Reduction of tumorigenicity by an interferon-γ-gene-transduced tumor on another syngeneic tumor in a murine model

To evaluate the effect of interferon-γ-genetransduced cells, DS mice were inoculated into their footpads with syngeneic mammary adenocarcinoma SC42 admixed with interferon-γ producing mammary adenocarcinoma SC115Kγ, which had been established by an interferon-γ-gene transduction in another syngeneic mammary adenocarcinoma SC115 using retroviral vectors. These mice rejected both tumor cells and developed resistance to subsequent challenges with either SC115 or SC42 cells inoculated into their opposite posterior footpads. These results thus indicate that systemic immunological memory to each of the independent tumor cell lines developed in these mice. Although the SC42 cells admixed with irradiated SC115Kγ cells were rejected by these mice, the SC42 cells admixed with irradiated SC115neoR, in which the neo-gene had been transduced, were observed to proliferate. Tumor rejection was reversed by an in vivo administration of anti-interferon-γ antibody, thus suggesting that locally produced interferon-γ plays an important role in tumor elimination and immunological memory induction. In conclusion, interferon-γ-gene-transduced tumor cells are therefore considered to have a therapeutic potential for other types of malignant tumor cell lines.     

Effect of αGal on corneal xenotransplantation in a mouse model

Choi HJ, Kim MK, Lee HJ, Jeong SH, Kang HJ, Park C‐S, Park C‐G, Kim SJ, Wee WR. Effect of αGal on corneal xenotransplantation in a mouse model. Xenotransplantation 2011; 18: 176–182. © 2011 John Wiley & Sons A/S. Abstract: Background: It has been reported that hyperacute rejection (HAR) does not occur after pig‐to‐nonhuman corneal xenotransplantation. However, considering that immune privilege is already disrupted in most human corneal recipients, and the expression of αGal can be gradually reduced after pig‐to‐rat corneal transplantation, the long‐term survival of corneal grafts from wild‐type pigs cannot be guaranteed. Accordingly, we aimed to investigate the effect of αGal on the change in anti‐Gal antibodies, using sensitized α1,3‐galactosyltransferase gene‐knockout (GTKO) mice recipients. Methods: C57BL/6 (B6) and GTKO mice were divided into 5 groups and underwent orthotopically full thickness cormeal transplantation as follows (n=4 for each group): (1) group 1: B6 to B6; (2) group 2: fresh porcine posterior corneal lamella to B6; (3) fresh porcine posterior corneal lamella to GTKO; (4) group 4: decellularized porcine posterior corneal lamella to GTKO, and (5) group 5: B6 to GTKO. Before transplantation, all GTKO recipients were sensitized using intraperitoneal injections of rabbit blood cells. Median survival times (MST) for the corneal grafts of the different groups were compared and plasma concentrations of IgG/IgM anti‐Gal antibodies were evaluated at 1 week, 2 weeks and 3 weeks post‐transplantation. Results: There were no differences in MSTs between groups. Although there was no HAR of fresh porcine posterior corneal grafts even in sensitized GTKO recipients, αGal expression was induced in the transplanted fresh porcine corneal grafts and plasma concentration of IgG anti‐Gal antibody was gradually increased in fresh porcine cornea‐grafted GTKO recipients. On the contrary, αGal expression did not increase in the grafts and plasma concentration of anti‐Gal antibodies did not change after transplantation using decellularized porcine corneas. Conclusions: Our findings suggest that αGal may affect the long‐term survival of porcine corneal xenografts via antibody‐mediated rejection, although αGal does not have an effect on acute rejection and decellularized porcine corneas may enable the long‐term survival of porcine corneal xenografts.     

Mass screening of prostate cancer in a Chinese population：the relationship between pathological features of prostate cancer and serum prostate specific antigen

Aim: To investigate the pathological features of the prostate biopsy through mass screening for prostate cancer in a Chinese cohort and their association with serum prostate specific antigen (PSA). Methods: A total of 12027 Chinese men in Changchun were screened for prostate cancer by means of the serum total prostate specific antigen tPSA test (by Elisa assay). Transrectal ultrasound-guided systematic six-sextant biopsies were performed on those whose serum tPSA value was > 4.0 ng/mL and those who had obstructive symptoms (despite their tPSA value) and were subject to subsequent pathological analysis with the aid of the statistic software SPSS 10.0 (SPSS. Inc., Chicago. USA). Results: Of the 12027 cases, 158 (including 137 patients whose serum tPSA values were 4.0 ng/mL and 21 patients [serum tPSA < 4.0 ng/mL] who had obstructive symptoms) undertook prostate biopsy. Of the 158 biopsies, 41 cases of prostatic carcinoma were found (25.9 %, 41/158). The moderately differentiated carcinoma and poorly differentiated carcinoma accounted for 61% and 34%, respectively. A significant linear positive correlation between the serum tPSA and the Gleason scores in the 41 cases of prostatic carcinoma (r = 0.312, P < 0.01) was established. A significant linear positive correlation between the serum tPSA value of the 41 prostatic carcinoma and the positive counts of carcinoma in sextant biopsies was established (r = 0.406, P < 0.01), indicating a significant linear relationship between serum tPSA and the size of tumor. Conclusion: This study was the first to conduct mass screening for prostate cancer by testing for serum tPSA values and the first to investigate the pathological features of prostate cancer in a cohort of Chinese men. Our results reveal that the moderately differentiated carcinoma is the most common type of prostate cancer. This study also has shown that the serum tPSA value in prostate cancer is associated with the Gleason score and the size of tumor.     

Breast cancer as a second primary in patients with prostate cancer--estrogen treatment or association with family history of cancer?

PURPOSE: In a large population based study we reported an increased risk of male breast cancer after prostate cancer. In the current study we performed a comprehensive investigation of whether treatment for prostate cancer and/or family history is responsible for the excess risk. MATERIALS AND METHODS: This study had 2 parts. 1) We performed a nested case-control study in 41 men who had previously been identified with first prostate cancer, followed by male breast cancer and in 81 matched controls with prostate cancer only. The medical records of these men were retrieved and clinical data such as stage, grade and treatment were extracted. 2) We also performed a family study including relatives of men with a diagnosis of prostate as well as breast cancer, irrespective of which was first. The 878 relatives were identified through parish offices and linked to the Swedish Cancer Registry to evaluate the occurrence of breast, prostate and other cancers and calculate if there were any excess risks for different cancers. RESULTS: Cases with prostate plus breast cancer received estrogen treatment more often than controls with prostate cancer only (p = 0.03). The period of estrogen treatment was longer in the cases, although it was not statistically significant. Mean time from prostate cancer diagnosis to breast cancer diagnosis was 47.6 months. Cases and controls did not differ in grade or stage. In the family study an increased risk of prostate cancer was found in relatives (SIR 2.14, 95% CI 1.09 to 3.18). For other cancers no significantly increased risks were found. In 2 families pedigree analysis using the BRCAPRO program (http://www3.utsouthwestern.edu/cancergene/) revealed an estimated 100% and 49% probability in families 1 and 2, respectively, that the proband was a BRCA2 carrier. CONCLUSIONS: Our data suggest that most of the increased risk of breast cancer following prostate cancer can be explained by estrogen treatment. However, in a small number of men with prostate as well as breast cancer pedigree analysis suggests that BRCA2 mutation might be the underlying cause.     

Human prostate cancer heterotransplants： a review on this experimental model

A common model used for preclinical research was in vitro human tumor cell culture. An alternative model was the direct implantation of a unique patient＇s tumor biopsy specimens into immunodeficient host mice. Published data from PubMed （http：//www.ncbi.nlm.nih.gov） and Current Contents Connect databases （http：//thomsonreuters.com/ products_services/science/science_roducts/a-z/current_contents_connect） were reviewed. Prostate cancer （PCa） heterotransplantation was evaluated using histopathology, morphology, cell differentiation, DNA content, tumor marker expression, metastases, tumor kinetics, tumor take rate and tumor vasculature in the first tumor heterotransplant. The heterotransplanted tumor retained the biological properties of the original tumor, such as morphology, degree of differentiation, pathology, secretory activity, expression of tumor markers and human vasculature. Human PCa heterotransplants have considerable experimental advantages over cell culture following xenotransplantation.     

Determination of pyruvate kinase type tumor M2 in human renal cell carcinoma: a suitable tumor marker?

Renal cell carcinoma (RCC) expresses an isoform of the glycolytic enzyme pyruvate kinase (type M2). The dimeric form (TuM2-PK) is over expressed in tumor cells and is detectable in blood with a sensitive enzyme-linked immunosorbent assay (ELISA). The aim of the present study was to evaluate the clinical value of TuM2-PK as a tumor marker for RCC. The TuM2-PK concentration in EDTA-plasma was determined quantitatively and immunologically using an ELISA. We measured the TuM2-PK plasma levels of 83 patients before and after surgery. Ninety-seven patients with various non-malignant diseases were also recruited as a control group. The control group displayed mean levels of 11.37 U/ml of TuM2-PK. Values were elevated in patients with RCC prior to surgery (mean 21.88 U/ml). The plasma levels increased after surgery until day 5 (mean 53.97 U/ml). At day 10, marker levels started to decrease without reaching preoperative values (mean 43.5 U/ml). Plasma levels in the renal vein (obtained during surgery) were not different from those in the peripheral blood. Follow-ups after 2-6 months showed a decrease to below preoperative levels (mean 16.3 U/ml). A significant difference was obtained by comparing the patients according to their Robson score. We found a significant difference (P < 0.01, Wilcoxon's two-sample test) in TuM2-PK levels between patients with RCC and the control group. Nevertheless, using the manufacturer's recommended cut-off value (15 U/ml), sensitivity was only 50.6% and specificity was 80.4%. Our results suggest that TuM2-PK is not a suitable tumor marker for RCC.     

Does smoking change expression patterns of the tumor suppressor and DNA repair genes in the prostate gland?

Objectives

Somatic mutations can be present in clonally expanded cell populations in nonmalignant tissues, which are detectable at tissue-level resolution. Some of the mutational changes may arise due to smoking. We aimed to find out changes in carcinogenic gene expressions related to smoking in nonmalignant prostate gland epithelia.

Limitations of the db/db mouse in translational wound healing research: Is the NONcNZO10 polygenic mouse model superior?

Murine models have provided valuable insights into the pathogenesis of both diabetes and chronic wounds. However, only a few published reports to date have investigated wound healing differences among the differing diabetic mouse models. The goal of the present study was to further define the wound healing deficiency phenotypes of streptozotocin‐induced (STZ‐induced), Akita, and db/db diabetic mice in comparison with a promising new polygenic strain of Type 2 diabetes (NONcNZO10) by using three specific wound models that targeted different critical processes in the pathogenesis of chronic wounds. Incisional, excisional, and ischemia/reperfusion wound models were established on mice of each strain. Wound healing parameters including tensile strength, epithelial gap, and wound necrosis were evaluated. In contrast to the other diabetic mice, the NONcNZO10 strain was found to have significant wound healing impairments in all wound healing models. Not only do the NONcNZO10 mice appear to better model human Type 2 diabetes, these provocative findings suggest that the mice may show more clinically relevant wound healing deficiencies than previous diabetic mouse models.