非亲缘异基因外周血干细胞移植重建白血病幼儿造血功能：1例报告

目的:分析非亲缘异基因外周血干细胞移植治疗幼儿急性非淋巴性白血病的可行性。方法:患儿,男,3岁,于2005-07-18为行造血干细胞移植入本院血液科骨髓移植病房,入院诊断为急性非淋巴细胞性白血病-M5b。经抗肿瘤药物治疗病情获得完全缓解。患儿首先接受清髓性预处理,然后接受同性别非亲缘异基因外周血造血干细胞移植。①移植预处理包括马利兰、阿糖胞苷和环磷酰胺。移植前依次用药为马利兰3.2mg/(kg·d)×4d,口服,于移植前6,7,8,9d给药;阿糖胞苷3.2g/(m2·d)×2d,于移植前4,5d给药;环磷酰胺54mg/(kg·d),于移植前2,3d给药。②急性移植物抗宿主病的预防用药包括环孢菌素A和氨甲蝶呤、抗胸腺细胞球蛋白及吗替麦考酚酯。供者接受粒细胞集落刺激因子动员4d后采集外周血造血干细胞,供、受者间HLA全相合,患者血型A,供者血型B,主次要均不合。结果:①患儿移植后早期获得造血重建,中性粒细胞>0.5×109L-1和血小板>50×109L-1的天数分别是12d和11d。②移植后1个月经DNA短串联重复序列多态性分析证明为供者型完全植入,移植后3个月查骨髓象正常。③移植后3,6个月定期行淋巴细胞亚群检查表明除CD19 ,CD4 细胞未恢复外,自然杀伤细胞在移植后3个月恢复正常,T淋巴细胞CD3 与CD8 、体液免疫球蛋白在移植后6个月中均获得重建。④整个移植过程顺利,未出现明显感染和重度急性移植物抗宿主病。移植后96d时出现Ⅰ度皮肤移植物抗宿主病,经加用激素治疗,皮疹消失。移植术后已随访观察12个月,患儿正常生活。结论:如果患儿有HLA完全相合的供者,非亲缘异基因外周血干细胞移植治疗儿童高危白血病是一种有效和安全的方法,对国内独生子女家庭拓宽供者来源有重要的实用价值。     

P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy

Multidrug-resistant (MDR) myeloma patients failing chemotherapy may express P-glycoprotein (PGP), which serves as an efflux pump protecting the neoplastic cells. Unknown is whether PGP expression might relate to prior cytotoxic drug exposure. To address this question, we studied 106 consecutive bone marrow samples from 104 myeloma patients with samples studied either before or after therapy and at the time of relapse. We performed an established immunocytochemical assay of PGP using an MDR-1- specific monoclonal antibody and correlated PGP status with prior chemotherapy dosage. Myeloma patients with no prior therapy had a low incidence of PGP expression (6%, 3/47), whereas those receiving chemotherapy had a significantly higher incidence (43%, 21/49) (P < .0001). A substantially higher incidence of PGP expression (50%, 83%, respectively) occurred when the total vincristine dose exceeded 20 mg and when doxorubicin exceeded 340 mg. In the 11 patients who received both high vincristine and doxorubicin dosages (> 20 mg, > 340 mg total dose) there was 100% incidence of PGP expression in the tumor cells. These data provided the basis for a predictive mathematical model from which dose-related PGP expression normograms were generated. Time with myeloma for PGP-negative patients (mean 33 months) had overlapping confidence limits with PGP-positive patients (mean 42 months), suggesting that disease duration was not a significant variable. PGP expression did not correlate with other clinical factors or immunophenotypic factors. Our findings indicate a strong correlation between PGP expression in myeloma and past chemotherapy in myeloma, in particular, related to prior exposure to the natural product agents vincristine and doxorubicin. Additionally, the proportion of PGP- positive plasma cells was significantly higher in the doxorubicin- treated patients than the nondoxorubicin-treated patients (87.7% v 65.17%; P = .013). Combined high vincristine and doxorubicin total dosage appear highly predictive of PGP expression.     

BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents

A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.     

Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis

A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (PCa), and loss of DAB2IP expression is frequently detected in metastatic PCa. However, the functional role of DAB2IP in PCa remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate-cancer specimens. Conversely, restoring DAB2IP in metastatic PCa cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear β-catenin/T-cell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for PCa metastasis.Prostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men (1). In the absence of metastasis, prostate cancer is largely a treatable disease. Thus, early diagnosis of patients who will develop PCa metastasis could reduce the mortality and morbidity associated with this disease. The development of metastasis depends on the migration and invasion of cancer cells from the primary tumor into the surrounding tissue. To acquire such invasive abilities, carcinoma cells may acquire unique phenotypic changes such as epithelial-to-mesenchymal transition (EMT). EMT is a highly conserved cellular process that allows polarized, generally immotile epithelial cells to convert to motile mesenchymal-appearing cells. This process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis (2 –4). During EMT, three major changes occur: (i) morphological changes from a cobblestone-like monolayer of epithelial cells to dispersed, spindle-shaped mesenchymal cells with migratory protrusions; (ii) changes of differentiation markers from cell–cell junction proteins and cytokeratin intermediate filaments to vimentin filaments and fibronectin; and (iii) acquisition of invasiveness through the extracellular matrix (4). Decreased E-cadherin expression or gain of vimentin expression is closely correlated with various indices of PCa progression, including grade, local invasiveness, dissemination into the blood, and tumor relapse after radiotherapy (5 –8).A recent study using genome-wide association data reveals that a single nucleotide polymorphism probe located in the first intron of DAB2IP gene associates with the risk of aggressive PCa (9). The functional role of DAB2IP in PCa is poorly understood. DAB2IP, also known as ASK1-interacting protein-1 (AIP1), a novel member of the Ras GTPase-activating protein family, has been implicated in cell-growth inhibition and apoptosis (10, 11). DAB2IP is down-regulated in various human cancers mainly because of altered epigenetic regulation of its promoter, such as by DNA hypermethylation and/or histone modification (12 –17). Thus, it is very likely that DAB2IP functions as a tumor suppressor in cancer development; however, its role and mechanism in cancer metastasis is largely unknown. In the current study, we show that loss of DAB2IP facilitates EMT leading to PCa metastasis.     

Ilizarov principles of deformity correction

Ilizarov frames provide a versatile fixation system for the management of bony deformities, fractures and their complications. The frames give stability, soft tissue preservation, adjustability and functionality allowing bone to realise its full osteogenic potential. It is important that we have a clear and concise understanding of the Ilizarov principles of deformity correction to best make use of this fixation system. In this review article, the history of Ilizarov frame, the basic sciences behind it, the mechanical principles governing its use and the clinical use of the fixation system are discussed.     

Treatment of pregnancy-related pelvic girdle and/or low back pain after delivery design of a randomized clinical trial within a comprehensive prognostic cohort study [ISRCTN08477490]

Background  

Pregnancy-related pelvic girdle and/or low back pain is a controversial syndrome because insight in etiology and prognosis is lacking. The controversy relates to factors eliciting pain and some prognostic factors such as the interpretation of pain at the symphysis. Recent research about treatment strategies also reflects those various opinions, in fact suggesting there is professional uncertainty about the optimal approach. Currently, physiotherapists often prescribe a pain-contingent treatment regime of relative rest and avoiding several day-to-day activities. Additionally, treatment more often includes an exercise program to guide rectification of the muscle imbalance and alignment of the pelvic girdle. Effectiveness of those interventions is not proven and the majority of the studies are methodologically flawed. Investigators draw particular attention to biomedical factors but there is growing evidence that important prognostic issues such as biopsychosocial factors appear to be even more important as point of action in a treatment program.     

A phase I study of Topotecan, as a radiosensitizer, for thoracic malignancies

PURPOSE: To determine the maximum-tolerated dose (MTD) of daily Topotecan with full-dose thoracic radiotherapy (XRT). METHODS AND MATERIALS: Patients with advanced thoracic malignancies requiring full dose radiation received daily I.V. Topotecan prior to each daily session of XRT to 60 Gy over 6 weeks. Dose levels (and subjects studied at each) have been 0.2 (N=7), 0.3 (N=5), 0.4 (N=7), and 0.5mg/m(2) per day (N=5) in a best-of-five design. Tumor response was assessed at 4-8 weeks after completion of therapy. RESULTS: From March 1995 to December 1999, a total of 24 patients were treated. The MTD of Topotecan was 0.4 mg/m(2) per day, based on dose limiting toxicities (DLTs) observed at 0.5 mg/m(2) per day, which were grade 4 hematological toxicities or diarrhea and grade 3 esophagitis. Tumor responses included: zero complete response (CR), nine partial responses (PR), five stable disease (SD), nine progressive disease (PD) and one not evaluated (NE). Additionally, local response was also assessed separately (within the XRT ports) and there were 10 PR, 12 SD, 1 PD, and 1 NE. CONCLUSION: the MTD of Topotecan with concomitant thoracic radiotherapy is 0.4 mg/m(2) per day. The DLTs observed were grade 4 diarrhea, grade 3 esophagitis and grade 4 hematological toxicities. Based on the known radiosensitizing effect of Topotecan, this dose is recommended for phase II testing.     

Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1

NAD(P)H:quinone oxidoreductase (NQO1) is elevated in human pancreatic cancers. We hypothesized that beta-lapachone, a novel 1,2-naphthoquinone with potential antitumor activity in cancer cells expressing elevated levels of NQO1, would induce cytotoxicity in pancreatic cancer cells, wherein this two-electron reductase was recently found elevated. beta-lapachone decreased clonogenic cell survival, metabolic cell viability, and anchorage- independent growth in soft agar. The cytotoxic in vitro effects of beta-lapachone were inhibited with coadministration of dicumarol, a specific inhibitor of NQO1. In preestablished human pancreatic tumor xenografts in nude mice, beta-lapachone demonstrated greater tumor growth inhibition when given intratumorally compared to when complexed with cyclodextrin to increase its bioavailability. Due to the poor prognosis of patients with pancreatic cancer and the limited effectiveness of surgery, chemotherapy, and radiation therapy, treatment regimens based on sound, tumor-specific rationales are desperately need for this disease.