Enhanced malignant conversion of benign mouse skin tumors by cisplatin

The chemotherapeutic agent cisplatin, reported to be a complete carcinogen in rodents and a tumor initiator for mouse skin, was tested for activity to enhance the conversion of carcinogen-induced skin papillomas to carcinomas. Initiation of mouse skin by 7,12-dimethylbenz[a]anthracene followed by 12 weeks of promotion by 12-O-tetradecanoylphorbol-13-acetate produced seven to eight papillomas/mouse. Ten weekly injections of 100 micrograms of cisplatin into these papilloma-bearing mice induced a 2.3-fold enhancement of conversion relative to the spontaneous rate of 1.9%. Even a single exposure to cisplatin in tumor-bearing mice increased the carcinoma incidence to the same extent as 10 exposures to urethane, an agent previously shown to enhance malignant conversion. At the dose tested, cisplatin was inactive as a complete carcinogen or a tumor promoter. Cisplatin-DNA adducts, measured in samples from skin, liver, and kidneys, were persistent for at least 4 weeks after the last exposure to cisplatin. Thus cisplatin is a relatively potent inducer of the putative genotoxic changes required for conversion of skin tumors from a benign to a malignant phenotype. The activity of cisplatin in the initiation and malignant conversion stages in this animal model for carcinogenesis suggests that patients given cisplatin-based chemotherapy are at increased risk for the development of treatment-induced second cancers.     

猪胸腰段脊髓火器贯通伤后p53基因的早期表达

目的:建立家猪胸腰段脊髓火器贯通伤模型和改良Allen's打击伤后全瘫模型,观察伤后促凋亡基因p53基因的早期表达。方法:实验于2005-05/08在解放军第一七五医院实验室完成。取健康雄性家猪20只,单纯随机分为3组:①火器伤组:9只,在全麻状态下制作胸腰段(L1～L2)脊髓火器伤模型,分为伤后1,3,6h3个时间处死。②打击伤组:9只,L1节段脊髓行改良Allen’s打击,致伤力为500g·cm,处死时间同前。③空白对照组:2只,只麻醉,不造模,伤后6h处死。伤后不同时间点(伤后1,3,6h)和不同节段(伤点、近伤点、中伤点及远伤点)取材,采用SP法进行P53蛋白免疫组化染色,用TJTY-300型全自动图像分析仪测量P53免疫组织化学染色阳性物质吸光度。结果:经补充后20只猪进入结果分析。①脊髓损伤后3h打击伤组伤点,火器伤组近伤段脊髓P53蛋白的表达高于空白对照组(P<0.001),随着时间推移,打击伤组和火器伤组P53蛋白的表达呈升高趋势(P<0.001),且火器伤组要高于打击伤组(P<0.0001)。②在脊髓损伤后6h,打击伤组仅在伤点和近伤段P53蛋白的表达高于空白对照组(5.57±0.82,3.21±0.43,P<0.05),而火器伤组近伤段、中伤段及远段伤均高于空白对照组(6.46±0.66,4.27±0.39,1.16±0.17,P<0.05)。结论:①细胞凋亡基因p53在脊髓损伤中的表达有一定的时空性,在脊髓损伤后3h出现P53蛋白表达量的增加。②脊髓火器伤的波及范围较打击伤更为广泛。     

The Common Cytokine Receptor γ Chain Plays an Essential Role in Regulating Lymphoid Homeostasis

In the immune system, there is a careful regulation not only of lymphoid development and proliferation, but also of the fate of activated and proliferating cells. Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles. Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation. The receptors for each of these cytokines contain the common cytokine receptor γ chain (γ_c), and it was previously shown that γ_c-deficient mice exhibit severely compromised development and responsiveness to IL-2, IL-4, and IL-7. Nevertheless, these mice exhibit an age-dependent accumulation of splenic CD4⁺ T cells, the majority of which have a phenotype typical of memory/activated cells. When γ_c-deficient mice were mated to DO11.10 T cell receptor (TCR) transgenic mice, only the T cells bearing endogenous TCRs had this phenotype, suggesting that its acquisition was TCR dependent. Not only do the CD4⁺ T cells from γ_c-deficient mice exhibit an activated phenotype and greatly enhanced incorporation of bromodeoxyuridine but, consistent with the lack of γ_c-dependent survival signals, they also exhibit an augmented rate of apoptosis. However, because the CD4⁺ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death. Thus, surprisingly, although γ_c-independent signals are sufficient to mediate expansion of CD4⁺ T cells in these mice, γ_c-dependent signals are required to regulate the fate of activated CD4⁺ T cells, underscoring the importance of γ_c-dependent signals in controlling lymphoid homeostasis.     

Mesenteric venous thrombosis in a patient with pancreatitis and protein C deficiency

Mesenteric vein thrombosis is an uncommon manifestation of hypercoagulable states. A case is reported of superior mesenteric vein (SMV) thrombosis in a patient with pancreatitis and protein C deficiency. A discussion of SMV thrombosis identification, management, and outcomes is included. The patient presented with a significant history of alcohol abuse and constant, midepigastric abdominal pain associated with nausea and vomiting. Amylase and lipase were elevated, and the patient was treated for pancreatitis. His symptoms initially responded to intravenous fluid hydration, but soon his clinical picture worsened, with increased nausea and vomiting, abdominal pain, and distension. Contrasted computed tomography of the abdomen revealed SMV thrombosis. A hypercoagulable workup revealed protein C deficiency. After a 3-month course of oral anticoagulant therapy, the SMV thrombosis resolved.     

Function of CD3 epsilon-mediated signals in T cell development

The T cell antigen receptor (TCR) and pre-TCR complexes are composed of multiple signal-transducing subunits (CD3 gamma, CD3 delta, CD3 epsilon, and zeta) that each contain one or more copies of a semiconserved functional motif, the immunoreceptor tyrosine-based activation motif (ITAM). Although biochemical studies indicate that individual TCR-ITAMs may bind selectively or with different affinity to various effector molecules, data from other experiments suggest that at least some ITAMs are functionally equivalent. In this study, we examined the role of CD3straightepsilon ITAM-mediated signals in T cell development by genetically reconstituting CD3 epsilon-deficient mice with transgenes encoding either wild-type or ITAM-mutant (signaling defective) forms of the protein. The results demonstrate that signals transduced by CD3 epsilon are not specifically required for T cell maturation but instead contribute quantitatively to TCR signaling in a manner similar to that previously observed for zeta chain. Unexpectedly, analysis of TCR-transgenic/CD3 epsilon-mutant mice reveals a potential role for CD3 epsilon signals in T cell survival.     

颈椎椎后肌肉组织中肌膜Na^＋-K^＋-ATP酶活性与颈椎病

目的:探讨颈椎椎后肌肉组织Na -K -ATP酶活性变化与颈椎病的关系。资料来源:应用计算机检索PubMed1988-01/2004-12相关骨骼肌损伤与肌组织Na -K -ATP酶关系的文献,检索词“Na -K pump,Na -K -ATPase,muscle”,限定文献语言种类为English。同时计算机检索CNKI1990-01/2005-12相关Na -K -ATP酶与骨骼肌损伤的关系及颈椎病发病病因的文献,检索词“Na -K -ATP酶,骨骼肌,颈椎病病因”,限定文献语言种类为中文。资料选择:对资料进行初审,选取包括Na -K -ATP酶与肌组织损伤关系的文献,开始查找全文。纳入标准:Na -K -ATP酶活性变化与骨骼肌损伤密切相关的文献研究。排除标准:重复研究,Meta分析类文章。资料提炼:共检索到939篇关于Na -K -ATP酶与骨骼肌损伤相关方面的文献,最终纳入20篇符合标准的文献。资料综合:众多研究表明,Na 、K 与骨骼肌的兴奋、收缩、疲劳有密切关系,而Na -K -ATP酶又是调节细胞内外Na 、K 浓度必不可少的高分子蛋白,也就是说,骨骼肌一系列活动均离不开Na -K -ATP酶,Na -K -ATP酶活性变化与骨骼肌损伤是相互影响的。而强迫屈颈体位作为颈椎病发病的危险因素之一,可使颈椎椎后肌肉Na -K -ATP酶活性降低,酶活性降低致使肌细胞损伤,并最终导致骨骼肌损伤而发病。结论:以颈椎椎后肌肉酶活性的变化来阐释中医药对颈椎病确切疗效的相关研究未见,这有待于进一步研究,以充分展示中医药在颈椎病等相关疾病中的治疗优势。     

Specific requirement for CD3ɛ in T cell development

T cell antigen receptor (TCR) and pre-TCR complexes are composed of clonotypic heterodimers in association with dimers of signal transducing invariant subunits (CD3γ, -δ, -, and ζ). The role of individual invariant subunits in T cell development has been investigated by generating gene-specific mutations in mice. Mutation of CD3γ, -δ, or ζ results in an incomplete block in development, characterized by reduced numbers of mature T cells that express low levels of TCR. In contrast, mature T cells are absent from CD3^−/− mice, and thymocyte development is arrested at the early CD4⁻CD8⁻ stage. Although these results suggest that CD3 is essential for pre-TCR and TCR expression/function, their interpretation is complicated by the fact that expression of the CD3γ and CD3δ genes also is reduced in CD3^−/− mice. Thus, it is unclear whether the phenotype of CD3^−/− mice reflects the collective effects of CD3γ, -δ, and - deficiency. By removing the selectable marker (PGK-NEO) from the targeted CD3 gene via Cre/loxP-mediated recombination, we generated mice that lack CD3 yet retain normal expression of the closely linked CD3γ and CD3δ genes. These (CD3^Δ/Δ) mice exhibited an early arrest in T cell development, similar to that of CD3^−/− mice. Moreover, the developmental defect could be rescued by expression of a CD3 transgene. These results identify an essential role for CD3 in T cell development not shared by the CD3γ, CD3δ, or ζ-family proteins and provide further evidence that PGK-NEO can influence the expression of genes in its proximity.     

Surgical downstaging and neo-adjuvant therapy in metastatic colorectal carcinoma with irinotecan drug-eluting beads: a multi-institutional study

Background:

Neoadjuvant chemotherapy for potentially resectable metastatic colorectal cancer (MCC) is becoming a more common treatment algorithm. The aim of the present study was to evaluate the efficacy of precision hepatic arterial Irinotecan therapy in unresectable MCC.

Methods:

An open-label, multi-centre, multi-national single arm study of MCC patients, who received hepatic arterial irinotecan. Primary endpoints were safety, tolerance and metastatic tumour resection.

Results:

Fifty-five patients with metastatic colorectal to the liver underwent a total of 90 hepatic arterial irinotecan treatments. The extent of liver involvement was <25% in 75% of the patients (n= 41), between 26 and 50% in 15% of the patients (n= 11) and >50% in 10% of the patients (n= 24). The median number of hepatic lesions was four (range 1–20), with a median total size of all target lesions of 9 cm (range 5.5–28 cm) with 50% of patients having bilobar tumour distribution. The median number of irinotecan treatments was two (range 1–5). The median treatment dose was 100 mg (range 100–200) with a median total hepatic treatment of 200 mg (range 200–650). The majority of treatments (86%) were performed as lobar infusion treatments, and 30% of patients were treated with concurrent simultaneous chemotherapy. Eleven (20%) patients demonstrated significant response and downstage of their disease or demonstrated stable disease without extra-hepatic disease progression allowing resection, ablation or resection and ablation. There were no post-operative deaths. Post-operative complications morbidity occurred in 18% of patients, with none of them hepatic related. Non-tumorous liver resected demonstrated no evidence of steatohepatitis from the irinotecan arterial infusion.

Conclusions:

Hepatic arterial infusion irinotecan drug-eluting beads is safe and effective in pre-surgical therapy and helpful in evaluating the biology of metastatic colorectal cancer to the liver prior to planned hepatic resection.     

Conservative management of rectal perforation after nerve sparing endoscopic extraperitoneal radical prostatectomy (NS EERPE) in a patient with a past history of polypectomy

Introduction

Rectal polypectomy causes thinning (or even perforation) of the rectal wall in addition to thermic injury at the polypectomy site.

Case report

We present a rare case of spontaneous rectal perforation after uncomplicated nerve sparing endoscopic extraperitoneal radical prostatectomy in a patient with a previous history of rectal polypectomy at the perforation site. The patient could be treated conservatively. There was complete healing of the fistula without any effect on functional results. This Conservative therapy for such rectal perforations is indicated if the patient''s general condition remains stable without any signs of infection.

Conclusions

Polypectomy is an important risk factor for rectal perforation during nsEERPE. Adequate time interval should be given to allow healing and avoid adding further thermal wall damage which may obscure healing leading to complications like fistula. Conservative therapy for small missed rectal perforations constitutes an attractive, feasible and non invasive treatment entity. Following this principle we have not faced this complication in following similar cases.