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Telomere length (TL) is considered an indicator of aging and age-related diseases, but longitudinal studies on TL changes and mortality are few. We therefore analyzed TL and longitudinal changes in TL in relation to all-cause, cardiovascular, and cancer mortality in 247 elderly Swedish men. TL was determined by the qPCR method at ages 71 and 81 and subsequent mortality cases were identified from the Swedish cause-of-death registry. Cox proportional hazard ratios were calculated during a mean follow-up of 7.4 years, during which 178 deaths occurred. Short telomeres at baseline was strongly associated with mortality risks, with a 40 to 70% increased risk of all-cause mortality, and a 2-fold increased risk of cancer mortality. Longitudinal changes in TL revealed shortening in 83% of individuals, whilst 10% extended their telomeres. TL attrition did not predict all-cause or cancer mortality, but we found a 60% decreased risk for cardiovascular mortality in those who shortened their telomeres. Our data show an increased risk of mortality in individuals with short baseline telomeres, but no relations to all-cause, and cancer mortality for changes in TL. Intriguingly, our data indicate lower risk of cardiovascular mortality with shortening of telomeres. The latter should be interpreted cautiously.

Epigenetic mechanisms play a key role in gastrointestinal cancer (GIC) development and progression, and most studies have been focused on aberrant DNA methylation and histone modifying enzymes. However, the histone H3–H4 chaperone ASF1A is an important factor regulating chromatin assembling and gene transcription, while it is currently unclear whether ASF1A is involved in cancer pathogenesis. The present study is thus designed to address this issue. Here we showed that ASF1A expression was widespread in GIC-derived cell lines and up-regulated in primary GIC. Higher levels of ASF1A expression predicted significantly shorter patient overall survival in colorectal cancer (P = 0.0012). The further analyses of the GEO dataset validate higher ASF1A expression as a prognostic factor for CRC patients. Mechanistically, ASF1A interacted with β-catenin and promoted the transcription of β-catenin target genes including c-MYC, cyclin D1, ZEB1 and LGR5, thereby stimulating proliferation, stemness and migration/invasion of GIC cells. β-Catenin inhibition abolished these effects of ASF1A. Moreover, the ASF1A-β-catenin-ZEB1 axis down-regulated E-Cadherin expression, thereby contributing to enhanced migration/invasion of GIC cells. ASF1A over-expression and depletion facilitated and inhibited in vivo tumor growth and/or metastasis in mouse xenograft models, respectively. Taken together, ASF1A is aberrantly over-expressed in GIC tumors and plays key roles in GIC development and progression by stimulating the transcription of β-catenin target genes. ASF1A may thus be a novel target for GIC therapy and a potential prognostic marker.

Telomerase activation via induction of the catalytic component telomerase reverse transcriptase (TERT) plays essential roles in malignant transformation. TERT promoter-activating mutations were recently identified as a novel mechanism to activate telomerase in hepatocellular carcinoma (HCC) and many other malignancies. In addition, single nucleotide polymorphisms (SNPs) in the TERT rs2736098 and rs2736100 are significantly associated with cancer susceptibility. It is currently unclear whether different germline TERT variants modify TERT promoter mutations. Here we analyzed the TERT promoter status and genotyped the TERT SNPs at rs2736098 and rs2736100 in patients with HCC. Thirty percent of HCCs harbored TERT promoter mutations and there was a significant difference in rs2736098 and rs2736100 genotypes between wt and mutant TERT promoter-bearing HCC tumors (P = 0.007 and 0.018, respectively). For rs2736100, the cancer risk genotype CC was significantly associated with a reduced incidence of TERT promoter mutations compared to AA + AC variants [Odds ratio (OR): 0.181, 95% Confidence interval (CI): 0.0543–0.601, P = 0.004]. The rs2736098_CT genotype was significantly associated with the TERT promoter mutation-positive tumors compared to the TT genotype (OR: 5.391, 95% CI: 1.234–23.553, P = 0.025). These differences in genotype distribution did not differ between patients with a wt TERT promoter and controls. The presence of TERT promoter mutations was not associated with clinico-pathological variables. Taken together, the germline TERT genetic background may significantly affect the onset of TERT promoter mutations in HCCs, which provides a better understanding of HCC-related TERT promoter mutations and telomerase regulation in cancer.

The STATCOM will have different effects on suppressing sub-synchronous resonance (SSR) phenomenon of the power system when connected to different locations. This paper makes a comparison of the effect of STATCOM connected to different locations for SSR suppression. By analyzing the equivalent circuit structure of the power system with the STATCOM connected to the generator port or grid side, it is indicated that the SSR of the power system will be suppressed better when the STATCOM is connected to the generator port. Based on the expansion topology of future Jinjie Power Plant, simulation model that STATCOM is connected to different locations for SSR suppression is built. Simulation results show that STATCOM connected to the generator port for SSR suppression is a little more effective than which connected to the grid side.

Rotor angle stability of meshed AC/DC system due to the decreased effective inertia with the high penetration of renewables has become a major challenge. An easy and feasible way to enhance the rotor stability of power system provided by Multi-terminal DC (MTDC) grid is to fast modulate the power reference of standard power sharing droop control of each converter based on the rotor speed deviations of the selected generators. However, this feedback based scheme does not consider the coordination of each converter, which cannot render an optimal solution for the stability issue of the system and cannot make full use of the connected converter capability. To overcome this, this paper proposes an optimal based control of MTDC grid for improving the rotor angle stability of power system. First, MTDC grid model is well established by the linearization of power flow equations of DC grid. Then AC/DC meshed system model with the power modulation control of DC grid is further established. Furthermore, the optimal based control of MTDC grid is deduced by the online minimization of the rotor angle deviations of generators and the control energy. Finally, the nonlinear numerical simulations of one simple three generators nine buses AC/DC meshed system have demonstrated the effectiveness of the proposed optimal based scheme in three phase fault and sudden load changes in AC system.

With the large-scale access of renewable energy, the problem of sub-synchronous oscillation (SSO) caused by the interaction between the direct-drive permanent magnetic synchronous generators (D-PMSGs)-based wind farm and weak AC grid has attracted people's attention. Focusing on this topic, the study presents an analysis of the SSO mechanism by establishing the double input and double output transfer function of the d axis and q axis currents. Because of the dynamic characteristics of PLL and the existence of grid-connected inductance, d axis and q axis current transfer functions are coupled and asymmetric, which introduced positive feedback into the closed-loop negative feedback system of current transfer functions. The positive feedback is related to controller parameters, PLL parameters, grid-connected inductance and operation conditions. The combination of some parameters may cause oscillation or instability of the system. In this paper, the root locus method is used to analyze the influence of these parameters on the stability of the system. Finally, eigenvalue analysis and electromagnetic transient simulation are used to verify the correctness of the method.

Subsynchronous oscillation (SSO) is a critical issue for the direct-drive permanent magnet synchronous generator (D-PMSG) based wind farm integrated to a weak onshore AC grid. To analyze the mechanism of the SSO phenomenon of D-PMSG based wind farm, widely used impedance-based stability analysis method is utilized in this paper. First, the impedance model based on the harmonic linearization theory of grid-connected D-PMSG is proposed, and the mechanism of sub/supsynchronous currents coupling is analyzed quantitatively for the first time. Then, based on the impedance model and relative stability criterion, the influence of wind farm operating parameters and grid impedance on stability is discussed. Simulations are carried out to verify the correctness of theoretical analysis.

The monthly nighttime light data observed by the Visible Infrared Imaging Radiometer Suite (VIIRS) sensor onboard the National Polar-orbiting Partnership (NPP) satellite are useful to assess human activities. However, noise in the VIIRS data and unstable power supply in many areas often limit its application in detecting anthropic activities. This study aims to develop a new method (i.e., Patches Denoising Method, PDM) to remove noise in the VIIRS monthly nighttime light data towards better information on anthropic activities. The new synthesized data were examined in the Sahel region where the intensity of nighttime light is often affected by unstable power supply. The results showed that the new data could capture more settlements correctly compared with the annual data released by the National Centers for Environmental Information (NCEI) of the National Oceanic and Atmospheric Administration (NOAA). This suggests that the Patches De-noising Method is a useful way to remove noise in the NPP-VIIRS monthly nighttime light data.

TERT promoter mutations occur in the majority of glioblastoma, bladder cancer (BC), and other malignancies while the ETS family transcription factors GABPA and its partner GABPB1 activate the mutant TERT promoter and telomerase in these tumors. GABPA depletion or the disruption of the GABPA/GABPB1 complex by knocking down GABPB1 was shown to inhibit telomerase, thereby eliminating the tumorigenic potential of glioblastoma cells. GABPA/B1 is thus suggested as a cancer therapeutic target. However, it is unclear about its role in BC. Here we unexpectedly observed that GABPA ablation inhibited TERT expression, but robustly increased proliferation, stem, and invasive phenotypes and cisplatin resistance in BC cells, while its overexpression exhibited opposite effects, and inhibited in vivo metastasizing in a xenograft transplant model. Mechanistically, GABPA directly activates the transcription of FoxA1 and GATA3, key transcription factors driving luminal differentiation of urothelial cells. Consistently, TCGA/GEO dataset analyses show that GABPA expression is correlated positively with luminal while negatively with basal signatures. Luminal tumors express higher GABPA than do basal ones. Lower GABPA expression is associated with the GABPA gene methylation or deletion (especially in basal subtype of BC tumors), and predicted significantly shorter patient survival based on TCGA and our cohort of BC patient analyses. Taken together, GABPA dictates luminal identity of BC cells and inhibits aggressive diseases in BC by promoting cellular differentiation despite its stimulatory effect on telomerase/TERT activation. Given these biological functions and its frequent methylation and/or deletion, GABPA serves as a tumor suppressor rather than oncogenic factor in BC. The GABPA effect on oncogenesis is context-dependent and its targeting for telomerase inhibition in BC may promote disease metastasizing.

The blue fluorescent nitrogen, phosphorus doped carbon dots (Tg N,P-CDs) deriving from Thelephora ganbajun Zang were successfully obtained by hydrothermal method. Tg N,P-CDs possessed excellent fluorescence features and displayed strong blue fluorescence emission at 444 nm under 356 excitation with good water solubility. Tg N,P-CDs exhibited low biotoxicity and excellent biocompatibility by live/dead bacterial differentiation, cell imaging and onion epidermal staining. Furthermore, the nanoprobes showed high selectivity and sensitivity in detecting 2,4-dinitrophenol (2,4-DNP) and 4-nitrophenol (4-NP), and excellent linear range of 0–50 μM (R2 = 0.9923) and 0–50 μM (R2 = 0.9926) with low detection limits of 35.09 nM and 78.62 nM for 2,4-DNP and 4-NP, respectively. The Tg N,P-CDs was successfully applied to determine 4-NP and 2,4-DNP in real water and soil samples. It revealed that the inner filter effect quenching mechanism dominated in quenching of Tg N,P-CDs fluorescent by 2,4-DNP and 4-NP. It provides a new insight on the bioimaging application and environmental pollutant detection.

Rainfall is a key driver of terrestrial vegetation. Clarifying the response mechanism of vegetation to rainfall can advance the understanding of expected changes in ecosystems under projected rainfall scenarios. Besides the rainfall amount over a period of time, the frequency, duration and intensity are of importance in driving ecosystem processes. The pulsating nature of rainfall forcing and of vegetation response applies particularly to arid and semi – arid regions and led to conceptualize the “pulse-reserve” paradigm, which we used to explain the approach we propose in this study. We introduce the Transfer Function Analysis (TFA) method in the frequency domain to capture the response of vegetation to rainfall at multiple temporal scales. The TFA method determines coherence, gain, and phase to characterize the existence, strength, and time-lag, respectively, of the vegetation response to rainfall at different temporal scales. Specifically, the coherence measures the existence of the response and only with a significant response are the gain and phase values significant and valuable for further analysis. The gain measures the strength of the relationship between fluctuations in vegetation growth and fluctuations in rainfall, while the phase value (i.e. the time-lag) measures how fluctuations in vegetation growth lag (or lead) fluctuations in rainfall. The TFA method was applied to the 34-years (1982–2015) NDVI3g and CHIRPS precipitation dataset in the Sahel-Sudano-Guinean region (20°W ~ 60°E, 0–25°E). The Sahelian zone was characterized by a significant vegetation response to rainfall across all inter- and intra- annual time-scales, while the Sudano-Guinean zone was dominated by significant response at annual or 6-month scales. The negative phase lag indicated that rainfall variation normally led NDVI change for most areas and across timescales. However, a positive phase observed in part of the tropical rainforest area indicated that NDVI changes led rainfall variations, which may be caused by the strong vegetation-rainfall feedback through recycling of precipitation by evapotranspiration. In summary, these results suggested that the TFA method is a powerful tool to quantify the vegetation-rainfall response regime across a range of timescales, as conceptualized by the “pulse-reserve” paradigm. Unraveling the response of fluctuations in vegetation growth to separate components of the forcing by precipitation might improve our understanding of environmental change in the past decades in the Sahel - Sudan - Guinean region.

Due to small size, strong fluorescence and low cytotoxicity, fluorescent carbon dots (CDs) attract people's attention. The CDs-Ws derived from Weissella sp. Kl-3 with bright blue photoluminescent were obtained via hydrothermal method. The CDs-Ws could selectively label dead bacterial and yeast cells, and show the potential for the differentiation of live/dead microbe. It showed that the prepared CDs-Ws had multicolor fluorescence emission properties, excellent biocompatibility and low biotoxicity with cell and in vivo imaging. In addition, CDs-Ws sensitized by ampicillin sodium was employed as fluorescence nanosensor (CDs-Ws-Amp Na) to detect Cr(VI) and VB12 based on inner filter effet mechanism. The linear correction was obtained for VB12 detection in 0–25 μM with 51.50 nM detection limit, and the linear range was 0–50 μM with 106.57 nM detection limits for Cr(VI) by CDs-Ws-Amp Na. The fluorescent nanosensor was used for detection of Cr(VI) in water and VB12 in serum and milk. It shows excellent potential in bioimaging, Cr(VI) and VB12 detection.

The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33–4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52–7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19–11.92, P

Urothelial cell carcinoma (UCC) includes urothelial bladder carcinoma (UBC), renal pelvic carcinoma (RPC) and ureter carcinoma (UC), and its incidence varies dependent on geographical areas and tumor locations, which indicates different oncogenic mechanisms and/or different genetic susceptibility/environment exposure. The activating mutations of the fibroblast growth factor receptor 3 (FGFR3) gene and telomerase reverse transcriptase (TERT) promoter are the most frequent genetic events in UCCs. These mutations have clinical utilities in UCC initial diagnostics, prognosis, recurrence monitoring and management. However, the vast majority of the results are obtained from studies of UCC patients in Western countries, and little has been known about these in Han Chinese patients. In the present study, we screened the FGFR3 gene and TERT promoter for mutations in 116 UBC, 91 RPC and 115 UC tumors from Han Chinese patients by using Sanger Sequencing. TERT promoter mutations occurred at a high frequency in these UCC patients, comparable with that seen in Western patients, however, the FGFR3 mutation was surprisingly lower, only 9.4% for UBCs, 8.8% for RPCs and 2.6% for UCs, respectively. Taken together, the FGFR3 gene is an infrequent target in the pathogenesis of Han Chinese UCCs, and its mutation detection and targeted therapy have limited clinical utility in these patients. Our results underscore the need for extensive characterization of cancer genomes from diverse patient populations, thereby contributing to precision medicine for cancer treatment and prevention.

Upper tract urothelial carcinomas (UTUCs) are originated from urothelium, and consist of renal pelvic carcinomas (RPCs) and ureter carcinomas (UCs). Most UTUCs have already become invasive when diagnosed and there is thus a need to identify high-risk populations for preventive intervention. Recent evidence has accumulated supporting common single nucleotide polymorphisms (SNPs) to be associated with increased risk of various malignancies. However, little is known about susceptibility loci in relation to UTUC development. We genotyped telomerase reverse transcriptase (TERT) rs2736100 variants, the SNP associated with a risk of multiple-types of cancer, in patients with UTUC (n = 212) and evaluated the relationship between the rs2736100 and UTUC risk by comparing to 289 healthy controls. Neither AA nor CC genotypes differed significantly between cases and controls, while the AC-carriers were associated with a reduced risk of UTUC compared to the homozygous AA (OR = 0.583; 95% CI: 0.388 - 0.875; P = 0.012) or AA + CC genotypes (0.613; 95% CI: 0.428 - 0.879; P = 0.010). Further analyses showed that the AC variant conferred a lower risk for early stage UTUCs or those with a wt TERT promoter. When UTUCs were sub-grouped into UCs and RPCs, the AC genotype still predicts a significantly lower risk for UC (P = 0.045, OR = 0.597, 95% CI: 0.370 - 0.963), while at a border line significance for RPC (P = 0.055, OR = 0.597, 95% CI: 0.324 - 0.976). Collectively, the rs2736100 AC variant predicts a reduced risk to develop UTUC.

Novel blue fluorescent carbon dots (CDs-CP) deriving from yeast Cryptococcus podzolicus 5–2 were successfully prepared via a facile and green hydrothermal synthesis method. It exhibited uniform particle size and possessed good excitation-dependent characteristic. The dead bacterial cells were selectively labled by the CDs-CP, but the live ones not, indicating good potential for the live/dead bacterial differentiation. It was found that the prepared CDs-CP showed low biotoxicity and excellent biocompatibility with multicolour fluorescence emission properties, which provided a new insight on the bioimaging application. In addition, the prepared CDs-CP exhibits high selectivity and sensitivity in Ag(I), 2,4-dinitrophenol (2,4-DNP) and 4-nitrophenol (4-NP) detection with excellent linear ranges of 0–15 μM (R2 = 0.9945), 0–30 μM (R2 = 0.9959) and 0–37.5 μM (R2 = 0.9982), respectively. The low detection limits of Ag(I), 2,4-DNP and 4-NP were 113.57 nM, 73.36 nM and 86.47 nM, respectively. It revealed that static quenching mechanism dominated in Ag(I) quenching of the CDs-CP fluorescent, while those of 2,4-DNP and 4-NP were inner filter effect. The fluorescent CDs-CP was successfully applied to determine the Ag(I), 2,4-DNP and 4-NP in real water samples with satisfactory results. Therefore, it is a good candidate for bioimaging application and environmental pollutant detection.

Telomerase is a ribonucleoprotein enzyme with telomerase reverse transcriptase (TERT) as a catalytic component. In normal human follicular thyroid cells or thyrocytes, telomerase is silent due to the TERT gene being tightly repressed. However, during the formation of thyroid carcinoma (TC), telomerase becomes activated via TERT induction. The TERT promoter’s gain-of-function mutation has recently been identified in TCs and many other malignancies. The mutation creates a de novo ETS-binding motif through which TERT transcription is de-repressed and telomerase is activated; through this, the mutant TERT promoter promotes the development of TC, contributes to disease aggressiveness and treatment resistance, and thereby leads to poor patient outcomes. From a clinical point of view, the strong association between the TERT promoter mutation and disease malignancy and aggressiveness holds great promise for its value in TC diagnostics, risk stratification, prognostication, treatment decision, and follow-up design. In the present review article, we summarize the recent findings of studies of TERT promoter mutations in TC and underscore the implications of TERT hyperactivity driven by genetic events in the pathogenesis and management of TC. Finally, the targeting of TERT promoter mutations and the disruption of telomere maintenance are considered as potential therapeutic strategies against TC.

The highly fluorescent nitrogen, phosphorus carbon dots (Gl N,P-CDs) and Gl CDs deriving from Ganoderma Lucidum were successfully prepared by a simple hydrothermal method. The Gl N,P-CDs exhibited low biotoxicity and good biocompatibility by cell imaging, onion skin staining and in vivo bioimaging. In addition, Gl N,P-CDs and Gl CDs showed high selectivity and sensitivity in detecting 2,4-dinitrophenol (2,4-DNP) and 4-nitrophenol (4-NP). Good linear range 0–37.5 μM (R2 = 0.9923) and 0–50 μM (R2 = 0.9944) for Gl CDs, and 0–30 μM (R2 = 0.9914) and 0–30 μM (R2 = 0.9976) for Gl N,P-CDs were obtained, and the low detection limits were 89.77 nM, 100.27 nM (Gl CDs) and 73.03 nM, 68.09 nM (Gl N,P-CDs) for 2,4-DNP and 4-NP, respectively. It revealed that the inner filter effect dominated in quenching of the Gl CDs and Gl N,P-CDs fluorescent by 2,4-DNP and 4-NP. The Gl N,P-CDs was successfully used to detect 2,4-DNP and 4-NP in real water and soil samples. It provided a new insight on the bioimaging application and environmental pollutants detection.

Highly blue fluorescence carbon dots (CDs-MCM) were successfully prepared via a simple hydrothermal method with citric acid and ethylene diamine tetraacetic acid doped mesoporous silica MCM-41. The CDs-MCM exhibited uniform particle size and possessed good excitation-dependent characteristic. It showed highly selectivity and sensitivity in detection of Cr(VI), folic acid and good linear ranges of 0–37.5[Formula: see text][Formula: see text]M ([Formula: see text]) and 0–50[Formula: see text][Formula: see text]M ([Formula: see text]). The low detection limits were 79.31[Formula: see text]nM and 118.73[Formula: see text]nM for Cr(VI) and folic acid, respectively. It revealed that inner filter effect dominated in Cr(VI) quenching of the CDs-MCM fluorescent, while that of folic acid belonged to static quenching. The CDs-MCM were successfully used to detect the Cr(Vl) and folic acid in water and vegetable samples with satisfactory results. It provided new insight into environmental Cr(VI) and folic acid detection.

Phenolic compounds, especially 4-nitrophenol (4-NP), and chromium (VI) are highly toxic environmental pollutants. Thus, it is significantly important to establish a rapid and sensitive sensor for 4-NP and Cr(VI) monitoring in environment. In this paper, a novel approach has been adopted where E. coli-derived CDs (CDs-WT) prepared by one step hydrothermal method previously and sensitized by ampicillin (turn-on) were used as fluorescence nanoprobe (CDs-WT-Amp) for 4-NP and Cr(VI) determination based on the inner filter effect quenching mechanism (turn-off). Then, the quenching fluorescence was reversed by addition of ampicillin (turn-on). The linear ranges of 4-NP and Cr(VI) detection were 0–50[Formula: see text][Formula: see text]M and 0–25[Formula: see text][Formula: see text]M, with the limits of detection 88.89[Formula: see text]nM and 64.75[Formula: see text]nM, respectively. The “turn-on-on-off-on” fluorescent nanosensor system was successfully used to determine Cr(VI) and 4-NP in water with satisfactory results. It shows that the “turn-on-off-on” nanoprobe has great promising potential for application to environmental pollutant detection.

A highly photoluminescent small-size carbon dots (CDs) deriving ampicillin sodium were successfully obtained via one-step hydrothermal method. The prepared CDs showed uniform particle size and possessed good excitation-dependent characteristic. The dead bacteria and yeast cells could be selectively stained by the CDs, but the live ones not. It indicated that the CDs possessed a good potential for the live/dead bacteria and yeast differentiation. Cell and plant leaf imaging showed that the prepared CDs possessed low biotoxicity, excellent biocompatibility and multicolor fluorescence emission properties making it a good candidate for bioimaging application. The probe exhibited high selectivity and sensitivity to detect Hg(II) and 2,4-dinitrophenol (2,4-DNP), and excellent linear range of 0–50 μM for Hg(II) (R2 = 0.9920) and 0–25 μM for 2,4-DNP (R2 = 0.9919), with low detection limits of 33.40 nM and 13.44 nM for Hg(II) and 2,4-DNP, respectively. It revealed that dynamic quenching mechanism dominated in Hg(II) quenching the CDs fluorescent, while the quenching mechanism of 2,4-DNP detection belonged to the inner filter effect. The sensor was successfully applied to determine the Hg(II) and 2,4-DNP in real water samples. It shows that the fluorescent nanoprobe shows great promising potential for the detection of environmental pollutants.

Objectives The single nucleotide polymorphisms (SNPs) at the TERT rs2736100 and rs2736098 are associated with multicancer susceptibility, however, published findings regarding renal cell carcinoma (RCC) risk are conflicting. In addition, the potential of these SNPs to predict outcomes in RCC remains unclear. The present study is designed to address these questions. Patients and Methods We recruited 343 patients with RCC and ethnic-/sex-matched healthy controls. TERT rs2736100 and rs2736098 SNPs were analyzed, and their relationships with relapse/survival were evaluated using univariate or multivariate Cox regression. Results The genotype distribution did not significantly differ between RCC patients and healthy controls. RCC patients carrying the rs2736100-CC/CA variants had significantly shorter progression-free and overall survival (PFS and OS) than did those AA-carriers (P = 0.009 and 0.032, respectively), while the rs2736098-AA variant was associated with shorter PFS and OS (P = 0.008 and 0.017, respectively). Multivariate analyses showed that rs2736100-CC/CA and rs2736098-AA predicted shorter PFS and OS independently of other established prognostic variables in RCCs. Furthermore, patients carrying both rs2736100-CC/CA and rs2736098-AA had shortest PFS and OS (P = 0.003 and 0.013, respectively) and the hazard ratio of relapse was 7.2 (95% confidence interval: 2.0–26.1). Conclusions There is no significant association between rs2736100/rs2736098 SNPs and RCC risk. rs2736100-CC/CA and rs2736098-AA variants serve as independent predictors of a poor prognosis in RCC. Given that blood or even urinary DNA can be used to genotype these germline variants before treatment, these 2 SNPs may serve as a potential marker for risk stratification.

Telomerase reverse transcriptase (TERT) 1 acts as a master regulator of cancer hallmarks, but underlying mechanisms remain incompletely understood. We show that TERT is required for the aberrant DNA methyltransferase 3 B (DNMT3B) 2 expression and cancer-specific methylation in hepatocellular carcinoma (HCC) 3 , through which AKT is activated. TERT depletion inhibited, while its over-expression promoted DNMT3B expression in HCC cells, respectively. Mechanistically, TERT cooperates with the transcription factor Sp1 to stimulate DNMT3B transcription. The tumor suppressors PTEN and RASSF1A were de-repressed following DNMT3B inhibition in TERT-depleted HCC cells. The PTEN promoter analysis demonstrated significantly reduced methylation in these cells. TERT silencing also led to diminished global DNA methylation. The analysis of the Cancer Genome Atlas (TCGA) 4 dataset showed that higher levels of TERT and DNMT3B expression predicted significantly shorter survival in HCC patients. Collectively, our findings establish TERT as an important contributor to cancer-specific DNA methylation and AKT hyperactivation in HCC cells. Given critical roles of both the aberrant DNA methylation and AKT activation in carcinogenesis, this TERT-regulated network or the TERT-DNMT3B-PTEN-AKT axis provides a biological explanation for multi-oncogenic activities of TERT and may be exploited in HCC treatment.

The ETS family transcription factor GABPA is suggested as an oncogenic element, which is further supported by the recent reporting of it as the sole ETS member to activate the mutant TERT promoter in thyroid carcinomas (TC). However, it remains unclear how GABPA contributes to TC pathogenesis. The present study is designed to address this issue. TERT expression was significantly diminished in TERT promoter-mutated TC cells upon GABPA inhibition. Surprisingly, GABPA depletion led to robustly increased cellular invasion independently of TERT promoter mutations and TERT expression. DICER1, a component of the microRNA machinery, was identified as a downstream effector of GABPA. GABPA facilitated Dicer1 transcription while its depletion reduced Dicer1 expression. The mutation of the GABPA binding site in the DICER1 promoter led to diminished basal levels of DICER1 promoter activity and abolishment of GABPA-stimulated promoter activity as well. The forced DICER1 expression abrogated the invasiveness of GABPA-depleted TC cells. Consistently, the analyses of 93 patients with papillary thyroid carcinoma (PTC) revealed a positive correlation between GABPA and DICER1 expression. GABPA expression was negatively associated with TERT expression and promoter mutations, in contrast to published observations in cancer cell lines. Lower GABPA expression was associated with distant metastasis and shorter overall/disease-free survival in PTC patients. Similar results were obtained for PTC cases in the TCGA dataset. In addition, a positive correlation between GABPA and DICER1 expression was seen in multiple types of malignancies. Taken together, despite its stimulatory effect on the mutant TERT promoter and telomerase activation, GABPA may itself act as a tumor suppressor rather than an oncogenic factor to inhibit invasion/metastasis in TCs and be a useful predictor for patient outcomes.

The TERT promoter and FGFR3 gene mutations are two of the most common genetic events in urothelial bladder cancer (UBC), and these mutation assays in patient urine have been shown to be promising biomarkers for UBC diagnosis and surveillance. These results were obtained mainly from studies of patients with UBC in Western countries, and little is known about such information in Han Chinese patients with UBC. In the present study, we addressed this issue by analyzing tumors from 182 Han Chinese patients with UBC and urine samples from 102 patients for mutations in the TERT promoter and FGFR3 and TERT mRNA expression in tumors and/or urine. TERT promoter and FGFR3 mutations were identified in 87 of 182 (47.8%) and 7 of 102 (6.7%) UBC cases, respectively. In 46 urine samples from patients with TERT promoter mutation-carrying tumors, the mutant promoter was detected in 24 (52%) prior to operation and disappeared in most examined urine samples (80%) taken 1 week after operation. TERT mRNA was detected in urine derived from 46 of 49 patients (94%) that was analyzed before operation independently of the presence of TERT promoter mutations. Collectively, FGFR3 mutations occur at a very low rate in Han Chinese UBC and cannot serve as diagnostic markers for Chinese patients. Han Chinese patients with UBC have relatively low TERT promoter mutation frequency compared with patients in Western countries, and simultaneous detection of both mutant TERT promoter and TERT mRNA improves sensitivity and specificity of urine-based diagnosis.

TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.

Observing and understanding changes in Africa is a hotspot in global ecological environmental research since the early 1970s. As possible causes of environmental degradation, frequent droughts and human activities attracted wide attention. Remote sensing of nighttime light provides an effective way to map human activities and assess their intensity. To identify settlements more effectively, this study focused on nighttime light in the northern Equatorial Africa and Sahel settlements to propose a new method, namely, the patches filtering method (PFM) to identify nighttime lights related to settlements from the National Polar-orbiting Partnership Visible Infrared Imaging Radiometer Suite (NPP-VIIRS) monthly nighttime light data by separating signal components induced by biomass burning, thereby generating a new annual image in 2016. The results show that PFM is useful for improving the quality of NPP-VIIRS monthly nighttime light data. Settlement lights were effectively separated from biomass burning lights, in addition to capturing the seasonality of biomass burning. We show that the new 2016 nighttime light image can very effectively identify even small settlements, notwithstanding their fragmentation and unstable power supply. We compared the image with earlier NPP-VIIRS annual nighttime light data from the National Oceanic and Atmospheric Administration (NOAA) National Center for Environmental Information (NCEI) for 2016 and the Sentinel-2 prototype Land Cover 20 m 2016 map of Africa released by the European Space Agency (ESA-S2-AFRICA-LC20). We found that the new annual nighttime light data performed best among the three datasets in capturing settlements, with a high recognition rate of 61.8%, and absolute superiority for settlements of 2.5 square kilometers or less. This shows that the method separates biomass burning signals very effectively, while retaining the relatively stable, although dim, lights of small settlements. The new 2016 annual image demonstrates good performance in identifying human settlements in sparsely populated areas toward a better understanding of human activities.

Telomerase, an RNA-dependent DNA polymerase with telomerase reverse transcriptase (TERT) as the catalytic component, is silent due to the tight repression of the TERT gene in most normal human somatic cells, whereas activated only in small subsets of cells, including stem cells, activated lymphocytes, and other highly proliferative cells. In contrast, telomerase activation via TERT induction is widespread in human malignant cells, which is a prerequisite for malignant transformation. It is well established that TERT/telomerase extends telomere length, thereby conferring sustained proliferation capacity to both normal and cancerous cells. The recent evidence has also accumulated that TERT/telomerase may participate in the physiological process and oncogenesis independently of its telomere-lengthening function. For instance, TERT is shown to interact with chromatin remodeling factors and to regulate DNA methylation, through which multiple cellular functions are attained. In the present review article, we summarize the non-canonical functions of TERT with a special emphasis on its cross-talk with epigenetics: How TERT contributes to epigenetic alterations in physiological processes and cancer, and how the aberrant epigenetics in turn facilitate TERT expression and function, eventually promoting cancer either initiation or progression or both. Finally, we briefly discuss clinical implications of the TERT-related methylation.

The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.

Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnstrom, A., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjoberg, J., Xu, D., Westerberg, L. S., Bjorkholm, M., Claesson, H.-E. Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.

Objectives: Chronic hepatitis B (CHB) is caused by infection of hepatitis B virus (HBV) and liver cirrhosis (LC) is its most common complication. The accumulated evidence indicates a genetic context of HBV infection phenotypes. Here we determine a potential association of CHB/LC with the genetic variant of telomerase reverse transcriptase (TERT), a key player in aging including immune-senescence. Methods: The study included 227 Chinese CHB patients and 315 sex/age-matched healthy controls. TERT rs2736098 and rs2736100 genotyping was performed using pre-designed TaqMan SNP genotyping assay kits. Leukocyte telomere length (LTL) was determined using quantitative PCR. Results: The rs2736098_CT/CC genotypes were significantly associated with risk of CHB compared to the TT one (OR 2.265, 95% CI 1.202–4.269, P=0.015). A similar association was also found in CHB patients with cirrhosis (CT/CC vs TT: OR 2.398, 95% CI 1.168–4.922, P=0.02). Further analyses showed that the rs2736098_TT genotype difference occurred between male controls and patients (P=0.008) and male CT/CC-carriers exhibited highly increased risk of CHB compared to male controls (CT+CC vs TT, OR 3.182, 95% CI 1.350–7.500, P=0.01). There was no difference in the rs2736100 variants between controls and CHB patients. LTL was not different between cases and controls. Conclusions: The TERT rs2736098_TT genotype is associated with a lower CHB and LC risk in Chinese males, which may have implications in CHB pathogenesis and prevention.

Upper tract urothelial carcinomas (UTUCs) are originated from urothelium, and consist predominantly of renal pelvic carcinomas (RPCs) and ureter carcinomas (UTs). The UTUC incidence has increased over the past two decades, and most UTUCs have become invasive when diagnosed. Therefore, it is urgently needed to identify high-risk populations for the preventive intervention and monitoring. Recent genome-wide association study has provided strong evidence that common single nucleotide polymorphisms (SNPs) are associated with susceptibility of various malignancies. However, little is known about the susceptibility loci to UTUC. Here we genotyped the telomerase reverse transcriptase (TERT) SNPs rs2736100 and rs2736098, two SNPs associated with a risk of other malignancies, in Han Chinese patients with UTUC (n = 217) and evaluated the relationship between the rs2736100 polymorphism and UTUC risk by comparing with that in 289 healthy controls. Genotyping was performed using a TaqMan® SNP Genotyping Assays kit. Neither AA nor CC genotypes differed significantly between cases and control subjects, while the AC carriers were associated with the reduced risk of UTUC (OR = 0.6043; 95% CI: 0.4039 - 0.9042; P = 0.0185). When RPCs (n = 100) and UTs (n = 117) were analyzed separately, such protective effect remained significant in UTs (OR = 0.5728; 95% CI: 0.3540 - 0.9269; P = 0.031). The AC genotype was lower in RPC patients than in controls, but the difference was not statistically significant (OR = 0.6484; 95% CI: 0.3811 - 1.103; P = 0.142). In conclusion, we show for the first time that the rs2736100 AC genotype is protective against UTUC development. Citation Format: Xiaotian Yuan, Ping Li, Magnus Björkholm, Dawei Xu. The TERT variant rs2736100_AC is associated with reduced risk of upper track urothelial carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3109.