Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
28
1
2009
Modern Concepts in the Diagnosis and Treatment of Vitamin D Deficiency and Its Clinical Consequences
1-4
10.1615/JEnvironPatholToxicolOncol.v28.i1.10
Richard
Edlich
Legacy Verified Level I Shock Trauma Center Pediatrics and Adults, Legacy Emanual Hospital; and Plastic Surgery, Biomedical Engineering and Emergency Medicine, University of Virginia Health System, USA
Allyson L.
Fisher
Legacy Emanuel Hospital, Portland, OR, USA
Margot E.
Chase
Legacy Emanuel Hospital, Portland, OR, USA
Carroll M.
Brock
Legacy Emanuel Hospital, Portland, OR, USA
K. Dean
Gubler
Surgical Critical Care, Legacy Verified Level I Shock Trauma Center for Pediatrics and Adults, Legacy Emanuel Hospital, Portland, OR, USA
William B.
Long III
Trauma Specialists LLP, Legacy Verified Level I Shock Trauma Center for Pediatrics and Adults, Legacy Emmanuel Hospital, Portland, OR, USA
vitamin D3
vitamin D deficiency
radioimmunoassay
sun exposure
high-performance liquid chromatography-tandem mass spectrometry
vitamin D3 supplementation
It is the purpose of this comprehensive report to outline a revolutionary strategy to prevent vitamin D deficiency in our nation. Vitamin D is a unique vitamin. Its metabolic product, calcitriol, is a profound secosteroid hormone that has impact on over 1000 genes in the human body. Recent clinical research has implicated vitamin D deficiency as a major factor in the etiology of rickets, a wide variety of cancers, as well as hypertension, stroke, heart attack, diabetes, bone fractures, periodontal disease, and even multiple sclerosis. There are two forms of vitamin D utilized in the human body: D2 and D3. Measurement of 25(OH)D is the most reliable method of detecting vitamin D deficiency. Several methods, including high-performance liquid chromatography (HPLC), chemoluminescence, and radioimmunoassay (RIA), have been developed for the measurement of total 25(OH)D levels. Prevention and treatment of vitamin D deficiency is accomplished by regulated sun exposure as well as vitamin D, supplementation. This information describing our plan to prevent vitamin D deficiency in the patients and employees of Legacy Health System is a landmark accomplishment that should be replicated in every healthcare setting in our country to prevent vitamin D deficiency.
Accelerated Proteasomal Activity Induced by Pb2+, Ga3+, or Cu2+ Exposure Does Not Induce Degradation of αt-Synuclein
5-24
10.1615/JEnvironPatholToxicolOncol.v28.i1.20
Nurit
Grunberg-Etkovitz
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Nirit
Lev
Laboratory of Neuroscience and Department of Neurology, FMRC, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel
Debby
Ickowicz
Laboratory of Neuroscience and Department of Neurology, FMRC, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel
Almog
Avital
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Daniel
Offen
Laboratory of Neuroscience and Department of Neurology, FMRC, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel
Zvi
Malik
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Israel
A53T mutant
heavy metals
heme-oxygenase-1
The involvement of environmental heavy metals in Parkinson's disease (PD) has been suggested by epidemiologic studies; however, the mechanism of this effect is unknown. PD is characterized by the aggregation of α-synuclein in Lewy bodies. We previously showed that Pb2+ accelerates proteasomal activity. Therefore, we examined the effect of Pb2+, Ga3+, and Cu2+ on α-synuclein in human SH-SY5Y cells. The heavy metals induced an increase in heme-oxygenase-1 levels without significant cell death or ROS generation. The metals inhibited ALA-dehydratase, which is the inhibitory subunit of the proteasome, thereby accelerating proteasomal activity and decreasing protein levels of CDK-1 and PBGD. However, α-synuclein protein levels increased after exposure to metals, similar to the effect obtained with the proteasome inhibitor, hemin, suggesting that α-synuclein is inaccessible to proteasomal degradation. Indeed, electron microscopy revealed the formation of aggresomes in Pb2+- or hemin-treated cells. Thus, although heavy metals enhance proteasomal activity, α-synuclein is protected from degradation, and its protein levels and aggregation are increased.
Siva-1 Promotes K-48 Polyubiquitination of TRAF2 and Inhibits TCR-Mediated Activation of NF-kappaB
25-38
10.1615/JEnvironPatholToxicolOncol.v28.i1.30
Radhika
Gudi
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
John
Barkinge
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
Sarah
Hawkins
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
Bellur
Prabhakar
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612
Prasad
Kanteti
Department of Microbiology and Immunology, University of Illinois at Chicago
Siva-1
NF-kappaB
AP-1
TRAF
K48
K63
NIK
TCR
The proapoptotic protein Siva-1 plays an important role in some of the extrinsic and intrinsic apoptosis signaling pathways in cancer cells. Previously, we showed that Siva-1 inhibited the activity of the prosurvival transcription factor NF-κB. In the present study, upon TCR cross-linking of Jurkat T leukemia cells, we demonstrated that the inhibitory target of Siva-1 is upstream of the IKK complex in the NF-κB signaling pathway. Additionally, Siva-1 also suppressed the activity of another crucial transcription factor AP-1, and a common mediator of both these pathways is the adaptor protein TRAF2. Further, we observed that Siva-1 indeed interacted with TRAF2 and negatively regulated its activity by promoting K48-hnked polyubiquitination. Siva-1 specifically interacted with the ring finger domain of TRAF2, which is essential for its E3 hgase activity and its ability to subsequently activate NF-κB. TCR cross-linking of Jurkat T cells that lacked Siva-1 revealed significantly lowered K48- but elevated K63-ubiquitinated TRAF2 levels upon TCR cross-linking, suggesting that the differential pattern of ubiquitination in these cells essentially contributed to a robust and sustained activation of NF-κB. The above results demonstrated an important role for endogenous Siva-1 in negatively regulating NF-κB activation by targeting TRAF2.
The Cyclooxygenase-2 Inhibitor Etoricoxib Is a Potent Chemopreventive Agent of Colon Carcinogenesis in the Rat Model
39-46
10.1615/JEnvironPatholToxicolOncol.v28.i1.40
Manpreet Kaur
Saini
Department of Biophysics, Panjab University, Chandigarh-160014, India
Pinky
Sharma
Department of Biophysics, Panjab University, Chandigarh-160014, India
Jasmeet
Kaur
Department of Biophysics, Panjab University, Chandigarh-160014, India
Sankar Nath
Sanyal
Department of Biophysics, Panjab University, Chandigarh, India 160014
etoricoxib
DMH
apoptosis
anti-inflammatory drugs
colon cancer
Cyclooxygenase-2 (COX-2), an inducible prostaglandin G/H synthase, is overexpressed in several human cancers, including colon cancer, and therefore the potential ability of a selective COX-2 inhibitor, etoricoxib, is considered in the prevention of the 1,2-dimethyl hydrazine (DMH)-induced colon carcinogenesis in the rat model. DMH was injected s.c. for 6 weeks, whereas etoricoxib was fed orally to the rats on a daily basis. The results showed that DMH produced a very high number of multiple plaque lesions (MPLs), putative neoplastic biomarkers, localized throughout the colon, whereas considerable regression was observed with etoricoxib treatment. In addition, the etoricoxib group was the only group that exhibited very few of these lesions. Histopathological analysis revealed extreme dysplasia, a few adenomas, and other carcinogenic changes in the DMH group, which are distinctly absent in the etoricoxib-treated group. COX-2 was also seen to be highly expressed following DMH treatment. The DMH treatment caused very few apoptotic cells, as determined by the TUNEL assay of the colonic mucosa in paraffin sections whose number greatly increased following etoricoxib treatment. Because all these changes were clearly reversed by etoricoxib in DMH-treated animals, and the use of etoricoxib alone did not produce a neoplastic effect per se, it appears that etoricoxib, a selective COX-2 inhibitor, might be a safe and potentially chemopreventive agent in colon cancer.
Revolutionary Advances in the Diagnosis and Treatment of Familial Adenomatous Polyposis
47-52
10.1615/JEnvironPatholToxicolOncol.v28.i1.50
Richard
Edlich
Legacy Verified Level I Shock Trauma Center Pediatrics and Adults, Legacy Emanual Hospital; and Plastic Surgery, Biomedical Engineering and Emergency Medicine, University of Virginia Health System, USA
Catherine L.
Cross
Legacy Emanuel Hospital, Portland, OR, USA
Courtney A.
Wack
Legacy Emanuel Hospital, Portland, OR, USA
Margot E.
Chase
Legacy Emanuel Hospital, Portland, OR, USA
K. Dean
Gubler
Surgical Critical Care, Legacy Verified Level I Shock Trauma Center for Pediatrics and Adults, Legacy Emanuel Hospital, Portland, OR, USA
William B.
Long III
Trauma Specialists LLP, Legacy Verified Level I Shock Trauma Center for Pediatrics and Adults, Legacy Emmanuel Hospital, Portland, OR, USA
Familial Adenomatous Polyposis
APC gene
Attenuated Polyposis
Attenuated Adenomatous Polyposis
colorectal cancer
During the last 25 years, there have been revolutionary advances in the treatment of Familial Adenomatous Polyposis (FAP). The purpose of this article is to describe the pathophysiology, genetic testing, surveillance, surgical interventions, and psychosocial issues. The genetic defect in FAP is germline mutation in the adenomatous polyposis coli (APC) gene. Syndromes once thought to be distinct from FAP are now recognized to be part of the phenotypic spectrum of FAP. Syndromes with a germline mutation in the APC gene include FAP, Gardner syndrome, Turcot syndrome, and Attenuated Adenomatous Polyposis Coli (AAPC). FAP is a germline mutation in the APC gene with onset of florid polyposis in childhood and development of colorectal cancer by age 30. Colectomy is advised because of the high risk of developing colorectal cancer. AAPC is a variant of this condition with later age of onset and milder clinical pheno-type. However, colectomy is advised once polyposis develops and polyps cannot be managed endoscopically. Despite the unique advances in genetic testing, psychosocial management of these syndromes remains to be a challenging problem.
Radioprotective Effects of Aloe Vera Leaf Extract on Swiss Albino Mice against Whole-Body Gamma Irradiation
53-61
10.1615/JEnvironPatholToxicolOncol.v28.i1.60
Pradeep Kumar
Goyal
Radiation and Cancer Biology Laboratory, Department of Zoology, University of Rajasthan, Jaipur - 302 004, India
Prashasnika
Gehlot
Radiation and Cancer Biology Laboratory, Department of Zoology, University of Rajasthan, Jaipur 302004, India
Aloe vera
skin
gamma radiation
LPO
GSH
DNA
catalase
SOD
Swiss albino mice
The skin, being a cell-renewal system, is one of the first organs to be affected in total-body irradiation during radiotherapy. An attempt has been made in the present study to explore radiation-induced biochemical alterations caused by whole-body gamma irradiation and their modulation in Swiss albino mice by Aloe vera leaf extract (AVE). Mice were selected for this study from an inbreed colony and divided into four different groups: I (double-distilled water-treated group): considered as normal; II (Aloe vera-treated group): the animals were administered 1 g/kg body-wt/day Aloe vera leaf extract; III (radiation-treated group): the animals were exposed to 6 Gy gamma radiation at the dose rate of 0.96 Gy/min; and IV (combination group): animals were administered Aloe vera leaf extract continuously for 15 consecutive days, and on the 15th day they were irradiated to 6 Gy gamma radiation after 30 minutes of extract administration. The animals from the above groups were autopsied after 6 hours, 24 hours, and at 3, 7, 14, and 21 days of radiation. Biochemical estimations of DNA, lipid peroxidation, glutathione, catalase, and superoxide-dismutase were made. Total DNA, catalase, superoxide dismutase (SOD) activity in the skin, and glutathione (GSH) in the liver and blood significantly decreased compared to normal, but lipid peroxidation (LPO) in the liver and blood increased in the irradiated control group. In contrast, in experimental animals, DNA, catalase, and SOD in the skin and GSH in the liver and blood increased significantly, whereas LPO in the liver and blood decreased in comparison to irradiated control animals. Thus, Aloe vera leaf extract is found to have damage-resistant properties against radiation-induced biochemical alterations in Swiss albino mice.
Correlation of FBX Dosimeter and Micronucleus Assay in Radiation Dosimetry of Gamma Chambers
63-73
10.1615/JEnvironPatholToxicolOncol.v28.i1.70
Manjoor
Ali
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai - 400085, India
Prabha
Tiwari
Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Mumbai - 400085, India
Amit
Kumar
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Kaushala Prasad
Mishra
Department of Life Sciences, University of Mumbai, Mumbai, India; Nehru Gram Bharati University, Allahabad, UP, India; Foundation for Education and Research, Mumbai, India; BM International Research Centre, Mumbai, India
Badri Narain
Pandey
Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
dose distribution
FBX dosimeter
micronuclei assay
biological dosimetry
dose rate
The aim of the present study is to determine the dose distribution in gamma irradiation chambers by chemical dosimetry and to establish its correlation with biological dosimetry. The dose-distribution studies of these two gamma chambers show that compared to the center point of the chambers, the dose rate was 17%−22% higher at the circumference. Moreover, the dose rate was 12%−18% lower at the bottom and top positions compared to the center point. It was interesting to observe that the dose rate determined by chemical dosimetry was well correlated with the number of micro-nucleus (MN) formations at different positions of the chamber. Our results suggest that the formation of the single MN/cell was better correlated with the dose rate than the double MN/cell, suggesting that the number of single MN/cells could be better biomarkers for determining the dose rate. These results provide a correlation between chemical and biological dosimetry, which may have relevance in the development of better bioassay techniques for radiation exposure.
Chromosomal Aberrations in Subjects Exposed to Ionizing Radiation
75-82
10.1615/JEnvironPatholToxicolOncol.v28.i1.80
Dubravka
Jovicic
Clinical Center of Serbia, Institute of Occupational Health and Radiological Protection "Dr. Dragomir Karajovic," Belgrade, Serbia
Snezana
Milacic
Clinical Center of Serbia, Institute of Occupational Health and Radiological Protection "Dr. Dragomir Karajovic," Belgrade, Serbia
Natasa
Milic
Institute for Medical Statistics and Informatic, Belgrade University School of Medicine, Belgrade, Serbia
Nenad
Bukvic
DIMIMP-Medical Genetic Section, University of Bari, Italy
Tanja D.
Vukov
Institute for Biological Research "Sinisa Stankovic," University of Belgrade, Belgrade, Serbia
chromosomal damage
dose rate
genetic effects
occupational and medical exposures
Occupational exposure to low doses of ionizing radiation is a particularly delicate subject for investigation, due to the cumulative effects of chronic exposure. It is extremely important to consider and to measure the biological response to given conditions of exposure. The aim of this study was to establish possible recovery from DNA damage in subjects professionally exposed to radiation in their working area by examinations for chromosomal aberrations (CA) at two different times. The first group (I) was composed of 30 professionally exposed subjects in whom unstable CA (dicentrics, ring, acentric fragments, chromatid, chromosomal breaks, and chromatid interchanges) were identified at time zero. After removal from the radiation area, they were re-examined 9 months later. The second group (II) contained 64 healthy individuals, not professionally exposed to ionizing radiation or other known mutagenic agents. In the group of exposed individuals, five (16.67%) subjects exhibited permanent unstable CAs, even after 9 months absence from the radiation. When the nonexposed and exposed groups were compared, an increase of unstable aberrations (p < 0.05) was observed in the exposed group. Nevertheless, a statistically significant decrease of dicentrics, acentric fragments, and ring frequencies was observed in exposed individuals after 9 months away from the radiation area. However, chromatid and isochromatid break frequencies increased slightly but not significantly after 9 months. The detected CAs corresponded to the total effective doses of radiation measured in our subjects. The existence of CAs in some individuals even after absence from the radiation area suggests that the time necessary for the damaged DNA to recover is extremely variable and indicates interindividual differences in radiosensitivity as well as differences in the cellular-reparation response.
A Paradox of Cadmium: A Carcinogen That Impairs the Capability of Human Breast Cancer Cells To Induce Angiogenesis
85-88
10.1615/JEnvironPatholToxicolOncol.v28.i1.90
Stefania
Pacini
Department of Anatomy, Histology and Forensic Medicine, University of Florence, Italy
Tiziana
Punzi
Department of Anatomy, Histology and Forensic Medicine, University of Florence, Italy
Gabriele
Morucci
Department of Anatomy, Histology and Forensic Medicine, University of Florence, Italy
Massimo
Gulisano
Department of Anatomy, Histology and Forensic Medicine, University of Florence, Italy
Marco
Ruggiero
Department of Experimental Pathology and Oncology, University of Florence, Italy
breast cancer
angiogenesis
cadmium
Cadmium, a highly persistent heavy metal, has been categorized as a human carcinogen. Even though it is known that cadmium acts as estrogens in breast cancer cells, several studies failed to demonstrate whether cadmium is a causal factor for breast cancer. The lack of a strong association between cadmium and breast cancer could be found in the antiangiogenic properties of this heavy metal, which might counteract its carcinogenic properties in the progression of breast cancer. In this study, we exposed estrogen-responsive breast cancer cells to subtoxic levels of cadmium, and we evaluated their angiogenic potential using the chick embryo chorioallantoic membrane assay. Exposure of breast cancer cells to subtoxic levels of cadmium significantly inhibited the angiogenic potential of the breast cancer cell line, suggesting the possibility that cadmium might negatively regulate the production of proangiogenic factors in breast cancer cells. Our results suggest that cadmium might exert a paradoxical effect in breast cancer: on the one hand, it could promote carcinogenesis, and, on the other hand, it could delay the onset of tumors by inhibiting breast cancer cell-induced angiogenesis.