A PSYCHOBIOLOGICAL APPROACH TO IMPROVE EXERCISE ADHERENCE

Studio I La percezione dello sforzo (RPE) \ue8 considerato un determinante negaitvo dell\u2019attivit\ue0 fisica. Questa sensazione \ue8 correlata all\u2019intensit\ue0 dell\u2019esercizio eseguito in un determinato momento. E\u2019 noto che l\u2019esercizio ad elevata intensit\ue0 \ue8 associato ad un tasso di aderenza minore se confrontato con uno ad intensit\ue0 pi\uf9 bassa. La caffeina \ue8 una delle sostanze pi\uf9 utilizzate in tutto il mondo. Inoltre, \ue8 stato ben definito che essa pu\uf2 migliorare le prestazioni in atleti anche grazie a un aumento della potenza prodotta. L\u2019effetto della caffeina sull\u2019 RPE in soggetti sedentari non \ue8 stato molto studiato e risulta controverso. E\u2019 stato indicato che RPE potrebbe non essere modificato a seguito di assunzione di caffeina in questa popolazione durante un esercizio sottomassimale aerobico. Lo scopo dello studio \ue8 stato quello di determinare gli effetti della caffeina in soggetti sedentari a livello della riduzione di RPE durante un esercizio sottomassimale aerobico. Inoltre, uno scopo secondario, \ue8 stato quello di determinare gli effetti della caffeina a livello cardiovascolare e fisiologico. 16 soggetti hanno partecipato allo studio effettuando quattro visite al laboratorio. In questo studio randomizzato incrociato, i partecipanti hanno effettuato una simulazione aerobica sottomassimale, assumendo in un ordine randomizzato 400,200 mg e placebo. E\u2019 stata trovata un\u2019 interazione significativa della caffeina su RPE (p0.05). Concludendo, questo studio ha dimostrato che l\u2019assunzione di 200mg di caffeina 15 minuti prima di un esercizio aerobico sottomassimale hanno prodotto una riduzione di RPE in soggetti sedentari. STUDIO II: E\u2019 ben noto che un\u2019attivit\ue0 fisica effettuata regolarmente, alla giusta intensit\ue0, durata e frequenza produca un miglioramento del fitness e dello stato generale di salute. Come revisionato da Dishman, l\u2019abitudine all\u2019esercizio fisico \ue8 determinata da diversi fattori. Studi precedenti effettuati per indagare l\u2019aderenza all\u2019attivit\ue0 fisica, sono stati focalizzati su interventi psicologici e comportamentali per cercare di migliorarne il livello. Ad oggi, solo pochi studi hanno focalizzato l\u2019attenzione su strategie nutrizionali per poter migliorare l\u2019aderenza all\u2019attivit\ue0 fisica. Lo scopo di questo studio \ue8 stato di implementare un protocollo di lavoro aerobico di 12 settimane, con una frequenza di 3 sedute di allenamento a settimana per verificare l\u2019efficacia dell\u2019assunzione di 200 mg di caffeina 60 minuti prima di ogni seduta di allenamento nell\u2019aumentare l\u2019aderenza ad un programma di allenamento ad elevata intensit\ue0. A seguito della randomizzazione, i soggetti hanno effettuato un test di VO2MAX per definire il proprio picco di Potenza [W] e le relative intensit\ue0 di allenamento per le prime 6 settimane. La stessa procedura \ue8 stata osservata dopo le prime sei settimane ed al termine dello studio. E stato inoltre chiesto ai soggetti di compilare un questionario iniziale relativo a IPAQ, EMI-2 e BRUMS, per poter definire qualsiasi differenza di attivit\ue0 fisica quitidiana oltre allo stato d\u2019animo e la motivazione. I parametri relativi all\u2019aderenza sono stati misurati a 6 e 12 settimane di allenamento per poter identificare differenze tra i due gruppi (CAF-PLAC). Risultati: attendance al programma di allenamento \ue8 risultata significativamente differente nelle settimane da 1 a 6 [CAF(12.92\ub13.75)PLAC(15.92\ub1 2.54)t(23)=-2.99,p=0.030],6 a 12 [CAF(4.00\ub15.34) PLAC(8.67 \ub1 5.34) t(23) =-4.67,p= 0.040] e nelle 12 settimane di allenamento [CAF(16.92 \ub1 7.98)PLAC(24.58\ub16.49)t(23)=-7.66,p=0.040]. La percentuale media di tempo completato \ue8 risultata significativamente differente nelle settimane da 1 a 6 CAF(68.01\ub119.46)PLAC(85.50\ub114.19) t(23) =-17.49,p=0. 018] e da 1 a 12 [CAF(47.01 \ub1 22.18)PLAC(68.29 \ub1 18.02) t(23) = -21.28, p = 0.015]. Il confronto del tempo medio di allenamento speso in ogni singola seduta di allenamento \ue8 stato trovato significativamente differente nelle sessioni 12,15,17,21,22,33,35(P0.05). I risultati relativi al questionari EMI-2 non hanno mostrato alcuna interazione nei confronti pre e post dei gruppi caff e plac in relazione ai parametri AFFILIATION(p=0.370),APPEARANCE(p =0.685),ENJOYMENT(p = 0.643),HEALTHPRESSURE(p = 0.855),HILLHEALTH AVOIDANCE(p=0.394),NIMBLENESS(p=0.597),POSITIVEHEALTH(p=0.227), REVITALISATION(p=0.324),SOCIALRECOGNITION(p=0.364),STRENGTHENDURANCE(p=0.696)and WEIGHTMANAGEMENT(p=0.929). Inoltre, solo per quanto riguarda I parametri AFFILIATION,POSITIVEHEALTH , \ue8 stato trovato un main effect del tempo(P0.05). I risultati relativi alla scala PACES non hanno mostrato alcuna interazione significativa tra caff e plac in riferimento al parametro PACESSCALESCORING(p=0.794). Nessun main effect del tempo \ue8 stato trovato (P>0.05). I risultati relativi al questionario IPAQ hanno mostrato un\u2019interazione significativa nel confronto pre-post tra i gruppi caff e plac in relazione ai parametri IPAQHIGHINTENSITYDAYS(p0.05). E\u2019 stato trovato un main effect significativo del tempo per i parametri IPAQHIGHINTENSITYDAYS, IPAQHIGHINTENSITYMINUTES (P<0.05). I risultati relativi ai parametri fisiologici e percettivi hanno mostrato la mancanza di qualsiasi interazione nel confronto pre-post tra I gruppi caff e plac in merito al PPO (p = 0.683). Lo stesso ha subito una significativa variazione nel tempo (P<0.05)(p = 0.003). L\u2019ANOVA effettuata per i parametri VO2 PEAK e HR pre-post non ha rilevato alcun cambiamento statisticamente significativo (VO2 PEAK (p = 0.462), HR (p = 0.856)). E\u2019 stato di fatto identificato un main effect del tempo per la variabile HR (p< 0.05, p = 0.001). L\u2019analisi dei dati relativi a RPE pre-post confrontando i due gruppi caff e plac non ha mostrato alcuna differenza significativa in termini di sforzo percepito durante ogni singola seduta (p = 0.487). E\u2019 stato identificato un main effect del tempo (p< 0.05,p=0.001). Tutti i dati sono presentati come media\ub1SD. Conclusioni: Questo studio ha dimostrato che non \ue8 presente alcun effetto della caffeina nella riduzione della percezione dello sforzo e miglioramento dell\u2019aderenza all\u2019attivit\ue0 fisica in soggetti sedentari. Inoltre, da un punto di vista fisiologico, a causa di una riduzione relativa al tempo totale di allenamento ed alla percentuale di tempo di allenamento completato, non abbiamo dimostrato alcun miglioramento del fitness aerobico. Dall\u2019altro lato, l\u2019aderenza all\u2019esercizio relativa al gruppo placebo \ue8 risultata essere significativamente differente rispetto al gruppo caffeina.Study I Rating of perceived exertion (RPE) is a negative determinant of physical activity. This conscious sensation is related to the intensity of the performed task. It is well known that high-intensity exercise is associated to a lower rate of adherence when compared to a moderate intensity regimen. Caffeine is one of the most widely used drugs in the world. Furthermore, it has been well established that it can enhances performance in athletes either by a higher power production. The effect of caffeine on RPE in unfit people is poorly understood and controversial. It has been suggested that RPE could be not affected by caffeine in this population during a sub-maximal aerobic exercise. The aim of this study was to establish whether caffeine affects RPE in sedentary healthy subjects during a sub-maximal aerobic exercise. A secondary aim was to determine the effects of caffeine on cardiovascular and physiological variables. 16 healthy subjects were involved in the study. In this randomised cross-over study participants visited the laboratory four times. After a VO2MAX determination each subject was asked to perform a sub-maximal aerobic simulation taking in a randomised order 400,200mg and placebo. There was a significant treatment x workload interaction of caffeine on RPE(p<0.05,p=0.006). Pairwises comparisons indicated that a dosage of 200 mg(M=15.66,SD=1.69)(p<0.05,p=0.014) and 400mg (M=15.47,SD=1.26)(p<0.05,p=0.000) of caffeine were significantly different in reducing RPE compared to placebo (M=16.94,SD=1.94). No significant differences were found between the 200,400mg of caffeine(p=1.000). No significant treatment x workload interaction was found on VO2(p=0.480). There was a significant main effect of workload on VO2 on the three different conditions(p<0.05,p=0.000). No treatment x workload interaction on VCO2(p=0.408). Significant main effect of workload(p<0.05,p=0.000) was found. No treatment x workload interaction on VE(p=0.388). Significant main effect of workload(p<0.05,p=0.000) was found. No treatment x workload interaction on HR(p=0.548). Significant main effect of workload (p<0.05,p=0.000) was found. No treatment x workload interaction on La(p=0.390). Significant main effect of workload (p<0.05,p=0.045). No treatment x workload interaction on RPM(p=0.659). A significant main effect of workload(p<0.05,p=0.004) was found. No significant treatment x workload interaction on SV(p=0.284). A significant main effect of workload(p<0.05,p=0.049) was found. No significant treatment x workload interaction on CO(p=0.285). A significant main effect of workload (p<0.05,p=0.001) was found. No significant treatment x workload interaction on SBP (p=0.538) A significant main effect of workload(p<0.05,p=0.001) was found. No significant treatment x workload interaction on DBP(p=0.972). There was not any significant main effect of workload(p= .194). In conclusion, this study demonstrated that 200 mg of caffeine taken on a chewing-gum based pill 15 minutes before a sub-maximal aerobic exercise were able to reduce RPE in sedentary individuals. STUDY II: It is well known that physical activity improves physical fitness and several health outcomes whether performed on a regular basis, at the right intensity, duration and frequency. As reviewed by Dishman physical activity behaviour is determined by several factors. Previous studies on exercise adherence have been focused on psychological and behavioural interventions in order to improve this behaviour. To date, there are just few studies that used nutritional strategies in order to improve exercise adherence. The aim of the study was to implement in a randomized controlled trial a 3 times per week for 12 weeks aerobic training in order to test the hypothesis that 200 mg of caffeine assumed before each training session could increase the adherence to a vigorous aerobic training program. After randomization, subjects performed a VO2 MAX in order to define the PPO [W] and training intensities for the first 6 weeks of training. Same procedures for the mid-test and post-test. Was also asked to each subject to perform a baseline mid and post-test assessment of IPAQ, EMI-2 and BRUMS questionnaires in order to detect any difference on the general level of physical activity during daily activities and on mood and motivation. Adherence parameters were measured at 6 and 12 weeks of training in order to detect differences between caffeine and placebo group. Subjects visited the gym 3 times/week for 12 weeks. Results: Attendance to the exercise program were significantly different on the weeks 1 to 6 [CAF(12.92\ub13.75)PLAC(15.92\ub1 2.54)t(23)=-2.99,p=0.030],6 to 12 [CAF(4.00\ub15.34) PLAC(8.67 \ub1 5.34) t(23) =-4.67,p= 0.040] and all the 12 weeks of training [CAF(16.92 \ub1 7.98)PLAC(24.58\ub16.49)t(23)=-7.66,p=0.040].The mean percentage of time completed was significantly different on the weeks 1 to 6 [CAF(68.01\ub119.46)PLAC(85.50\ub114.19) t(23) =-17.49,p=0. 018] and from week 1 to 12 [CAF(47.01 \ub1 22.18)PLAC(68.29 \ub1 18.02) t(23) = -21.28, p = 0.015]. The comparison of mean total time performed for each training was found significantly different at session 12,15,17,21,22,33,35(P0,05). The EMI2 results did not show any interaction between the pre\u2013post test comparisons between caf and plac groups on AFFILIATION(p = 0.370),APPEARANCE(p =0.685),ENJOYMENT(p = 0.643),HEALTHPRESSURE(p = 0.855),HILLHEALTH AVOIDANCE(p=0.394),NIMBLENESS(p=0.597),POSITIVEHEALTH(p=0.227), REVITALISATION(p=0.324),SOCIALRECOGNITION(p=0.364),STRENGTHENDURANCE(p=0.696)and WEIGHTMANAGEMENT(p=0.929). A significant main effect of time was found on AFFILIATION,POSITIVEHEALTH (P0.05). PACES scale results did not show any significant interaction between caf and plac on PACESSCALESCORING(p=0.794). No main effect of time (p= 0.095). The IPAQ results presented a significant treatment x workload interaction on the pre-post comparisons between caf and plac on IPAQHIGHINTENSITYDAYS (p0.05). Main effect of time was found significantly different for IPAQHIGHINTENSITYDAYS,IPAQHIGHINTENSITYMINUTES (P<0.05) PHYSIOLOGICAL PARAMETERS: The pre-post test analysis of the PPO did not show a significant treatment x workload interaction between caf and plac (p = 0.683). Significant main effect of time (P<0.05)(p = 0.003). ANOVAs performed on VO2 PEAK and HR pre-post test did not reveal a significant treatment x workload interaction (VO2 PEAK (p = 0.462), HR (p = 0.856)). Significant main effect of time for HR (p< 0.05, p = 0.001). The data analysis of RPE pre-post test comparing caf and plac groups, did not reveal a significant difference accounted for the effort perceived during each training sessions (p = 0.487). Significant main effect of time(p< 0.05,p=0.001). All the data are presented by mean\ub1SD. Conclusions: This study demonstrated that there is not any effect of caffeine on perception of effort and adherence improvement in sedentary subjects. From a physiological point of view, due to a reduction in total time of training and percentage of total training completed we do not have demonstrated an improvement in aerobic fitness. On the other hand, adherence for the placebo group was significantly different compared to caffeine

Telomerase Efficiently Elongates Highly Transcribing Telomeres in Human Cancer Cells

RNA polymerase II transcribes the physical ends of linear eukaryotic chromosomes into a variety of long non-coding RNA molecules including telomeric repeat-containing RNA (TERRA). Since TERRA discovery, advances have been made in the characterization of TERRA biogenesis and regulation; on the contrary its associated functions remain elusive. Most of the biological roles so far proposed for TERRA are indeed based on in vitro experiments carried out using short TERRA-like RNA oligonucleotides. In particular, it has been suggested that TERRA inhibits telomerase activity. We have exploited two alternative cellular systems to test whether TERRA and/or telomere transcription influence telomerase-mediated telomere elongation in human cancer cells. In cells lacking the two DNA methyltransferases DNMT1 and DNMT3b, TERRA transcription and steady-state levels are greatly increased while telomerase is able to elongate telomeres normally. Similarly, telomerase can efficiently elongate transgenic inducible telomeres whose transcription has been experimentally augmented. Our data challenge the current hypothesis that TERRA functions as a general inhibitor of telomerase and suggest that telomere length homeostasis is maintained independently of TERRA and telomere transcription

Gene Expression Analysis of an EGFR Indirectly Related Pathway Identified PTEN and MMP9 as Reliable Diagnostic Markers for Human Glial Tumor Specimens

In this study the mRNA levels of five EGFR indirectly related genes, EGFR, HB-EGF, ADAM17, PTEN, and MMP9, have been assessed by Real-time PCR in a panel of 37 glioblastoma multiforme specimens and in 5 normal brain samples; as a result, in glioblastoma, ADAM17 and PTEN expression was significantly lower than in normal brain samples, and, in particular, a statistically significant inverse correlation was found between PTEN and MMP9 mRNA levels. To verify if this correlation was conserved in gliomas, PTEN and MMP9 expression was further investigated in an additional panel of 16 anaplastic astrocytoma specimens and, in parallel, in different human normal and astrocytic tumor cell lines. In anaplastic astrocytomas PTEN expression was significantly higher than in glioblastoma multiforme, but no significant correlation was found between PTEN and MMP9 expression. PTEN and MMP9 mRNA levels were also employed to identify subgroups of specimens within the different glioma malignancy grades and to define a gene expression-based diagnostic classification scheme. In conclusion, this gene expression survey highlighted that the combined measurement of PTEN and MMP9 transcripts might represent a novel reliable tool for the differential diagnosis of high-grade gliomas, and it also suggested a functional link involving these genes in glial tumors

Characterization of SMG-9, an essential component of the nonsense-mediated mRNA decay SMG1C complex

SMG-9 is part of a protein kinase complex, SMG1C, which consists of the SMG-1 kinase, SMG-8 and SMG-9. SMG1C mediated phosphorylation of Upf1 triggers nonsense-mediated mRNA decay (NMD), a eukaryotic surveillance pathway that detects and targets for degradation mRNAs harboring premature translation termination codons. Here, we have characterized SMG-9, showing that it comprises an N-terminal 180 residue intrinsically disordered region (IDR) followed by a well-folded C-terminal domain. Both domains are required for SMG-1 binding and the integrity of the SMG1C complex, whereas the C-terminus is sufficient to interact with SMG-8. In addition, we have found that SMG-9 assembles in vivo into SMG-9:SMG-9 and, most likely, SMG-8:SMG-9 complexes that are not constituents of SMG1C. SMG-9 self-association is driven by interactions between the C-terminal domains and surprisingly, some SMG-9 oligomers are completely devoid of SMG-1 and SMG-8. We propose that SMG-9 has biological functions beyond SMG1C, as part of distinct SMG-9-containing complexes. Some of these complexes may function as intermediates potentially regulating SMG1C assembly, tuning the activity of SMG-1 with the NMD machinery. The structural malleability of IDRs could facilitate the transit of SMG-9 through several macromolecular complexes

Distinct Differences in Chromatin Structure at Subtelomeric X and Y' Elements in Budding Yeast

In Saccharomyces cerevisiae, all ends of telomeric DNA contain telomeric repeats of (TG1–3), but the number and position of subtelomeric X and Y' repeat elements vary. Using chromatin immunoprecipitation and genome-wide analyses, we here demonstrate that the subtelomeric X and Y' elements have distinct structural and functional properties. Y' elements are transcriptionally active and highly enriched in nucleosomes, whereas X elements are repressed and devoid of nucleosomes. In contrast to X elements, the Y' elements also lack the classical hallmarks of heterochromatin, such as high Sir3 and Rap1 occupancy as well as low levels of histone H4 lysine 16 acetylation. Our analyses suggest that the presence of X and Y' elements govern chromatin structure and transcription activity at individual chromosome ends

Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription

Tumours and immortalized cells avoid telomere attrition by using either the ribonucleoprotein enzyme telomerase or a recombination-based alternative lengthening of telomeres (ALT) mechanism. Available evidence from mice suggests that the epigenetic state of the telomere may influence the mechanism of telomere maintenance, but this has not been directly tested in human cancer. Here we investigated cytosine methylation directly adjacent to the telomere as a marker of the telomere's epigenetic state in a panel of human cell lines. We find that while ALT cells show highly heterogeneous patterns of subtelomeric methylation, subtelomeric regions in telomerase-positive cells invariably show denser methylation than normal cells, being almost completely methylated. When compared to matched normal and ALT cells, telomerase-positive cells also exhibit reduced levels of the telomeric repeat-containing-RNA (TERRA), whose transcription originates in the subtelomere. Our results are consistent with the notion that TERRA may inhibit telomerase: the heavy cytosine methylation we observe in telomerase-positive cells may reflect selection for TERRA silencing in order to facilitate telomerase activity at the telomere. These data suggest that the epigenetic differences between telomerase-positive and ALT cells may underlie the mechanism of telomere maintenance in human tumorigenesis and highlight the broad reaching consequences of epigenetic dysregulation in cancer

Functions of the Nonsense-Mediated mRNA Decay Pathway in Drosophila Development

Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that degrades transcripts containing premature translation termination codons, and it also influences expression of certain wild-type transcripts. Although the biochemical mechanisms of NMD have been studied intensively, its developmental functions and importance are less clear. Here, we describe the isolation and characterization of Drosophila “photoshop” mutations, which increase expression of green fluorescent protein and other transgenes. Mapping and molecular analyses show that photoshop mutations are loss-of-function mutations in the Drosophila homologs of NMD genes Upf1, Upf2, and Smg1. We find that Upf1 and Upf2 are broadly active during development, and they are required for NMD as well as for proper expression of dozens of wild-type genes during development and for larval viability. Genetic mosaic analysis shows that Upf1 and Upf2 are required for growth and/or survival of imaginal cell clones, but this defect can be overcome if surrounding wild-type cells are eliminated. By contrast, we find that the PI3K-related kinase Smg1 potentiates but is not required for NMD or for viability, implying that the Upf1 phosphorylation cycle that is required for mammalian and Caenorhabditis elegans NMD has a more limited role during Drosophila development. Finally, we show that the SV40 3′ UTR, present in many Drosophila transgenes, targets the transgenes for regulation by the NMD pathway. The results establish that the Drosophila NMD pathway is broadly active and essential for development, and one critical function of the pathway is to endow proliferating imaginal cells with a competitive growth advantage that prevents them from being overtaken by other proliferating cells

A siRNA-Based Screen for Genes Involved in Chromosome End Protection

Telomeres are nucleoprotein complexes which protect the ends of linear chromosomes from detection as DNA damage and provide a sequence buffer against replication-associated shortening. In mammals, telomeres consist of repetitive DNA sequence (TTAGGG) and associated proteins. The telomeric core complex is called shelterin and is comprised of the proteins TRF1, TRF2, POT1, TIN2, TPP1 and RAP1. Excessive telomere shortening or de-protection of telomeres through the loss of shelterin subunits allows the detection of telomeres as DNA damage, which can be visualized as DNA damage protein foci at chromosome ends called TIF (Telomere Dysfunction-Induced Foci). We sought to exploit the TIF phenotype as marker for telomere dysfunction to identify novel genes involved in telomere protection by siRNA-mediated knock-down of a set of 386 candidates. Here we report the establishment, specificity and feasibility of such a screen and the results of the genes tested. Only one of the candidate genes showed a unique TIF phenotype comparable to the suppression of the main shelterin components TRF2 or TRF1 and that gene was identified as a TRF1-like pseudogene. We also identified a weak TIF phenotype for SKIIP (SNW1), a splicing factor and transcriptional co-activator. However, the knock-down of SKIIP also induced a general, not telomere-specific DNA damage response, which complicates conclusions about a telomeric role. In summary, this report is a technical demonstration of the feasibility of a cell-based screen for telomere deprotection with the potential of scaling it to a high-throughput approach

Nonsense-Mediated mRNA Decay Impacts MSI-Driven Carcinogenesis and Anti-Tumor Immunity in Colorectal Cancers

Nonsense-mediated mRNA Decay (NMD) degrades mutant mRNAs containing premature termination codon (PTC-mRNAs). Here we evaluate the consequence of NMD activity in colorectal cancers (CRCs) showing microsatellite instability (MSI) whose progression is associated with the accumulation of PTC-mRNAs encoding immunogenic proteins due to frameshift mutations in coding repeat sequences. Inhibition of UPF1, one of the major NMD factors, was achieved by siRNA in the HCT116 MSI CRC cell line and the resulting changes in gene expression were studied using expression microarrays. The impact of NMD activity was also investigated in primary MSI CRCs by quantifying the expression of several mRNAs relative to their mutational status and to endogenous UPF1 and UPF2 expression. Host immunity developed against MSI cancer cells was appreciated by quantifying the number of CD3ε-positive tumor-infiltrating lymphocytes (TILs). UPF1 silencing led to the up-regulation of 1251 genes in HCT116, among which a proportion of them (i.e. 38%) significantly higher than expected by chance contained a coding microsatellite (P<2×10−16). In MSI primary CRCs, UPF1 was significantly over-expressed compared to normal adjacent mucosa (P<0.002). Our data provided evidence for differential decay of PTC-mRNAs compared to wild-type that was positively correlated to UPF1 endogenous expression level (P = 0.02). A negative effect of UPF1 and UPF2 expression on the host's anti-tumor response was observed (P<0.01). Overall, our results show that NMD deeply influences MSI-driven tumorigenesis at the molecular level and indicate a functional negative impact of this system on anti-tumor immunity whose intensity has been recurrently shown to be an independent factor of favorable outcome in CRCs

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes. METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNalpha group for an additional 3.5 years. Significant telomere loss in naive T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with naive CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index. CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in naive T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined