[Retracted] Expression of USP22 and Survivin is an indicator of malignant behavior in hepatocellular carcinoma.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that a pair of data panels showing the results of immunohistochemical staining experiments in Fig. 1 on p. 2210 had already appeared in a previously published paper (Zhang Y, Li Y, Lin C, Ding J, Liao G and Tang B: Aberrant upregulation of 14­3­3σ and EZH2 expression serves as an inferior prognostic biomarker for hepatocellular carcinoma. PLos ONE 9: e107251, 2014).  Owing to the fact that the contentious data in the above article had already been published prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 47: 2208­2216, 2015; DOI: 10.3892/ijo.2015.3214].

Depletion of PARP10 inhibits the growth and metastatic potential of oral squamous cell carcinoma.

Background: Although poly (ADP-ribose) polymerase family member 10 (PARP10) has been implicated in the progression of multiple cancer types, its role in oral squamous cell carcinoma (OSCC) remains unknown. This study aimed to examine the function of PARP10 in OSCC and investigate the underlying mechanisms. Methods: The expression of PARP10 in OSCC was investigated in OSCC patient cohorts. Kaplan-Meier curve analysis was performed to assess the association between PARP10 and prognosis in OSCC. Correlation between PARP10 expression and the related variables was analyzed by χ2 test. CKK-8, transwell assay, western blot, immunohistochemistry, immunofluorescence, and bioinformatic analysis, were applied to clarify the role of PARP10 in OSCC. Results: PARP10 was found to be markedly elevated in OSCC tissues. The upregulation of PARP10 predicted shorter overall survival and disease-specific survival and was significantly correlated with several malignant features. Moreover, depletion of PARP10 markedly inhibited the proliferation, migration, and invasion of OSCC cells, and promoted OSCC cell apoptosis, and resulted in alterations of relevant proteins. Furthermore, a positive correlation was observed between the expression of PARP10 and Ki67, PARP1, MMP2, and VEGF. In addition, depletion of PARP10 impaired the PI3K-AKT and MAPK signaling pathways. Conclusion: PARP10 is involved in the progression of OSCC via regulation of PI3K-AKT and MAPK signaling pathways.

ER-α36 mediates gastric cancer cell invasion.

Estrogen evidently exerts a protective role against gastric cancer. Accordingly, we evaluated the relationship between the expression of the estrogen receptor ER-α36 and the clinicopathologic features in gastric cancer. ER-α36 expression levels differed among the tumor center, invasion front, and vascular metastases. The effects of E2ß (17ß-Estradiol, E2ß) on invasion ability in SGC7901, High36 (with ER-α36 upregulation), and Low36 (with ER-α36 downregulation) cells were evaluated using Transwell assays. Furthermore, the c-Src signaling pathway was inhibited using PP2 and the effects on E2ß-induced increases in E-cadherin, MMP2, and MMP9 were evaluated using western blotting. ER-α36, c-Src, MMP2, and E-cadherin levels were also evaluated in tumor xenografts. We found that 0.1 nM E2ß promoted gastric cancer cell invasion by reducing E-cadherin expression and increasing MMP2 and MMP9 levels. The upregulation of ER-α36 promoted gastric cancer cell invasion and the downregulation of ER-α36 reduced the invasive ability of cells. The levels of ER-α36, c-Src, and MMP2 were the highest in tumor xenografts using High36 cells, intermediate in tumor xenografts using SGC7901 cells, and lowest in tumor xenografts using Low36 cells. The opposite results were obtained for E-cadherin expression. ER-α36 enhanced gastric cancer cell invasion by the activation of membrane-initiated c-Src signaling pathways. In particular, treatment with E2ß and ER-α36 influenced gastric cancer cell invasion. Furthermore, c-Src was involved in the ER-α36-mediated estrogen signaling pathway and cell invasion.

Role of HOXB7 in promoting gastric cancer progression and oxaliplatin (L-OHP) resistance.

BACKGROUND AND AIM: Our study aimed to investigate the ways by which HOXB7 affects gastric cancer progression and oxaliplatin (L-OHP) resistance. METHODS: First, the expression of HOXB7 in paired cancer and paracancerous tissues of L-OHP-sensitive and L-OHP-resistant gastric cancer patients was qualitatively and quantitatively analyzed by immunohistochemistry. Then, the expression of HOXB7 in these tissues was further quantitatively analyzed at protein and transcriptional levels. The expression of HOXB7 in the SGC-7901 L-OHP-resistant gastric cancer cell line was further verified by immunofluorescence, western blot, and RT-qPCR. In addition, by transfecting the SGC-7901 cell line, control (sh-con) and HOXB-7-silenced (sh-HOXB7) gastric cancer cell lines were created. Subsequently, the migratory and invasive abilities of these cells were determined by the transwell assay. The proliferation rate of both control and HOXB-7-silenced cells induced by varying concentrations of L-OHP was detected by the CCK-8 assay, while the degree of apoptosis in the same cells induced by 60 µM L-OHP was detected by flow cytometry. RESULTS AND CONCLUSION: Results suggested that HOXB7 was overexpressed in both the tissues of L-OHP-resistant gastric cancer patients and the SGC-7901 gastric cancer cell line. Moreover, HOXB7 promoted the migratory and invasive abilities of gastric cancer cells. By silencing HOXB7 protein expression, the proliferation rate of L-OHP-resistant gastric cancer cells decreased considerably, while their degree of apoptosis increased significantly. These results showed that HOXB7 promoted gastric cancer progression and L-OHP resistance.

Nationwide survey of cervical cytology laboratory practices in China.

INTRODUCTION: Cervical cancer rates in China remain high, with only limited opportunistic screening in urban centers and large mostly unscreened rural areas. Cervical cytology practices in China have been changing over the last decade with introduction of The Bethesda System reporting terminology, liquid-based cytology (LBC), and programs for cervical cytology screening of underserved rural populations. An effort was undertaken for the first time to collect nationwide data on cervical cytology laboratory practices in China, a possible first step toward increased standardization and potential development of nationwide cytology quality benchmarks. MATERIALS AND METHODS: Data on cervical cytology practices from 1572 laboratories operating in 26 nationwide Provisional Level Administrative Divisions was collected in an online survey approved through the Obstetrics and Gynecology Hospital of Fudan University in Shanghai. RESULTS: Over 90% of cervical cytology laboratories in China now solely use Bethesda System reporting terminology. LBC is now the most commonly utilized form of cervical cytology, with lower-cost Chinese-manufactured LBC formulations used in almost 70% of laboratories. Nationwide, significantly higher abnormal cytology rates were reported with LBC than with the conventional Papanicolaou smear (CPS); however, the CPS remains a useful low-cost alternative as China strives to extend cervical screening to large underserved rural areas. CONCLUSIONS: Abnormal cytology rates were not significantly different when different levels of hospitals were compared. The survey identified nationwide opportunities for cytology quality improvement, including low rates of reporting of unsatisfactory cases and low rates for atypical glandular cells.

Mechanism of cadmium poisoning on testicular injury in mice.

Cadmium is a heavy metal that is toxic to humans and the reproductive system. The present study aimed to investigate the mechanisms of cadmium-induced reproductive toxicity in a male Institute of Cancer Research mouse model of cadmium poisoning. Changes in luteinizing hormone receptor (LHR), 17α-hydroxylase and endothelial nitric oxide (NO) synthase (eNOS) expression levels were examined. A total of 24 male mice (4-week-old) were randomly divided into four groups (normal control group and low, medium and high cadmium groups) and subjected to gavage treatment with normal saline or cadmium-containing saline solutions for 8 weeks prior to sacrifice. To assess testicular injury, serum androgen levels were determined by ELISA, testicular tissue pathological changes were evaluated using hematoxylin and eosin staining. In addition, LHR, 17α-hydroxylase and eNOS expressions levels were examined by western blotting, and apoptosis was examined with a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results demonstrated that the severity of testes injury increased with cadmium concentration. In addition, LHR, 17α-hydroxylase and eNOS expression levels increased with low and medium concentrations of cadmium; however, they were decreased following treatment with high concentrations of cadmium. The results from the present study demonstrated that cadmium altered LHR, 17α-hydroxylase and eNOS expression levels in testicular stromal cells, which may impact testosterone synthesis. Furthermore, NO was suggested to be involved in cadmium-induced testicular injury by measurements of eNOS expression in testicular stromal cells.

Expression of USP22 and the chromosomal passenger complex is an indicator of malignant progression in oral squamous cell carcinoma.

Oral cancer is a common cancer of the head and neck. Oral squamous cell carcinoma (OSCC) represents almost 90% of the total cases of head and neck cancer. Ubiquitin-specific protease 22 (USP22) is a deubiquitinating hydrolase, and it is highly expressed in various types of cancer, which also typically have a poor prognosis. Aurora-B and Survivin, which belong to the chromosomal passenger complex, are also highly expressed in a number of types of cancer. In the present study, USP22 expression and its associations with Aurora-B and Survivin, and the clinicopathological features in OSCC were explored. USP22 is highly expressed in OSCC. Overexpression of USP22 is associated with lymph node metastasis and histological grade (P<0.01). Additionally, the expression of USP22 was positively associated with Aurora-B (P<0.01), Survivin (P<0.01), and Ki-67 (P<0.01). Furthermore, USP22 small interfering RNA inhibited cell growth and reduced the expression levels of Aurora-B, Survivin and Cyclin B, together with the upregulation of cyclin-dependent kinase inhibitor 1A (p21). These data suggest that USP22, Aurora-B and Survivin promote the OSCC development and may represent novel targets for OSCC diagnosis and treatment in the future.

Expression of survivin, MUC2 and MUC5 in colorectal cancer and their association with clinicopathological characteristics.

Survivin is a bifunctional protein that suppresses apoptosis and regulates cell division, and is highly expressed in various cancer types. Mucins are high-molecular-weight, heavily glycosylated proteins. In the present study, the association between survivin, mucin 2 (MUC2) and MUC5 expression, and the clinicopathological features of colorectal cancer (CRC) were investigated. The immunohistochemistry and western blotting results demonstrated that survivin was highly expressed in CRC tissues and rarely expressed in normal colon tissues. Moreover, the overexpression of survivin and MUC5 was strongly associated with lymph node metastasis, poor cellular differentiation, advanced tumor stage and a poor prognosis in CRC. By contrast, low expression of MUC2 was significantly associated with lymph node metastasis, poor cellular differentiation and an advanced tumor stage in CRC. The results of the present study suggest that survivin, MUC2 and MUC5 levels may be associated with tumor progression and could be used to aid the early diagnosis and clinical characterization of CRC.

MPTP Induces Systemic Parkinsonism in Middle-Aged Cynomolgus Monkeys: Clinical Evolution and Outcomes.

In this study, we developed a systemic PD model in middle-aged cynomolgus monkeys using individualized low-dose MPTP, to explore effective indicators for the early prediction of clinical outcomes. MPTP was not stopped until the animals showed typical PD motor symptoms on days 10 to 13 after MPTP administration when the Kurlan score reached 10; this abrogated the differences in individual susceptibility to MPTP. The clinical symptoms persisted, peaking on days 3 to 12 after MPTP withdrawal (rapid progress stage), and then the Kurlan score plateaued. A Kurlan score at the end of the rapid progress stage >15 reflected stable or slowly-progressive PD, while a score <15 indicated spontaneous recovery. The entire clinical evolution and outcome of the systemic PD model was characterized in this study, thus providing options for therapeutic and translational research.

PARP6 acts as a tumor suppressor via downregulating Survivin expression in colorectal cancer.

Poly (ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and are involved in a variety of biological processes. PARP6 is a novel member, and our previous findings suggest that PARP6 may act as a tumor suppressor via suppressing cell cycle progression. However, it is still unclear that PARP6 function besides growth suppression in colorectal cancer (CRC). In this study, we examined tumor suppressive roles of PAPR6 in CRC cells both in vitro and in vivo. We found that PARP6 inhibited colony formation, invasion and migration as well as cell proliferation. Moreover, ectopic overexpression of PARP6 decreased Survivin expression, which acts as an oncogene and is involved in apoptosis and mitosis. We confirmed the inverse correlation between PARP6 and Survivin expression in CRC cases by immunohistochemistry. Importantly, CRC cases with downregulation of PARP6 and upregulation of Survivin showed poor prognosis. In summary, PARP6 acts as a tumor suppressor via downregulating Survivin expression in CRC. PARP6 can be a novel diagnostic and therapeutic target together with Survivin for CRC.

Downregulation of betaine homocysteine methyltransferase (BHMT) in hepatocellular carcinoma associates with poor prognosis.

Betaine homocysteine methyltransferase (BHMT) catalyzes the synthesis of methionine using betaine and homocysteine (Hcy), which is restricted to the liver and kidney. Impaired BHMT pathway has been associated with hepatocellular carcinogenesis in Bhmt-/- mice model, and decreased BHMT was observed in a small sample of human hepatocellular carcinoma (HCC) patients. However, the prognostic significance of BHMT in HCC has not been elucidated. This study aimed to examine the expression of BHMT in HCC and investigate the relationship between its expression and prognosis of HCC patients. BHMT expression was analyzed in 68 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), 115 paraffin-embedded HCC sections (primary cohort), and 65 paraffin-embedded HCC sections (validation cohort) using immunohistochemistry (IHC). The results of IHC analysis showed that BHMT was decreased in tumorous tissues in 85.2 % (58/68) of cases compared to the corresponding adjacent non-tumorous liver tissues. Further correlation analyses indicated that the decreased BHMT expression was closely correlated with serum α-fetoprotein (AFP) (p = 0.011), tumor size (p = 0.039), and vascular invasion (p = 0.017). Moreover, HCC patients with low BHMT expression had shorter overall survival (OS) and time to recurrence (TTR) than those with high BHMT expression in both primary cohort (p < 0.0001) and validation cohort (p < 0.05) assessed by the Kaplan-Meier method. In addition, multivariate analysis showed that BHMT was an independent prognostic factor for OS and TTR in the two cohorts (all p < 0.005). Collectively, our study demonstrated that BHMT could be served as a potential prognostic marker for HCC patients.

Expression of USP22 and Survivin is an indicator of malignant behavior in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor type, ranking as the third leading cause of all cancer-related deaths in the world. The post-surgical 5-year survival rate is low, largely due to the high recurrence rate. Therefore, the identification of target molecules that control the biological characteristics of HCC is of great importance. Ubiquitin-specific protease 22 (USP22) is a newly discovered deubiquitinating enzyme and is a cancer stem cell marker that plays a role in tumorigenesis, therapy resistance and cell cycle progression. Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is known to function either as an inhibitor for apoptosis or as a regulator of cell division. Levels of survivin are correlated with the aggressiveness of tumors and a poor prognosis in various cancers including HCC. In the present study, we examined the USP22 expression and its association with survivin expression and clinicopathological features in HCC. First, we examined the expression of USP22 and survivin in 151 HCC cases by immunohistochemistry. High expression of USP22 and survivin was frequently observed in HCC cases, in comparison with normal adjacent liver tissues. Expression of USP22 and survivin was well correlated with malignant behavior including tumor size, stage and differentiation in HCC cases. Importantly, HCC patients with high expression of USP22 and survivin showed poor prognosis. USP22 expression was well correlated with survivin expression in HCC cases. This correlation was confirmed in HCC cell lines and tissues by RT-PCR and western blot analysis. Next, to investigate the biological role of USP22 in HCC, we examined the effect of USP22 knockdown on the cell growth and the expression of cell cycle-related protein including survivin in HCC cells. USP22 siRNA suppressed cell growth. Moreover, USP22 siRNA decreased survivin expression together with upregulation of CDK inhibitor, p21 and downregulation of cyclin B. These findings suggest that USP22 may be involved in HCC progression in cooperation with survivin. We suggest that USP22 can be useful as a new prognostic marker and therapeutic target in HCC patients.

Effects of high-fat diet on 1,2-dimethylhydrazine-induced aberrant crypt foci and colorectal tumours in rats.

Obesity is one of the leading causes of numerous types of cancer. The present study investigated the impact of a high-fat diet on 1,2-dimethylhydrazine (DMH)-induced colorectal cancer (CRC) in F344 rats. A total of 16 male F344 rats aged 4 weeks were randomly divided into two groups (8 rats/group). Rats in group A were fed a basal diet with a moderate fat (MF) content, while rats in group B were fed a high-fat diet. Upon reaching 5 weeks of age, the rats were injected subcutaneously with DMH (20 mg/kg body weight). DMH was administered once a week for 8 consecutive weeks. All the rats were sacrificed 34 weeks after the first DMH injection and dissected to obtain samples of colorectal tissues. The tissues were examined under a microscope for the presence of aberrant crypt foci (ACFs) and subjected to histopathological analysis. The results showed that at the end of the 34-week experiment, body weights and visceral fat levels were significantly higher in the high-fat diet group compared to the basal diet group. In addition, the incidences of colorectal ACF, adenoma and adenocarcinoma were markedly elevated in the high-fat diet group compared to the basal diet group. These results indicate that the consumption of a high-fat diet promotes the development and progression of CRC and the control of fat intake may prevent CRC.

Inhibitory effect of various breads on DMH-induced aberrant crypt foci and colorectal tumours in rats.

Bread is rich in dietary fibre and many phytochemical compounds, which may influence chemoprevention of colon cancer. In the present study, we evaluated the effect of three kinds of bread on DMH-induced colorectal tumours in F344 rats. F344 rats were divided into four groups (Steinmetz Three-Grain bread, Steinmetz Country bread, White bread, and MF). All groups were injected with 1,2-dimethylhydrazine (DMH, 20 mg/kg body weight) once a week for 8 consecutive weeks from 5 weeks of age. To investigate the antioxidant effect of bread, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging rate of bread and the serum levels of 8-hydroxy-deoxyguanosine (8-OHdG) in rats were examined. The number of colorectal aberrant crypt foci (ACF) and the incidence of colorectal tumours were studied after 34 weeks of DMH treatment. The Steinmetz Three-Grain and Steinmetz Country bread groups had higher scavenging rates of the DPPH free radical and lower serum levels of 8-OHdG and incidence of ACF, adenomas, and adenocarcinomas of colon than the White bread and MF group. Steinmetz Three-Grain bread and Steinmetz Country bread have various ingredient combinations that may inhibit colorectal cancer progression.

Effects of extremely low-frequency electromagnetic fields (ELF-EMF) exposure on B6C3F1 mice.

OBJECTIVE: Long-term exposure study was conducted to investigate the effects of extremely low-frequency electromagnetic field on the tumor promotion process and fertility. METHODS: Ten pregnant C57BL/6NCrj mice were exposed to 50 Hz field 500 mG for 1 week (12 h per day), and 24 male and 42 female B6C3F1mice born from them were further exposed up to 15.5 months. As a control group, 10 pregnant mice were bred without exposure, and 30 produced male and 32 female mice were observed without exposure for the same period. RESULTS: Mean body weights of exposed groups of male and female mice were decreased significantly than those of the control groups. In exposed mice, there was no increased incidence of liver and lung tumor. In female mice, the incidence of chronic myeloid leukemia [3/42 (7%)] in the exposed group was significantly greater than in the control group. The size of seminiferous tubules in the EMF exposed groups were significantly less than the control group. CONCLUSIONS: These data support the hypothesis that long-term exposure of 50 Hz magnetic fields is a significant risk factor for neoplastic development and fertility in mice.

Biochanin A promotes proliferation that involves a feedback loop of microRNA-375 and estrogen receptor alpha in breast cancer cells.

BACKGROUND: Biochanin A and formononetin are O-methylated isoflavones that are isolated from the root of Astragalus membranaceus, and have antitumorigenic effects. Our previous studies found that formononetin triggered growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. We performed in vivo and in vitro studies to further investigate the potential effect of biochanin A in promoting cell proliferation in estrogen receptor (ER)-positive cells, and to elucidate underlying mechanisms. METHODS: ERα-positive breast cancer cells (T47D, MCF-7) were treated with biochanin A. The MTT assay and flow cytometry were used to assess cell proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were quantified using real-time polymerase chain reaction. Compared with the control, low biochanin A concentrations (2-6 µM) stimulated ERα-positive cell proliferation (T47D, MCF-7). The more sensitive T47D cells were used to study the relevant signaling pathway. RESULTS: After treatment with biochanin A, ERα, miR-375, and Bcl-2 expression was significantly upregulated. Additionally, in the in vivo studies, uterine weight in ovariectomized mice treated with biochanin A increased significantly. CONCLUSION: This study demonstrated that biochanin A promoted ERα-positive cell proliferation through miR-375 activation and this mechanism is possibly involving in a miR-375 and ERα feedback loop.

Expression of cluster of differentiation-95 and relevant signaling molecules in liver cancer.

The present study investigated the protein expression levels of cluster of differentiation (CD)95, caspase­8, caspase­3 and poly(ADP­ribose) polymerase 1 (PARP1) in liver cancer and its association with clinical pathological parameters. The results demonstrated that the expression of CD95 correlated with histological differentiation, liver cirrhosis, lymph node metastasis and distant metastasis (P<0.05), however, no correlations with gender, age, quantity of tumor nodules or T stage were observed (P>0.05). The expression of CD95 was upregulated using a plasmid, which led to an increase in the expression levels of caspase­8 and caspase­3 and a decrease in the expression of PARP1. Upregulation of CD95 also promoted the apoptosis of the liver cancer cells. These results indicated that CD95 was associated with liver cancer and promoted the apoptosis of liver cancer cells by caspase­8, caspase­3 and PARP1.

Up-regulating of RASD1 and apoptosis of DU-145 human prostate cancer cells induced by formononetin in vitro.

Prostate cancer is one of the most prevalent malignant cancers in men. The isoflavone formononetin is a main active component of red clover plants. In the present study, we assessed the effect of formononetin on human prostate cancer DU-145 cells in vitro, and elucidated possible mechanisms. DU-145 cells were treated with different concentrations of formononetin and cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 and flow cytometry, and protein levels of RASD1, Bcl-2 and Bax by Western blotting. The results showed that formononetin inhibited the proliferation of DU-145 cells in a dose-dependent manner. DU-145 cells treated with different concentrations of formononetin displayed obvious morphological changes of apoptosis under fluorescence microscopy. In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax. The level of RASD1 reached its maximum at 48 h post-treatment, and rapidly decreased thereafter. Together, we present evidence that formononetin triggered cell apoptosis through the mitochondrial apoptotic pathway by up-regulating RASD1.

CtBP1 is involved in epithelial-mesenchymal transition and is a potential therapeutic target for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly invasive type of cancer. Metastasis is the leading cause of mortality of advanced HCC patients. In the metastasis cascade, cancer cells undergo epithelial-mesenchymal transition resulting in the loss of cell­to­cell adhesion, migration and invasion into the stroma. Loss of E-cadherin expression is a key molecular event in epithelial-mesenchymal transition through several regulatory mechanisms including epigenetic modification, regulation by inhibitory transcriptional factors and deletion of chromosome 16q24 locus. C-terminal binding protein 1 (CtBP1) functions as a corepressor binding to several transcriptional factors and suppresses E-cadherin expression. We found that CtBP1 was upregulated in HCC when compared with paired normal liver tissues and was inversely correlated with E-cadherin expression in HCC by immunohistochemical assay using tissue array. Western blot analysis confirmed the results of the immunohistochemical assays. When CtBP1 was knocked down by siRNA in HepG2 cells (a human HCC cell line), E-cadherin was upregulated and the invasive ability of HepG2 cells was inhibited. In addition, following CtBP1 knockdown, the cell viability was decreased along with increased apoptosis rather than cell cycle arrest. These data suggest a pivotal role of CtBP1 in EMT of HCC, and its potential as a therapeutic target in human disease.

Age-related decline in motor behavior and striatal dopamine transporter in cynomolgus monkeys.

Advanced human aging is associated with progressive declines of motor function and a risk factor for Parkinson's disease, which mainly involves central nigrostriatal dopaminergic system. The present study investigated age-related changes in motor behaviors and alterations of the number of nigrostriatal dopaminergic terminals in non-human primates. A total of 30 cynomolgus monkeys (Macaca fascicularis) of age 3.5-15.5 years were studied. Motor behaviors including upper limb movement time and the amount of overall home cage activity were quantitatively assessed using a modified movement assessment panel and a newly developed webcam-based monitoring system. The function of the dopaminergic system was semi-quantitatively measured by (99m)Tc-TRODAT-1 uptake rates, a dopamine transporter (DAT) specific radiopharmaceutical with SPECT imaging. The results showed a significant decline in motor behaviors associated with aging which were significantly correlated with age-related decreases of (99m)Tc-TRODAT-1 uptake. A further partial correlation analysis independent of age indicated that age contributed to the relationship between striatal DAT levels and motor behaviors. Our results indicate that normal aging-related dopamine physiology influences certain aspects of motor behaviors and suggest that aging-associated dysfunction in the nigrostriatal dopaminergic system may be an important factor contributing to the decline of motor behaviors in aging cynomolgus monkeys.