ダエキセン センボウ サイボウ ニオケル matrix metalloproteinase-9 ヨクセイ ト ドウカン サイボウ ニオケル aquaporin-5 ユウドウ キコウ : シェーグレン ショウコウグン ダエキセン スイブンピツ キノウ ノ サイセイ

Our previous in vitro study suggested that the suppression by cepharanthin of tumor necrosis factor (TNF)-α-induced matrix metalloproteinase (MMP)-9 could prevent the destruction of the acinar structure in Sjogren's syndrome (SS) salivary glands. In this study, we demonstrated that the in vivo administration of cepharanthin resulted in the prevention of severe damage to acinar tissues in the murine model of human SS. Cepharanthin was intraperitoneally administered five times a week at a dose of 0, 10, or 100μg/mouse to 4 to 10 week-old thymectomized female NFS/sld mice. Mononuclear cell infiltrates and the destruction of acinar tissue in the salivary and lacrimal glands were extensively observed in the control mice ; however, in the mice treated with cepharanthin for 6 weeks, both a significant decrease in the mononuclear cell infiltrates and an improvement of the severe damage to the acinar tissues were evident in the salivary and lacrimal glands. Immunohistochemical analysis revealed that phosphorylated IκB-α and MMP-9 were more strongly stained in the acinar cells of the control mice than in those of the cepharanthin-treated mice. In addition, although the lack of staining for type IV collagen was partially observed in the acinar tissues of the control mice, the continuity of type IV collagen was detected in the acinar tissues of the cepharanthin-treated mice. According to the results of a TUNEL analysis, the destruction of acinar tissues was attributed to the induction of apoptosis, suggesting that cepharanthin inhibits apoptosis by suppressing phosphorylation of IκB-α, followed by the prevention of MMP-9 activation. Our findings suggest that cepharanthin may be a promising agent for use in preventing the destruction of acinar tissues in murine SS. Moreover, to investigate the possibility that salivary gland cells, especially ductal cells, surviving in the salivary gland tissues of SS could acquire the functional expression of membrane water channel aquaporin-5 (AQP5), because ductal cells, but not acinar cells, preferentially survive and/or proliferate in SS salivary glands. Thus, in this study, we demonstrate that an immortalized normal human salivary gland ductal cell (NS-SV-DC) line, lacking the expression of AQP5, acquires AQP5 gene expression in response to treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA demethylating agent. Confocal microscopic analysis revealed the localization of AQP5 expression mainly at the apical and lateral sides of the plasma membrane. The expressed AQP5 protein was functionally active because AQP5 expression resulted in a significant increase in the osmotically directed net fluid rate across monolayers of NS-SV-DC cells. By the analysis of bisulfite sequencing of CpG islands in the AQP5 promoter, hypermethylation within the consensus Sp1-binding sites was commonly observed in parental cell clones, whereas demethylation at the CGs, one in the second consensus Sp1 element and the other outside of the third consensus Sp1 element in the AQP5 promoter, was detected in NS-SV-DC cells after treatment with 5-Aza-CdR. By analyzing the luciferase activity of transfected AQP5 promoter vectors, it became evident that demethylation at the CGs cooperatively functions between these two sites to induce AQP5 expression. Our data, therefore, suggest that treatment of ductal cells with 5-Aza-CdR could result in the expression of the AQP5 gene, thereby leading to increased fluid secretion from ductal cells in SS salivary glands

Cerebral Glycogen Distribution and Aging

In the brain, glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated cerebral glycogen of the mouse by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well‐defined glycogen immunoreactive signals compared with the conventional periodic acid‐Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity (IR) was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was low in the white matter and most of the subcortical structures. Additionally, glycogen distribution in the hippocampal CA3‐CA1 and striatum had a ‘patchy’ appearance with glycogen‐rich and glycogen‐poor astrocytes appearing in alternation. The glycogen patches were more evident with large‐molecule glycogen in young adult mice but they were hardly observable in aged mice (1–2 years old). Our results reveal brain region‐dependent glycogen accumulation and possibly metabolic heterogeneity of astrocytes

Self-Organized Synchronous Calcium Transients in a Cultured Human Neural Network Derived from Cerebral Organoids

The cerebrum is a major center for brain function, and its activity is derived from the assembly of activated cells in neural networks. It is currently difficult to study complex human cerebral neuronal network activity. Here, using cerebral organoids, we report self-organized and complex human neural network activities that include synchronized and non-synchronized patterns. Self-organized neuronal network formation was observed following a dissociation culture of human embryonic stem cell-derived cerebral organoids. The spontaneous individual and synchronized activity of the network was measured via calcium imaging, and subsequent analysis enabled the examination of detailed cell activity patterns, providing simultaneous raster plots, cluster analyses, and cell distribution data. Finally, we demonstrated the feasibility of our system to assess drug-inducible dynamic changes of the network activity. The comprehensive functional analysis of human neuronal networks using this system may offer a powerful tool to access human brain function

Therapeutic Value of Lymph Node Dissection Along the Superior Mesenteric Vein and the Posterior Surface of the Pancreatic Head in Gastric Cancer Located in theLower Third of the Stomach

【Background】 Therapeutic value of lymph node dissection along the superior mesenteric vein (14v) and the posterior surface of the pancreatic head (13) remains unclear in gastric cancer patients. 【Methods】 We reviewed 355 patients with advanced gastric cancer in the lower third of the stomach who had undergone gastrectomy at our hospital. 【Results】 The frequency of lymph node (LN) metastasis was 10.2% and 7.4% in stations 13 and 14v, respectively. The frequency of station 13 metastasis was 26.8% for T3/T4 tumors with group 2 LNs metastasis and 1.4% for all other tumors. The frequency of station 14v metastasis was 22.2% for T3/T4 tumors with group 2 LNs metastasis and 1.8% for all other tumors. The therapeutic values for dissecting LN stations 13 and 14v were 1.9 and 0.9, respectively, similar to the therapeutic value for group 2 LN dissection. 【Conclusion】 Because metastasis to stations 13 and 14v occurs frequently in patients with T3/T4 gastric cancer located in the lower third of the stomach who also have metastasis to group 2 LNs, stations 13 and 14v should be dissected in these patients

Postoperative Serum Albumin is a Potential Prognostic Factor for Older Patients with Gastric Cancer

【Background】 The incidence of gastric cancer (GC) among older adults is increasing. Therefore, determining postoperative age-associated prognostic factors is clinically important. This study retrospectively investigated the prognostic significance of serum albumin level in older GC patients. 【Methods】 We enrolled 135 patients aged ? 75 years, who underwent gastrectomies with histopathological diagnoses of gastric adenocarcinoma. 【Results】 Preoperative albumin (pre-Alb) levels in patients with advanced GC and stage III/IV GC were significantly lower than those in patients with early GC (P = 0.0032) and stage I/II GC (P = 0.006), respectively. Postoperative albumin (post-Alb) levels (measured 1 month after surgery) in male patients and in patients with advanced GC were significantly lower than those in female patients (P = 0.024) and those with early GC (P = 0.044), respectively. Post-Alb levels of patients who died of other diseases were significantly lower than those who were still living (P = 0.0004). Prognosis of patients with high post-Alb levels (? 4g/dL) was significantly better than that of patients with low post-Alb levels (< 4g/dL; P = 0.045); and in multivariate analysis, post-Alb level was an independent prognostic indicator. 【Conclusion】 Post-Alb level is a useful predictive factor for the prognosis of older GC patients. Postoperative nutritional support might help improve the prognosis of older GC patients

Variant Spectrum of von Hippel-Lindau Disease and Its Genomic Heterogeneity in Japan

Von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80-90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one novel variant). The deleterious variants were significantly enriched in VHL disease Type 1. Interestingly, five synonymous or non-synonymous variants within exon 2 caused exon 2 skipping, which is the first report of exon 2 skipping caused by several missense variants. Whole genome and target deep sequencing analysis were performed for 22 unsolved cases with no variant identified and found three cases with VHL mosaicism (variant allele frequency: 2.5-22%), one with mobile element insertion in the VHL promoter region, and two with a pathogenic variant of BAP1 or SDHB. The variants associated with VHL disease are heterogeneous, and for more accuracy of the genetic diagnosis of VHL disease, comprehensive genome and DNA/RNA analyses are required to detect VHL mosaicism, complicated structure variants and other related gene variants

Etude système de diodes lasers à verrouillage de modes pour la radio-sur-fibre en bande millimétrique

Ce travail de thèse s inscrit dans la recherche des solutions économiquementviables pour des réseaux personnels à hauts débits (plusieurs Gbps à plusieursdizaines de Gbps) opérationnels en bande millimétrique autour de 60 GHz. Aucas où ces réseaux servent un nombre élevé d utilisateurs, ils comprendront unemultitude d antennes afin d assurer l accès sans fil rapide. Afin de réduire aumaximum le coût d un module d antenne, les réseaux doivent fournir un signalanalogue à des porteuses millimetriques. Une solution prometteuse pour les systèmesde distribution qui correspond à ces besoins sont des structures à fibreoptique, laquelle permet une transmission à faibles pertes et à haute bande passante.On parle de l approche "radio-sur-fibre" (en anglais, radio-over-fiber). Laproblématique est de pouvoir générer et moduler un signal aux fréquences millimétriqueslors de la transmission optique - et ce avec des composant bas coûts.La technique utilisée dans le cadre de cette thèse est l emploi des diodes laser àverrouillage de modes. Ces derniers vont pouvoir générer des hautes fréquencestout en ne nécessitant qu une alimentation continue, et ils peuvent être modulésde manière directe ou externe. Les lasers à semi-conducteurs employés ici sontd une génération encore à l état d étude puisqu il s agit des lasers à boites (ouîlots) quantiques. Ces lasers ont montrés de très bonnes capacités à générer dessignaux électriques aux fréquences autour de 60 GHz, bien qu ayant encore, pourl instant, à une stabilité de fréquence (ou de phase) limitée. Dans le cadre des systèmesde communication opto/micro-ondes, peu de travaux approfondis ont étémenés sur ces structures.Au cours de cette thèse, plusieurs études ont été effectuées. La première portesur les propriétés générales d un système construit à partir de ce type de laser(puissances disponibles, figure de bruit, linéarité etc.). Une deuxième étude aété consacrée aux effets de la propagation des signaux dans les systèmes baséssur les lasers à verrouillage de modes, notamment de la dispersion chromatiquelaquelle a un effet considérable sur les distances de transmission. Les deux étudesmettent en avant l importance d une limitation du nombre de modes générés parla diode laser afin d optimiser non seulement le gain du lien et la puissance RFrécupérée, mais aussi la figure de bruit du système. Lors d une troisième étude, lastabilité en fréquence/phase s est révélée critique, car le bruit de fréquence/phaselimite la qualité de la transmission en introduisant un plancher d erreur mêmepour des rapports signal-a-bruit très élevés. Des différentes générations de lasersà boites (îlots) quantiques et à verrouillage de modes ont été testées. Le problèmedu bruit de fréquence et de phase persiste et ne peut pas être résolu en utilisantles techniques classiques comme les boucles à verrouillage de phase conventionnelles.Une solution pour ce problème a été développée pour les systèmes detransmission; elle permet simultanément un ajustement de fréquence supérieure(précision de quelques Hz à quelques kHz) à celle donnée par le processus de fabricationdes diodes lasers (précision de quelques GHz), ainsi qu une stabilisationde fréquence et de phase.This dissertation is related to the search for an economically sustainable solutionfor high data rate (several Gbps to several tens of Gbps) personal area networksoperating in the millimeter-wave region around 60 GHz. If such networks supplya large number of users, they need to encompass a multitude of antenna pointsin order to assure wireless access to the network. With the aim of reducing thecost of an antenna module, the networks should at best provide quasi "readyto-radiate" signals to the modules, i.e. at millimeter-wave carrier frequencies.Thanks to their low transmission loss and their high bandwidth, optical fiber distributionarchitectures represent a promising solution. The technique is referredto as the so-called "radio-over-fiber" approach whereby the analog radio signalwill be transported to the access point by an optical wave. The challenge herebyis the generation and modulation of an optical signal by a millimeter-wave radiosignal using preferably cost-efficient system components. The technique proposedherein is based on the use of mode-locked laser diodes which can generatesignals at very high frequencies under the condition of continuous current supply.Mode-locked laser diodes can be modulated both directly and externally. Thediodes employed in this work are based on so-called quantum dots (or quantumdashes); these are material structures which are themselves still subject to intensivephysical research. Signals at millimeter-wave frequencies (around 60 GHz)can easily be generated by such lasers. However, their frequency and phase stabilityis as yet limited. In the context of radio-over-fiber communication systems,these structures have not yet been studied in detail.In the course of this dissertation, several aspects are considered. A first systemstudy treats the basic properties of a system built from this type of laser source(available signal power, system noise figure, linearity etc.). A second study isdevoted to an investigation of propagation effects like dispersion, which considerablyinfluence the attainable transmission distances. An essential result of bothstudies is the importance of limiting the laser spectrum to a small number of lasermodes for an optimization of link gain, generated RF power, and system noisefigure. A third study deals with the limited frequency and phase stability whichturn out to be critical factors for transmission quality. The study of several generationsof quantum dot/dash lasers has revealed that the problems of frequencyand phase noise persist and cannot be solved using classical techniques involvinge.g. conventional phase-locked loops. In this dissertation, a solution is presentedwhich not only allows a more precise adjustment of the laser frequency (precisionin the order of Hz to kHz) than that given by the manufacturing process of thelaser (precision in the order of GHz), but also enables a stabilization of frequencyand phase.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Carcinosarcoma of Stomach Confined to the Mucosa

Carcinosarcoma is a malignant tumor composed of both epithelial and mesenchymal malignant tumor components. A 78-year-old man was transferred to our hospital because of hematemesis and tarry stool. An emergency gastrointestinal endoscopic examination revealed active bleeding from an ulcerative lesion on the posterior wall of the gastric body; endoscopic hemostasis was successfully performed. A gastrointestinal endoscopy performed two months later showed a polypoid lesion at the same place where the ulcer had been. The biopsy specimen was histologically diagnosed as well to moderately differentiated tubular adenocarcinoma. The patient underwent a laparoscopic distal gastrectomy with D2 lymph node dissection under a diagnosis of gastric adenocarcinoma. A 28 × 15 mm polypoid tumor was resected from the gastric body, and was found on microscopic examination to consist of both carcinoma and sarcoma components, showing atypical spindle cells, which were positive for α-smooth muscular actin, calponin, and h-caldesmon, but negative for CD34, CD117 (c-kit), desmin, and dog 1. These findings led to a diagnosis of gastric carcinosarcoma. The tumor was confined to the mucous membrane. Lymph node metastasis was found in one node and contained only the carcinoma component. The postoperative course was uneventful. The patient lived without recurrence for 2 years. Carcinosarcoma of the stomach is a rare tumor with high malignant potential and poor prognosis. Careful follow up is required for early detection of any recurrence

Less Invasive Surgery for Remnant Stomach Cancer After Esophago-proximal Gastrectomy with ICG-guided Blood Flow Evaluation : A Case Report

The standard procedure for remnant gastric cancer after esophago-proximal gastrectomy is total resection of the remnant stomach considering blood supply. However, sometimes surgery may be too invasive due to severe adhesion in the thoracic and mediastinal cavity. The blood supply to the remnant stomach depends on the right gastroepiploic artery and the right gastric artery. Therefore, preservation of the proximal region of the remnant stomach is thought to be anatomically impossible. We report a case of remnant gastric cancer that developed more than 12 years after lower thoracic esophagectomy plus proximal gastrectomy for Siewert Type I squamous cell carcinoma. We used intra-operative indocyanine green (ICG) venous-injection to evaluate blood flow and distal gastrectomy of the remnant stomach was performed by preserving the proximal stomach in the thoracic cavity through an abdominal approach. There were no complications of the remnant stomach or the anastomosis to the jejunum after surgery. In this case, we focused on the blood supply by collateral circulation through the anastomotic line from the remnant esophagus. After confirming blood supply with intra-operative evaluation using ICG fluorescence, less-invasive distal gastrectomy was successfully performed. As the intra-operative ICGbased evaluation for blood supply is a simple and safe method, it might be useful for determining the resection margin of various organs and be effective for the introduction of less invasive surgery. Here, we report a case and a review of the literature