Influence of L-serine on the Effects of Anticancer Drugs on Esophageal Cancer

食道がんが局所に進行する病変の場合には、術前化学放射線療法などでがんを縮小させてから手術を行うことが一般的である。これまでの研究で、術前化学放射線療法前の食道がん患者において、L-serine の血中濃度が高いと食道がんに対する術前化学放射線療法の治療効果が出にくく、その長期予後も悪い可能性が明らかになっている。そこで本研究では、ヒト食道扁平上皮がん細胞株を用いて、L-serine が食道がんに対して使用される抗がん剤である cisplatin と 5-fluorouracil の効果に及ぼす影響について検討した。その結果、cisplatin や 5-fluorouracil がヒト食道扁平上皮がん細胞株の細胞増殖を阻害することを確認できた。さらに、L-serine 自身がヒト食道扁平上皮がん細胞株の細胞増殖に影響を与えない濃度であっても、cisplatin や 5-fluorouracil の細胞増殖阻害効果を抑制できることを明らかにした。これらの結果は、L-serine の体内レベルが高い場合には、cisplatin や 5-fluorouracil による治療効果が抑制される可能性を示唆している。食道がんに対する化学放射線療法治療の際にL-serine の低減が、その治療効果の向上が期待できるかもしれない。When esophageal cancer progresses locally, it is common to perform surgery after shrinking the cancer with preoperative chemoradiotherapy. Previous studies have shown the possibility that in the patients with esophageal cancer before preoperative chemoradiotherapy, if the blood concentration of L-serine is higher, the therapeutic effects of preoperative chemoradiotherapy against esophageal cancer is not better, and the longterm prognosis is also poor. In this study, we investigated the effects of L-serine on the effects of anticancer drugs cisplatin and 5-fluorouracil against esophageal cancer using human esophageal squamous cell carcinoma cell lines. As a result, we confirmed that cisplatin and 5-fluorouracil can inhibit cell proliferation of human esophageal squamous cell carcinoma cell lines. Furthermore, even at the concentrations where L-serine itself did not affect cell proliferation in human esophageal squamous cell carcinoma cell lines, it could suppress the inhibitory effects of cisplatin and 5-fluorouracil on cell proliferation. These results suggest the possibility that the higher levels of L-serine in the body may lead to suppression of the therapeutic effects of cisplatin and 5-fluorouracil, and reduction of L-serine may be expected to improve these therapeutic effects.departmental bulletin pape

Rikkunshito Ameliorates Cancer Cachexia Partly through Elevation of Glucarate in Plasma

Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient’s morbidity and mortality. We previously showed that rikkunshito (RKT), a Japanese traditional herbal medicine (Kampo), ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ) in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma

Training - A Strategic HRM Function

People are the most important and valuable resources every organization has in the form of its employees. There is a realization that people sub system is a critical dimension in organizational effectiveness. Training is an important and integral part of HRD and is crucial to organizational effectiveness. Many organizations appreciate the value of adequate, consistent and long term investment in such functions. Training helps employees to prepare for change to face the challenges. Training helps individual to acquire competencies necessary to achieve organizational objectives. Every organization wants to prosper and grows. New materials, new products, new systems and techniques and above all new and constantly increasing customer expectations means that people have to learn. Training improves the capability of an organization. So training plays an important role in the effectiveness of people at work. Training has implication for productivity, health and safety at work and personal development

Inhibitory Effects of Glycyrrhetinic Acid on DNA Polymerase and Inflammatory Activities

We investigated the inhibitory effect of three glycyrrhizin derivatives, such as Glycyrrhizin (compound 1), dipotassium glycyrrhizate (compound 2) and glycyrrhetinic acid (compound 3), on the activity of mammalian pols. Among these derivatives, compound 3 was the strongest inhibitor of mammalian pols α, β, κ, and λ, which belong to the B, A, Y, and X families of pols, respectively, whereas compounds 1 and 2 showed moderate inhibition. Among the these derivatives tested, compound 3 displayed strongest suppression of the production of tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in a cell-culture system using mouse macrophages RAW264.7 and peritoneal macrophages derived from mice. Moreover, compound 3 was found to inhibit the action of nuclear factor-κB (NF-κB) in engineered human embryonic kidney (HEK) 293 cells. In addition, compound 3 caused greater reduction of 12-O-tetradecanoylphorbol-13-acetate-(TPA-) induced acute inflammation in mouse ear than compounds 1 and 2. In conclusion, this study has identified compound 3, which is the aglycone of compounds 1 and 2, as a promising anti-inflammatory candidate based on mammalian pol inhibition

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

Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity

Previously, we reported that vitamin K3 (VK3), but not VK1 or VK2 (=MK-4), inhibits the activity of human DNA polymerase γ (pol γ). In this study, we chemically synthesized three intermediate compounds between VK2 and VK3, namely MK-3, MK-2 and MK-1, and investigated the inhibitory effects of all five compounds on the activity of mammalian pols. Among these compounds, MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B, Y and X families of pols, respectively; whereas VK3 was the strongest inhibitor of human pol γ, an A-family pol. MK-2 potently inhibited the activity of all animal species of pol tested, and its inhibitory effect on pol λ activity was the strongest with an IC50 value of 24.6 μM. However, MK-2 did not affect the activity of plant or prokaryotic pols, or that of other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. Because we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these compounds could inhibit inflammatory responses. Among the five compounds tested, MK-2 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear. In addition, in a cell culture system using mouse macrophages, MK-2 displayed the strongest suppression of the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS). Moreover, MK-2 was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of MK-2 in mice led to suppression of TNF-α production in serum. In conclusion, this study has identified VK2 and VK3 intermediates, such as MK-2, that are promising anti-inflammatory candidates

Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence