Volume 11, Issue 16

Lee Y, Sun D, Ori AP, Lu AT, Seeboth A, Harris SE, Deary IJ, Marioni RE, Soerensen M, Mengel-From J, Hjelmborg J, Christensen K, Wilson JG, et al, . Epigenome-wide association study of leukocyte telomere length. . 11:5876-5894. https://doi.org/10.18632/aging.102230

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                TY  - JOUR
                AU  - Lee, Yunsung 
                AU  - Sun, Dianjianyi 
                AU  - Ori, Anil P.S. 
                AU  - Lu, Ake T. 
                AU  - Seeboth, Anne 
                AU  - Harris, Sarah E. 
                AU  - Deary, Ian J. 
                AU  - Marioni, Riccardo E. 
                AU  - Soerensen, Mette 
                AU  - Mengel-From, Jonas 
                AU  - Hjelmborg, Jacob 
                AU  - Christensen, Kaare 
                AU  - Wilson, James G. 
                AU  - Levy, Daniel 
                AU  - Reiner, Alex P. 
                AU  - Chen, Wei 
                AU  - Li, Shengxu 
                AU  - Harris, Jennifer R. 
                AU  - Magnus, Per 
                AU  - Aviv, Abraham 
                AU  - Jugessur, Astanand 
                AU  - Horvath, Steve 
                TI  - Epigenome-wide association study of leukocyte telomere length
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102230
                DO  - 10.18632/aging.102230
                SP  - 5876
                EP  - 5894
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Lee, Yunsung 
                AU  - Sun, Dianjianyi 
                AU  - Ori, Anil P.S. 
                AU  - Lu, Ake T. 
                AU  - Seeboth, Anne 
                AU  - Harris, Sarah E. 
                AU  - Deary, Ian J. 
                AU  - Marioni, Riccardo E. 
                AU  - Soerensen, Mette 
                AU  - Mengel-From, Jonas 
                AU  - Hjelmborg, Jacob 
                AU  - Christensen, Kaare 
                AU  - Wilson, James G. 
                AU  - Levy, Daniel 
                AU  - Reiner, Alex P. 
                AU  - Chen, Wei 
                AU  - Li, Shengxu 
                AU  - Harris, Jennifer R. 
                AU  - Magnus, Per 
                AU  - Aviv, Abraham 
                AU  - Jugessur, Astanand 
                AU  - Horvath, Steve 
                TI  - Epigenome-wide association study of leukocyte telomere length
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102230
                DO  - 10.18632/aging.102230
                SP  - 5876
                EP  - 5894
                PY  - 
                AB  - Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) &#x2013; the Framingham Heart Study, the Jackson Heart Study, the Women&#x2019;s Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P&lt;1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.
                ER  -

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DNA methylation-based estimator of telomere length

Ake T. Lu, Anne Seeboth, Pei-Chien Tsai, Dianjianyi Sun, Austin Quach, Alex P. Reiner, Charles Kooperberg, Luigi Ferrucci, Lifang Hou, Andrea A. Baccarelli, Yun Li, Sarah E. Harris, Janie Corley, Adele Taylor, Ian J. Deary, James D. Stewart, Eric A. Whitsel, Themistocles L. Assimes, Wei Chen, Shengxu Li, Massimo Mangino, Jordana T. Bell, James G. Wilson, Abraham Aviv, Riccardo E. Marioni, Kenneth Raj, Steve Horvath,

https://doi.org/10.18632/aging.102173 pp 5895—5923

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Lu AT, Seeboth A, Tsai P, Sun D, Quach A, Reiner AP, Kooperberg C, Ferrucci L, Hou L, Baccarelli AA, Li Y, Harris SE, Corley J, et al, . DNA methylation-based estimator of telomere length. . 11:5895-5923. https://doi.org/10.18632/aging.102173

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Provider: 
                TY  - JOUR
                AU  - Lu, Ake T. 
                AU  - Seeboth, Anne 
                AU  - Tsai, Pei-Chien 
                AU  - Sun, Dianjianyi 
                AU  - Quach, Austin 
                AU  - Reiner, Alex P. 
                AU  - Kooperberg, Charles 
                AU  - Ferrucci, Luigi 
                AU  - Hou, Lifang 
                AU  - Baccarelli, Andrea A. 
                AU  - Li, Yun 
                AU  - Harris, Sarah E. 
                AU  - Corley, Janie 
                AU  - Taylor, Adele 
                AU  - Deary, Ian J. 
                AU  - Stewart, James D. 
                AU  - Whitsel, Eric A. 
                AU  - Assimes, Themistocles L. 
                AU  - Chen, Wei 
                AU  - Li, Shengxu 
                AU  - Mangino, Massimo 
                AU  - Bell, Jordana T. 
                AU  - Wilson, James G. 
                AU  - Aviv, Abraham 
                AU  - Marioni, Riccardo E. 
                AU  - Raj, Kenneth 
                AU  - Horvath, Steve 
                TI  - DNA methylation-based estimator of telomere length
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102173
                DO  - 10.18632/aging.102173
                SP  - 5895
                EP  - 5923
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Lu, Ake T. 
                AU  - Seeboth, Anne 
                AU  - Tsai, Pei-Chien 
                AU  - Sun, Dianjianyi 
                AU  - Quach, Austin 
                AU  - Reiner, Alex P. 
                AU  - Kooperberg, Charles 
                AU  - Ferrucci, Luigi 
                AU  - Hou, Lifang 
                AU  - Baccarelli, Andrea A. 
                AU  - Li, Yun 
                AU  - Harris, Sarah E. 
                AU  - Corley, Janie 
                AU  - Taylor, Adele 
                AU  - Deary, Ian J. 
                AU  - Stewart, James D. 
                AU  - Whitsel, Eric A. 
                AU  - Assimes, Themistocles L. 
                AU  - Chen, Wei 
                AU  - Li, Shengxu 
                AU  - Mangino, Massimo 
                AU  - Bell, Jordana T. 
                AU  - Wilson, James G. 
                AU  - Aviv, Abraham 
                AU  - Marioni, Riccardo E. 
                AU  - Raj, Kenneth 
                AU  - Horvath, Steve 
                TI  - DNA methylation-based estimator of telomere length
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102173
                DO  - 10.18632/aging.102173
                SP  - 5895
                EP  - 5923
                PY  - 
                AB  - Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women&apos;s Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.
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Cognitive impairment in heart failure is associated with altered Wnt signaling in the hippocampus

Camilo Toledo, Claudia Lucero, David C. Andrade, Hugo S. Díaz, Karla G. Schwarz, Katherin V. Pereyra, Alexis Arce-Álvarez, Nicolás A. López, Milka Martinez, Nibaldo C. Inestrosa, Rodrigo Del Rio,

https://doi.org/10.18632/aging.102150 pp 5924—5942

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Toledo C, Lucero C, Andrade DC, Díaz HS, Schwarz KG, Pereyra KV, Arce-Álvarez A, López NA, Martinez M, Inestrosa NC, Del Rio R, . Cognitive impairment in heart failure is associated with altered Wnt signaling in the hippocampus. . 11:5924-5942. https://doi.org/10.18632/aging.102150

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                TY  - JOUR
                AU  - Toledo, Camilo 
                AU  - Lucero, Claudia 
                AU  - Andrade, David C. 
                AU  - Díaz, Hugo S. 
                AU  - Schwarz, Karla G. 
                AU  - Pereyra, Katherin V. 
                AU  - Arce-Álvarez, Alexis 
                AU  - López, Nicolás A. 
                AU  - Martinez, Milka 
                AU  - Inestrosa, Nibaldo C. 
                AU  - Del Rio, Rodrigo 
                TI  - Cognitive impairment in heart failure is associated with altered Wnt signaling in the hippocampus
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102150
                DO  - 10.18632/aging.102150
                SP  - 5924
                EP  - 5942
                PY  - 
                AB  - Age represents the highest risk factor for death due to cardiovascular disease. Heart failure (HF) is the most common cardiovascular disease in elder population and it is associated with cognitive impairment (CI), diminishing learning and memory process affecting life quality and mortality in these patients. In HF, CI has been associated with inadequate O2 supply to the brain; however, an important subset of HF patients displays CI with almost no alteration in cerebral blood flow. Importantly, nothing is known about the pathophysiological mechanisms underpinning CI in HF with no change in brain tissue perfusion. Here, we aimed to study memory performance and learning function in a rodent model of HF that shows no change in blood flow going to the brain. We found that HF rats presented learning impairments and memory loss. In addition, HF rats displayed a decreased level of Wnt/&#x3B2;-catenin signaling downstream elements in the hippocampus, one pathway implicated largely in aging diseases. Taken together, our results suggest that in HF rats CI is associated with dysfunction of the Wnt/&#x3B2;-catenin signaling pathway. The mechanisms involved in the alterations of Wnt/&#x3B2;-catenin signaling in HF and its contribution to the development/maintenance of CI deserves future investigations.
                ER  -

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Discovering markers of healthy aging: a prospective study in a Danish male birth cohort

Kiyana Zarnani, Thomas E. Nichols, Fidel Alfaro-Almagro, Birgitte Fagerlund, Martin Lauritzen, Egill Rostrup, Stephen M. Smith,

https://doi.org/10.18632/aging.102151 pp 5943—5974

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Zarnani K, Nichols TE, Alfaro-Almagro F, Fagerlund B, Lauritzen M, Rostrup E, Smith SM, . Discovering markers of healthy aging: a prospective study in a Danish male birth cohort. . 11:5943-5974. https://doi.org/10.18632/aging.102151

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                TY  - JOUR
                AU  - Zarnani, Kiyana 
                AU  - Nichols, Thomas E. 
                AU  - Alfaro-Almagro, Fidel 
                AU  - Fagerlund, Birgitte 
                AU  - Lauritzen, Martin 
                AU  - Rostrup, Egill 
                AU  - Smith, Stephen M. 
                TI  - Discovering markers of healthy aging: a prospective study in a Danish male birth cohort
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102151
                DO  - 10.18632/aging.102151
                SP  - 5943
                EP  - 5974
                PY  - 
                AB  - There is a pressing need to identify markers of cognitive and neural decline in healthy late-midlife participants. We explored the relationship between cross-sectional structural brain-imaging derived phenotypes (IDPs) and cognitive ability, demographic, health and lifestyle factors (non-IDPs). Participants were recruited from the 1953 Danish Male Birth Cohort (N=193). Applying an extreme group design, members were selected in 2 groups based on cognitive change between IQ at age ~20y (IQ-20) and age ~57y (IQ-57). Subjects showing the highest (n=95) and lowest (n=98) change were selected (at age ~57) for assessments on multiple IDPs and non-IDPs. We investigated the relationship between 453 IDPs and 70 non-IDPs through pairwise correlation and multivariate canonical correlation analysis (CCA) models. Significant pairwise associations included positive associations between IQ-20 and gray-matter volume of the temporal pole. CCA identified a richer pattern - a single &#x201C;positive-negative&#x201D; mode of population co-variation coupling individual cross-subject variations in IDPs to an extensive range of non-IDP measures (r = 0.75, Pcorrected &lt; 0.01). Specifically, this mode linked higher cognitive performance, positive early-life social factors, and mental health to a larger brain volume of several brain structures, overall volume, and microstructural properties of some white matter tracts. Interestingly, both statistical models identified IQ-20 and gray-matter volume of the temporal pole as important contributors to the inter-individual variation observed. The converging patterns provide novel insight into the importance of early adulthood intelligence as a significant marker of late-midlife neural decline and motivates additional study.
                ER  -

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LINC00511 promotes the malignant phenotype of clear cell renal cell carcinoma by sponging microRNA-625 and thereby increasing cyclin D1 expression

Huanghao Deng, Changkun Huang, Yinhuai Wang, Hongyi Jiang, Shuang Peng, Xiaokun Zhao,

https://doi.org/10.18632/aging.102156 pp 5975—5991

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Deng H, Huang C, Wang Y, Jiang H, Peng S, Zhao X, . LINC00511 promotes the malignant phenotype of clear cell renal cell carcinoma by sponging microRNA-625 and thereby increasing cyclin D1 expression. . 11:5975-5991. https://doi.org/10.18632/aging.102156

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                TY  - JOUR
                AU  - Deng, Huanghao 
                AU  - Huang, Changkun 
                AU  - Wang, Yinhuai 
                AU  - Jiang, Hongyi 
                AU  - Peng, Shuang 
                AU  - Zhao, Xiaokun 
                TI  - LINC00511 promotes the malignant phenotype of clear cell renal cell carcinoma by sponging microRNA-625 and thereby increasing cyclin D1 expression
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102156
                DO  - 10.18632/aging.102156
                SP  - 5975
                EP  - 5991
                PY  - 
                AB  - The expression pattern and detailed roles of long noncoding RNA LINC00511 in clear cell renal cell carcinoma (ccRCC) remain unknown. We measured LINC00511 expression in ccRCC. We clarified the clinical characteristics associated with LINC00511 in ccRCC. We examined the biological roles of LINC00511 in the progression of ccRCC, and we identified the potential mechanisms involved. LINC00511 was upregulated in ccRCC tissues and cell lines. High LINC00511 expression significantly correlated with TNM classification, lymph node metastasis, and short overall survival among patients with ccRCC. Additionally, LINC00511 knockdown restricted ccRCC cell proliferation, colony formation, and metastasis in vitro; accelerated cell cycle arrest at G0&#x2013;G1 and apoptosis in vitro; and decreased tumor growth in vivo. Investigation of the mechanism revealed that LINC00511 directly interacted with microRNA-625 (miR-625), and the inhibitory effects of the LINC00511 knockdown on malignant characteristics were neutralized by miR-625 silencing. Furthermore, cyclin D1 (CCND1) was identified as a direct target of miR-625 in ccRCC cells. The tumor-suppressive activity of miR-625 upregulation on ccRCC cells was reversed by CCND1 reintroduction. In conclusion, LINC00511 serves as a competing endogenous RNA that regulates CCND1 expression by sponging miR-625 in ccRCC. Hence, the LINC00511/miR-625/CCND1 pathway might be a promising therapeutic target in ccRCC.
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LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts

Mengna Li, Li Li, Xiaofeng Zhang, Huijuan Zhao, Min Wei, Wanying Zhai, Baoxi Wang, Yan Yan,

https://doi.org/10.18632/aging.102159 pp 5992—6013

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Li M, Li L, Zhang X, Zhao H, Wei M, Zhai W, Wang B, Yan Y, . LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts. . 11:5992-6013. https://doi.org/10.18632/aging.102159

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                TY  - JOUR
                AU  - Li, Mengna 
                AU  - Li, Li 
                AU  - Zhang, Xiaofeng 
                AU  - Zhao, Huijuan 
                AU  - Wei, Min 
                AU  - Zhai, Wanying 
                AU  - Wang, Baoxi 
                AU  - Yan, Yan 
                TI  - LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102159
                DO  - 10.18632/aging.102159
                SP  - 5992
                EP  - 6013
                PY  - 
                AB  - Ultraviolet (UV) irradiation from the sunlight is a major etiologic factor for premature skin aging. Long noncoding RNAs (lncRNAs) are involved in various biological processes, and their roles in UV irradiation-induced skin aging have recently been described. Previously, we found that the lncRNA RP11-670E13.6 was up-regulated and delayed cellular senescence in UVB-irradiated primary human dermal fibroblasts. Here, we performed further investigations of RP11-670E13.6 function. The results showed that this lncRNA directly bound to miR-663a and functioned as a sponge for miR-663a to modulate the derepression of Cdk4 and Cdk6, thereby delaying cellular senescence during UV irradiation-induced skin photoaging. Moreover, we found that RP11-670E13.6 may facilitate DNA damage repair by increasing ATM and &#x3B3;H2A.X levels. In addition, heterogeneous nuclear ribonucleoprotein H physically interacted with RP11-670E13.6 and blocked its expression. Collectively, our results suggested that the RP11-670E13.6/miR-663a/CDK4 and RP11-670E13.6/miR-663a/CDK6 axis, which may function as competitive endogenous RNA networks, played important roles in UVB-induced cellular senescence.
                ER  -

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MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin

Xin Liu, Liangliang Liu, Hongbo Zhang, Yan Shao, Ziyu Chen, Xiaofeng Feng, Hang Fang, Chang Zhao, Jianying Pan, Haiyan Zhang, Chun Zeng, Daozhang Cai,

https://doi.org/10.18632/aging.102160 pp 6014—6028

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Liu X, Liu L, Zhang H, Shao Y, Chen Z, Feng X, Fang H, Zhao C, Pan J, Zhang H, Zeng C, Cai D, . MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin. . 11:6014-6028. https://doi.org/10.18632/aging.102160

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                TY  - JOUR
                AU  - Liu, Xin 
                AU  - Liu, Liangliang 
                AU  - Zhang, Hongbo 
                AU  - Shao, Yan 
                AU  - Chen, Ziyu 
                AU  - Feng, Xiaofeng 
                AU  - Fang, Hang 
                AU  - Zhao, Chang 
                AU  - Pan, Jianying 
                AU  - Zhang, Haiyan 
                AU  - Zeng, Chun 
                AU  - Cai, Daozhang 
                TI  - MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102160
                DO  - 10.18632/aging.102160
                SP  - 6014
                EP  - 6028
                PY  - 
                AB  - Osteoarthritis (OA) is an aging-related chronic degenerative disease characterized by the degradation of chondrocyte extracellular matrix (ECM). Previous studies have suggested that microRNAs (miRNAs) are associated with OA, but the role of miR-146b in OA remains unclear. The aim of this study was to determine the role of miR-146b in OA progression. The effect of miR-146b on ECM degradation were studied in mouse chondrocytes transfected with miRNA and treated with IL-1&#x3B2;. Cell viability and the expression levels of proteolytic enzymes in the transfected cells were assessed by real-time RT-PCR, ELISA and Western blots. We found downregulation of miR-146b expression in chondrocytes dramatically inhibited IL-1&#x3B2;-induced caspase activation and proteolytic enzyme expression via influencing its targeted Alpha-2-macroglobulin (A2M). Luciferase reporter assays confirmed that A2M mRNA was negatively regulated by miR-146b in chondrocytes. Intra-articular injection of antago-miR-146b against miR-146b effectively protected mice from the progression of DMM-induced osteoarthritis by inhibiting cartilage proteoglycan degradation. Our study indicates that miR-146b plays a critical role in the progression of injury-induced osteoarthritis by directly targeting A2M expression to elevate the proteolytic enzyme production and stimulate chondrocytes apoptosis, and miR-146b as well as A2M could be therapeutic targets.
                ER  -

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Identification of 9 key genes and small molecule drugs in clear cell renal cell carcinoma

Yongwen Luo, Dexin Shen, Liang Chen, Gang Wang, Xuefeng Liu, Kaiyu Qian, Yu Xiao, Xinghuan Wang, Lingao Ju,

https://doi.org/10.18632/aging.102161 pp 6029—6052

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Luo Y, Shen D, Chen L, Wang G, Liu X, Qian K, Xiao Y, Wang X, Ju L, . Identification of 9 key genes and small molecule drugs in clear cell renal cell carcinoma. . 11:6029-6052. https://doi.org/10.18632/aging.102161

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                TY  - JOUR
                AU  - Luo, Yongwen 
                AU  - Shen, Dexin 
                AU  - Chen, Liang 
                AU  - Wang, Gang 
                AU  - Liu, Xuefeng 
                AU  - Qian, Kaiyu 
                AU  - Xiao, Yu 
                AU  - Wang, Xinghuan 
                AU  - Ju, Lingao 
                TI  - Identification of 9 key genes and small molecule drugs in clear cell renal cell carcinoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102161
                DO  - 10.18632/aging.102161
                SP  - 6029
                EP  - 6052
                PY  - 
                AB  - Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor that the underlying molecular mechanisms are largely unclear. This study aimed to elucidate the key candidate genes and pathways in ccRCC by integrated bioinformatics analysis. 1387 differentially expressed genes were identified based on three expression profile datasets, including 673 upregulated genes and 714 downregulated genes. Then we used weighted correlation network analysis to identify 6 modules associated with pathological stage and grade, blue module was the most relevant module. GO and KEGG pathway analyses showed that genes in blue module were enriched in cell cycle and metabolic related pathways. Further, 25 hub genes in blue module were identified as hub genes. Based on GEPIA database, 9 genes were associated with progression and prognosis of ccRCC patients, including PTTG1, RRM2, TOP2A, UHRF1, CEP55, BIRC5, UBE2C, FOXM1 and CDC20. Then multivariate Cox regression showed that the risk score base on 9 key genes signature was a clinically independent prognostic factor for ccRCC patients. Moreover, we screened out several new small molecule drugs that have the potential to treat ccRCC. Few of them were identified as biomarkers in ccRCC. In conclusion, our research identified 9 potential prognostic genes and several candidate small molecule drugs for ccRCC treatment.
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LINC01198 promotes proliferation and temozolomide resistance in a NEDD4-1-dependent manner, repressing PTEN expression in glioma

Wei-Lin Chen, Hong-Jin Chen, Guo-Qiang Hou, Xiao-Hua Zhang, Jian-Wei Ge,

https://doi.org/10.18632/aging.102162 pp 6053—6068

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Chen W, Chen H, Hou G, Zhang X, Ge J, . LINC01198 promotes proliferation and temozolomide resistance in a NEDD4-1-dependent manner, repressing PTEN expression in glioma. . 11:6053-6068. https://doi.org/10.18632/aging.102162

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                TY  - JOUR
                AU  - Chen, Wei-Lin 
                AU  - Chen, Hong-Jin 
                AU  - Hou, Guo-Qiang 
                AU  - Zhang, Xiao-Hua 
                AU  - Ge, Jian-Wei 
                TI  - LINC01198 promotes proliferation and temozolomide resistance in a NEDD4-1-dependent manner, repressing PTEN expression in glioma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102162
                DO  - 10.18632/aging.102162
                SP  - 6053
                EP  - 6068
                PY  - 
                AB  - Background: Dysregulation of numerous lncRNAs has been recently confirmed in glioma; however, the majority of their roles and mechanisms involved in this notorious disease remain largely unclear. This study aims to explore the roles and molecular mechanisms of LINC01198 implicated in the proliferation and chemoresistance in glioma.Results: LINC01198 was elevated in glioma, and this predicted a poorer prognosis for patients with glioma. LINC01198 knockdown inhibited, while LINC01198 overexpression promoted, glioma cell proliferation and resistance to temozolomide. Mechanistically, NEDD4-1 (neural precursor cell expressed, developmentally downregulated 4, E3 ubiquitin protein ligase) and phosphatase and tensin homolog (PTEN) were recruited by LINC01198, which functioned as a scaffold. Moreover, we showed that LINC01198 exerted its oncogenic activities by enhancing the NEDD4-1-dependent repression of PTEN.Conclusions: Our study elucidated the role of oncogenic LINC01198 in glioma proliferation and temozolomide resistance, and this role may serve as a promising target for glioma therapy.Methods: LINC01198 expression in glioma tissues and that in paired normal tissues were measured by qRT-PCR. The functional roles of LINC01198 in glioma were demonstrated by a series of in vitro experiments. CCK-8 assay, RNA pulldown, RNA immunoprecipitation and western blotting were used to demonstrate the potential mechanisms of LINC01198.
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FAM83A signaling induces epithelial-mesenchymal transition by the PI3K/AKT/Snail pathway in NSCLC

Fengrui Zhou, Jianxiong Geng, Shanqi Xu, Qingwei Meng, Kexin Chen, Fang Liu, Fang Yang, Bo Pan, Yan Yu,

https://doi.org/10.18632/aging.102163 pp 6069—6088

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Zhou F, Geng J, Xu S, Meng Q, Chen K, Liu F, Yang F, Pan B, Yu Y, . FAM83A signaling induces epithelial-mesenchymal transition by the PI3K/AKT/Snail pathway in NSCLC. . 11:6069-6088. https://doi.org/10.18632/aging.102163

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                TY  - JOUR
                AU  - Zhou, Fengrui 
                AU  - Geng, Jianxiong 
                AU  - Xu, Shanqi 
                AU  - Meng, Qingwei 
                AU  - Chen, Kexin 
                AU  - Liu, Fang 
                AU  - Yang, Fang 
                AU  - Pan, Bo 
                AU  - Yu, Yan 
                TI  - FAM83A signaling induces epithelial-mesenchymal transition by the PI3K/AKT/Snail pathway in NSCLC
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102163
                DO  - 10.18632/aging.102163
                SP  - 6069
                EP  - 6088
                PY  - 
                AB  - Family with sequence similarity 83, member A (FAM83A), as a potential tumor promoter, was reported to contribute to the progression of several malignant tumors. However, the significance of FAM83A in invasion and metastasis of non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that FAM83A expression was significantly increased in NSCLC tissues. High expression of FAM83A was positively associated with tumor metastasis and poor survival of NSCLC patients. Functional experiments revealed that FAM83A knockdown could suppress NSCLC cell migration and invasion both in vivo and in vitro. While opposite results were observed in FAM83A-transfected cells. Mechanically, we found that FAM83A promoted NSCLC cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) via PI3K/ATK/Snail signaling. Rescue experiment demonstrated that inhibition of either AKT or Snail could partially counteract the promoting effect of FAM83A overexpression in NSCLC metastasis. Taken together, our findings are the first time to demonstrate that increased expression of FAM83A in NSCLC was correlated with EMT and tumor metastasis, which may provide a novel therapeutic target in NSCLC treatment.
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Copy number variations primed lncRNAs deregulation contribute to poor prognosis in colorectal cancer

Huimin Liu, Xiaoyu Gu, Guihua Wang, Ying Huang, Shaoqing Ju, Jianfei Huang, Xudong Wang,

https://doi.org/10.18632/aging.102168 pp 6089—6108

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Liu H, Gu X, Wang G, Huang Y, Ju S, Huang J, Wang X, . Copy number variations primed lncRNAs deregulation contribute to poor prognosis in colorectal cancer. . 11:6089-6108. https://doi.org/10.18632/aging.102168

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                TY  - JOUR
                AU  - Liu, Huimin 
                AU  - Gu, Xiaoyu 
                AU  - Wang, Guihua 
                AU  - Huang, Ying 
                AU  - Ju, Shaoqing 
                AU  - Huang, Jianfei 
                AU  - Wang, Xudong 
                TI  - Copy number variations primed lncRNAs deregulation contribute to poor prognosis in colorectal cancer
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102168
                DO  - 10.18632/aging.102168
                SP  - 6089
                EP  - 6108
                PY  - 
                AB  - Copy number variations (CNVs) are crucial genetic change elements in malignancies, and lncRNAs deregulation induced by genomic and epigenomic aberrations plays key driving role in tumorigenesis, including colorectal cancer (CRC). However, effects of CNVs associated with lncRNAs in CRC is largely unknown. Here, we perform integrative analysis considering messenger RNA expression levels, DNA methylation and DNA copy numbers from 289 cases of CRC specimens. There are five prognostic subtypes of CRC determined by multi-omics integration, and differentially expressed lncRNAs (DE-lncRNAs) are acquired among five subtypes and normal cases. Finally, CNVs pattern matched with DE-lncRNAs reveals a signature including 10 lncRNAs (LOC101927604, LOC105377267, CASC15, LINC-PINT, CLDN10-AS1, C14orf132, LMF1, LINC00675, CCDC144NL-AS1, LOC284454), conspicuously contributing to poor prognosis in CRC, which can be validated in another independent dataset. Together, our research is interested in copy number changes relevant with lncRNAs, not only expending the spectrum of CNVs, but also perfecting the regulation network of lncRNAs in CRC. The main purpose is to provide novel biomarkers for prognostic managements of CRC patients.
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Analysis of transcription factor- and ncRNA-mediated potential pathogenic gene modules in Alzheimer’s disease

Cuihua Zou, Jie Wang, Xiaohua Huang, Chongdong Jian, Donghua Zou, Xuebin Li,

https://doi.org/10.18632/aging.102169 pp 6109—6119

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Zou C, Wang J, Huang X, Jian C, Zou D, Li X, . Analysis of transcription factor- and ncRNA-mediated potential pathogenic gene modules in Alzheimer’s disease. . 11:6109-6119. https://doi.org/10.18632/aging.102169

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                TY  - JOUR
                AU  - Zou, Cuihua 
                AU  - Wang, Jie 
                AU  - Huang, Xiaohua 
                AU  - Jian, Chongdong 
                AU  - Zou, Donghua 
                AU  - Li, Xuebin 
                TI  - Analysis of transcription factor- and ncRNA-mediated potential pathogenic gene modules in Alzheimer’s disease
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102169
                DO  - 10.18632/aging.102169
                SP  - 6109
                EP  - 6119
                PY  - 
                AB  - Alzheimer&#x2019;s disease (AD) is a progressive neurodegenerative disease that ranks as the fourth most common cause of death in developed countries. In our study, genes differentially expressed between AD and healthy individuals were identified and used to construct protein-protein interaction (PPI) networks. The AD-related PPI network was used to identify functional modules, and enrichment analysis showed that they were significantly involved in &#x201C;Alzheimer&#x2019;s disease&#x201D;, &#x201C;apoptosis&#x201D;, and related pathways. We predicted non-coding RNAs and transcription factors that may regulate the functional modules. The expression of hub genes and transcription factors was validated in an independent data set. The results in this study provide several candidates for further research on mechanisms of AD pathogenesis.
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MicroRNA-181a protects against pericyte apoptosis via directly targeting FOXO1: implication for ameliorated cognitive deficits in APP/PS1 mice

Qingbin Wu, Xiaochen Yuan, Jing Bai, Ruiqin Han, Zhigang Li, Honggang Zhang, Ruijuan Xiu,

https://doi.org/10.18632/aging.102171 pp 6120—6133

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Wu Q, Yuan X, Bai J, Han R, Li Z, Zhang H, Xiu R, . MicroRNA-181a protects against pericyte apoptosis via directly targeting FOXO1: implication for ameliorated cognitive deficits in APP/PS1 mice. . 11:6120-6133. https://doi.org/10.18632/aging.102171

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                TY  - JOUR
                AU  - Wu, Qingbin 
                AU  - Yuan, Xiaochen 
                AU  - Bai, Jing 
                AU  - Han, Ruiqin 
                AU  - Li, Zhigang 
                AU  - Zhang, Honggang 
                AU  - Xiu, Ruijuan 
                TI  - MicroRNA-181a protects against pericyte apoptosis via directly targeting FOXO1: implication for ameliorated cognitive deficits in APP/PS1 mice
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102171
                DO  - 10.18632/aging.102171
                SP  - 6120
                EP  - 6133
                PY  - 
                AB  - MicroRNAs (miRNAs) have emerged as critical regulators in the pathology of Alzheimer&#x2019;s disease (AD). MiR-181a is associated with hippocampal memory formation and aberrantly expressed in patients with mild cognitive impairment (MCI), however, little is known about its role and underlying mechanism involved in AD. Here, we report that miR-181a expression declines in APP/PS1 mice, synchronous with the increase in amyloid &#x3B2; (A&#x3B2;) level, which suggests a reverse correlation between miR-181a level and AD development. Additionally, lentiviral overexpression of miR-181a via intrahippocampal injection ameliorates cognitive deficits and amyloid plaque deposition in APP/PS1 mice, indicating a beneficial role of miR-181a against AD progression. Moreover, miR-181a decelerates pericyte loss and blood-brain barrier breakdown in APP/PS1 mice. Furthermore, miR-181a protects against A&#x3B2; accumulation-induced pericyte apoptosis in vitro, which is attributed to the negative regulation of FOXO1 by miR-181a, since FOXO1 restoration abolishes miR-181a protective role against pericyte apoptosis. Altogether, these results may identify miR-181a as a novel regulator of AD pathology, and also implicate that the protection of miR-181a in blood-brain barrier pericytes may underlie its ameliorating effect on APP/PS1 mice.
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Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg/N-end rule pathway proteolytic activity

Olga I. Kechko, Irina Yu. Petrushanko, Christopher S. Brower, Alexei A. Adzhubei, Alexey A. Moskalev, Konstantin I. Piatkov, Vladimir A. Mitkevich, Alexander A. Makarov,

https://doi.org/10.18632/aging.102177 pp 6134—6152

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Kechko OI, Petrushanko IY, Brower CS, Adzhubei AA, Moskalev AA, Piatkov KI, Mitkevich VA, Makarov AA, . Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg/N-end rule pathway proteolytic activity. . 11:6134-6152. https://doi.org/10.18632/aging.102177

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                TY  - JOUR
                AU  - Kechko, Olga I. 
                AU  - Petrushanko, Irina Yu. 
                AU  - Brower, Christopher S. 
                AU  - Adzhubei, Alexei A. 
                AU  - Moskalev, Alexey A. 
                AU  - Piatkov, Konstantin I. 
                AU  - Mitkevich, Vladimir A. 
                AU  - Makarov, Alexander A. 
                TI  - Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg/N-end rule pathway proteolytic activity
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102177
                DO  - 10.18632/aging.102177
                SP  - 6134
                EP  - 6152
                PY  - 
                AB  - Alzheimer&#x2019;s disease (AD) is accompanied by the dysfunction of intracellular protein homeostasis systems, in particular the ubiquitin-proteasome system (UPS). Beta-amyloid peptide (A&#x3B2;), which is involved in the processes of neurodegeneration in AD, is a substrate of this system, however its effect on UPS activity is still poorly explored. Here we found that A&#x3B2; peptides inhibited the proteolytic activity of the antiapoptotic Arg/N-end rule pathway that is a part of UPS. We identified arginyltransferase Ate1 as a specific component of the Arg/N-end rule pathway targeted by A&#x3B2;s. A&#x3B2; bearing the familial English H6R mutation, known to cause early-onset AD, had an even greater inhibitory effect on protein degradation through the Arg/N-end rule pathway than intact A&#x3B2;. This effect was associated with a significant decrease in Ate1-1 and Ate1-3 catalytic activity. We also found that the loss of Ate1 in neuroblastoma Neuro-2a cells eliminated the apoptosis-inducing effects of A&#x3B2; peptides. Together, our results show that the apoptotic effect of A&#x3B2; peptides is linked to their impairment of Ate1 catalytic activity leading to suppression of the Arg/N-end rule pathway proteolytic activity and ultimately cell death.
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Prognostic value of genome-wide DNA methylation patterns in noncoding miRNAs and lncRNAs in uveal melanomas

Zheng Zheng, Dan Xu, Keqing Shi, Minfeng Chen, Fan Lu,

https://doi.org/10.18632/aging.102178 pp 6153—6174

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Zheng Z, Xu D, Shi K, Chen M, Lu F, . Prognostic value of genome-wide DNA methylation patterns in noncoding miRNAs and lncRNAs in uveal melanomas. . 11:6153-6174. https://doi.org/10.18632/aging.102178

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                TY  - JOUR
                AU  - Zheng, Zheng 
                AU  - Xu, Dan 
                AU  - Shi, Keqing 
                AU  - Chen, Minfeng 
                AU  - Lu, Fan 
                TI  - Prognostic value of genome-wide DNA methylation patterns in noncoding miRNAs and lncRNAs in uveal melanomas
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102178
                DO  - 10.18632/aging.102178
                SP  - 6153
                EP  - 6174
                PY  - 
                AB  - Background: Uveal melanomas are the most common primary intraocular malignant tumors in adults, associated with a high metastasis rate and a low 5-year survival rate. It is a clinic urgency and importance to identify prognostic factors for UVMs.Results: 55 aberrantly methylated sites of miRNAs and 47 aberrantly methylated sites of lncRNAs were observed between Alive &lt; 2 years group and Alive &gt; 2 years group of UVMs. Two prognostic classifiers were generated. For 13- miRNAs-CpG-classifier, the AUC were 0.958, 0.848 and 0.824 at 1 year, 2 years and 3 years, respectively. For 9- lncRNAs-CpG-classifier, the AUC were 0.943, 0.869 and 0.866 at 1 year, 2 years and 3 years, respectively.Conclusion: The correlation between genome-wide DNA methylation patterns of miRNAs and lncRNAs and the overall survival in UVMs were identified in this study. This novel finding shed new light on developing biomarkers of prognosis for UVMs.Methods: DNA methylation profiles of noncoding miRNAs and lncRNAs for UVMs were accessed from The Cancer Genome Atlas. Then the prognostic value was analyzed by least absolute shrinkage and selection operator method Cox regression and tested by Time-dependent Receiver Operating Characteristic curve.
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Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy

Daniel Moreno-Blas, Elisa Gorostieta-Salas, Alexander Pommer-Alba, Gabriel Muciño-Hernández, Cristian Gerónimo-Olvera, Luis Angel Maciel-Barón, Mina Konigsberg, Lourdes Massieu, Susana Castro-Obregón,

https://doi.org/10.18632/aging.102181 pp 6175—6198

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Moreno-Blas D, Gorostieta-Salas E, Pommer-Alba A, Muciño-Hernández G, Gerónimo-Olvera C, Maciel-Barón LA, Konigsberg M, Massieu L, Castro-Obregón S, . Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy. . 11:6175-6198. https://doi.org/10.18632/aging.102181

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                TY  - JOUR
                AU  - Moreno-Blas, Daniel 
                AU  - Gorostieta-Salas, Elisa 
                AU  - Pommer-Alba, Alexander 
                AU  - Muciño-Hernández, Gabriel 
                AU  - Gerónimo-Olvera, Cristian 
                AU  - Maciel-Barón, Luis Angel 
                AU  - Konigsberg, Mina 
                AU  - Massieu, Lourdes 
                AU  - Castro-Obregón, Susana 
                TI  - Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102181
                DO  - 10.18632/aging.102181
                SP  - 6175
                EP  - 6198
                PY  - 
                AB  - Senescent cells accumulate in various tissues and organs with aging altering surrounding tissue due to an active secretome, and at least in mice their elimination extends healthy lifespan and ameliorates several chronic diseases. Whether all cell types senesce, including post-mitotic cells, has been poorly described mainly because cellular senescence was defined as a permanent cell cycle arrest. Nevertheless, neurons with features of senescence have been described in old rodent and human brains. In this study we characterized an in vitro model useful to study the molecular basis of senescence of primary rat cortical cells that recapitulates senescent features described in brain aging. We found that in long-term cultures, rat primary cortical neurons displayed features of cellular senescence before glial cells did, and developed a functional senescence-associated secretory phenotype able to induce paracrine premature senescence of mouse embryonic fibroblasts but proliferation of rat glial cells. Functional autophagy seems to prevent neuronal senescence, as we observed an autophagic flux reduction in senescent neurons both in vitro and in vivo, and autophagy impairment induced cortical cell senescence while autophagy stimulation inhibited it. Our findings suggest that aging-associated dysfunctional autophagy contributes to senescence transition also in neuronal cells.
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Attenuated BK channel function promotes overactive bladder in a rat model of obesity

Ning Li, Honglin Ding, Peng Zhang, Zizheng Li, Yili Liu, Ping Wang,

https://doi.org/10.18632/aging.102182 pp 6199—6216

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Li N, Ding H, Zhang P, Li Z, Liu Y, Wang P, . Attenuated BK channel function promotes overactive bladder in a rat model of obesity. . 11:6199-6216. https://doi.org/10.18632/aging.102182

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                TY  - JOUR
                AU  - Li, Ning 
                AU  - Ding, Honglin 
                AU  - Zhang, Peng 
                AU  - Li, Zizheng 
                AU  - Liu, Yili 
                AU  - Wang, Ping 
                TI  - Attenuated BK channel function promotes overactive bladder in a rat model of obesity
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102182
                DO  - 10.18632/aging.102182
                SP  - 6199
                EP  - 6216
                PY  - 
                AB  - Overactive bladder (OAB) is mostly observed in obese individuals, and is associated with enhanced excitability and contractility of the detrusor smooth muscle (DSM). Large-conductance voltage- and Ca2+-activated K+ (BK) channels reduce the excitability and contractility of the DSM. We tested whether obesity-induced OAB is associated with altered BK channel expression and activity in the DSM. Seven-week-old female Sprague-Dawley rats (N=80) were fed a normal or high-fat diet (HFD) for 12 weeks. HFD-fed rats exhibited a higher average bodyweight and urodynamically established detrusor overactivity. mRNA levels of the Kcnma1 (BK&#x3B1; subunit) and Kcnmb1 (BK&#x3B2;1 subunit) in whole tissues and cells from the DSM were reduced in HFD-fed rats. A selective BK channel opener, NS1619, was then applied to DSM cells from the two groups of rats. Patch-clamp techniques revealed that spontaneous transient outward currents, NS1619-induced activation of spontaneous transient outward currents, and whole-cell BK currents, as well as NS1619-induced membrane hyperpolarization, were attenuated in DSM cells from HFD-fed rats. The relaxation effect of NS1619 on contractility was reduced in DSM strips from HFD-fed rats. Thus, impaired expression of Kcnma1 and Kcnmb1 in the DSM contributes to obesity-induced OAB, suggesting that BK channels could be a useful treatment targets in OAB.
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Risk estimation before progression to mild cognitive impairment and Alzheimer’s disease: an AD resemblance atrophy index

Lei Zhao, Yishan Luo, Darson Lew, Wenyan Liu, Lisa Au, Vincent Mok, Lin Shi, for the Alzheimer Disease Neuroimaging Initiative,

https://doi.org/10.18632/aging.102184 pp 6217—6236

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Zhao L, Luo Y, Lew D, Liu W, Au L, Mok V, Shi L, , . Risk estimation before progression to mild cognitive impairment and Alzheimer’s disease: an AD resemblance atrophy index. . 11:6217-6236. https://doi.org/10.18632/aging.102184

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                TY  - JOUR
                AU  - Zhao, Lei 
                AU  - Luo, Yishan 
                AU  - Lew, Darson 
                AU  - Liu, Wenyan 
                AU  - Au, Lisa 
                AU  - Mok, Vincent 
                AU  - Shi, Lin 
                AU  - ,  
                TI  - Risk estimation before progression to mild cognitive impairment and Alzheimer’s disease: an AD resemblance atrophy index
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102184
                DO  - 10.18632/aging.102184
                SP  - 6217
                EP  - 6236
                PY  - 
                AB  - To realize an individual-level risk evaluation of progression of early Alzheimer&#x2019;s disease (AD), we applied an AD resemblance atrophy index (AD-RAI) to differentiate the subjects at risk of progression from normal subjects (NC) to mild cognitive impairment (MCI) and from MCI to AD. We included 183 subjects with a two-year follow-up: 50 NC stable (NCs), 23 NC-to-MCI converters (NCc), 50 MCI stable (MCIs), 35 MCI-to-AD converters (MCIc), 25 AD stable (ADs). ANCOVA analyses were used to identify baseline brain atrophy in converters compared with non-converters. To explore the relative merits of AD-RAI over individual regional volumetric measures in prediction of disease progression, we searched for the optimal cutoff for each measure in logistic regressions and plotted the longitudinal trajectories of these brain volumetric measures in converters and non-converters. Baseline AD-RAI performed the best in differentiating NCc from NCs (odds ratio 26.35, AUC 0.740) and MCIc from MCIs (odds ratio 8.91, AUC 0.771). The AD-RAI presented greater increase in the second year for NCc vs. NCs but not for MCIc vs. MCIs. Baseline AD-RAIs were also associated with CSF-based and PET-based AD biomarkers. These results showed the potential of AD-RAI in early risk estimation before progression to MCI/AD at an individual-level.
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Prognostic value of long non-coding RNA signatures in bladder cancer

Anbang He, Shiming He, Ding Peng, Yonghao Zhan, Yifan Li, Zhicong Chen, Yanqing Gong, Xuesong Li, Liqun Zhou,

https://doi.org/10.18632/aging.102185 pp 6237—6251

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He A, He S, Peng D, Zhan Y, Li Y, Chen Z, Gong Y, Li X, Zhou L, . Prognostic value of long non-coding RNA signatures in bladder cancer. . 11:6237-6251. https://doi.org/10.18632/aging.102185

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                TY  - JOUR
                AU  - He, Anbang 
                AU  - He, Shiming 
                AU  - Peng, Ding 
                AU  - Zhan, Yonghao 
                AU  - Li, Yifan 
                AU  - Chen, Zhicong 
                AU  - Gong, Yanqing 
                AU  - Li, Xuesong 
                AU  - Zhou, Liqun 
                TI  - Prognostic value of long non-coding RNA signatures in bladder cancer
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102185
                DO  - 10.18632/aging.102185
                SP  - 6237
                EP  - 6251
                PY  - 
                AB  - Bladder cancer (BLCA) is a devastating cancer whose early diagnosis can ensure better prognosis. Aim of this study was to evaluate the potential utility of lncRNAs in constructing lncRNA-based classifiers of BLCA prognosis and recurrence. Based on the data concerning BLCA retrieved from TCGA, lncRNA-based classifiers for OS and RFS were built using the least absolute shrinkage and selection operation (LASSO) Cox regression model in the training cohorts. More specifically, a 14-lncRNA-based classifier for OS and a 12-lncRNA-based classifier for RFS were constructed using the LASSO Cox regression. According to the prediction value, patients were divided into high/low-risk groups based on the cut-off of the median risk-score. The log-rank test showed significant differences in OS and RFS between low- and high-risk groups in the training, validation and whole cohorts. In the time-dependent ROC curve analysis, the AUCs for OS in the first, third, and fifth year were 0.734, 0.78, and 0.78 respectively, whereas the prediction capability of the 14-lncRNA classifier was superior to a previously published lncRNA classifier. As for the RFS, the AUCs in the first, third, and fifth year were 0.755, 0.715, and 0.740 respectively. In summary, the two-lncRNA-based classifiers could serve as novel and independent prognostic factors for OS and RFS individually.
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Prognostic value of preoperative hematological markers combined with molecular pathology in patients with diffuse gliomas

Zhen-Yu Zhang, Yun-Bo Zhan, Feng-Jiang Zhang, Bin Yu, Yu-Chen Ji, Jin-Qiao Zhou, Ya-Hui Bai, Yan-Min Wang, Li Wang, Yan Jing, Wen-Chao Duan, Chen Sun, Tao Sun, Hai-Biao Zhao, Ke Li, Wen-Qing Wang, Ruo-Yan Li, Hong-Wei Sun, Guang Zhai, Shu-Kai Wang, Xin-Ting Wei, Bo Yang, Dong-Ming Yan, Xian-Zhi Liu, Wei-Wei Wang,

https://doi.org/10.18632/aging.102186 pp 6252—6272

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Zhang Z, Zhan Y, Zhang F, Yu B, Ji Y, Zhou J, Bai Y, Wang Y, Wang L, Jing Y, Duan W, Sun C, Sun T, et al, . Prognostic value of preoperative hematological markers combined with molecular pathology in patients with diffuse gliomas. . 11:6252-6272. https://doi.org/10.18632/aging.102186

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                TY  - JOUR
                AU  - Zhang, Zhen-Yu 
                AU  - Zhan, Yun-Bo 
                AU  - Zhang, Feng-Jiang 
                AU  - Yu, Bin 
                AU  - Ji, Yu-Chen 
                AU  - Zhou, Jin-Qiao 
                AU  - Bai, Ya-Hui 
                AU  - Wang, Yan-Min 
                AU  - Wang, Li 
                AU  - Jing, Yan 
                AU  - Duan, Wen-Chao 
                AU  - Sun, Chen 
                AU  - Sun, Tao 
                AU  - Zhao, Hai-Biao 
                AU  - Li, Ke 
                AU  - Wang, Wen-Qing 
                AU  - Li, Ruo-Yan 
                AU  - Sun, Hong-Wei 
                AU  - Zhai, Guang 
                AU  - Wang, Shu-Kai 
                AU  - Wei, Xin-Ting 
                AU  - Yang, Bo 
                AU  - Yan, Dong-Ming 
                AU  - Liu, Xian-Zhi 
                AU  - Wang, Wei-Wei 
                TI  - Prognostic value of preoperative hematological markers combined with molecular pathology in patients with diffuse gliomas
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102186
                DO  - 10.18632/aging.102186
                SP  - 6252
                EP  - 6272
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Zhang, Zhen-Yu 
                AU  - Zhan, Yun-Bo 
                AU  - Zhang, Feng-Jiang 
                AU  - Yu, Bin 
                AU  - Ji, Yu-Chen 
                AU  - Zhou, Jin-Qiao 
                AU  - Bai, Ya-Hui 
                AU  - Wang, Yan-Min 
                AU  - Wang, Li 
                AU  - Jing, Yan 
                AU  - Duan, Wen-Chao 
                AU  - Sun, Chen 
                AU  - Sun, Tao 
                AU  - Zhao, Hai-Biao 
                AU  - Li, Ke 
                AU  - Wang, Wen-Qing 
                AU  - Li, Ruo-Yan 
                AU  - Sun, Hong-Wei 
                AU  - Zhai, Guang 
                AU  - Wang, Shu-Kai 
                AU  - Wei, Xin-Ting 
                AU  - Yang, Bo 
                AU  - Yan, Dong-Ming 
                AU  - Liu, Xian-Zhi 
                AU  - Wang, Wei-Wei 
                TI  - Prognostic value of preoperative hematological markers combined with molecular pathology in patients with diffuse gliomas
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102186
                DO  - 10.18632/aging.102186
                SP  - 6252
                EP  - 6272
                PY  - 
                AB  - The prediction of clinical outcome for patients with infiltrative gliomas is challenging. Although preoperative hematological markers have been proposed as predictors of survival in glioma and other cancers, systematic investigations that combine these data with other relevant clinical variables are needed to improve prognostic accuracy and patient outcomes. We investigated the prognostic value of preoperative hematological markers, alone and in combination with molecular pathology, for the survival of 592 patients with Grade II-IV diffuse gliomas. On univariate analysis, increased neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), and decreased albumin-to-globulin ratio (AGR), all predicted poor prognosis in Grade II/III gliomas. Multivariate analysis incorporating tumor status based on the presence of IDH mutations, TERT promoter mutations, and 1p/19q codeletion showed that in lower-grade gliomas, high NLR predicted poorer survival for the triple-negative, IDH mutation only, TERT mutation only, and IDH and TERT mutation groups. NLR was an independent prognostic factor in Grade IV glioma. We therefore propose a prognostic model for diffuse gliomas based on the presence of IDH and TERT promoter mutations, 1p/19q codeletion, and NLR. This model classifies lower-grade gliomas into nine subgroups that can be combined into four main risk groups based on survival projections.
                ER  -

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Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma

Chuan-Yuan Wei, Meng-Xuan Zhu, Peng-Fei Zhang, Xuan Yang, Lu Wang, Jiang-Hui Ying, Wen-Jie Luan, Cheng Chen, Jia-Qi Liu, Ming Zhu, Yan-wen Yang, Zi-Hao Feng, Fa-Zhi Qi, Jian-Ying Gu,

https://doi.org/10.18632/aging.102187 pp 6273—6285

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Wei C, Zhu M, Zhang P, Yang X, Wang L, Ying J, Luan W, Chen C, Liu J, Zhu M, Yang Y, Feng Z, Qi F, et al, . Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma. . 11:6273-6285. https://doi.org/10.18632/aging.102187

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                TY  - JOUR
                AU  - Wei, Chuan-Yuan 
                AU  - Zhu, Meng-Xuan 
                AU  - Zhang, Peng-Fei 
                AU  - Yang, Xuan 
                AU  - Wang, Lu 
                AU  - Ying, Jiang-Hui 
                AU  - Luan, Wen-Jie 
                AU  - Chen, Cheng 
                AU  - Liu, Jia-Qi 
                AU  - Zhu, Ming 
                AU  - Yang, Yan-wen 
                AU  - Feng, Zi-Hao 
                AU  - Qi, Fa-Zhi 
                AU  - Gu, Jian-Ying 
                TI  - Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102187
                DO  - 10.18632/aging.102187
                SP  - 6273
                EP  - 6285
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Wei, Chuan-Yuan 
                AU  - Zhu, Meng-Xuan 
                AU  - Zhang, Peng-Fei 
                AU  - Yang, Xuan 
                AU  - Wang, Lu 
                AU  - Ying, Jiang-Hui 
                AU  - Luan, Wen-Jie 
                AU  - Chen, Cheng 
                AU  - Liu, Jia-Qi 
                AU  - Zhu, Ming 
                AU  - Yang, Yan-wen 
                AU  - Feng, Zi-Hao 
                AU  - Qi, Fa-Zhi 
                AU  - Gu, Jian-Ying 
                TI  - Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102187
                DO  - 10.18632/aging.102187
                SP  - 6273
                EP  - 6285
                PY  - 
                AB  - Background: In our previous study, kindlin-2 promoted skin wound healing and decreased the permeability of neovascularization during angiogenesis. Herein, we explored the biological function and underlying mechanism of kindlin-2 in cutaneous melanoma.Methods and Results: Through a series of in vitro assays, we found that high levels of kindlin-2 promoted migration and invasion of melanoma cells without influencing cell proliferation. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses showed that upregulated kindlin-2 promoted the cellular epithelial-mesenchymal transition (EMT). Importantly, we found that melanoma cells overexpressing kindlin-2 promoted angiogenesis and VEGFA secretion in vitro and facilitated tumour growth and lung metastasis in vivo. To unveil the underlying mechanism, we conducted Next-generation sequencing (NGS) and differential expression analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that overlapping differentially expressed genes (DEGs) were primarily enriched in the TGF-&#x3B2;, mTOR and VEGF signalling pathways. Then, we confirmed that the mTOR/VEGFA pathway was activated during the process of kindlin-2-induced melanoma progression and angiogenesis. Moreover, we demonstrated that kindlin-2 was significantly overexpressed in clinical melanoma samples and that a high level of kindlin-2 predicted a poor prognosis.Conclusions: Taken together, these findings showed that kindlin-2 promotes angiogenesis and tumour progression via the mTOR/VEGFA pathway.
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Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis

Yunhai Li, Dejuan Yang, Ping Chen, Xuedong Yin, Jiazheng Sun, Hongzhong Li, Guosheng Ren,

https://doi.org/10.18632/aging.102188 pp 6286—6311

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Li Y, Yang D, Chen P, Yin X, Sun J, Li H, Ren G, . Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis. . 11:6286-6311. https://doi.org/10.18632/aging.102188

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                TY  - JOUR
                AU  - Li, Yunhai 
                AU  - Yang, Dejuan 
                AU  - Chen, Ping 
                AU  - Yin, Xuedong 
                AU  - Sun, Jiazheng 
                AU  - Li, Hongzhong 
                AU  - Ren, Guosheng 
                TI  - Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102188
                DO  - 10.18632/aging.102188
                SP  - 6286
                EP  - 6311
                PY  - 
                AB  - Different neoadjuvant chemotherapies are available for triple-negative breast cancer (TNBC). Here, we performed a network meta-analysis to evaluate the pathological complete response (pCR) benefit and safety of treatment regimens. Pairwise and Bayesian network meta-analyses were performed to compare direct and indirect evidence, respectively. Twenty-three studies involving 12 regimens namely standard chemotherapeutic agents, bevacizumab (B)-, platinum salts (P)-, B plus P (BP)-, poly(ADP-ribose) polymerase inhibitors (Pi)-, P plus Pi (PPi)-, capecitabine (Ca)-, gemcitabine (Ge)-, zoledronic acid (Za)-, everolimus (E)-, P plus E (PE)-, and gefitinib (G)-containing regimens. The results showed that P-, B-, PPi-, and Za-containing regimens achieved higher pCR than standard chemotherapeutic agents. BP-containing regimens had a better pCR than B-containing regimens. In indirect comparisons, Za-, BP-, P-, and B-containing regimens were the top four strategies with the highest probability for pCR. Benefit-risk analysis showed that B-containing regimens had the highest acceptability of being the best treatment for better pCR achievement with fewer SAEs. The addition of P, B, BP, PPi, and Za to standard chemotherapeutic agents enhanced the pCR, but a balance between efficacy and safety should be carefully considered. B-containing regimens might be the best choice for neoadjuvant chemotherapy due to its better efficacy and tolerability.
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Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma

Xuesi Dong, Ruyang Zhang, Jieyu He, Linjing Lai, Raphael N. Alolga, Sipeng Shen, Ying Zhu, Dongfang You, Lijuan Lin, Chao Chen, Yang Zhao, Weiwei Duan, Li Su, Andrea Shafer, Moran Salama, Thomas Fleischer, Maria Moksnes Bjaanæs, Anna Karlsson, Maria Planck, Rui Wang, Johan Staaf, Åslaug Helland, Manel Esteller, Yongyue Wei, Feng Chen, David C. Christiani,

https://doi.org/10.18632/aging.102189 pp 6312—6335

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Dong X, Zhang R, He J, Lai L, Alolga RN, Shen S, Zhu Y, You D, Lin L, Chen C, Zhao Y, Duan W, Su L, et al, . Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma. . 11:6312-6335. https://doi.org/10.18632/aging.102189

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                TY  - JOUR
                AU  - Dong, Xuesi 
                AU  - Zhang, Ruyang 
                AU  - He, Jieyu 
                AU  - Lai, Linjing 
                AU  - Alolga, Raphael N. 
                AU  - Shen, Sipeng 
                AU  - Zhu, Ying 
                AU  - You, Dongfang 
                AU  - Lin, Lijuan 
                AU  - Chen, Chao 
                AU  - Zhao, Yang 
                AU  - Duan, Weiwei 
                AU  - Su, Li 
                AU  - Shafer, Andrea 
                AU  - Salama, Moran 
                AU  - Fleischer, Thomas 
                AU  - Bjaanæs, Maria Moksnes 
                AU  - Karlsson, Anna 
                AU  - Planck, Maria 
                AU  - Wang, Rui 
                AU  - Staaf, Johan 
                AU  - Helland, Åslaug 
                AU  - Esteller, Manel 
                AU  - Wei, Yongyue 
                AU  - Chen, Feng 
                AU  - Christiani, David C. 
                TI  - Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102189
                DO  - 10.18632/aging.102189
                SP  - 6312
                EP  - 6335
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Dong, Xuesi 
                AU  - Zhang, Ruyang 
                AU  - He, Jieyu 
                AU  - Lai, Linjing 
                AU  - Alolga, Raphael N. 
                AU  - Shen, Sipeng 
                AU  - Zhu, Ying 
                AU  - You, Dongfang 
                AU  - Lin, Lijuan 
                AU  - Chen, Chao 
                AU  - Zhao, Yang 
                AU  - Duan, Weiwei 
                AU  - Su, Li 
                AU  - Shafer, Andrea 
                AU  - Salama, Moran 
                AU  - Fleischer, Thomas 
                AU  - Bjaanæs, Maria Moksnes 
                AU  - Karlsson, Anna 
                AU  - Planck, Maria 
                AU  - Wang, Rui 
                AU  - Staaf, Johan 
                AU  - Helland, Åslaug 
                AU  - Esteller, Manel 
                AU  - Wei, Yongyue 
                AU  - Chen, Feng 
                AU  - Christiani, David C. 
                TI  - Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102189
                DO  - 10.18632/aging.102189
                SP  - 6312
                EP  - 6335
                PY  - 
                AB  - Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups (Pdiscovery = 0.01 and Pvalidation = 2.71&#xD7;10-3). Further, potential functional DNA methylation&#x2013;gene expression&#x2013;overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk.
                ER  -

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Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence

Alberto Granzotto, Manuela Bomba, Vanessa Castelli, Riccardo Navarra, Noemi Massetti, Marco d’Aurora, Marco Onofrj, Ilaria Cicalini, Piero del Boccio, Valentina Gatta, Annamaria Cimini, Daniele Piomelli, Stefano L. Sensi,

https://doi.org/10.18632/aging.102191 pp 6336—6357

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Granzotto A, Bomba M, Castelli V, Navarra R, Massetti N, d’Aurora M, Onofrj M, Cicalini I, del Boccio P, Gatta V, Cimini A, Piomelli D, Sensi SL, . Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence. . 11:6336-6357. https://doi.org/10.18632/aging.102191

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Provider: 
 TY - JOUR
 AU - Granzotto, Alberto 
 AU - Bomba, Manuela 
 AU - Castelli, Vanessa 
 AU - Navarra, Riccardo 
 AU - Massetti, Noemi 
 AU - d’Aurora, Marco 
 AU - Onofrj, Marco 
 AU - Cicalini, Ilaria 
 AU - del Boccio, Piero 
 AU - Gatta, Valentina 
 AU - Cimini, Annamaria 
 AU - Piomelli, Daniele 
 AU - Sensi, Stefano L. 
 TI - Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence
 JO - 
 JA - 
 VL - 11
 IS - 16
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.102191
 DO - 10.18632/aging.102191
 SP - 6336
 EP - 6357
 PY - 
 ER -

Provider: 
 TY - JOUR
 AU - Granzotto, Alberto 
 AU - Bomba, Manuela 
 AU - Castelli, Vanessa 
 AU - Navarra, Riccardo 
 AU - Massetti, Noemi 
 AU - d’Aurora, Marco 
 AU - Onofrj, Marco 
 AU - Cicalini, Ilaria 
 AU - del Boccio, Piero 
 AU - Gatta, Valentina 
 AU - Cimini, Annamaria 
 AU - Piomelli, Daniele 
 AU - Sensi, Stefano L. 
 TI - Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence
 JO - 
 JA - 
 VL - 11
 IS - 16
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.102191
 DO - 10.18632/aging.102191
 SP - 6336
 EP - 6357
 PY - 
 AB - Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, &#x2018;aged&#x2019; neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.
 ER -

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Platelet activation in diabetic mice models: the role of vascular endothelial cell-derived protein disulfide isomerase-mediated GP IIb/IIIa receptor activation

Ran-Ran Qin, Hui Zhu, Feng Wang, Ming Song, Pei-Lin Lin, Yan-Qiu Xing, Wei Zhang, Ming Zhong, Zhi-Hao Wang,

https://doi.org/10.18632/aging.102192 pp 6358—6370

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Qin R, Zhu H, Wang F, Song M, Lin P, Xing Y, Zhang W, Zhong M, Wang Z, . Platelet activation in diabetic mice models: the role of vascular endothelial cell-derived protein disulfide isomerase-mediated GP IIb/IIIa receptor activation. . 11:6358-6370. https://doi.org/10.18632/aging.102192

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                TY  - JOUR
                AU  - Qin, Ran-Ran 
                AU  - Zhu, Hui 
                AU  - Wang, Feng 
                AU  - Song, Ming 
                AU  - Lin, Pei-Lin 
                AU  - Xing, Yan-Qiu 
                AU  - Zhang, Wei 
                AU  - Zhong, Ming 
                AU  - Wang, Zhi-Hao 
                TI  - Platelet activation in diabetic mice models: the role of vascular endothelial cell-derived protein disulfide isomerase-mediated GP IIb/IIIa receptor activation
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102192
                DO  - 10.18632/aging.102192
                SP  - 6358
                EP  - 6370
                PY  - 
                AB  - GP IIb/IIIa receptor activation plays an important role in thrombosis. The mechanism of early activation of GP IIb/IIIa receptors in diabetic conditions remains unknown. The purpose of this study was to investigate the release of Endothelial microparticle (EMP)-associated protein disulfide isomerase (PDI) after endothelial cell injury induced in diabetes and the changes in platelet activation. We produced an animal model of type 2 diabetes mellitus using ApoE&#x2212;/&#x2212; mice. Normal ApoE&#x2212;/&#x2212; and diabetic mice were allocated to four groups (n = 15): normal diet, normal diet plus rutin, diabetic, and diabetes plus rutin. The EMP-PDI content and GP IIb/IIIa expression of mice platelets were determined. In addition, EMPs obtained from the four groups were pretreated with the PDI inhibitor rutin; then, their effects on the platelets of normal C57 mice were characterized. Compared with the normal diet group, the diabetic group had significantly increased plasma EMP-PDI content and accelerated platelet activation by increased GP IIb/IIIa expression. In conclusion, EMP-PDI promotes early platelet activation through glycoprotein (GP) IIb/IIIa receptors present on platelet surface in the diabetic state. However, this process could be partially suppressed by the administration of rutin.
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MiR-27a promotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling

Chen Cai, Shaoxiong Min, Bo Yan, Wen Liu, Xiao Yang, Liuxun Li, Ting Wang, Anmin Jin,

https://doi.org/10.18632/aging.102194 pp 6371—6384

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Cai C, Min S, Yan B, Liu W, Yang X, Li L, Wang T, Jin A, . MiR-27a promotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling. . 11:6371-6384. https://doi.org/10.18632/aging.102194

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                TY  - JOUR
                AU  - Cai, Chen 
                AU  - Min, Shaoxiong 
                AU  - Yan, Bo 
                AU  - Liu, Wen 
                AU  - Yang, Xiao 
                AU  - Li, Liuxun 
                AU  - Wang, Ting 
                AU  - Jin, Anmin 
                TI  - MiR-27a promotes the autophagy and apoptosis of IL-1β treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102194
                DO  - 10.18632/aging.102194
                SP  - 6371
                EP  - 6384
                PY  - 
                AB  - Osteoarthritis (OA) is a common degenerative joint disorder, which involves articular cartilage degeneration as well as joint inflammatory reactions. The recent studies have identified microRNA (miRNA) as one of the epigenetic mechanisms for the regulation of gene expression. Here we aim to reveal the role of miRNA in the regulation of gene expression in articular chondrocytes and its significance in the OA pathogenesis. In the present study, miRNA profiling was performed using OA cartilage and normal healthy cartilage tissues. As compared to their levels in normal cells and tissues, miR-27a expression was found to be upregulated in OA cartilage and IL-1&#x3B2;-treated articular chondrocytes. TUNEL staining, as well as flow cytometry with Annexin V-FITC/PI double labeling indicated that miR-27a inhibition reduced the apoptosis of IL-1&#x3B2;-treated articular chondrocytes. Bioinformatics prediction and the dual-luciferase reporter assay indicated that miR-27a targeted the 3&#x2032;-UTR of the PI3K gene to silence it. The PI3K mRNA level in OA cartilage and IL-1&#x3B2;-treated articular chondrocytes was also downregulated, comparing with normal cells and tissues. Transfection of chondrocytes transfected with the miR-27a inhibitor upregulated the PI3K expression. This study demonstrated miR-27a is a regulator of the PI3K-Akt-mTOR axis in human chondrocytes and could participate in OA pathogenesis.
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Low triiodothyronine syndrome is associated with hemorrhagic transformation in patients with acute ischaemic stroke

Gui-Qian Huang, Ya-Ying Zeng, Qian-Qian Cheng, Hao-Ran Cheng, Yi-Ting Ruan, Cheng-Xiang Yuan, Yun-Bin Chen, Wei-Lei He, Hui-Jun Chen, Jin-Cai He,

https://doi.org/10.18632/aging.102195 pp 6385—6397

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Huang G, Zeng Y, Cheng Q, Cheng H, Ruan Y, Yuan C, Chen Y, He W, Chen H, He J, . Low triiodothyronine syndrome is associated with hemorrhagic transformation in patients with acute ischaemic stroke. . 11:6385-6397. https://doi.org/10.18632/aging.102195

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                TY  - JOUR
                AU  - Huang, Gui-Qian 
                AU  - Zeng, Ya-Ying 
                AU  - Cheng, Qian-Qian 
                AU  - Cheng, Hao-Ran 
                AU  - Ruan, Yi-Ting 
                AU  - Yuan, Cheng-Xiang 
                AU  - Chen, Yun-Bin 
                AU  - He, Wei-Lei 
                AU  - Chen, Hui-Jun 
                AU  - He, Jin-Cai 
                TI  - Low triiodothyronine syndrome is associated with hemorrhagic transformation in patients with acute ischaemic stroke
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102195
                DO  - 10.18632/aging.102195
                SP  - 6385
                EP  - 6397
                PY  - 
                AB  - Hemorrhagic transformation (HT) is a severe complication occurring in acute ischemic stroke (AIS) patients. We explored the association between low triiodothyronine (T3) syndrome and HT in AIS patients. A total of 208 consecutive participants with HT and 208 age- and sex-matched stroke patients without HT were enrolled in this study. HT was diagnosed by follow-up imaging assessment, and was radiologically classified as hemorrhagic infarction (HI) type 1 or 2 or parenchymal hematoma (PH) type 1 or 2. HT was also classified into asymptomatic or symptomatic. The incidence of low T3 syndrome was significantly higher among patients who developed HT than among those without HT. Moreover, the more severe the HT, the lower the detected T3 levels. Multivariate-adjusted binary logistic regression showed that low T3 syndrome was an independent risk factor for HT and symptomatic HT in AIS patients. Low T3 syndrome was also significantly associated with a higher risk of PH, but not with the risk of HI. Thus, low T3 syndrome was independently associated with the risk of HT, symptomatic HT, and severe HT (PH) in AIS patients, which suggests monitoring T3 could be a useful means of preventing HT in patients with ischemic stroke.
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Comprehensive transcriptomic analysis indicates brain regional specific alterations in type 2 diabetes

Zhe Zhou, Yizhang Zhu, Yang Liu, Yuxin Yin,

https://doi.org/10.18632/aging.102196 pp 6398—6421

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Zhou Z, Zhu Y, Liu Y, Yin Y, . Comprehensive transcriptomic analysis indicates brain regional specific alterations in type 2 diabetes. . 11:6398-6421. https://doi.org/10.18632/aging.102196

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                TY  - JOUR
                AU  - Zhou, Zhe 
                AU  - Zhu, Yizhang 
                AU  - Liu, Yang 
                AU  - Yin, Yuxin 
                TI  - Comprehensive transcriptomic analysis indicates brain regional specific alterations in type 2 diabetes
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102196
                DO  - 10.18632/aging.102196
                SP  - 6398
                EP  - 6421
                PY  - 
                AB  - Type 2 diabetes (T2D) can result in a number of comorbidities involving various organs including heart, eye, kidney and even the brain. However, little is known about the molecular basis of T2D associated brain disorders. In this study, we performed a comprehensive transcriptomic analysis in a total of 304 T2D samples and 608 matched control samples from thirteen distinct brain regions. We observed prominent difference among transcriptomic profiles of diverse brain regions in T2D. The most striking change was found in caudate with thousands of T2D-associated genes identified, followed by hippocampus, while nearly no transcriptomic change was observed in other brain regions. Functional analysis of T2D-associated genes revealed impaired synaptic functions and an association with neurodegenerative diseases. Co-expression analysis of caudate transcriptomic profiles unveiled a core regional specific module that was disorganized in T2D. Sub-modules consisting of regional markers were enriched in T2D risk single nucleotide polymorphisms (SNPs) and implied a causal link with T2D. Hub genes of this module include NSF and ADD2, the former of which has been associated with T2D and neurogenerative diseases. Thus, our work provides useful information for further studies in T2D associated brain disorders.
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A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma

Jue Yang, Yongqiang Zhang, Hui Song,

https://doi.org/10.18632/aging.102197 pp 6422—6439

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Yang J, Zhang Y, Song H, . A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma. . 11:6422-6439. https://doi.org/10.18632/aging.102197

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                TY  - JOUR
                AU  - Yang, Jue 
                AU  - Zhang, Yongqiang 
                AU  - Song, Hui 
                TI  - A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102197
                DO  - 10.18632/aging.102197
                SP  - 6422
                EP  - 6439
                PY  - 
                AB  - The immune system is critical in modulating cancer progression. Pseudogenes are a special type of long non-coding RNAs that regulate different tumorigenic processes. However, the potential roles of pseudogenes in tumor-immune interaction remain largely unclear. Here, we reported that pseudogene RP11-424C20.2 and its parental gene UHRF1 were frequently up-regulated and positively correlated in liver hepatocellular carcinoma (LIHC) and thymoma (THYM), but associated with distinct clinical outcomes. We further found that RP11-424C20.2 may act as a competing endogenous RNA (ceRNA) to increase UHRF1 expression through sponging miR-378a-3p. Functional enrichment analysis showed a strong association of UHRF1 with immune-related biological processes. We also observed that UHRF1 expression significantly correlated with immune infiltration, and different types of tumor-infiltrating immune cells displayed different impacts on clinical outcomes. Furthermore, UHRF1 expression in LIHC and THYM showed an opposite correlation with biomarkers from monocyte, dendritic cell, Th1 and T cell exhaustion. Mechanism investigations revealed that RP11-424C20.2/UHRF1 axis regulated immune escape of LIHC and THYM at least partly through IFN-&#x3B3;-mediated CLTA-4 and PD-L1 pathway. These findings demonstrate a disparate role of RP11-424C20.2/UHRF1 axis in LIHC and THYM via regulating immune infiltrates, and also indicate a therapeutic value for UHRF1 inhibitors in combination with anti-PD-L1/CLTA-4 blockade.
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FOXP2 contributes to the cognitive impairment in chronic patients with schizophrenia

Xiaoe Lang, Wenzhong Zhang, Xinxin Song, Guangya Zhang, Xiangdong Du, Yongjie Zhou, Zezhi Li, Xiang Yang Zhang,

https://doi.org/10.18632/aging.102198 pp 6440—6448

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Lang X, Zhang W, Song X, Zhang G, Du X, Zhou Y, Li Z, Zhang XY, . FOXP2 contributes to the cognitive impairment in chronic patients with schizophrenia. . 11:6440-6448. https://doi.org/10.18632/aging.102198

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Provider: 
 TY - JOUR
 AU - Lang, Xiaoe 
 AU - Zhang, Wenzhong 
 AU - Song, Xinxin 
 AU - Zhang, Guangya 
 AU - Du, Xiangdong 
 AU - Zhou, Yongjie 
 AU - Li, Zezhi 
 AU - Zhang, Xiang Yang
 TI - FOXP2 contributes to the cognitive impairment in chronic patients with schizophrenia
 JO - 
 JA - 
 VL - 11
 IS - 16
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.102198
 DO - 10.18632/aging.102198
 SP - 6440
 EP - 6448
 PY - 
 AB - The forkhead-box P2 (FOXP2), involving in language and memory function, has been identified as susceptibility to schizophrenia. However, no study examined the role of FOXP2 on cognitive impairment in schizophrenia. Total 1106 inpatients with schizophrenia and 404 controls were recruited and genotyped. Among them, 867 patients and 402 controls were assessed through the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). SHEsis software was used to investigate the association of FOXP2 rs10447760 with schizophrenia, followed by logistic regression. The model of covariance (ANCOVA) and multivariate analysis were conducted to investigate the effect of FOXP2 rs10447760 on cognitive impairment in schizophrenia. No differences in the genotypic and allelic frequencies of the FOXP2 rs10447760 were found between patients and controls (both p&gt; 0.05). Except for the visuospatial/constructional score (p &gt; 0.05), other five RBANS scores were lower in patients compared to controls (all p &lt; 0.0001). Interestingly, we found immediate memory score was lower in patients carrying genotype CT compared to genotype CC (F=5.19, p=0.02), adjusting for confounding data. Our study suggested that FOXP2 rs10447760 has no effect on the susceptibility to schizophrenia, while it may be associated with its cognitive impairment, especially immediate memory in chronic schizophrenia.
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Quantitative analysis of the human ovarian carcinoma mitochondrial phosphoproteome

Na Li, Shehua Qian, Biao Li, Xianquan Zhan,

https://doi.org/10.18632/aging.102199 pp 6449—6468

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Li N, Qian S, Li B, Zhan X, . Quantitative analysis of the human ovarian carcinoma mitochondrial phosphoproteome. . 11:6449-6468. https://doi.org/10.18632/aging.102199

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                TY  - JOUR
                AU  - Li, Na 
                AU  - Qian, Shehua 
                AU  - Li, Biao 
                AU  - Zhan, Xianquan 
                TI  - Quantitative analysis of the human ovarian carcinoma mitochondrial phosphoproteome
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102199
                DO  - 10.18632/aging.102199
                SP  - 6449
                EP  - 6468
                PY  - 
                AB  - To investigate the existence and their potential biological roles of mitochondrial phosphoproteins (mtPPs) in human ovarian carcinoma (OC), mitochondria purified from OC and control tissues were analyzed with TiO2 enrichment-based iTRAQ quantitative proteomics. Totally 67 mtPPs with 124 phosphorylation sites were identified, which of them included 48 differential mtPPs (mtDPPs). Eighteen mtPPs were reported previously in OCs, and they were consistent in this study compared to previous literature. GO analysis revealed those mtPPs were involved in multiple cellular processes. PPI network indicated that those mtPPs were correlated mutually, and some mtPPs acted as hub molecules, such as EIF2S2, RPLP0, RPLP2, CFL1, MYH10, HSP90, HSPD1, PSMA3, TMX1, VDAC2, VDAC3, TOMM22, and TOMM20. Totally 32 mtPP-pathway systems (p&lt;0.05) were enriched and clustered into 15 groups, including mitophagy, apoptosis, deubiquitination, signaling by VEGF, RHO-GTPase effectors, mitochondrial protein import, translation initiation, RNA transport, cellular responses to stress, and c-MYC transcriptional activation. Totally 29 mtPPs contained a certain protein domains. Upstream regulation analysis showed that TP53, TGFB1, dexamethasone, and thapsigargin might act as inhibitors, and L-dopa and forskolin might act as activators. This study provided novel insights into mitochondrial protein phosphorylations and their potential roles in OC pathogenesis and offered new biomarker resource for OCs.
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Identification and validation of four hub genes involved in the plaque deterioration of atherosclerosis

Peipei Chen, Yuexin Chen, Wei Wu, Lianfeng Chen, Xufei Yang, Shuyang Zhang,

https://doi.org/10.18632/aging.102200 pp 6469—6489

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Chen P, Chen Y, Wu W, Chen L, Yang X, Zhang S, . Identification and validation of four hub genes involved in the plaque deterioration of atherosclerosis. . 11:6469-6489. https://doi.org/10.18632/aging.102200

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                TY  - JOUR
                AU  - Chen, Peipei 
                AU  - Chen, Yuexin 
                AU  - Wu, Wei 
                AU  - Chen, Lianfeng 
                AU  - Yang, Xufei 
                AU  - Zhang, Shuyang 
                TI  - Identification and validation of four hub genes involved in the plaque deterioration of atherosclerosis
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102200
                DO  - 10.18632/aging.102200
                SP  - 6469
                EP  - 6489
                PY  - 
                AB  - In recent years, intense research has been conducted to explore the diagnostic value of mRNA expression differences in atherosclerosis (AS). Nevertheless, because various technology platforms are applied and sample sizes are small, the results are inconsistent among the studies. We conducted a comprehensive analysis of a total of 161 tissue samples from 4 published studies after evaluating 230 datasets from the Gene Expression Omnibus and ArrayExpress. Adopting the newly published robust rank aggregation approach, combined with Kyoto Encyclopedia of Genes and Genomes pathway analysis, Gene Ontology functional enrichment analysis, and protein-protein interaction network construction, we identified four significantly upregulated genes (CCL4, CCL18, MMP9 and SPP1) for diagnosing AS, even in the advanced stage. Then, we performed gene set enrichment analysis to identify the pathways that were most affected by altered mRNA expression in atherosclerotic plaques. We found that four hub genes cooperatively targeted lipid metabolism and inflammatory immune-related pathways and validated their high expression levels in ruptured plaques by qRT-PCR, western blot analysis and immunohistochemical staining. In summary, our study showed that these genes can be used as interventional targets for plaque progression, and the results suggested we should focus on small changes in these key indicators in the clinical setting.
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Down-regulation of Cav1.3 in auditory pathway promotes age-related hearing loss by enhancing calcium-mediated oxidative stress in male mice

Fan Qi, Rongsheng Zhang, Jin Chen, Fei Zhao, Yanbo Sun, Zhihui Du, Dan Bing, Pengjun Li, Shengli Shao, Hongmei Zhu, Hanqi Chu,

https://doi.org/10.18632/aging.102203 pp 6490—6502

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Qi F, Zhang R, Chen J, Zhao F, Sun Y, Du Z, Bing D, Li P, Shao S, Zhu H, Chu H, . Down-regulation of Cav1.3 in auditory pathway promotes age-related hearing loss by enhancing calcium-mediated oxidative stress in male mice. . 11:6490-6502. https://doi.org/10.18632/aging.102203

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                TY  - JOUR
                AU  - Qi, Fan 
                AU  - Zhang, Rongsheng 
                AU  - Chen, Jin 
                AU  - Zhao, Fei 
                AU  - Sun, Yanbo 
                AU  - Du, Zhihui 
                AU  - Bing, Dan 
                AU  - Li, Pengjun 
                AU  - Shao, Shengli 
                AU  - Zhu, Hongmei 
                AU  - Chu, Hanqi 
                TI  - Down-regulation of Cav1.3 in auditory pathway promotes age-related hearing loss by enhancing calcium-mediated oxidative stress in male mice
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102203
                DO  - 10.18632/aging.102203
                SP  - 6490
                EP  - 6502
                PY  - 
                AB  - In this study, age related Cav1.3 expression in cochlea and auditory cortex of C57BL/6J male mice was evaluated. It was found that the expression of Cav1.3 in cochlea decreased with aging whereas this phenomenon was not observed in neuron of auditory cortex. The correlation between decreased expression of Cav1.3 and age-related hearing losses was studied in vitro, after Cav1.3 was knocked out, the rate of apoptosis of hair cells increased after being subjected to ROS stresses, accompanied with enhanced senescence. Further, Cav1.3 knock down also interfered with the electrophysiology of hair cells. The effect was further confirmed in vivo, after Cav1.3 knocked down by injection of AAV, hearing impairment was observed in C57BL/6J male mice subjected to senescence and this was accompanied by increased loss of hair cells in cochlea. The effect was further confirmed in 3D organ culture, increased loss of hair cells after Cav1.3 was knocked down under ROS stresses.Mechanistically, Cav1.3 knock out resulted in decreased intracellular calcium which subsequently reduced the inactivation of ROS from complex I, and finally resulted in increased intracellular ROS and enhanced senescence.Collectively, these findings confirmed that Cav1.3 could protect cells in auditory pathway from oxidative stresses, and decreased expression of Cav1.3 in auditory pathway could contribute to hearing losses by enhancement of calcium-mediated oxidative stress.
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Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma

Wen-Hao Xu, Yue Xu, Jun Wang, Xi Tian, Junlong Wu, Fang-Ning Wan, Hong-Kai Wang, Yuan-Yuan Qu, Hai-Liang Zhang, Ding-Wei Ye,

https://doi.org/10.18632/aging.102206 pp 6503—6521

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Xu W, Xu Y, Wang J, Tian X, Wu J, Wan F, Wang H, Qu Y, Zhang H, Ye D, . Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma. . 11:6503-6521. https://doi.org/10.18632/aging.102206

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                TY  - JOUR
                AU  - Xu, Wen-Hao 
                AU  - Xu, Yue 
                AU  - Wang, Jun 
                AU  - Tian, Xi 
                AU  - Wu, Junlong 
                AU  - Wan, Fang-Ning 
                AU  - Wang, Hong-Kai 
                AU  - Qu, Yuan-Yuan 
                AU  - Zhang, Hai-Liang 
                AU  - Ye, Ding-Wei 
                TI  - Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102206
                DO  - 10.18632/aging.102206
                SP  - 6503
                EP  - 6521
                PY  - 
                AB  - Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan&#x2013;Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all p&lt;0.01). Genetic mutation of PLOD1/2/3 was present in ~3% of ccRCC patients and was associated with significantly poorer prognosis compared with expression of wild-type PLOD1/2/3 (p&lt;0.001). This study thus identifies tumor expression of wild-type or mutated PLOD1/2/3 mRNA as a potential predictive biomarker for ccRCC patients and sheds light on the underlying molecular pathogenesis of ccRCC.
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Strict target blood pressure management for reducing the stroke risk according to 2017 ACC/AHA blood pressure guideline

Peng Zhao, Jie Liu, Conglin Wang, Wei Zhao, Yanqiu Zhang, Hongfei Gu, Jun Tu, Jinghua Wang, Xianjia Ning,

https://doi.org/10.18632/aging.102207 pp 6522—6534

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Zhao P, Liu J, Wang C, Zhao W, Zhang Y, Gu H, Tu J, Wang J, Ning X, . Strict target blood pressure management for reducing the stroke risk according to 2017 ACC/AHA blood pressure guideline. . 11:6522-6534. https://doi.org/10.18632/aging.102207

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                TY  - JOUR
                AU  - Zhao, Peng 
                AU  - Liu, Jie 
                AU  - Wang, Conglin 
                AU  - Zhao, Wei 
                AU  - Zhang, Yanqiu 
                AU  - Gu, Hongfei 
                AU  - Tu, Jun 
                AU  - Wang, Jinghua 
                AU  - Ning, Xianjia 
                TI  - Strict target blood pressure management for reducing the stroke risk according to 2017 ACC/AHA blood pressure guideline
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102207
                DO  - 10.18632/aging.102207
                SP  - 6522
                EP  - 6534
                PY  - 
                AB  - Background and Purpose: We explored the new BP thresholds and their impact on first-ever stroke risk determinations.Results: During a mean following-up period of 21.85 years, 638 first-ever strokes occurred among 3906 participants. After adjusting for covariates, the hazard ratios for ischemic stroke (IS) in men aged &lt;60 years were significant higher in participants with elevated BP, stage 1 hypertension, and stage 2 hypertension than normal BP (all P&lt;0.05); an increased risk of intracerebral hemorrhage (ICH) was also observed for those with stage 2 hypertension. Similarly, in women aged, the risk of stroke increased for those with stage 2 hypertension both in &lt;60 years and in &#x2265;60 years. Moreover, more than 60% of incident strokes were attributed to systolic BP (SBP) &#x2265;120mmHg and diastolic BP (DBP) &lt;80mmHg in men aged &lt;60 years.Conclusions: Elevated BP increases the risk of developing stroke, particularly in the absence of routine BP measurements and hypertension treatment. A strict BP management target (SBP, &lt;120 mmHg; DBP, &lt;80 mmHg) should be adopted for young and middle-aged men.Methods: This population-based cohort study was conducted between October 1991 and January 2018. The association of BP categories, defined by the 2017 ACC/AHA BP guideline, with first-ever stroke risk was assessed using Cox regression models.
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Mitochondrial bioenergetic changes during development as an indicator of C. elegans health-span

Silvia Maglioni, Danielle F. Mello, Alfonso Schiavi, Joel N. Meyer, Natascia Ventura,

https://doi.org/10.18632/aging.102208 pp 6535—6554

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Maglioni S, Mello DF, Schiavi A, Meyer JN, Ventura N, . Mitochondrial bioenergetic changes during development as an indicator of C. elegans health-span. . 11:6535-6554. https://doi.org/10.18632/aging.102208

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Provider: 
 TY - JOUR
 AU - Maglioni, Silvia 
 AU - Mello, Danielle F. 
 AU - Schiavi, Alfonso 
 AU - Meyer, Joel N. 
 AU - Ventura, Natascia 
 TI - Mitochondrial bioenergetic changes during development as an indicator of C. elegans health-span
 JO - 
 JA - 
 VL - 11
 IS - 16
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.102208
 DO - 10.18632/aging.102208
 SP - 6535
 EP - 6554
 PY - 
 AB - Mild suppression of mitochondrial activity has beneficial effects across species. The nematode Caenorhabditis elegans is a versatile, genetically tractable model organism widely employed for aging studies, which has led to the identification of many of the known evolutionarily conserved mechanisms regulating lifespan. In C. elegans the pro-longevity effect of reducing mitochondrial function, for example by RNA interference, is only achieved if mitochondrial stress is applied during larval development. Surprisingly, a careful analysis of changes in mitochondrial functions resulting from such treatments during the developmental windows in which pro-longevity signals are programmed has never been carried out. Thus, although the powerful C. elegans genetics have led to the identification of different molecular mechanisms causally involved in mitochondrial stress control of longevity, specific functional mitochondrial biomarkers indicative or predictive of lifespan remain to be identified. To fill this gap, we systematically characterized multiple mitochondrial functional parameters at an early developmental stage in animals that are long-lived due to mild knockdown of twelve different mitochondrial proteins and correlated these parameters with animals&#x2019; lifespan. We found that basal oxygen consumption rate and ATP-linked respiration positively correlate with lifespan extension and propose the testable hypothesis that the Bioenergetic Health Index can be used as a proxy to predict health-span outcomes.
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LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice

Marco Malavolta, Serena Dato, Francesco Villa, Francesco De Rango, Francesca Iannone, Anna Ferrario, Anna Maciag, Elena Ciaglia, Antonio D'amato, Albino Carrizzo, Andrea Basso, Fiorenza Orlando, Mauro Provinciali, Paolo Madeddu, Giuseppe Passarino, Carmine Vecchione, Giuseppina Rose, Annibale A Puca,

https://doi.org/10.18632/aging.102209 pp 6555—6568

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Malavolta M, Dato S, Villa F, Rango FD, Iannone F, Ferrario A, Maciag A, Ciaglia E, D'amato A, Carrizzo A, Basso A, Orlando F, Provinciali M, et al, . LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice. . 11:6555-6568. https://doi.org/10.18632/aging.102209

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                TY  - JOUR
                AU  - Malavolta, Marco 
                AU  - Dato, Serena 
                AU  - Villa, Francesco 
                AU  - Rango, Francesco De 
                AU  - Iannone, Francesca 
                AU  - Ferrario, Anna 
                AU  - Maciag, Anna 
                AU  - Ciaglia, Elena 
                AU  - D'amato, Antonio 
                AU  - Carrizzo, Albino 
                AU  - Basso, Andrea 
                AU  - Orlando, Fiorenza 
                AU  - Provinciali, Mauro 
                AU  - Madeddu, Paolo 
                AU  - Passarino, Giuseppe 
                AU  - Vecchione, Carmine 
                AU  - Rose, Giuseppina 
                AU  - Puca, Annibale A 
                TI  - LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102209
                DO  - 10.18632/aging.102209
                SP  - 6555
                EP  - 6568
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Malavolta, Marco 
                AU  - Dato, Serena 
                AU  - Villa, Francesco 
                AU  - Rango, Francesco De 
                AU  - Iannone, Francesca 
                AU  - Ferrario, Anna 
                AU  - Maciag, Anna 
                AU  - Ciaglia, Elena 
                AU  - D'amato, Antonio 
                AU  - Carrizzo, Albino 
                AU  - Basso, Andrea 
                AU  - Orlando, Fiorenza 
                AU  - Provinciali, Mauro 
                AU  - Madeddu, Paolo 
                AU  - Passarino, Giuseppe 
                AU  - Vecchione, Carmine 
                AU  - Rose, Giuseppina 
                AU  - Puca, Annibale A 
                TI  - LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102209
                DO  - 10.18632/aging.102209
                SP  - 6555
                EP  - 6568
                PY  - 
                AB  - Background: There is an increasing concern about age-related frailty because of the growing number of elderly people in the general population. The Longevity-Associated Variant (LAV) of the human BPIFB4 gene was found to correct endothelial dysfunction, one of the mechanisms underlying frailty, in aging mice whereas the RV-BPIFB4 variant induced opposite effects. Thus, we newly hypothesize that, besides being associated with life expectancy, BPIFB4 polymorphisms can predict frailty.Aim and Results: Here we investigated if the BPIFB4 haplotypes, LAV, wild-type (WT) and RV, differentially associate with frailty in a cohort of 237 elderly subjects from Calabria region in Southern Italy. Moreover, we studied the effect of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer on the progression of frailty in aging mice. We found an inverse correlation of the homozygous LAV-BPIFB4 haplotype with frailty in elderly subjects. Conversely, carriers of the RV-BPIFB4 haplotype showed an increase in the frailty status and risk of death. Moreover, in old mice, LAV-BPIFB4 gene transfer delayed frailty progression.Conclusions: These data indicate that specific BPIFB4 haplotypes could represent useful genetic markers of frailty. In addition, horizontal transfer of a healthy gene variant can attenuate frailty in aging organisms.
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Genetic variants of ADAMTS7 confer risk for ischaemic stroke in the Chinese population

Linfa Chen, Weidong Hu, Shengnan Li, Shaoyu Yao, Mengxu Wang, Xinglan Chen, Shaofeng Chen, Fu Deng, Peiyi Zhu, Keshen Li, Wangtao Zhong, Bin Zhao, Guoda Ma, You Li,

https://doi.org/10.18632/aging.102211 pp 6569—6583

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Chen L, Hu W, Li S, Yao S, Wang M, Chen X, Chen S, Deng F, Zhu P, Li K, Zhong W, Zhao B, Ma G, et al, . Genetic variants of ADAMTS7 confer risk for ischaemic stroke in the Chinese population. . 11:6569-6583. https://doi.org/10.18632/aging.102211

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Provider: 
 TY - JOUR
 AU - Chen, Linfa 
 AU - Hu, Weidong 
 AU - Li, Shengnan 
 AU - Yao, Shaoyu 
 AU - Wang, Mengxu 
 AU - Chen, Xinglan 
 AU - Chen, Shaofeng 
 AU - Deng, Fu 
 AU - Zhu, Peiyi 
 AU - Li, Keshen 
 AU - Zhong, Wangtao 
 AU - Zhao, Bin 
 AU - Ma, Guoda 
 AU - Li, You 
 TI - Genetic variants of ADAMTS7 confer risk for ischaemic stroke in the Chinese population
 JO - 
 JA - 
 VL - 11
 IS - 16
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.102211
 DO - 10.18632/aging.102211
 SP - 6569
 EP - 6583
 PY - 
 AB - Large-scale genome-wide association analyses show an association between ADAMTS7 variations and coronary risk. However, the link between ADAMTS7 variability and ischaemic stroke (IS) has yet to be determined. This study evaluated ADAMTS7 variants with respect to the risk of IS. Genetic association analyses were performed in two independent case-control cohorts with 1279 patients with IS and 1268 age-matched healthy controls. Four variant genotypes of the ADAMTS7 gene were identified using the Multiplex SNaPshot assay. The rs3825807, rs11634042, and rs7173743 variants of ADAMTS7 were related to lower IS risk in both initial and replication cohort. The G-T-T-C and G-T-C-C haplotypes are significantly less prevalent in the IS group than in the control group. Further stratification according to IS subtypes indicated that carriers with the variant alleles of the rs3825807, rs11634042 and rs7173743 variants of ADAMTS7conferred a lower risk of developing large-artery atherosclerosis stroke subtype. Also, the mutated rs3825807 G allele, as well as the mutated rs11634042 T allele of ADAMTS7, are linked to a significant reduction of ADAMTS7 in patients with IS. Our findings confirm the role of ADAMTS7 in the pathophysiology of IS, with potentially significant implications for the prevention, treatment, and development of novel therapies for IS.
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Role and mechanism of cardiac insulin resistance in occurrence of heart failure caused by myocardial hypertrophy

Liling Zheng, Bingbing Li, Sihuang Lin, Liangcai Chen, Hongmu Li,

https://doi.org/10.18632/aging.102212 pp 6584—6590

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Zheng L, Li B, Lin S, Chen L, Li H, . Role and mechanism of cardiac insulin resistance in occurrence of heart failure caused by myocardial hypertrophy. . 11:6584-6590. https://doi.org/10.18632/aging.102212

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                TY  - JOUR
                AU  - Zheng, Liling 
                AU  - Li, Bingbing 
                AU  - Lin, Sihuang 
                AU  - Chen, Liangcai 
                AU  - Li, Hongmu 
                TI  - Role and mechanism of cardiac insulin resistance in occurrence of heart failure caused by myocardial hypertrophy
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102212
                DO  - 10.18632/aging.102212
                SP  - 6584
                EP  - 6590
                PY  - 
                AB  - Cardiac insulin resistance plays an important role in the development of heart failure, but the underlying mechanisms remain unclear. Here, we found that hypertrophic hearts exhibit normal cardiac glucose oxidation rates, but reduced fatty acid oxidation rates, compared to Sham controls under basal (no insulin) conditions. Furthermore, insulin stimulation attenuated insulin&#x2019;s effects on cardiac substrate utilization, suggesting the development of cardiac insulin resistance. Consistent with insulin resistance, p38-MAPK protein levels were reduced in hypertrophic hearts. By contrast, systemic hyperinsulin-euglycemic clamp indicated normal insulin sensitivity. Finally, electron microscopy revealed severe mitochondrial damage in the hypertrophic myocardium. Our results indicate that that cardiac insulin resistance caused by cardiac hypertrophy is associated with mitochondrial damage and cardiac dysfunction. Moreover, our findings suggest that cardiac insulin resistance is independent of systemic insulin resistance, which is also a risk factor for heart failure.
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In silico clinical trials for anti-aging therapies

Javier A. Menendez, Elisabet Cuyàs, Núria Folguera-Blasco, Sara Verdura, Begoña Martin-Castillo, Jorge Joven, Tomás Alarcón,

https://doi.org/10.18632/aging.102180 pp 6591—6601

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Menendez JA, Cuyàs E, Folguera-Blasco N, Verdura S, Martin-Castillo B, Joven J, Alarcón T, . In silico clinical trials for anti-aging therapies. . 11:6591-6601. https://doi.org/10.18632/aging.102180

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 TY - JOUR
 AU - Menendez, Javier A. 
 AU - Cuyàs, Elisabet 
 AU - Folguera-Blasco, Núria 
 AU - Verdura, Sara 
 AU - Martin-Castillo, Begoña 
 AU - Joven, Jorge 
 AU - Alarcón, Tomás 
 TI - In silico clinical trials for anti-aging therapies
 JO - 
 JA - 
 VL - 11
 IS - 16
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.102180
 DO - 10.18632/aging.102180
 SP - 6591
 EP - 6601
 PY - 
 AB - Therapeutic strategies targeting the hallmarks of aging can be broadly grouped into four categories, namely systemic (blood) factors, metabolic manipulation (diet regimens and dietary restriction mimetics), suppression of cellular senescence (senolytics), and cellular reprogramming, which likely have common characteristics and mechanisms of action. In evaluating the potential synergism of combining such strategies, however, we should consider the possibility of constraining trade-off phenotypes such as impairment in wound healing and immune response, tissue dysfunction and tumorigenesis. Moreover, we are rapidly learning that the benefit/risk ratio of aging-targeted interventions largely depends on intra- and inter-individual variations of susceptibility to the healthspan-, resilience-, and/or lifespan-promoting effects of the interventions. Here, we exemplify how computationally-generated proxies of the efficacy of a given lifespan/healthspan-promoting approach can predict the impact of baseline epigenetic heterogeneity on the positive outcomes of ketogenic diet and mTOR inhibition as single or combined anti-aging strategies. We therefore propose that stochastic biomathematical modeling and computational simulation platforms should be developed as in silico strategies to accelerate the performance of clinical trials targeting human aging, and to provide personalized approaches and robust biomarkers of healthy aging at the individual-to-population levels.
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Pathophysiology of aged lymphatic vessels

Tongyao Shang, Jiangjiu Liang, Carolyn M. Kapron, Ju Liu,

https://doi.org/10.18632/aging.102213 pp 6602—6613

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Shang T, Liang J, Kapron CM, Liu J, . Pathophysiology of aged lymphatic vessels. . 11:6602-6613. https://doi.org/10.18632/aging.102213

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                TY  - JOUR
                AU  - Shang, Tongyao 
                AU  - Liang, Jiangjiu 
                AU  - Kapron, Carolyn M. 
                AU  - Liu, Ju 
                TI  - Pathophysiology of aged lymphatic vessels
                JO  - 
                JA  - 
                VL  - 11
                IS  - 16
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.102213
                DO  - 10.18632/aging.102213
                SP  - 6602
                EP  - 6613
                PY  - 
                AB  - Lymphatic vessels maintain body homeostasis by recirculation of fluid and cells. Cell senescence induces lymphatic dysfunction. Impaired contractile function is caused by low muscle cell investiture and decrease of nitric oxide in aged lymphatic collectors, leading to poor drainage of lymph. Aging-induced loss of endothelial glycocalyx and production of inflammatory cytokines increases permeability of lymphatic vessels. In addition, aging-associated basal activation of mast cells delays immune response. In this review, we summarize the structural and pathological changes of aged lymphatic vessels, and discuss the underlying molecular mechanisms.
                ER  -

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Volume 11, Issue 16

About the Cover

Editorials

Matthew E. Pamenter, Daniel Munro,

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Álvaro García-Ropero, Carlos G Santos-Gallego, Juan J. Badimon,

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Huibin Tang, Joseph B. Shrager, Daniel Goldman,

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Nikhil Panicker, Arthi Kanthasamy, Anumantha G. Kanthasamy,

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Xiao-Hong Sun,

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Research Papers

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Camilo Toledo, Claudia Lucero, David C. Andrade, Hugo S. Díaz, Karla G. Schwarz, Katherin V. Pereyra, Alexis Arce-Álvarez, Nicolás A. López, Milka Martinez, Nibaldo C. Inestrosa, Rodrigo Del Rio,

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Kiyana Zarnani, Thomas E. Nichols, Fidel Alfaro-Almagro, Birgitte Fagerlund, Martin Lauritzen, Egill Rostrup, Stephen M. Smith,

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Huanghao Deng, Changkun Huang, Yinhuai Wang, Hongyi Jiang, Shuang Peng, Xiaokun Zhao,

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Mengna Li, Li Li, Xiaofeng Zhang, Huijuan Zhao, Min Wei, Wanying Zhai, Baoxi Wang, Yan Yan,

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Xin Liu, Liangliang Liu, Hongbo Zhang, Yan Shao, Ziyu Chen, Xiaofeng Feng, Hang Fang, Chang Zhao, Jianying Pan, Haiyan Zhang, Chun Zeng, Daozhang Cai,

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Yongwen Luo, Dexin Shen, Liang Chen, Gang Wang, Xuefeng Liu, Kaiyu Qian, Yu Xiao, Xinghuan Wang, Lingao Ju,

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Wei-Lin Chen, Hong-Jin Chen, Guo-Qiang Hou, Xiao-Hua Zhang, Jian-Wei Ge,

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Fengrui Zhou, Jianxiong Geng, Shanqi Xu, Qingwei Meng, Kexin Chen, Fang Liu, Fang Yang, Bo Pan, Yan Yu,

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Huimin Liu, Xiaoyu Gu, Guihua Wang, Ying Huang, Shaoqing Ju, Jianfei Huang, Xudong Wang,

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Cuihua Zou, Jie Wang, Xiaohua Huang, Chongdong Jian, Donghua Zou, Xuebin Li,

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Qingbin Wu, Xiaochen Yuan, Jing Bai, Ruiqin Han, Zhigang Li, Honggang Zhang, Ruijuan Xiu,

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Olga I. Kechko, Irina Yu. Petrushanko, Christopher S. Brower, Alexei A. Adzhubei, Alexey A. Moskalev, Konstantin I. Piatkov, Vladimir A. Mitkevich, Alexander A. Makarov,

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Zheng Zheng, Dan Xu, Keqing Shi, Minfeng Chen, Fan Lu,

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