous cell cancer patients with distant organ metastasis.

Microtubules with 15 subunits in cockroach epidermal cells.

Since Ledbetter and Porter (1964) described the 13 subunits which are visible in cross sections of negatively stained plant microtubules, subsequent observations have generally confirmed this number. By using Mizuhira's fixative composed of tannic acid and glutaraldehyde, it is easyto demonstrate the subunits of microtublules without optical reinforcement Cytoplasmic microtubules and sperm axonemes, fixed with Mizuhira's fixtive, similarly show 13 subunits (Mizuhira's and Futaesaku, 1971, 1972; Futaesaky et al., 1972; Tilney et al., 1973). This paper will describe a particular type of microtubule in insect epidermal cells fixed with the above fixative. The number of the subunits is found to be 15 in tranverse sections.

Reinvestigation of the fine structure of Reinke's crystal in the human testicular interstitial cell.

Testicular biopsy materials of men were examined with the electron microscope equipped with a tilling stage. An optical transformation method was applied for the electron microscope images. An attempt was made to clarify relationships between the contour and the internal pattern of Reinke's crystal in the interstitial cell. The shape of this crystal is a hexagonal prism. Three types of internal patterns are observed in relation to the main planes of the crystal. The crystal consists of 50-A-thick filaments. It is trigonal, a = 300 A, c = 450 A, being similar to catalase crystals studied by X-ray diffraction and electron microscopy (20), but the dimensions are different. Dislocations of Reinke's crystal are also analyzed. In some interstitial cells without Reinke's crystal, specially arranged 50-A-thick filaments are observed. They are similar in arrangement to the pattern within Reinke's crystal, but not so closely compacted. Morphological similarities and dissimilarities between this crystal and other crystal and crystalloid structures are discussed.

Dacomitinib, a second-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to treat non-small cell lung cancer.

Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4 tyrosine kinase. On September 27, 2018, the United States Food and Drug Administration (FDA) approved dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations. On January 8, 2019, the Ministry of Health, Labour and Welfare of Japan approved this second-generation EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR mutation-positive inoperable or recurrent NSCLC. The European Commission also approved dacomitinib on April 3, 2019, as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Approval of dacomitinib was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050; ClinicalTrials.gov Identifier NCT01774721) which demonstrated the safety and efficacy of dacomitinib compared to gefitinib in 452 patients with unresectable and metastatic NSCLC. Dacomitinib represents a powerful new treatment option compared with first-generation EGFR-TKIs. In this paper, we review the clinical and preclinical studies of dacomitinib and discuss the drug's clinical value.

Role of Rab3 GDP/GTP exchange protein in synaptic vesicle trafficking at the mouse neuromuscular junction.

The Rab3 small G protein family consists of four members, Rab3A, -3B, -3C, and -3D. Of these members, Rab3A regulates Ca(2+)-dependent neurotransmitter release. These small G proteins are activated by Rab3 GDP/GTP exchange protein (Rab3 GEP). To determine the function of Rab3 GEP during neurotransmitter release, we have knocked out Rab3 GEP in mice. Rab3 GEP-/- mice developed normally but died immediately after birth. Embryos at E18.5 showed no evoked action potentials of the diaphragm and gastrocnemius muscles in response to electrical stimulation of the phrenic and sciatic nerves, respectively. In contrast, axonal conduction of the spinal cord and the phrenic nerve was not impaired. Total numbers of synaptic vesicles, especially those docked at the presynaptic plasma membrane, were reduced at the neuromuscular junction approximately 10-fold compared with controls, whereas postsynaptic structures and functions appeared normal. Thus, Rab3 GEP is essential for neurotransmitter release and probably for formation and trafficking of the synaptic vesicles.

Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation.

Amyloid beta (Abeta) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress have been implicated in Abeta-induced neurotoxicity. We have reported that apoptosis signal-regulating kinase 1 (ASK1) is required for ROS- and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Abeta-induced neuronal cell death. Abeta activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1-/- neurons were defective in Abeta-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Abeta-induced neurotoxicity, which plays a central role in Alzheimer's disease.