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The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a critical component of the Hedgehog (Hh) signalling pathway, which is essential for morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As data were not available on the role of Gli-1 expression in oesophageal cancer progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was further correlated with the absence of both Gli-1 nuclear expression and residual tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-node metastasis, and six out of seven died within 13 months. Furthermore, patients with Gli-1 nuclear-positive cancers showed significantly poorer prognoses than those without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS 0 vs 54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%, P=0.001). Our study provides the first evidence that Gli-1 nuclear expression is a strong and independent predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT. [ABSTRACT FROM AUTHOR]

Abstract: A new method for estimating reactivity parameters, such as moderator temperature coefficient (MTC) and void reactivity coefficient (VRC), is proposed using steady-state noise data. In order to solve the ill-posed problem of reactivity parameter estimation, a concept of a gray box model is newly introduced. The gray box model includes a first principle based model and a black-box fitting model. The former model acts as a priori knowledge based constraints in a parameter estimation problem. After establishing the gray box and noise source models, the maximum likelihood estimation method based on Kalman filter is applied. Furthermore, it is shown that the frequency domain approach of the gray box model is useful in the case of VRC estimation. The effectiveness of the proposed algorithms is shown through numerical simulation and actual plant data analysis. [Copyright &y& Elsevier]

We examined the expression of the midkine (MK) and a-fetoprotein (AFP) genes in 15 paired human specimens obtained from hepatocellular carcinoma (HCC) and the corresponding noncancerous regions of the same patients. A total of 14 HCC but none of the noncancerous specimens were positive for the MK mRNA. In contrast, three HCC specimens and one corresponding noncancerous sample out of the three AFP-positive HCC cases expressed the AFP gene. A 2.3-kb genomic fragment in the regulatory region of the MK gene could activate a fused reporter gene in both AFP-producing and -nonproducing HCC lines, and the MK fragment-mediated transcriptional activity was comparable to the AFP enhancer-linked AFP promoter in AFP-producing cell lines. The AFP-producing but not AFP-nonproducing HCC cell lines that were transfected with the MK promoter-linked herpes simplex virus-thymidine kinase (HSV-TK) gene became susceptible to a prodrug ganciclovir to a similar degree of the HCC transfected with the enhancer-linked AFP promoter-fused HSV-TK gene. These data suggest that the MK promoter can activate a therapeutic gene preferentially in HCC and is as useful as the AFP promoter in clinical settings.British Journal of Cancer (2003) 89, 1086-1090. doi:10.1038/sj.bjc.6601246 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Suicide gene therapy using ganciclovir (GCV) with transfection of the herpes thymidine kinase (HSVtk) gene has been studied for cancer therapy. The present study demonstrates an efficient method of suicide gene therapy for multiple hepatic tumors, involving repetitive transfection of the HSVtk gene driven by the alpha-fetoprotein (AFP) promoter using hemagglutinating virus of Japan (HVJ)-liposomes. AFP-producing cells (HUH7) and AFP-nonproducing cells (LS180) were injected subcutaneously (s.c.) to establish tumors in nude mice. Two plasmid constructs, bacterial LacZ gene driven by the AFP promoter (AFPLacZ), and HSVtk gene driven by the AFP promoter (AFPTK1) were encapsulated into the HVJ-liposome and used. When AFPLacZ was injected into the s.c. tumors, expression of LacZ gene was confined to HUH7 tumors. Repeated transfection of AFPTK1 followed by GCV treatment markedly suppressed growth of HUH7 tumors, and apoptosis of HUH7 cells was recognized in the tumor. Next, HUH7 cells were injected into the portal vein in severe combined immunodeficiency mice to establish a hepatic tumor model. After inoculation with the tumor, HVJliposomes containing the AFPTK1 plasmid vector were injected into the portal vein via the splenic hilum, followed by GCV treatment. This gene therapy significantly inhibited the growth of tumors in the liver and markedly improved survival. Three injections of the AFPTK1 plasmid vector completely inhibited tumor growth. This procedure seems to have great potential for the treatment of multiple hepatic tumors. [ABSTRACT FROM AUTHOR]

The retinoblastoma gene, RB, participates in the regulation of the G1/S-phase transition and in p53-mediated apoptosis. We have previously reported that stably transfected RB functions as a growth and tumour suppressor in HTB9 human bladder carcinoma cells, which carry a mutation of the p53 gene at codon 280 and lack RB expression. To elucidate the potential role of RB in the regulation of p53-mediated apoptosis, we transfected a wt p53 expression plasmid under the control of the human cytomegalovirus promoter into parental and RB-transfected HTB9 cells. The p53(+)/RB(-)cells were susceptible to apoptosis under various experimental conditions: 1) incubation in serum-free culture for 72 h, 2) short-term (6 h) or long-term (48 h) exposure to etoposide, and 3) culturing in soft agar. In contrast, p53(+)/RB(+)cells were significantly resistant to apoptosis under similar conditions and exhibited efficient growth arrest, as measured by laser scanning cytometry. Tumorigenicity in nude mice of parental HTB9 cells was lost by exogenous expression of wt p53. Likewise, none of mice injected subcutaneously with either p53(-)/RB(+)or p53(+)/RB(+)cells developed tumours, indicating that RB allows suppression of tumorigenesis, regardless of p53 status. These results suggest that the growth-inhibitory function of RB may overcome the ability of wt p53 to induce apoptosis. [ABSTRACT FROM AUTHOR]