Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis

Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division–associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division–related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis

How technology transfer really occurs on the factory floor: a case of a major Japanese automotive die manufacturer in the United States

Global competition requires increased technology transfer across national boundaries for global business opportunities. Previous studies on technology transfer have assumed that both transferor and transferee possess linguistic competence, and mainly focused on the types and the nature of the technology transferred. When examining international technology transfer between linguistically and culturally very different countries, companies face additional challenges. Through a different theoretical lens in organizational learning, we contribute to the literature on knowledge transfer by proposing and confirming demonstrability and drawability as two new constructs that affect knowledge transfer.

Calorie Restriction Suppresses the Progression of Radiation-Induced Intestinal Tumours in C3B6F1 ApcMin/+ Mice

Background/Aim: Progress in cancer treatment and diagnosis has made second cancer after medical radiation exposure a particular concern among childhoodcancer survivors. Calorie restriction (CR) is a broadly effective cancer prevention strategy, although its effects on radiation-induced intestinal tumours are unclear. Here we examined the cancer-preventative efficacy of a CR diet at different starting ages on radiation induction of intestinal tumours in mice. Materials and Methods: Male C3B6F1 ApcMin/+ mice were irradiated with 0 or 2 Gy of X-rays at 2 weeks of age. After an interval of 2, 8 or 18 weeks, mice were fed with a non-CR (95 kcal/week/mouse) or CR (65 kcal/week/mouse) diet. Intestinal tumours were evaluated for number, size distribution and malignancy. Results: CR suppressed the size and progression of both spontaneous and radiation-induced intestinal tumours depending on age at starting of CR. CR diets were effective even administered to adult mice. Conclusion: CR was effective for suppression of tumour progression, which was accelerated by radiation exposure. Use of CR might be a useful cancer-prevention strategy for radiation-induced tumours of the intestinal tract

Age dependency of Ikaros and Pten alterations in radiation-induced T-cell lymphoma

Background: Radiation carcinogenesis is greatly dependent on the age-at-exposure. Previous studies on the survivors of A-bombing and Chernobyl accident have indicated that there is an age difference in incidence and causal gene involved in both leukemia and thyroid cancer. The data on underlying mechanism of age dependency, however, is still limited. In this study, mouse T-cell lymphoma (TL) model was used for investigating the different effect of ionizing radiation to infant age and young adult age-at-exposure. We aimed to clarify the age dependent change of the affected molecular pathways of radiation-induced mouse T-cell lymphomagenesis.Materials and Methods: We analyzed the three groups of TLs developed after irradiation to female B6C3F1 mice weekly to 1.2 Gy X-ray for 4 consecutive weeks starting at infant (1 week of age), prepubertal (4 weeks of age) and adult (8 weeks of age). Loss of heterozygosity (LOH) analyses on chromosome 11, 12 and 19 were performed by PCR using genomic DNA of TLs. Mutations of the Ikaros and Pten were analyzed by sequencing of cDNA and genomic DNA, Western blotting, and array CGH.Results and Discussion: The frequency of LOH on chromosome 11 in 1W-TLs (27%; 4/15) was lower than those in 4W (46%; 6/13) and 8W-TLs (63%; 5/8). In contrast, the frequency of LOH on chromosome 19 in 1W-TLs (60%; 9/15) was higher than those in 4W-TLs (31%; 4/13) and 8W-TLs (13%; 1/8). Thus, LOH frequency was altered dependent on the age-at-exposure. Array CGH analysis revealed that intragenic deletion within Ikaros locus, which is mapped on chromosome 11, was characteristic in 1W-TLs, which produced aberrant Ikaros isoform, a lack of exon 5. On the other hand, different size deletions were found in each allele in 8W-TLs; one is intragenic deletion and the other is wide deletion including whole Ikaros locus. This type deletion caused null expression of Ikaros. In 4W-TLs, either type of deletion was found. Thus, deletion type in Ikaros region was different depend on the age-at-exposure. Array-CGH analysis revealed that the genomic copy number of the defined region of chromosome 19 in 1W-TLs was unchanged despite LOH, suggesting the LOH was caused by mitotic recombination. Therefore, it is considered that one allele deletion or intragenic mutation was formed at first and then the mitotic recombination occurred, resulting in homozygous deletion or homozygous intragenic mutations in 1W-TLs. Mutation frequency of Pten was higher than that in 4W- and 8W-TLs.Conclusion: Ikaros mutation was more involved in older age-at-exposure for T-cell lymphomagenesis, while Pten mutation was more involved in younger age-at-exposure. These results suggest that a target gene of radiation-induced T-cell lymphomagenesis and molecular mechanism of mutation change as a function of age-at-exposure.Childhood Cancer 2012 -International scientific conference on early exposure and childhood cancer

Kinetics of cytokine mRNA and protein expression by plastic adherent cells in the thymus after split-dose irradiation

Whole body irradiation causes significant apoptosis in various tissues such as the thymus. If apoptotic cells outnumber the phagocytic capacity of macrophages, apoptosis becomes secondary necrosis, inducing inflammatory cytokine expression in macrophages. Radiation also induces thymic lymphomas in C57BL/6 mice after four consecutive irradiations with 1.6 Gy X-rays with nearly 100% incidence. Since cancer development is modulated by a microenvironment involving macrophages, we examined the kinetics of thymocyte number and plastic adherent cell number in the thymus as well as cytokine mRNA expression by plastic adherent cells in the thymus after split-dose irradiation. Upon split-dose irradiation, thymocyte number changed dramatically, whereas plastic adherent cell number did not. Among cytokine mRNAs tested, IL-1, IL-11 and IL-12p40 mRNAs were up regulated 2 days after the 1st and 2nd, 3rd and 4th, and 2nd and 3rd irradiations, respectively. On the other hand, TNF- mRNA was up regulated 2 days after the 3rd irradiation and 2 weeks after the 4th irradiation. The level of IL-11 protein was also increased 2 days after 3rd and 4th irradiations. These results suggest that, upon split-dose irradiation, macrophages in the thymus produce various cytokines in a time-dependent manner, thereby contributing to induction of thymic lymphomas

The effects of short-term calorie restriction on mutations in the spleen cells of infant-irradiated mice.

The risk of cancer due to exposure to ionizing radiation is higher in infants than in adults. In a previous study, the effect of adult-onset calorie restriction (CR) on carcinogenesis in mice after early-life exposure to X-rays was examined (Shang, Y, Kakinuma, S, Yamauchi, K, et al. Cancer prevention by adult-onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice. Int J Cancer. 2014; 135: 1038-47). The results showed that the tumor frequency was reduced in the CR group. However, the mechanism of tumor suppression by CR is not yet clear. In this study, we examined the effects of CR on radiation-induced mutations using gpt delta mice, which are useful to analyze mutations in various tissues throughout the whole body. Infant male mice (1-week old) were exposed to 3.8 Gy X-rays and fed a control (95 kcal/week/mouse) or CR (65 kcal/week/mouse) diet from adult stage (7-weeks old). Mice were sacrificed at the age of 7 weeks, 8 weeks and 100 days, and organs (spleen, liver, lung, thymus) were harvested. Mutations at the gpt gene in the DNA from the spleen were analyzed by using a gpt assay protocol that detects primarily point mutations in the gpt gene. The results showed that mutation frequencies were decreased in CR groups compared with non-CR groups. Sequence analysis of the gpt gene in mutants revealed a reduction in the G:C to T:A transversion in CR groups. Since it is known that 8-oxoguanine could result in this base substitution and that CR has an effect of reducing oxidative stress, these results indicate that the suppression of oxidative stress by CR is the cause of the reduction of this transversion