1: Folia Med (Plovdiv). 2008 Oct-Dec;50(4):17-23.

Molecular link(s) between hepatoblastoma pathogenesis and exposure to
di-(2-ethylhexyl)phthalate: a hypothesis.

Salvatore M, Lorenzetti S, Maranghi F, Mantovani A, Taruscio D.

Department of Cell Biology and Neurosciences, National Centre for Rare Diseases, 
Rome, Italy.

Hepatoblastoma (HB) is the most important primary liver cancer in children,
accounting for up to 1% of all paediatric malignancies. It affects mostly infants
and young children between the age of 6 months and 3 years. Predisposing genetic 
factors for HB have been identified and scientific evidence clearly points out HB
as a multi-factorial condition based on both genetic and environmental factors.
Nevertheless, a clear understanding of the pathogenesis is yet lacking. The
present review will focus on the impact of exposure to environmental chemicals,
such as di-(2-ethylhexyl)phthalate (DEHP), and recognized risk factors, such as
intrauterine growth retardation (IUGR), on HB establishment via altered
signalling pathways (Wnt and IGF). The hypothesis linking the impairment of IGF2 
foetal/adult switching and exposure to DEHP is discussed as a way forward to
support HB prevention and early diagnosis.

Publication Types: 
    Review

PMID: 19209526 [PubMed - indexed for MEDLINE]

2: Vet Comp Oncol. 2008 Mar;6(1):55-64.

Use of imiquimod 5% cream (Aldara) in cats with multicentric squamous cell
carcinoma in situ: 12 cases (2002-2005).

Gill VL, Bergman PJ, Baer KE, Craft D, Leung C.

Donaldson-Atwood Cancer Clinic, The Animal Medical Center, New York, NY 10021,
USA. virginia.gill@amcny.org

Multicentric squamous cell carcinoma in situ (MSCCIS) is a variant of squamous
cell carcinoma in cats, commonly referred to as Bowen's-like disease. Imiquimod
5% cream (Aldara) is a novel immune response modifier (IRM) that has been
reported as a successful treatment for Bowen's disease in humans. The purpose of 
this study was to describe clinical findings, treatment protocols and survival in
cats with MSCCIS treated with imiquimod 5% cream and to examine the effects of
imiquimod 5% cream in cats with MSCCIS. The expression of papillomavirus
group-specific antigen in the study population was also determined. From review
of medical records, 12 cats were identified with a histologic diagnosis of MSCCIS
and treatment with imiquimod 5% cream. Initial lesions responded to imiquimod 5% 
cream in all cats. Most cats (75%) developed new lesions. New lesions also
responded to imiquimod 5% cream in all cats treated. Five cats (41%) had side
effects suspected to be associated with the use of imiquimod 5% cream, including 
local erythema (25%), increased liver enzymes and neutropenia (8%), and partial
anorexia and vomiting (8%). Kaplan-Meier median treatment duration and median
survival time probabilities for cats in this study were 1189 days, respectively. 
A time to failure model was generated as many cats were censored from analysis
well before the aforementioned projected median. This model resulted in a shorter
median survival time of 243 days. No patient-related, tumour-related or
treatment-related prognostic variables were identified. No expression for
papilloma group-specific antigen was found. Imiquimod 5% cream appears to be well
tolerated in the majority of cats, and further studies are warranted to further
examine its usefulness in cats with this disease.

PMID: 19178663 [PubMed - indexed for MEDLINE]

3: Comp Med. 2008 Dec;58(6):542-50.

Quantitative tomography of early-onset spontaneous AA amyloidosis in interleukin 
6 transgenic mice.

Wall JS, Richey T, Allen A, Donnell R, Kennel SJ, Solomon A.

Human Immunology and Cancer Program, Graduate School of Medicine, University of
Tennessee, Knoxville, TN, USA. jwall@mc.utmck.edu

Mice that constitutively express the human interleukin 6 (huIL6) protein from a
heritable transgene (H2-L(d)-IL-6) express high levels of the acute-phase
reactant, serum amyloid protein A, a liver-derived apoprotein of high-density
lipoprotein that is the precursor of AA amyloid. Typically at approximately 5 mo 
of age B6(C)- Tg(H2-L(d)-IL-6)Kish (H2/huIL-6) animals begin to develop splenic
deposits of AA amyloid, which progress to involve the liver, kidney, and
vasculature, ultimately resulting in death due to severe systemic AA amyloidosis 
at 8 to 9 mo of age. These mice provide a robust model in which to study novel
therapeutic and diagnostic imaging agents for AA amyloidosis. We recently have
noted a change in onset of spontaneous disease, as evidenced by 2 female
transgenic mice that were found moribund at only 5 mo of age. Extensive
hepatosplenic amyloid deposits in both mice were identified and quantified by
single-photon emission computed tomography, which further revealed heterogeneous 
distribution of radiotracer in the spleen indicating a distinction between
amyloid-laden red pulp and the disease-free lymphoid follicles. The AA nature of 
the deposits was evidenced immunohistochemically and by mass spectrometric
analyses of extracted amyloid fibrils. Our studies have documented the
manifestation of early-onset, severe, spontaneous AA amyloidosis in 2- to
5-mo-old H2/ huIL-6 mice; we hypothesize that this disease is due to genetic
rather than environmental factors.

Publication Types: 
    Research Support, N.I.H., Extramural

PMID: 19149411 [PubMed - indexed for MEDLINE]

4: Cancer Prev Res (Phila Pa). 2008 Sep;1(4):233-40. Epub 2008 Mar 19.

Comment in:
    Cancer Prev Res (Phila Pa). 2008 Sep;1(4):219-22.

Long-term epigenetic therapy with oral zebularine has minimal side effects and
prevents intestinal tumors in mice.

Yoo CB, Chuang JC, Byun HM, Egger G, Yang AS, Dubeau L, Long T, Laird PW, Marquez
VE, Jones PA.

Department of Biochemistry and Molecular Biology, Keck School of Medicine,
University of Southern California, Los Angeles, California 90033-9181, USA.

Recent successes in the application of epigenetic drugs for the treatment of
myelodysplastic syndrome have raised questions on the safety of long-term
administration of DNA methylation inhibitors. We treated preweaned cancer prone
Apc(Min/+) (Min) mice continuously with the DNA methylation inhibitor zebularine 
in their drinking water to determine the effects of the drug on normal mouse
development as well as cancer prevention. Zebularine caused a tissue-specific
reduction in DNA methylation at B1 short interspersed nucleotide elements in the 
small and large intestines of female Min mice but not in other organs examined
after chronic oral treatment. No significant difference in the average weights of
mice was observed during the treatment. In addition, analysis of global gene
expression of colonic epithelial cells from the females indicated that only 3% to
6% of the genes were affected in their expression. We did not detect toxicity and
abnormalities from the histopathologic analysis of liver and intestinal tissues. 
Lastly, we tested whether prevention of tumorigenesis can be achieved with
chronic oral administration of zebularine in Min mice. The average number of
polyps in Min females decreased from 58 to 1, whereas the average polyp number
remained unaffected in Min males possibly due to differential activity of
aldehyde oxidase. Taken together, our results show for the first time that
long-term oral administration of zebularine causes a gender-specific abrogation
of intestinal tumors while causing a tissue-specific DNA demethylation.
Importantly, prolonged treatment of mice with epigenetic drugs resulted in only
minor developmental and histologic changes.

Publication Types: 
    Evaluation Studies

PMID: 19138966 [PubMed - indexed for MEDLINE]

5: Cancer Prev Res (Phila Pa). 2008 Jun;1(1):65-76. Epub 2008 Mar 31.

Dietary energy balance modulates signaling through the Akt/mammalian target of
rapamycin pathways in multiple epithelial tissues.

Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD, DiGiovanni J.

Science Park-Research Division, The University of Texas M. D. Anderson Cancer
Center, Smithville, TX 78957, USA.

The prevalence of obesity, an established risk factor for several types of
cancer, has increased steadily over the past several decades in the United
States. New targets and strategies for offsetting the effect of obesity on cancer
risk are urgently needed. In the present study, we examined the effect of dietary
energy balance manipulation on steady-state signaling in multiple epithelial
tissues, with a focus on the Akt and mammalian target of rapamycin (mTOR)
pathways. For these experiments, male FVB/N and C57BL/6 and female ICR mice were 
maintained on a control (10 kcal% fat) diet, a diet-induced obesity (DIO; 60
kcal% fat) regimen, or a 30% calorie restriction (CR) regimen for 15 to 17 weeks.
Relative to the control group, the DIO regimen increased, whereas CR decreased,
circulating insulin-like growth factor-I (IGF-I) as has previously been reported.
Western blot analyses showed that the DIO regimen enhanced, whereas CR inhibited,
activation of Akt and mTOR, regardless of epithelial tissue or genetic
background. In contrast, activation of AMP-activated protein kinase was modulated
by dietary energy balance manipulation in the liver but not in the epidermis or
dorsolateral prostate. Western blot analyses of epidermal extracts taken from ICR
mice also revealed reduced activation of both the IGF-I receptor and epidermal
growth factor receptor in CR mice, compared with control mice or mice maintained 
on the DIO regimen. Taken together, these novel findings suggest that dietary
energy balance modulates signaling through cell-surface receptors (i.e., IGF-I
receptor and epidermal growth factor receptor), affecting activation of multiple 
downstream pathways including Akt and mTOR, thus providing important dietary and 
pharmacologic targets for disrupting the obesity-cancer link.

Publication Types: 
    Research Support, N.I.H., Extramural

PMID: 19138937 [PubMed - indexed for MEDLINE]