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Multi-targets inhibitor 6-bromo-indirubin-3'-oxime (BIO) has diverse biological effects on cancer cells. The key component of the β-catenin destruction complex glycogen synthase kinase 3β (GSK-3β), one of the major target for BIO, polyubiquitination and degradation of the main oncoprotein β-catenin in colorectal cancer (CRC). In the present study, we evaluated the effect of BIO on drug resistance and biological properties of CRC cells. Whole-genome transcriptional profiling revealed that differentially expressed genes were mainly centered on well-characterized signaling pathways including stem cell, cell adhesion and cell growth in BIO-treated CRC cells. BIO treatment downregulated migration and invasion abilities of CRC cells, accompanying with MMP-9 downregulated and E-cadherin upregulated CRC cells. BIO treatment decreased apoptosis induced by 5-Fu/DDP in CRC SW480 cells. In addition, BIO treatment reversed the 5-Fu-induced CD133+ cell downregulation trend in CRC SW620 cells. After incubation with BIO, the expression levels of EpCAM, TERT and DCAMKL-1 proteins were upregulated in CRC cells. BIO treatment downregulated the activity of GSK-3β, upregulated and transported β-catenin to the nucleus in CRC cells. Our findings reveal that BIO treatment upregulated stemness, adhesive and chemoresistance of CRC cells. GSK-3β inhibition and WNT/β-catenin activation by BIO, may partly result in the biological behavior alterations in CRC cells.

// Feng Luo 1, * , Jinbang Li 1, * , Shigang Wu 1 , Xuefang Wu 1 , Meixiang Chen 1 , Xueyun Zhong 2 , Kunping Liu 1 1 Department of Pathology, Qingyuan People’s Hospital, Jinan University, Qingyuan 511518, China 2 Department of Pathology, Medical College, Jinan University, Guangzhou 510632, China * These authors have contributed equally to this work Correspondence to: Kunping Liu, email: gdqylkp@163.com Xueyun Zhong, email: tzxy@jnu.edu.cn Keywords: colorectal cancer, drug resistance, WNT signaling pathway, EMT, cancer stem cells Received: March 14, 2016 Accepted: August 11, 2016 Published: August 24, 2016 ABSTRACT Metastases cause recurrence and mortality for patients with colorectal carcinomas (CRC). In present study, we evaluated heterogeneity on drug resistance and its underlying mechanism between metastatic and primary CRC. Immunohistochemical results from clinical tissue microarray (TMA) suggested that the expression concordance rates of cancer stem cells (CSCs) and drug resistance relative proteins between lymph-node metastatic and primary CRC foci were low. The apoptotic and proliferation indexes in metastasis CRC specimens were decreased compared with primary. In vitro experimental results indicated that the migration and invasion abilities were upregulated in metastatic cells SW620 compared with primary cells SW480, the cellular efflux ability and WNT/β-catenin activity were also upregulated in SW620 cells. After 5-fluorouracil (5-Fu) treatment, the reduction in the proportion of cell apoptosis, CD133 and TERT expression levels in SW620 were lower than that in SW480 cells. Bioinformatics analysis in whole-genome transcriptional profiling results between metastatic and primary CRC cells suggested that differentially expressed genes were mainly centered on well-characterized signaling pathways including WNT/β-catenin, cell cycle and cell junction. Collectively, heterogeneity of drug resistant was present between metastatic and primary CRC specimens and cell lines, the abnormal activation of WNT/β-catenin signaling pathway could be a potential molecular leading to drug resistant ability enhancing in metastatic CRC cells.

This study investigated the relationship between obesity and executive function, and between executive function and fall risk (as estimated from select gait parameters). Of the 39 young adults (age = 21.3 ± 2.6 years) recruited from the local university population via email announcement, 19 were in the obese group (based upon BMI and body fat percentage) and 20 were in the nonobese comparison group. Executive function was assessed using standardized tests including the Stroop test for selective attention; Trail Making test for divided attention, visuomotor tracking, and cognitive flexibility; the Verbal Fluency test for semantic memory; and the Digit-span test for working memory. Participants performed single- and dual-task walking (walking while talking) to evaluate fall risk during gait as measured by minimum toe clearance, required coefficient of friction, stance time, and stance-time variability. The obese group had lower scores for selective attention, semantic memory, and working memory. All participants had gait changes suggestive of a higher fall risk, for example, lower minimum toe clearance, longer stance time, and increased stance variability, during dual-task walking compared with single-task walking, and executive function scores (selective attention) were associated with gait (stance-time variability) during dual-task walking. RESULTS indicate obesity was negatively associated with executive function among young adults and could increase fall risk.© The Author(s) 2016. Language: en

Falls due to slipping are a serious concern, with slipping estimated to cause 40-50% of all fall-related injuries. Epidemiological data indicates that older and obese adults experience more falls than young, non-obese individuals. An increasingly heavier and older U.S. population and workforce may be exacerbating the problem of slip-induced falls. The purpose of this study was to investigate the effects of obesity and age on slip severity and rate of falling resulting from laboratory-induced slips. Four groups of participants (young obese, young non-obese, older obese, older non-obese) were slipped while walking at a self-selected, slightly hurried pace. Slip severity (slip distance, slip duration, mean slip speed and peak slip speed) and slip outcome (fall or recovery) were compared between groups. Obese individuals experienced 22% faster slips than non-obese individuals in terms of mean slip speed (p=0.022). Obesity did not affect slip distance, slip duration or peak slip speed. Obese individuals also exhibited a higher rate of falls; 32% of obese individuals fell compared to 10% of non-obese (p=0.005). Obese individuals were more than eight times more likely to experience a fall than non-obese individuals when adjusting for age, gender and gait speed. No age effects were found for slip severity or slip outcome. These results, along with epidemiological data reporting higher fall rates among the obese, indicate that obesity may be a significant risk factor for experiencing slip-induced falls. Slip severity thresholds were also reported that may have value in developing controls for fall prevention.

Aberrant Wnt signaling pathway is associated with a wide array of tumor types and plays an important role in the drug resistance of cancer stem cells (CSCs). To explore the effects and mechanism of WNT signaling pathway inhibitor XAV939 on drug resistance in colon cancer cells, the colon cancer cells SW480 and SW620 were treated with 5-fluorouracil (5-FU)/cisplatin (DDP) alone or combined with XAV939. Cell cycle distribution, apoptosis level and the percentage of CD133+ cells were detected by flow cytometry. The protein expression of Axin, β-catenin, EpCAM, TERT and DCAMKL-1 was detected by western blotting. XAV939 upregulated Axin , decreased the total and nuclei of β-catenin in SW480 and SW620 cells. Furthermore, XAV939 significantly downregulated the CSC markers EpCAM, TERT and DCAMKL-1 in SW480 cells, as well as EpCAM in SW620 cells. No significant difference was found in the apoptosis of SW480 and SW620 cells with XAV939 treatment, but XAV939 significantly increased apoptosis induced by 5-FU/DDP in SW480 cells, whereas, the effects were slight in SW620 cells. Collectively, we show for the first time that the WNT signaling pathway inhibitor XAV939 was able to significantly increase the apoptosis induced by 5-FU/DDP, accompanied by the protein expression level alternation of β-catenin, Axin and CSC markers in colon cancer cells. Axin, an important component of Wnt/β-catenin signaling pathway could be a potential molecular target for reversing multidrug resistance in colon cancer.

Impaired foot plantar sensitivity has been hypothesized among individuals who are obese, and may contribute to their impaired balanced during quiet standing. The objective of this study was to investigate the effects of obesity on plantar sensitivity, and explore the relationship between plantar sensitivity and balance during quiet standing. Thirty-nine young adults from the university population participated in the study including 19 obese and 20 non-obese adults. Plantar sensitivity was measured as the force threshold at which an increasing force applied to the plantar surface of the foot was first perceived, and the force threshold at which a decreasing force was last perceived. Measurements were obtained while standing, and at two locations on the plantar surface of the dominant foot. Postural sway during quiet standing was then measured under three different sensory conditions. Results indicated less sensitive plantar sensitivity and increased postural sway among the obese, and statistically significant correlations between plantar sensitivity and postural sway that were characterized as weak to moderate in strength. As such, impaired plantar sensitivity among individuals who are obese may be a mechanism by which obesity degrades standing balance among these individuals.

This study examines the predictive ability of fall risks among community dwelling elderly using wearable wireless sensors. Forty-eight community-dwelling elderly (17 non-fallers and 31 fallers) participated in the study. Timed up and go test, sit-to-stand test and ten-meter walking test were carried out. Activitiesspecific Balance Confidence (ABC) Scale was also obtained. The results showed fairly good predictive ability of fall risks among older adults, with stance time, walking velocity and timed up and go time being promising of indicating fall risks. Further investigation is warranted to better understand the signals from the wearable sensors and justify the model. Larger sample size is also warranted to validate the model.

The purpose of this study was to describe antecedents and characteristics of nonfatal fall-related injuries among health care workers in the United States. A special request was made for the Bureau of Labor Statistics to obtain nonfatal fall-related injury data from 2008 to 2010. Overall, workers in the nursing-related profession had the highest percentages of workplace fall-related injuries. Ninety-one percent of these injured workers were female, and more than 50% were between the ages of 45 and 64 years. More than 25% of fall injuries resulted in 31 or more workdays being lost. This study indicated that the most affected body parts were the lower extremities, with most injuries resulting in sprains, strains, and tears. Accordingly, this 3-year study revealed that a high number of fall injuries occurred at night for health care workers compared to other workers in the U.S. private sector.

To explore the effects and mechanism of glycogen synthase kinase 3β (GSK-3β) inhibitor (2'Z,3'E)-6-bromo-indirubin-3'-oxime (BIO) on drug resistance in colon cancer cells.The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil (5-FU) and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 (Rh123) were detected by flow cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), β-catenin, E2F-1 and Bcl-2 were detected by Western blot. β-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope.BIO up-regulated β-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 cells. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G(2)/M phase cells, and reduced the cell apoptosis induced by 5-FU in SW480 cells, whereas the effects were slight or not obvious in SW620 cells.GSK-3β was involved in drug resistance regulation, and activation of β-catenin and inhibition of E2F-1 may be the most responsible for the enhancement of 5-FU chemotherapy resistance induced by GSK-3β inhibitor BIO in colon cancer.

Obesity is associated with structural and functional limitations with impairment of normal gait. Although falls have been identified as the most common cause of injuries in the obese, the mechanisms associated with increased fall risk among the obese population are still unknown. The purpose of this study was to investigate the influence of gait adaptations of the obese individuals and its implication on risk of slip initiations as measured by friction demand characteristics. To exclude the aging and gender effects, a total of ten healthy young male adults participated in the study. Kinematic and kinetic data were collected using a three-dimensional motion analysis system and force plates while subjects were walking at their self-selected walking pace. Results indicated that young obese adults walked similarly as their lean counterparts except for exhibiting greater step width and higher transversal friction demand, suggesting that slip-induced fall risks are similar along the horizontal direction, but increased along the transversal direction under certain floor conditions.

Obese aging population is increasing in the United States, and obese elderly experience fall twice as frequent as their lean counterparts. However, the mechanisms of older obese adults fall are still not clear. It is not known whether the obese elderly has more functional mobility impairments than their lean counterparts, and consequently have increased risks of falls. It was hypothesized that obese elderly have more functional mobility impairments compared with their healthy weight counterparts. Six lean and six obese community-dwelling elderly participated in the study. “Timed up & go” test was used to quantify the functional mobility for both lean and obese elderly. Stopwatch and custom-made inertial measurement units were used to obtain the temporal and kinematic parameters. The results showed that there is no significant difference in overall time to complete the “timed up & go” task, but significant difference in anterior posterior acceleration, time to reach the peak extension angular velocity from initiation and double support time between lean and obese groups of participants. Therefore, we concluded that older obese adults have some functional mobility impairments compared with their lean counterparts but the completion time of the “timed up & go” test may not be able to differentiate these individuals. Our results also suggested that obese elderly might have more muscular impairments than their healthy weight counterparts, which can result in higher fall risks. Future studies are warranted to investigate the mechanisms of increased fall risks among obese elderly.

Approximately 25% to 27% of women sustain a fall during pregnancy, and falls are associated with serious injuries and can affect pregnancy outcomes. The objective of the current study was to identify intrinsic factors associated with pregnancy that may contribute to women's increased risk of falls. A literature search (Medline and Pubmed) identified articles published between January 1980 and June 2013 that measured associations between pregnancy and fall risks, using an existing fall accident investigation framework. The results indicated that physiological, biomechanical, and psychological changes associated with pregnancy may influence the initiation, detection, and recovery phases of falls and increase the risk of falls in this population. Considering the logistic difficulties and ethnic concerns in recruiting pregnant women to participate in this investigation of fall risk factors, identification of these factors could establish effective fall prevention and intervention programs for pregnant women and improve birth outcomes. [Workplace Health Saf 2014;62(10):403-408.].

e13592 Background: GSK-3β participates in a variety of important physiological processes. However, the roles of GSK-3 β in the biological properties and drug resistance of tumor cells remains contr...