Cancer chemotherapy and somatic cell mutation

The occurrence of a second neoplasm is one of the major obstacles in cancer chemotherapy. The elucidation of the genotoxic effects induced by anti-cancer drugs is considered to be helpful in identifying the degree of cancer risk. Numerous investigations on cancer patients after chemotherapy have demonstrated: (i) an increase in the in vivo somatic cell mutant frequency (Mf) at three genetic loci, including hypoxanthine–guanine phosphoribosyl-transferase (hprt), glycophorin A (GPA), and the T-cell receptor (TCR), and (ii) alterations in the mutational spectra of hprt mutants. However, the time required for and the degree of such changes are quite variable among patients even if they have received the same chemotherapy, suggesting the existence of underlying genetic factor(s). Accordingly, some cancer patients prior to chemotherapy as well as patients with cancer-prone syndrome have been found to show an elevated Mf. Based on the information obtained from somatic cell mutation assays, an individualized chemotherapy should be considered in order to minimize the risk of a second neoplasm.     

On the Application of Fuzzy Decision Theory in Chemotherapy

1IntreductionTheliteratUreonmulti-Criteriondecisionmaking(MCDM)problemshas~tremendouslyintherecentpast.TwomajorareashaveevolvedwhiChbothconcentrateondecisionmakingwithseveralcriteria:multiobjectivedecisionmaking(MODM)andmulti-attributedecisionmaking(MADM).TheformerconcentratesoncontinuousdecisionspaceandthelatterfocusesonproblemswithdiscreteSPace.FuzzysettheoryhascontributedtoMODMproblemsaswellastheMADMProblems.ThegeneralMODMproblemcanbedeft.edLllasfollows:Twostagescangenerallybe…     

Treatment of Gaucher disease with an enzyme inhibitor

The hypothesis is offered predicting that Caucher patients could be treated with a drug that slows the synthesis of glucosylceramide, the lipid that accumulates in this disorder. The present therapeutic approach involves augmenting the defective enzyme, glucosylceramide -glucosidase, with exogenous -glucosidase isolated from human tissue. This spectacularly expensive mode of treatment should be replaceable with a suitable enzyme inhibitor that simply slows formation of the lipid and matches the rate of synthesis with the rate of the defective, slowly working -glucosidase. Several drugs that possess this ability are available, the best known of which is 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a designer inhibitor that resembles the synthase's substrate and product. PDMP has been found to be effective in mice, rats, fish, and a wide variety of cultured cells. Its use, at suitable dosages, seems to be harmless, although long-term tests have not been made. The lack of suitable animal models of Gaucher disease has made it difficult to test the hypothesis adequately, but PDMP does rapidly lower the levels of glucosylceramide in normal animal tissues and the animals evidently do well with the lowered levels of glucosylceramide and its more complex glycolipid metabolites.Abbreviations PDMP 1-phenyl-2-decanoylamino-3-morpholino-1-propanol - GlcCer glucosylceramide - i.p. intraperitoneal     

Use of VIRAZOLE® to eradicate odontoglossum ringspot virus from in vitro cultures of Cymbidium Sw.

Odontoglossum Ringspot Virus has been eradicated from Cymbidium Sw. through chemotherapy based on incorporation of ribavirin (VIRAZOLE^®) into the in vitro culture medium of protocorms. Applications of the virustatic agent for several consecutive subcultures freed protocorms of the virus. Acclimated plantlets regenerated from those protocorms are healthy as determinated by enzyme-linked immunosorbent assay (ELISA). No resurgence of virus occurred over a period of 5 years. Besides, trueness to type was total at flowering level and the batch grown was perfectly homogeneous.To secure fast and effective eradication of the virus during the consecutive subcultures of protocorms with ribavirin, three factors proved to be of prime importance: accurate isolation of new growths from initial tissues, VIRAZOLE^® concentration and frequency of transplanting in new media.     

Biochemical characteristics,metabolism, and antitumor activity of several acetylated hexosamines

We have synthesized several potential inhibitors and/or modifiers of the carbohydrate portion of plasma membrane glycoconjugates. These include fluorinated and actylated analogs of D-glucosamine, D-galactosamine, and D-mannosamine. These compounds have been tested to determine their effects on both [¹⁴C] glucosamine and [³H] leucine incorporation into glycoconjugate and on cell growth and viability using P-288 murine lymphoma cells maintained in tissue culture. The most cytotoxic agent tested was 2-acetamido-2-deoxy-1,3,4,6-tetra-O-acetyl-β-D-glucopyranose or simply β-pentaacetylglucosamine which prevented cell growth at 10^?4–10^?3 M. β-Pentaacetylglucosamine cytotoxicity was correlated with its high lipid solubility, having an octanol/water partition coefficient of 0.424 as compared with 0.278 for the β-anomer and 0.017 for N-acetylglucosamine. In vitro metabolism studies with [¹⁴C]-and/or [³H]-labeled pentaacetylglucosamine have indicated intracellular de-O-acetylation leading to the biosynthesis of UDP-N-acetylglucosamine, followed by the incorporation of this sugar into cellular glycoprotein. Concomitant with the formation of increased amounts of this nucleotide sugar, intracellular UTP and CTP pools fell to one third normal within 3 h after the administration of 1 mM pentaacetylglucosamine. At present it is unclear whether the cytotoxicity of β-pentaacetylglucosamine or other similar agents is due to alterations in nucleotide and nucleotide-sugar pools causing a decrease in energy charge and polynucleotide biosynthesis or is due to a direct effect on membrane glycoconjugate biosynthesis.     

The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy.

During the aparasitaemic period following chemotherapy of all three strains of T. brucei infections in mice, successful transmission as shown by subsequent parasitaemia, was regularly achieved following the inoculation of homogenates of brain tissue into recipient mice. Transmission with blood obtained at the same time was consistently negative and in the case of T. brucei TREU 667, homogenates of other organs were non-infective. The implications of this central nervous system involvement are discussed with particular reference to its use as a model for relapsing infections after therapy in man.     

FBXW7 suppresses epithelial‐mesenchymal transition and chemo‐resistance of non‐small‐cell lung cancer cells by targeting snai1 for ubiquitin‐dependent degradation

Objectives

FBXW7 acts as a tumour suppressor by targeting at various oncoproteins for ubiquitin‐mediated degradation. However, the clinical significance and the involving regulatory mechanisms of FBXW7 manipulation of NSCLC regeneration and therapy response are not clear.

Materials and Methods

Immunohistochemical staining and qRT‐PCR were applied to detect FBXW7 and Snai1 expression in 100 samples of NSCLC and matched tumour‐adjacent tissues. FBXW7 manipulation of cancer biological functions were studied by using MTT assay, immunoblotting, flow cytometry, transwells, wound healing assay, and sphere‐formation assays. Immunofluorescence and co‐immunoprecipitation were used to analyse the possible interaction between Snai1 and FBXW7.

Results

We detected the decreased FBXW7 expression in majority of the NSCLC tissues, and lower FBXW7 level was correlated with advanced TNM stage. Furthermore, those patients with decreased FBXW7 expression tend to have both poorer 5‐year survival outcomes, and shorter disease‐free survival, comparing to those with higher FBXW7 levels. Functionally, we found that FBXW7 enforcement suppressed NSCLC progression by inducing cell growth arrest, increasing chemo‐sensitivity and inhibiting Epithelial‐mesenchymal Transition (EMT) progress. Results further showed that FBXW7 could interact with Snai1 directly to degrade its expression through ubiquitylating alternation in NSCLC, which could be partially abrogated by restoring Snai1 expression.

Conclusions

FBXW7 conduction of tumour suppression was partly through degrading Snai1 directly for ubiquitylating regulation in NSCLC

     

益生菌联合抗幽门螺杆菌治疗对消化性溃疡患者的疗效

目的 探讨益生菌联合抗幽门螺杆菌（H. pylori）治疗对消化性溃疡患者的疗效及其对患者肠道菌群的影响。方法 将120例经14C呼气试验（14C-UBT）检测确定为H. pylori感染阳性的消化性溃疡患者随机分为观察组和对照组,每组60例。其中,对照组采用四联疗法（奥美拉唑+阿莫西林+克拉霉素+铋剂）治疗,观察组采用四联疗法联合益生菌治疗;比较两组患者H. pylori根除情况、溃疡愈合质量及不良反应情况。治疗前后留取全部患者的新鲜粪便标本进行细菌培养,比较两组患者肠道菌群数量和肠道微生物定植抗力（B/E值）。结果 观察组患者H. pylori根除率和溃疡愈合率分别为88.3%、95.0%,显著高于对照组的70.0%和76.7%（P＜0.05）,不良反应率为3.3%,显著低于对照组的20.0%（P＜0.05）。与治疗前比,对照组患者治疗后肠道内产气荚膜梭菌、双歧杆菌及乳杆菌数量显著减少（P＜0.05）,肠杆菌、肠球菌及酵母菌数量显著增加（P＜0.05）,B/E值显著降低（P＜0.05）;观察组患者治疗后双歧杆菌和乳杆菌均显著增加（P＜0.05）,产气荚膜梭菌显著减少（P＜0.05）,肠杆菌、肠球菌及酵母菌无明显变化（P＞0.05）,B/E值显著升高（P＜0.05）。结论 常规抗H. pylori治疗易引起消化性溃疡患者肠道菌群紊乱,降低肠道定植抗力。益生菌联合治疗可有效改善患者肠道微生态,提高H. pylori根除率和溃疡愈合质量,减少不良反应。     

Gut microbiome in gastrointestinal cancer: a friend or foe?

The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.     

化疗性静脉炎小鼠模型的建立

目的通过静脉注射盖诺(vinorelbine,VNB)为化疗性静脉炎(chemotherapy induced phlebitis,CIP)研究,提供效果稳定的CIP模型。方法49只成年小鼠随机分为6个实验组和1个对照组。实验组小鼠分别从右侧鼠尾静脉注射不同浓度的等体积VNB溶液,对照组则注射等体积生理盐水。注射后第5天对CIP临床表现进行分级评价后处死。制作石蜡切片并进行镜下分级。结果随注射VNB浓度及剂量的增加,小鼠静脉炎发生率也逐渐增高,但浓度剂量过高动物出现中毒死亡。用3.2mg/ml的VNB按38mg/kg注射组CIP发生率达100%,无动物死亡,出现红斑、水肿、条索状改变等典型CIP临床症状和内皮脱落、炎细胞浸润、组织水肿等CIP镜下改变,对照组未出现类似变化。结论本实验通过鼠尾静脉注射VNB成功建立了小鼠CIP模型。