X-RAY REPAIR CROSS-COMPLEMENTING GROUP 1 （XRCC1） Arg 399 Gin POLYMORPHISM AND AFLATOXIN B1 （AFB1）-RELATED HEPATOCELLULAR CARCINOMA （HCC） IN GUANGXI POPULATION

In Guangxi Zhuang Autonomous Region,Hepatocellular carcinoma(HCC)is one of the maincancer killers,the incidence rate of which is5～40/1,000,000per year.Clinic-epidemiological evidencesuggests AFB1exposure is the most cause[1].However,the exact mechanisms of AFB1hepatocarcinogenesishave not been fully elucidated.Recently,there is agrowing realization that genetic constitution is ofimportance in determining individual’s susceptibility toHCC.This genetic susceptibility may result frominhe…     

双侧原发乳腺癌（附1例）

双侧原发乳腺癌（附１例）苏毅主治医师金理华新疆人民医院肿瘤科（８３０００１）原发双侧乳腺癌较少见，尤其为病理组织类型不同的原发双侧乳癌更为少见。现报告１例如下：患者女，５２岁，发现左乳无痛肿块三个月，右乳无痛肿块一周，于１９９０年３月２７日以＂双侧乳...     

EB病毒潜伏膜蛋白1（LMP1）的研究进展

EB病毒与鼻咽癌、Burkitt's淋巴瘤、传染性单核细胞增多症、霍奇金病和某些因机体免疫力下降而产生的淋巴增生性疾病密切相关,其中EB病毒与鼻咽癌的关系尤为受到重视.EB病毒潜伏膜蛋白1(LMP1)在细胞的恶性转化中起着相当重要的作用,又与鼻咽癌病人的治疗和预后有着密切的关系,本文就EB病毒潜伏膜蛋白1的研究近况与鼻咽癌治疗与预后判断进行综述.     

亨廷顿蛋白相关蛋白1（HAP1）的研究进展

亨廷顿病（huntington’s disease,HD）是一种遗传性神经退化性疾病,其发生癌症的危险性明显低于其一级亲属及一般人群,预示着HD患者体内应该存在某些可以抑制肿瘤发生发展的生物活性物质。近些年来亨廷顿相关蛋白1（huntingtin-associated protein 1,HAP1）因与亨廷顿蛋白相互作用并直接或间接影响了HD的发病机制从而倍受关注,论文就HAP1近些年的研究进展作一概括阐述,以期为预测肿瘤发生发展提供一种功能性分子标志物。     

骨髓增生异常综合征（MDS）1例

骨髓增生异常综合征（ＭＤＳ）１例程远，李瑞红，时瑞兰患者男，１６岁。农民，因无明显诱因出现全身乏力、食欲不振、头晕、牙龈出血入院。既往体健，查体：面色苍白、体温３７．８℃，无出血点及黄染，牙龈未见肿胀，心肺（一），浅表淋巴结无肿大，肝脾未触及，胸骨无...     

乳腺癌易感基因（BRCA1）研究进展

全文就乳腺癌易感基因BRCA1的生物学特性、功能及研究成果作一综述。     

Immunohistochemical expression of prostate tumour overexpressed 1 (PTOV1) in atypical adenomatous hyperplasia (AAH) of the prostate

Background

Prostate tumour overexpressed 1, PTOV1, was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer (PCa). It has been suggested that overexpression of PTOV1 can contribute to the proliferative status of prostate tumour cells and thus to their biological behaviour.

Methods

PTOV1 and Ki67 were immunohistochemically evaluated in PCa, atypical adenomatous hyperplasia (AAH), high-grade prostatic intraepithelial neoplasia (HGPIN), and normal-looking epithelium (NEp) of the transition zone (TZ) in 40 radical prostatectomies with pT2a Gleason score 6 PCa (20 with AAH and 20 with HGPIN) and in 10 simple prostatectomies (SPs) (5 with AAH and 5 with HGPIN). The aim was to evaluate PTOV1 protein expression as a marker for tumor development and progression from AAH to PCa.

Results

The proportions of PTOV1 and Ki67 positive cells increased from NEp through AAH and HGPIN to PCa. In particular, the mean Hscore of PTOV1 expression in AAH was 110.90, i.e., close to three times that of NEp (40.76), similar to that of HGPIN (105.61) and lower than that of PCa (137.03). The mean values in AAH and HGPIN associated with cancer in the RPs were slightly higher than in the SPs.

Conclusion

Our findings related to PTOV1 expression in AAH, similar to those in HGPIN, provide additional evidence linking AAH to prostatic adenocarcinoma.     

CUG-binding protein 1 (CUGBP1) expression and prognosis of non-small cell lung cancer

Background and aims

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. As CUGBP1 may also play a great role in tumor genesis and deterioration, the purpose of this study was to detect the expression of CUGBP1 mRNA and CUGBP1 and assess the prognostic significance of CUGBP1 in NSCLC.

Methods

Expression of CUGBP1 mRNA and CUGBP was detected by Semi-quantitative PCR and Immunohistochemistry, respectively, from 57 NSCLC patients. The percentage of CUGBP1 mRNA and CUGBP1 expression was correlated with clinical characteristics using χ ² test. The prognostic significance was assessed by univariate and multivariate analyses in the Cox hazard model.

Results

The expression of CUGBP1 mRNA and CUGBP1 was over-expressed in cancer group and was correlated with TNM stage and Differentiation. By both univariate and multivariate survival analyses, CUGBP1 expression (P = 0.0074, HR = 3.701, 95 % CI 1.420–9.648), TNM-stage (HR = 4.043, 95 % CI 2.098–7.794) and age (HR = 3.207, 95 % CI 1.544–6.664) were noted to be independent indicators of a shorter postsurgical survival.

Conclusions

The expression of CUGBP1 independently predicted a shorter postsurgical survival in NSCLC.     

The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC)

Background

The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression.

Methods

Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as “% stromal”, and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry.

Results

TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (p = 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (p = 0.0383), but overall survival (OS) showed no significance (p = 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (p = 0.0032, p = 0.0002).

Conclusion

The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.

     

Detection and characterisation of multi-drug resistance protein 1 (MRP-1) in human mitochondria

Background:

Overexpression of plasma membrane multi-drug resistance protein 1 (MRP-1) can lead to multidrug resistance. In this study, we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues.

Methods:

MRP-1 expression and subcellular localisation in normal and cancer cells and tissues was examined by differential centrifugation and western blotting, and immunofluorescence microscopy. Viable mitochondria were isolated and MRP-1 efflux activity measured using the calcein-AM functional assay. MRP-1 expression was increased using retroviral infection and specific overexpression confirmed by RNA array. Cell viability was determined by trypan blue exclusion and annexin V-propidium iodide labelling of cells.

Results:

MRP-1 was detected in the mitochondria of cancer and normal cells and tissues. The efflux activity of mitochondrial MRP-1 was more efficient (55–64%) than that of plasma membrane MRP-1 (11–22% P<0.001). Induced MRP-1 expression resulted in a preferential increase in mitochondrial MRP-1, suggesting selective targeting to this organelle. Treatment with a non-lethal concentration of doxorubicin (0.85 n, 8 h) increased mitochondrial and plasma membrane MRP-1, increasing resistance to MRP-1 substrates. For the first time, we have identified MRP-1 with efflux activity in human mitochondria.

Conclusion:

Mitochondrial MRP-1 may be an exciting new therapeutic target where historically MRP-1 inhibitor strategies have limited clinical success.     

Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1)

Background

Hematologic toxicity represents a major side effect of cytotoxic chemotherapy frequently preventing adequately dosed chemotherapy application and impeding therapeutic success. Transgenic (over)expression of chemotherapy resistance (CTX-R) genes in hematopoietic stem- and progenitor cells represents a potential strategy to overcome this problem. To apply this concept in the context of acute myeloid leukemia and myelodysplasia, we have investigated the overexpression of the multidrug resistance 1 (MDR1) and the cytidine deaminase (CDD) gene conferring resistance to anthracyclines and cytarabine (Ara-C), the two most important drugs in the treatment of these diseases.

Methods

State-of-the-art, third generation, self-inactivating (SIN) lentiviral vectors were utilized to overexpress a human CDD-cDNA and a codon-optimized human MDR1-cDNA corrected for cryptic splice sites from a spleen focus forming virus derived internal promoter. Studies were performed in myeloid 32D cells as well as primary lineage marker negative (lin^?) murine bone marrow cells and flow cytometric analysis of suspension cultures and clonogenic analysis of vector transduced cells following cytotoxic drug challenge were utilized as read outs.

Results

Efficient chemoprotection of CDD and MDR1 transduced hematopoietic 32D as well as primary lin^? cells was proven in the context of Ara-C and anthracycline application. Both, CTX-R transduced 32D as well as primary hematopoietic cells displayed marked resistance at concentrations 5–20 times the LD₅₀ of non-transduced control cells. Moreover, simultaneous CDD/MDR1 gene transfer resulted in similar protection levels even when combined Ara-C anthracycline treatment was applied. Furthermore, significant enrichment of transduced cells was observed upon cytotoxic drug administration.

Conclusions

Our data demonstrate efficient chemoprotection as well as enrichment of transduced cells in hematopoietic cell lines as well as primary murine hematopoietic progenitor cells following Ara-C and/or anthracycline application, arguing for the efficacy as well as feasibility of our approach and warranting further evaluation of this concept.

     

Doxorubicin-induced suppression of poly(ADP-ribose) polymerase-1 (PARP-1) activity and expression and its implication for PARP inhibitors in clinical trials

Purpose

Monozygotic twins provide an excellent tool to study environmental effects on human health. Poly(ADP-ribose) polymerase-1 (PARP-1) is an important enzyme primarily involved in DNA repair and genomic stability and is under clinical investigation as a target for anticancer therapy. As a part of a PARP pharmacogenetics study, elderly male monozygotic twins, one healthy and the other with a Trojani grade 3 sarcoma treated with doxorubicin (DOX: 142.5 mg/m²), were recruited for the study.

Methods

PARP activity and expression were measured in peripheral blood mononuclear cells (PBMCs) by methods validated to GCLP standard and used as a pharmacodynamic endpoint for clinical trials.

Results

The mean PARP activity for the patient before treatment was 160 pmol PAR/10⁶ cells and was similar to that of his brother (130 pmol PAR/10⁶ cells). There was approximately ninefold decrease (P = 0.001) in PARP activity in a second sample from the patient taken 21 days after the first DOX administration (17 pmol PAR/10⁶ cells) and a decrease in PARP-1 expression. Investigations into BALB/C mice revealed that DOX treatment (5 mg/kg) resulted in a significant transient decrease in PARP activity after 1 h (63% control, P ? 0.05) and 24 h (53% control, P ? 0.05) but that PARP activity was restored 1 week after DOX treatment (86% control, P = 0.24).

Conclusions

We showed here that administration of DOX can have a profound effect on the measured level of PARP activity and expression in PBMCs from patients and animals. Results obtained in clinical trials where PARP activity is used as a pharmacodynamic marker of PARP inhibition could reflect the effect of a chemotherapeutic on PBMCs rather than the effectiveness of a tested PARP inhibitor.     

Overexpression of forkhead box protein M1 (FOXM1) plays a critical role in colorectal cancer

Background

The forkhead box M1 (FOXM1), an important regulator of cell differentiation and proliferation, is overexpressed in a number of aggressive human carcinomas. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. The aim of this study was to evaluate the role of FOXM1 in CRC tumorigenesis.

Methods

We investigated FOXM1 expression in 103 cases of primary CRC and matched normal tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on CRC proliferation and metastasis using in vitro models of CRC.

Results

The results showed that high expression of FOXM1 staining was 85.44 % (88/103) in 103 cases of CRC and 20.39 % (21/103) in 103 cases of adjacent non-cancerous tissue samples; the difference of FOXM1 expression between two groups was statistically significant (P < 0.001). Silencing of FOXM1 inhibited the proliferation of CRC cells, and the invasion and migration of CRC cells were distinctly suppressed. Furthermore, FOXM1 knockdown led to substantial reductions in VEGF-A levels in CRC cell lines.

Conclusions

Our data suggest that the pathogenesis of CRC maybe mediated by FOXM1, and FOXM1 could represent selective targets for the molecularly targeted treatments of CRC.

     

Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) in breast cancer - correlation with traditional prognostic factors

Background

Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) play a key role in tumour invasion and metastasis. High levels of both proteolytic enzymes are associated with poor prognosis in breast cancer patients. The purpose of this study was to evaluate the correlation between traditional prognostic factors and uPA and PAI-1 expression in primary tumour of breast cancer patients.

Patients and methods.

606 primary breast cancer patients were enrolled in the prospective study in the Department of gynaecological oncology and breast oncology at the University Medical Centre Maribor between the years 2004 and 2010. We evaluated the traditional prognostic factors (age, menopausal status, tumour size, pathohistological type, histologic grade, lymph node status, lymphovascular invasion and hormone receptor status), together with uPA and PAI-1. We used Spearman’s rank correlation, Mann Whitney U test and χ² test for statistical analysis.

Results

Our findings indicate a positive correlation between uPA and tumour size (p < 0.001), grade (p < 0.001), histological type (p < 0.001), lymphovascular invasion (p = 0.01) and a negative correlation between uPA and hormone receptor status (p < 0.001). They also indicate a positive correlation between PAI-1 and tumour size (p = 0.004), grade (p < 0.001), pathohistological type (p < 0.001) and negative correlation between PAI-1 and hormone receptor status (p = 0.002).

Conclusions

Our study showed a relationship between uPA and PAI-1 and traditional prognostic factors. Their role as prognostic and predictive factors remains to be further evaluated.