Yau-Hua Yu

The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers

Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemness-maintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs.

Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated.ResultsInitially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (memGRP78+) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 memGRP78+ HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both in vitro and in vivo. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN.ConclusionsIn summary, memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.

Exploring How Peak Leg Power and Usual Gait Speed Are Linked to Late-Life Disability: Data from the National Health and Nutrition Examination Survey (NHANES), 1999–2002

Kuo HK, Leveille SG, Yen CJ, Chai HM, Chang CH, Yeh YC, Yu YH, Bean JF: Exploring leg power and gait speed in late-life disability: Data from the National Health and Nutrition Examination Survey (NHANES), 1999–2002. Am J Phys Med Rehabil 2006;85:650–658. Objective:To investigate the relation of both peak leg power and usual gait speed in their association with varying domains of late-life disability. Design:Participants (≥60 yrs of age, n = 1753) were from the National Health and Nutrition Examination Survey, 1999–2002. Disability in activities of daily living, instrumental activities of daily living, leisure and social activities, lower limb mobility, and general physical activities was obtained by self-report. Peak muscle power was the product of isokinetic peak leg torque and peak force velocity. Functional limitations were evaluated via usual gait speed, which was obtained from a 20-foot timed walk. Results:Low usual gait speed was associated with disability independent of basic demographics, cognitive performance, co-morbidities, health behaviors, and inflammatory markers. The odds ratios for disabilities in activities of daily living, instrumental activities of daily living, leisure and social activities, lower limb mobility, and general physical activities for each standard-deviation increase in walking speed were 0.72 (95% confidence interval [CI], 0.59–0.87), 0.63 (95% CI, 0.52–0.77), 0.57 (95% CI, 0.45–0.72), 0.56 (95% CI, 0.47–0.67), and 0.74 (95% CI, 0.64–0.85), respectively. The odds ratios for disabilities in activities of daily living, instrumental activities of daily living, leisure and social activities, lower limb mobility, and general physical activities for each standard-deviation increase in leg power were 0.70 (95% CI, 0.55–0.89), 0.67 (95% CI, 0.53–0.86), 0.62 (95% CI, 0.47–0.83), 0.58 (95% CI, 0.47–0.72), and 0.73 (95% CI, 0.61–0.87), respectively. Supplementary adjustment for walking speed mildly attenuated the relation of leg power to disability. Conclusion:Peak leg power and habitual gait speed were associated with varying domains of late-life disability. The association between peak leg power and disability seems to be partially mediated through usual gait speed.

Cognitive Function, Habitual Gait Speed, and Late-Life Disability in the National Health and Nutrition Examination Survey (NHANES) 1999–2002

Background: Both cognitive function and gait speed are important correlates of disability. However, little is known about the combined effect of cognitive function and gait speed on multiple domains of disability as well as about the role of gait speed in the association between cognitive function and late-life disability. Objective: To investigate (1) how cognition and habitual gait speed are related to late-life disability; (2) the role of habitual gait speed in the cognitiondisability association; and (3) the combined effect of cognitive function and habitual gait speed on late-life disability. Method: Participants (>60 years, n = 2,481) were from the National Health and Nutrition Examination Survey 1999–2002. Disability in activities of daily living (ADL), instrumental ADL (IADL), leisure and social activities (LSA), and lower extremity mobility (LEM) was obtained by self-report. Cognitive function was measured by a 2-min timed Digit Symbol Substitution Test (DSST), an executive function measure from the Wechsler Adult Intelligence Test. Habitual gait speed was obtained from a 20-foot timed walk. Multiple logistic regression was used to assess the association between cognitive function and disability. Results: Cognitive function was associated with decreased likelihood for disability in each domain. The odds ratios (ORs) for disability in ADL, IADL, LSA, and LEM for each standard deviation (SD) increase in the DSST score were 0.47 (95% confidence interval [CI] = 0.34–0.64), 0.53 (95% CI = 0.42–0.67), 0.61 (95% CI = 0.47–0.79), and 0.73 (95% CI = 0.61–0.86), respectively, in the multi-variable models. After additional adjustment for habitual gait speed in the cognition-disability relationship, DSST score was no longer a significant correlate for LSA and LEM disability. The strength of the association between DSST score and disability in ADL/IADL was also diminished. The attenuated association between cognition and disability implies that limitation in gait speed likely mediates the association between cognitive function and disability. We found additive effects of cognition and habitual gait speed on late-life disability. The OR of disability in respective domains were lowest among participants with high-DSST score (high executive function) and with high gait speed. In contrast, the OR tended to be highest among participants with low-DSST score (low executive function) and low gait speed. Conclusion: Cognitive function was associated with multiple domains of disability. There was a joint effect of cognitive function and gait speed on late-life disability. This study also suggested that habitual gait speed partially mediated the inverse association between cognitive function and late-life disability, providing a mechanistic explanation in the context of disablement process.

The Evolving Transcriptome of Head and Neck Squamous Cell Carcinoma: A Systematic Review

Background Numerous studies were performed to illuminate mechanisms of tumorigenesis and metastases from gene expression profiles of Head and Neck Squamous Cell Carcinoma (HNSCC). The objective of this review is to conduct a network-based meta-analysis to identify the underlying biological signatures of the HNSCC transcriptome. Methods and Findings We included 63 HNSCC transcriptomic studies into three specific categories of comparisons: Pre, premalignant lesions v.s. normal; TvN, primary tumors v.s. normal; and Meta, metastatic or invasive v.s. primary tumors. Reported genes extracted from the literature were systematically analyzed. Participation of differential gene activities across three progressive stages deciphered the evolving nature of HNSCC. In total, 1442 genes were verified, i.e. reported at least twice, with ECM1, EMP1, CXCL10 and POSTN shown to be highly reported across all three stages. Knowledge-based networks of the HNSCC transcriptome were constructed, demonstrating integrin signaling and antigen presentation pathways as highly enriched. Notably, functional estimates derived from topological characteristics of integrin signaling networks identified such important genes as ITGA3 and ITGA5, which were supported by findings of invasiveness in vitro [1]. Moreover, we computed genome-wide probabilities of reporting differential gene activities for the Pre, TvN, and Meta stages, respectively. Results highlighted chromosomal regions of 6p21, 19p13 and 19q13, where genomic alterations were shown to be correlated with the nodal status of HNSCC [2]. Conclusions By means of a systems-biology approach via network-based meta-analyses, we provided a deeper insight into the evolving nature of the HNSCC transcriptome. Enriched canonical signaling pathways, hot-spots of transcriptional profiles across the genome, as well as topologically significant genes derived from network analyses were highlighted for each of the three progressive stages, Pre, TvN, and Meta, respectively.

Metabolic risks, white matter hyperintensities, and arterial stiffness in high-functioning healthy adults

BACKGROUND Arterial stiffness, an age-related feature and measured noninvasively by pulse wave velocity (PWV), is associated with a variety of cardiovascular diseases. Although white matter lesion (WML), representing cerebrovascular micro-angiopathy, is typically considered as a preclinical cardiovascular disease, little is know about the association between PWV and WML. The aim of this study is to examine the association between PWV and WML. METHOD We examined the extent of white matter lesion on cranial magnetic resonance imaging of 93 participants (mean 72.46 years) from the annual Health Examination for the Elderly Program in the National Taiwan University Hospital. Two subtypes of WML including periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) were graded according to Fazekas et al. The brachial-ankle PWV (baPWV) and heart-ankle PWV (haPWV) were measured using an automatic waveform analyzer. RESULTS PVH and DWHM were found in 71 (76%) and 58 (62%) participants. Various degree of WML was observed in 80 (86%) participants. Hypertension, use of anti-hypertensive medications, and elevated blood pressure were identified as risk factors of WML. The baPWV and haPWV were correlated with many metabolic risks, including systolic blood pressure, pulse pressure, and serum triglycerides. The baPWV and haPWV were greater in participants with higher grades of WML in the multivariate analyses. The receiver operating characteristics analyses demonstrated that area under curves for haPWV to identify moderate-to-severe PVH and DWMH were 0.78 (95% confidence interval [CI] 0.66-0.91) and 0.72 (95% CI 0.59-0.85), respectively. CONCLUSION Greater PWV is associated with higher grades of WML among high-functioning older adults. Our findings support the notion that measurement of arterial stiffness is useful in clinical practice for detection of preclinical cerebrovascular disease.

Functional Network Reconstruction Reveals Somatic Stemness Genetic Maps and Dedifferentiation‐Like Transcriptome Reprogramming Induced by GATA2

Somatic stem cell transplantation holds great promise in regenerative medicine. The best‐characterized adult stem cells are mesenchymal stem cells (MSCs), neural stem cells (NSCs), and CD133+ hematopoietic stem cells (HSCs). The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro. Understanding genes responsible for stem cell properties and their interactions will help on this issue. The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem‐like state. We performed a systemic study on human CD133+ HSCs, NSCs, MSCs, and embryonic stem cells and two different progenies of CD133+ HSCs, microvascular endothelial cells (MVECs) and peripheral blood mononuclear cells. Genes abundant in each or in all three somatic stem cells were identified. We also observed complex genetic networks functioning in postnatal stem cells, in which several genes, such as PTPN11 and DHFR, acted as hubs to maintain the stability and connectivity of the whole genetic network. Eighty‐seven HSC genes, including ANGPT1 and GATA2, were independently identified by comparing CD34+CD33−CD38− hematopoietic stem cells with CD34+ precursors and various matured progenies. Introducing GATA2 into MVECs resulted in dedifferentiation‐like transcriptome reprogramming, with HSC genes (such as ANGPT1) being up and endothelial genes (such as EPHB2) being down. This study provides a foundation for a more detailed understanding of human somatic stem cells. Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem‐like status.

Inverse association between insulin resistance and gait speed in nondiabetic older men: results from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002

BackgroundRecent studies have revealed the associations between insulin resistance (IR) and geriatric conditions such as frailty and cognitive impairment. However, little is known about the relation of IR to physical impairment and limitation in the aging process, eg. slow gait speed and poor muscle strength. The aim of this study is to determine the effect of IR in performance-based physical function, specifically gait speed and leg strength, among nondiabetic older adults.MethodsCross-sectional data were from the population-based National Health and Nutrition Examination Survey (1999-2002). A total of 1168 nondiabetic adults (≥ 50 years) with nonmissing values in fasting measures of insulin and glucose, habitual gait speed (HGS), and leg strength were analyzed. IR was assessed by homeostasis model assessment (HOMA-IR), whereas HGS and peak leg strength by the 20-foot timed walk test and an isokinetic dynamometer, respectively. We used multiple linear regression to examine the association between IR and performance-based physical function.ResultsIR was inversely associated with gait speed among the men. After adjusting demographics, body mass index, alcohol consumption, smoking status, chronic co-morbidities, and markers of nutrition and cardiovascular risk, each increment of 1 standard deviation in the HOMA-IR level was associated with a 0.04 m/sec decrease (p = 0.003) in the HGS in men. We did not find such association among the women. The IR-HGS association was not changed after further adjustment of leg strength. Last, HOMA-IR was not demonstrated in association with peak leg strength.ConclusionIR is inversely associated with HGS among older men without diabetes. The results suggest that IR, an important indicator of gait function among men, could be further investigated as an intervenable target to prevent walking limitation.

The Association Between Serum Folate Levels and Periodontal Disease in Older Adults: Data from the National Health and Nutrition Examination Survey 2001/02

OBJECTIVES: To assess the relationship between serum folate levels and periodontal disease in older adults.

Gender-Specific Association Between Self-reported Sleep Duration and Falls in High-Functioning Older Adults

BACKGROUND Prior studies have shown that sleep disturbances are related to falling and its risk factors, such as poorer cognition, depression, and physical function. However, little is know about the gender-specific associations between falling and sleep duration. METHODS Study participants were from the annual Health Examination for the Elderly Program in the National Taiwan University Hospital (135 women and 121 men, mean age 72.2 years). Self-reported sleep duration was grouped into three categories: less than 5, 5-7.9, and 8 or more hours. Short sleep duration was defined as sleep duration less than 5 hours. Falling during the previous 12 months was ascertained by self-report questionnaire. The association of sleep duration with falling was examined by using multiple logistic regression. We approximated risk ratio (RR) of falls from the adjusted odds ratio (OR) after correction of falls incidence in the previous year. RESULTS Sleep duration was inversely associated with falling among women. After adjusting for multiple confounding factors including use of antihypertensives and psychotropic medications, the OR of falls for each hour decrease in sleep duration was 1.95 (95% confidence interval [CI] 1.24-3.06). Moreover, women with sleep deprivation had a greater odds of falls within the last year than those with longer sleep durations. The estimated RR of falls comparing women with short sleep duration (sleep <5 hours) with those without was 2.98 (95% CI 1.32-4.62). We did not find an association among men. CONCLUSION Sleep deprivation is independently associated with falls in women but not in men. Short sleep duration may be an indicator to identify women at risk for falling.