自噬调节与肿瘤治疗相关的研究进展

目的:总结自噬及其调节机制的文献,探讨自噬与肿瘤的关系和调节自噬在肿瘤治疗中的作用。方法:应用PubMed文献检索系统和中国生物医学文献服务系统(SinoMed),以"自噬、肿瘤形成、耐药和放疗抵抗"为关键词,检索2007-01-2012-03有关自噬的发生和调节及其在肿瘤治疗中作用的文献。纳入标准:1)自噬的过程和调节机制;2)自噬与肿瘤的关系;3)调节自噬与肿瘤治疗。根据纳入标准,符合分析的文献37篇。结果:抑癌基因和自噬相关基因的突变常导致自噬调节障碍,并且与肿瘤形成密切相关。应用自噬抑制剂和基因干扰技术调节自噬使细胞内自噬活动维持在合适的水平,对于肿瘤的预防和提高放、化疗敏感性具有积极的作用。结论:自噬可以作为肿瘤治疗的潜在干预靶点,调节自噬能为肿瘤治疗研究提供新的策略。     

饮食与恶性肿瘤的治疗

饮食调整作为恶性肿瘤常规治疗的补充,正受到越来越多的关注.膳食成分决定了血液中的营养成分,因此也决定了体内细胞微环境中的营养成分.改变肿瘤细胞的代谢环境能够影响其代谢活动、对药物的敏感性及增殖能力,调整饮食可以对恶性肿瘤的进展和治疗产生影响. 1 限制饮食 限制饮食可以提高恶性肿瘤的治疗效果,主要方式包括以下几种.①禁食:间歇性禁食可以预防老年小鼠发生淋巴瘤.在多种肿瘤小鼠异种移植模型中,延长禁食周期联合化疗能够显著改善小鼠对治疗的反应,主要机制可能是降低了胰岛素样生长因子1的表达水平.②葡萄糖:葡萄糖是肿瘤细胞能量合成的原料,并可诱导促癌信号.高葡萄糖有助于恶性肿瘤的发生发展.     

肿瘤与精准营养:未来已来

全球恶性肿瘤发病人数和死亡人数仍呈逐年上升趋势,严重威胁人类健康与生命,造成巨大的疾病负担。 在人口 众多,且老龄化日益加重的中国,这种趋势尤其严重。 肿瘤的预防和治疗已纳入国家卫生健康政策纲要与国民营养计划。 肿 瘤的发生、发展是遗传因素和环境因素等共同作用的结果。 随着科学的发展,已确定了营养水平是影响肿瘤预防与治疗的重 要因素。 精准营养是摒弃“一刀切”的营养方式,根据生活方式、饮食环境暴露、遗传学、微生物学、代谢组学、生物标志物等将 人群分为不同的亚组,形成更科学合理的饮食建议方案或营养干预策略。 肿瘤的发生、发展常伴随着营养的失衡与代谢的紊 乱,因此本文围绕肿瘤与营养的关系,探讨肿瘤与营养代谢组学(包括一碳代谢及其叶酸调控的代谢)的研究进展与发展方 向,以期在未来建立更适合中国人群的肿瘤与精准营养全方位、全生命周期管理标准与指南,最终降低肿瘤的发生率和肿瘤 的疾病负担,提高肿瘤的治疗效果,改善肿瘤患者的生活质量,并提升健康水平。     

抗炎饮食预防肿瘤的专家共识

肿瘤是严重威胁人类生命健康的恶性消耗性疾病,其发生率和死亡率逐年增加。 影响肿瘤发生、发展的因素复 杂,其中饮食作为主要的可预防因素,其潜在作用不容忽视。 饮食具有促炎特性和抗炎特性,不合理的膳食所引起的机体长 期慢性炎症与肿瘤密切相关,并降低了肿瘤的治疗效果。 科学合理的膳食可改善机体慢性炎症状态,改变肿瘤微环境,从而 达到预防肿瘤发生和促进患者康复的作用。 能够客观评估膳食对机体的炎症效应,无论对科学研究还是临床防治都具有积 极意义。 膳食炎症指数(DII)是一种评估个人膳食炎症潜能的新方法,具有客观、方便、可重现的特点,近些年较多研究探索 了 DII 与多种肿瘤的关系。 本共识以 DII 为研究工具,总结了促炎性饮食与各类肿瘤的发病关系,并提出肿瘤防治的抗炎性 膳食模式,从抗炎饮食角度为肿瘤患者提供预防和辅助治疗策略。 提倡科学健康的饮食行为,鼓励居民调整膳食结构,为肿 瘤患者的营养治疗提供新策略。     

细胞自噬在肿瘤中的作用

自噬为一种细胞的自我消耗过程,其具有潜在的抗肿瘤生物学活性,亦与肿瘤耐药有关.该文从自噬的调节机制入手,综述自噬参与肿瘤发生的机制,自噬在肿瘤治疗中的作用及应用,以期为自噬在临床上的应用提供依据.     

《中国恶性肿瘤营养治疗通路专家共识（2018）》解读：外科空肠造瘘

恶性肿瘤患者大多处于营养不良状态，尤其是消化道肿瘤患者。由于上消化道肿瘤患者多伴长期进食受限，肿瘤本身的消耗，加上手术创伤性应激反应以及术后短期内需要禁食，患者全身营养情况将进一步恶化；营养状况的恶化将导致患者围术期并发症增加、住院时间延长，甚至死亡风险增加。因此，对这类患者围术期的营养治疗显得尤为重要。外科空肠造瘘是肠内营养的主要途径之一，它使得上消化道肿瘤患者可以术后早期并长期接受肠内营养，补充患者因进食困难或者长期进食量少所引起的营养不足，从而降低患者术后并发症的发生率及缩短住院时间，提高手术疗效，改善患者临床结局。本文主要从外科空肠造瘘的进展、适应证及并发症等方面介绍目前的研究现状。     

自噬相关基因及信号通路在口腔肿瘤发生发展中的影响

自噬是依赖溶酶体进行的一种高保守的细胞自我保护行为,可作为促进或预防癌症的重要因素。自噬作用与肿瘤的类型及发展程度相关,对自噬途径的了解有助于提高肿瘤的诊断和治疗。研究表明自噬与口腔肿瘤的发生发展密切相关,自噬相关基因及信号通路对口腔肿瘤起着双重调节作用。本文综述了在口腔肿瘤中自噬相关调节机制及治疗作用的最新进展。     

免疫营养在消化道恶性肿瘤放化疗中的应用

在我国,消化道恶性肿瘤的发病率及死亡率一直处于较高水平,手术及放化疗是其主要治疗手段。 50% ~70%的消化 道恶性肿瘤患者由于机体的高代谢及应激反应等出现营养不良风险,对于接受手术或放化疗的老年患者,营养不良风险会进 一步增加。 放化疗引起的厌食、恶心、呕吐及吸收功能障碍等易导致患者体重丢失和营养不良风险增加或出现营养不良,增 加放化疗不良反应风险,导致放化疗疗效降低,甚至治疗中断,从而影响患者的生活质量及预后。 因此,营养治疗对放化疗肿 瘤患者至关重要。 近年来,免疫营养素在临床上被广泛应用于消化道恶性肿瘤患者的营养治疗,已成为肿瘤营养治疗的一个 发展方向。 免疫营养有助于改善消化道恶性肿瘤放化疗患者的免疫功能及炎症水平,增强患者对放化疗的耐受性及敏感性, 提升化疗疗效,提高患者生活质量,延长生存期等,但免疫营养在消化道恶性肿瘤放化疗患者中的作用效果报道不一,仍待深 入研究。 本文就国内外免疫营养在消化道恶性肿瘤放化疗患者中的研究现状进行综述,以探索免疫营养对消化道恶性肿瘤 放化疗患者的理想治疗策略,对于未来改善患者生活质量及疾病转归提供潜在的参考价值。     

糖脂代谢异常对恶性肿瘤影响的研究进展

肿瘤是全球主要的死亡原因之一,其发病率正在逐年上升。糖脂代谢异常可导致多种恶性肿瘤的发病率及死亡率 增加,如乳腺癌、肝癌、胰腺癌、结直肠癌等。糖脂代谢异常导致肿瘤进展的多种机制,包括影响细胞代谢、引起机体炎症与免 疫失调、抑制肿瘤细胞凋亡以及促进肿瘤细胞增殖和转移等,然而尚不清楚导致恶性肿瘤发生、发展的主要原因。此外,糖脂 代谢异常与恶性肿瘤的相互作用限制药物的选择、增加恶性肿瘤化学耐药性、影响手术疗效和患者预后,使恶性肿瘤治疗方案 的制定更具挑战性。二甲双胍与他汀类药物可降低多种肿瘤的风险,但相关的临床前瞻性试验尚无定论。因此,本文对糖脂 代谢紊乱与恶性肿瘤相关的研究进展进行阐述,旨在探讨糖脂代谢异常与恶性肿瘤发生的相关性,以及促进恶性肿瘤生长与 进展的潜在病理生理机制,最后将讨论降糖、降脂策略在治疗恶性肿瘤中的潜在作用。     

肿瘤代谢重编程与营养调节对肿瘤的影响

代谢重编程是肿瘤的重要特征之一,几乎在所有的肿瘤发生、发展过程中都会被观察到。肿瘤细胞通过重编程营养物质的获取和代谢方式,来满足其对能量、生物大分子合成以及维持氧化还原平衡的需求。由于代谢重编程在肿瘤发生和发展中起到重要作用,靶向肿瘤代谢已经成为国际上抗肿瘤药物研发的热点之一。近年来,以限制特定肿瘤代谢过程为目标的营养调节作为一种新的干预手段开始被临床试验所重视,该治疗方法利用限制肿瘤特定营养来实现一系列的生物学效应,在维持正常的细胞、器官和系统功能的前提下,促进肿瘤细胞对化疗药物的敏感性。本文将对肿瘤代谢重编程在近年来的一些重要进展进行总结,也将讨论营养调节治疗的当前进展,综合讨论饮食和代谢干预在肿瘤治疗中的作用,并提供临床前和初步临床试验依据。     

The medically important dematiaceous fungi and their identification

Dematiaceous fungi include a large group of organisms that are darkly pigmented (dark brown, olivaceous, or black). In most cases the pigment is melanin, and specifically, dihydroxynaphthalene melanin. The diseases produced include chromoblastomycosis, eumycotic mycetoma, and phaeohyphomycosis. Phaeohyphomycosis is a new classification for a diverse group of previously known entities grouped together on the basis of finding dematiaceous hyphal and/or yeast-like forms in tissue; tissue involvement may be superficial, cutaneous and corneal, subcutaneous, or systemic. Identification of these fungi is based mostly upon morphology. Important structures include annellides (Phaeoannellomyces, Exophiala), phialides (Phialophora, Wangiella), adelophialides (Phialemonium without collarettes, Lecythophora with collarettes), differentiation of conidiophores (Xylohypha versus Cladosporium) and conidial hilum, septation and germination (Bipolaris, Drechslera, Exserohilum). Useful laboratory tests include the 12% gelatin test (controversial), nitrate assimilation (W. dermatitidis is negative, most other species are positive), and determination of temperature maxima (especially 37 degrees C for E. jeanselmei, 40 degrees C for W. dermatitidis and B. spicifera, 42 degrees C for X. bantiana, and 45 degrees C for Dactylaria constricta var. gallopava and Scedosporium inflatum).     

Laboratory Techniques Alternative to In Vivo Experiments for Studying the Liberation, Penetration and Fungicidal Action of Topical Antimycotic Agents in the Skin, Including Ciclopiroxolamine

Summary: Short-term experiments on excised skin (human, pig) gave the following results: 1. In the tissue activity test with direct inoculation (D-TAT) commercial preparations of the non-azole antimycotics ciclopiroxolamine, tolnaftate and naftifine, produced higher inhibitory activity against Trichophyton mentagrophytes (standard strain) in various levels of the horny layer than were produced by the azole antimycotics econazole, miconazole, clotrimazole, oxiconazole and bifonazole. Fast drying solutions of antimycotics invariably gave higher inhibitory activities than creams. In the ultrafiltration tissue activity test (UFT- TAT) against Candida albicans (2 strains), antimycotic agents ranked in order of effectiveness as follows: ciclopiroxolamine – most of the azole antimycotics – bifonazole and naftifine. 2. In tests of fungicidal activity against T. mentagrophytes (2 strains) and Microsporum gypseum (1 strain) the first step was to inoculate the skin surface. After the horny layer had been penetrated by fungal mycelia, antimycotic agents of documented fungicidal potency, chiefly in the form of creams, were applied to the skin surface and left to act for up to 18 hours. The horny layer and epidermis were then scraped off and the concentration of viable fungi was determined. Ciclopiroxolamine cream and lotion produced by far the greatest diminution in viable fungi; creams containing oxiconazole and naftifine were moderately effective and those containing tioconazole and bifonazole produced a relatively small decrease in viable fungi. To avoid erroneous results it is important to homogenize and dilute the skin scrapings; if this is not done certain antimycotics will give misleadingly high fungal killing rates. At this early stage the scatter of results is still wide and minor differences in efficacy cannot as yet be detected with certainty. 3. From the results of various comparative tests it is evident that pig skin can be used as a substitute for human skin in the tests listed under 1. and 2. above. This discovery may make a valuable contribution towards limiting the need for experiments on living animals and trials on human beings. Zusammenfassung: In Kurzzeitversuchen an exzidierter Haut (Mensch, Schwein) wurde gefunden: 1. Im Gewebeaktivitätstest mit direkter Inokulation (D-GAT) wurde mit Handelspräparaten der Nichtazol-Antimykotika Ciclopiroxolamin, Tolnaftat und Naftifin in verschiedenen Hornschichtniveaus eine höhere Hemmaktivität gegenüber Trichophyton mentagrophytes (Standard-Stamm) erzielt als mit solchen der Azol-Antimykotika Econazol, Miconazol, Clotrimazol, Oxiconazol und Bifonazol. Rasch trocknende Lösungen von Antimykotika ergaben durchweg höhere Hemmaktivitäten als Cremes. Im Ultrafiltrations-Gewebeaktivitätstest (UFT-GAT) gegenüber Candida albicans (2 Stämme) ergab sich nach erzielter Wirksamkeit die Rangfolge Ciclopiroxolamine – Mehrzahl der Azolantimykotika – Bifonazol und Naftifin. 2. In Fungizidie-Testen gegenüber T. mentagrophytes (2 Stämme) und Microsporum gypseum (1 Stamm) wurde zunächst die Hautoberfläche inokuliert. Nach Durchdringung der Hornschicht mit Pilzmyzelien wirkten auf die Hautoberfläche bis zu 18 Stunden lang überwiegend Cremes von als fungizid publizierten Antimykotika ein. Während sich in abgeschabter Hornschicht und Epidermis der so bearbeiteten Hautoberflächen mit Ciclopiroxolamin-Creme und -Lotion die weitaus höchste Verminderung lebensfähiger Keime ergab, bewirkten Cremes mit Oxiconazol und Naftifin eine mittlere und solche mit Tioconazol und Bifonazol eine relativ niedrige Keimeliminierung. Zur Vermeidung von fehlerhaften Ergebuissen mußten Homogenisierung und Verdünnung der Hautschabsel erfolgen, anderenfalls bei mehreren Antimykotika eine zu hohe Keimabtötung vorgetäuscht worden wäre. Wegen der vorerst noch hohen Streuung der Ergebnisse können kleinere Wirksamkeitsunterschiede noch nicht sicher erfaßt werden. 3. Nach dem Ergebnis verschiedener Vergleichstests kann in den Testen zu 1. und 2. Schweinehaut als Ersatz für Haut vom Menschen dienen und dürfte damit wesentlich zur Einschränkung von Versuchen am lebenden Tier und von Prüfungen am Menschen beitragen.     

Efficiency of crude and purified fungal antigens in serodiagnosis to discriminate mycotic from other respiratory diseases

Mycotic immunodiagnosis was performed in 186 hospitalized patients with different respiratory diseases, mostly considered as tuberculosis and others with a doubtful diagnosis. Crude histoplasmin, coccidioidin, paracoccidioidin, blastomycin, candidin, aspergillin, and sporotrichin, as well as purified polysaccharide-protein complexes (PPC) of Histoplasma capsulatum, Coccidioides immitis, and Paracoccidioides brasiliensis were used as antigens. Immune tests used included skin test (ST), gel immunodiffusion (ID), counterimmunoelectrophoresis (CIE), complement fixation (CF), and ELISA. A possible association with candidosis was observed in 17% of patients with tuberculosis and diabetes; one presumptive paracoccidioidomycosis, one confirmed aspergillosis, and six cases of active histoplasmosis were determined. Candidin ST showed 29% of positive reactions with an increased frequency in patients between 31 and 55 years of age. CF test showed the highest positivity percentages with crude antigens, specially for Candida antigen (26.3%) and histoplasmin (18.2%). Cross reactions were evident with crude antigens but decreased when PPC's were used in ELISA.     

Isoconazole nitrate in the treatment of tropical dermatomycoses

Summary. A total of 54 patients with culturally proven tropical dermatomycoses, comprising 23 with various types of dermatophytoses, one with foot infection due to Trichosporon beigelii and one with foot infection due to Geotrichum candidum , two with candidoses of the groin and 27 with pityriasis versicolor, were included in a clinical trial of efficacy of 1% isoconazole cream (Travogen^R, Schering, Berlin, Germany). Five patients were not evaluable. A clinical and mycological cure was achieved in 29 cases in 3–4 weeks. In 15 (31%) of the remaining patients treatment was required for 5–6 weeks, while another three patients required treatment for 8 weeks. In two patients the disease proved to be resistant to treatment with the drug.
Zusammenfassung. Insgesamt 54 Patienten mit kulturell gesicherter Dermatomykose, (23 unterschiedliche Dermatophytosen, eine Trichosporon beigelii - und eine Geotrichum candidum -Fußinfektion, 2 Candidosen der Leistengegend und 27 Pityriasis versicolor) wurden in einer klinischen Wirksamkeits-studie mit 1% iger Isoconazol-Creme (Travogen^R, Schering, Berlin, Deutschland) behandelt. Fünf Patienten waren nicht auswertbar. Eine klinische und mykologische Heilung wurde bei 47 von 49 Patienten (96%) erreicht. Bei 29 patienten (59%) wurde die Heilung bereits nach 3–4 Wochen Behandlung erreicht. Weitere 15 Patienten (31%) benötigten 5–6 Wochen und drei Patienten 8 Wochen Behandlungsdauer. Zwei Mykosesituationen erwiesen sich als therapieresistent.     

Orale Langzeitbehandlung von Onychomykosen mit Ketoconazol

Zusammenfassung: An der Studie zur Wirksamkeit und Anwendungssicherheit von Ketoconazol nahmen 27 Männer im Alter von 20 bis 80 (Median: 57) Jahre, davon 18 mit Onychomykosen und 9 als KontroUen bei den Laborwertbestimmungen, teil. Während des ersten Behandlungsmonats erhielten je 9 Patienten 200 mg und 400 mg Ketoconazol täglich. Danach wurden beide Gruppen 6 Monate mit 200 mg/d weiterbehandelt. Die klinische Beurteilung sowie hämatologische, biochemische und Plasmaspiegeluntersu-chungen erfolgten mindestens monafich, mykologische Untersuchungen wurden vor Aufnahme und bei Beendigung der Therapie vorgenommen. Erne letzte klinische Unter-suchung erfolgte 1 Jahr nach Beginn der Studie. Nach 7 Monaten Behandlung wurden 23 von 30 Nägeln mit “gebessert” bis “stark gebessert” beurteilt, nach dem behandlungsfreien Intervall galt dies für 28 von 30 Nägeln. Die Plasmaspiegel waren mit 200 mg/d ausreichend und uber den Behandlungszeit-raum konstant. Dies spricht für gute orale Resorption und Abwesenheit von Enzyminduktion. Die Laborwerte zeigten im Vergleich zu den Kontrollen und den Werten vor Behandlung keine signifikanten Abweichungen, so daß myelo-, nephro- und hepatotoxische Wirkungen von 400 bzw. 200 mg/d ausgeschlossen werden können. Der Lipidhaushalt wurde nicht beeinfluat und es trat unter Therapie als Folge der Ketoconazolwirkung lediglich Lanosterin im Serum auf. Nach Beendigung der Therapie ging der Lanosteringehalt schnell zurück. Damit erweist sich Ketoconazol in den angewandten Dosen als ein gut verträgliches und zur Langzeitbehandlung von Onychomykosen geeignetes Antimykotikum. Summary: Twenty-seven males with a median age of 57 (range: 20 to 80) years took part in this study on the efficacy and safety of ketoconazole. Eighteen men suffered from onychomycosis; nine served as controls in the safety evaluation. During the first month of treatment, nine patients received 200 mg and the nine other 400 mg ketoconazole daily. Then the treatment was uniformly continued with 200 mg/d for 6 months. Clinical evaluation and haematological, biochemical and plasma level investigations were carried out at least at monthly intervals; mycological controls were performed at the start and end of therapy. A final clinical evaluation was carried out one year after the start of the study. After 7 months of treatment, moderate or definite clinical improvement was obtained in 23 out of 30 nails. After 5 more months without antimycotic treatment this was the case in 28 of 30 nails. Plasma levels obtained with 200 mg ketoconazole daily were adequate and constant during the entire treatment period. This indicates a good oral resorption as well as the absence of induction of hepatic enzymes. The laboratory values did not show significant deviations as compared with the controls or with the pretreatment values. This excludes myelo-, nephro- and hepatotoxic effects of 400 and 200 mg ketoconazole daily. The lipid metabolism was not influenced, the only difference was the occurrence of lanosterol in the serum, which is a result of the mechanism of action of ketoconazole. After the medication period the lanosterol levels subsided rapidly. In the applied doses ketoconazole is a well-tolerated and effective drug for the systemic long-term treatment of onychomycosis.     

Large-scale molecular characterization and analysis of gastric cancer

The recent effort by The Cancer Genome Atlas （TCGA） Network has revealed that gastric cancer, which is a leading cause of cancerrelated deaths worldwide with a 5-year survival rate less than 25%, is a much more heterogeneous disease than previously thought. And yet, conventional treatment approaches and clinical trials have assumed it is a single disease. Although it is well known that under the microscope, gastric cancer cells appear quite different, the current classification scheme recognizes two main categories of gastric cancer： diffuse and intestinal.     

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma''s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.     

Endometrial cancers and predisposition

As nearly 5% of all endometrial cancers occur because of a predisposition, this possibility has systematically to be explored. The hallmarks of predisposition, a young age at diagnosis, a personal or a familial history of cancer, have to be searched systematically. The identification of a predisposition in a family has a major impact on the management of the proband or his relatives. The endometrial cancer main predisposition is Lynch's syndrome. In this review, we will focus on this condition and describe its clinical manifestations, the underlying molecular mechanisms, the cancer risks and the management guidelines. We will also get onto some far less frequent other predispositions.