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Daniela Scarabino, Martina Peconi, Franca Pelliccia, Rosa Maria Corbo
We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70⁻100 years). After nine years of follow-up, mortality data were collected, and sub-samples of long-lived/not long-lived were defined. TERT VNTR MNS16A L/L genotype and TERT rs2853691 A/G or G/G genotypes were found to be associated with a significantly higher risk to die before the age of 90 years, and with a significantly lower age at death...
January 25, 2019: Genes
Diana Avetyan, Roksana Zakharyan, Martin Petrek, Arsen Arakelyan
Telomeres are protective fragments on chromosome ends involved in maintaining genome stability, preventing chromosomal fusions, regulation of cell division. It was shown that telomere attrition rate is accelerated in age-related diseases, as well as in response to physiological and psychosocial stress. The aim of this study was to evaluate relative leukocyte telomere length (LTL) in patients with post traumatic stress disorder (PTSD), as well as to investigate association of functional SNPs of telomerase TERC and TERT genes with LTL and PTSD...
January 21, 2019: Journal of Psychiatric Research
Ayodeji Adegunsoye, Rekha Vij, Imre Noth
Fibrotic interstitial lung diseases have a high mortality rate with an unpredictable disease course and clinical features that frequently overlap. Recent data indicate important roles for genomics in the mechanisms underlying susceptibility and progression of pulmonary fibrosis, and the impact of these genomic markers on pharmacotherapy and their contribution to outcomes is increasingly recognized. Interstitial lung abnormalities, frequently considered representative of early interstitial lung disease (ILD), have been consistently associated with the MUC5B promoter polymorphism, a common gene variant...
January 17, 2019: Chest
Ilaria Laudadio, Francesca Orso, Gianluca Azzalin, Carlo Calabrò, Francesco Berardinelli, Elisa Coluzzi, Silvia Gioiosa, Daniela Taverna, Antonella Sgura, Claudia Carissimi, Valerio Fulci
Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders. Taking advantage of gain- and loss-of-function approaches, we show that Argonaute 2 (AGO2) promotes telomerase activity and stimulates the association between TERT and TERC AGO2 depletion results in shorter telomeres as well as in lower proliferation rates in vitro and in vivo We also demonstrate that AGO2 interacts with TERC and with a newly identified sRNA ( terc -sRNA), arising from the H/ACA box of TERC Notably, terc -sRNA is sufficient to enhance telomerase activity when overexpressed...
December 27, 2018: EMBO Reports
Meng-Wan Zhang, Peng Zhao, Wing-Ho Yung, Yuan Sheng, Ya Ke, Zhong-Ming Qian
To test the hypothesis that iron accumulation in tissues with age is a key harmful factor for the development of aging, we established heterochronic parabiosis-pairings and investigated changes in serum iron, the expression of major iron transport proteins and iron contents, as well as telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and telomere length in the liver, kidney and heart of Y-O(O) (old pairing with young), Y-O(Y) (young pairing with old), O-O (pairings between two old) and Y-Y (pairings between two young) mice...
December 16, 2018: Aging
Melek Erdem, Özlem Tüfekçi, Şebnem Yılmaz, İnci Alacacıoğlu, Hale Ören
Dyskeratosis congenita (DC) is a rare inherited syndrome characterized by classical mucocutaneous features and the presence of other clinical features including bone marrow failure, pulmonary fibrosis, liver cirrhosis, and a predisposition to cancer. The symptoms develop at various ages and may manifest over time. Gene mutations associated with DC, such as DC1, TERC, TERT, TINF2, NHP2, NOP10, ACD, CTC1, NAF1, PARN, POT1, RTEL1, STN1, and WRAP53, have been identified in about 70% of patients. Since the number of patients with DC is small and the effect of genetic pathogenic variant may affect the phenotype, we wanted to present the clinical features and course of illness in a patient with NHP2 gene mutation (compound heterozygote for the NHP2 mutations c...
November 23, 2018: Acta Haematologica
Zaineb Akram, Parvez Ahmed, Sachiko Kajigaya, Tariq Mahmood Satti, Humayoon Shafique Satti, Qamar Un Nisa Chaudhary, Fernanda Gutierrez-Rodrigues, Pilar F Ibanez, Xingmin Feng, Syed Kamran Mahmood, Tariq Ghafoor, Nighat Shahbaz, Mehreen Ali Khan, Aneesa Sultan
Aplastic anemia (AA) is the most serious non-malignant blood disorder in Pakistan, ranked second in prevalence, after thalassemia. We investigated various epidemiological, clinical, and genetic factors of AA in a Pakistani cohort of 214 patients reporting at our hospital between June 2014 and December 2015. A control group of 214 healthy subjects was included for comparison of epidemiological and clinical features. Epidemiological data revealed 2.75-fold higher frequency of AA among males. A single peak of disease onset was observed between ages 10 and 29 years followed by a steady decline...
November 13, 2018: Annals of Hematology
Daniele Campa, Martina Matarazzi, William Greenhalf, Maarten Bijlsma, Kai-Uwe Saum, Claudio Pasquali, Hanneke van Laarhoven, Andrea Szentesi, Francesca Federici, Pavel Vodicka, Niccola Funel, Raffaele Pezzilli, H Bas Bueno-de-Mesquita, Ludmila Vodickova, Daniela Basso, Ofure Obazee, Thilo Hackert, Pavel Soucek, Katarina Cuk, Jörg Kaiser, Cosimo Sperti, Martin Lovecek, Gabriele Capurso, Beatrice Mohelnikova-Duchonova, Kay-Tee Khaw, Anna-Katharina König, Juozas Kupcinskas, Rudolf Kaaks, Franco Bambi, Livia Archibugi, Andrea Mambrini, Giulia Martina Cavestro, Stefano Landi, Péter Hegyi, Jakob R Izbicki, Domenica Gioffreda, Carlo Federico Zambon, Francesca Tavano, Renata Talar-Wojnarowska, Krzysztof Jamroziak, Timothy J Key, Gianfranco Delle Fave, Oliver Strobel, Laimas Jonaitis, Angelo Andriulli, Rita T Lawlor, Felice Pirozzi, Verena Katzke, Chiara Valsuani, Yogesh K Vashist, Hermann Brenner, Federico Canzian
Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium...
October 16, 2018: International Journal of Cancer. Journal International du Cancer
Niko Välimäki, Heli Kuisma, Annukka Pasanen, Oskari Heikinheimo, Jari Sjöberg, Ralf Bützow, Nanna Sarvilinna, Hanna-Riikka Heinonen, Jaana Tolvanen, Simona Bramante, Tomas Tanskanen, Juha Auvinen, Outi Uimari, Amjad Alkodsi, Rainer Lehtonen, Eevi Kaasinen, Kimmo Palin, Lauri A Aaltonen
Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM ...
September 18, 2018: ELife
Shyam Sushama Jose, Federico Tidu, Petra Burilova, Tomas Kepak, Kamila Bendickova, Jan Fric
Telomeropathies are rare disorders associated with impaired telomere length control mechanisms that frequently result from genetic mutations in the telomerase complex. Dyskeratosis congenita is a congenital progressive telomeropathy in which mutation in the telomerase RNA component ( TERC ) impairs telomere maintenance leading to accelerated cellular senescence and clinical outcomes resembling premature aging. The most severe clinical feature is perturbed hematopoiesis and bone-marrow failure, but the underlying mechanisms are not fully understood...
2018: Frontiers in Genetics
Scott A Booth, Glenn D Wadley, Francine Z Marques, Mary E Wlodek, Fadi J Charchar
BACKGROUND AND AIMS: Fetal and postnatal growth restriction predispose to cardiovascular disease (CVD) in adulthood. Telomeres are repetitive DNA-protein structures that protect chromosome ends, and the loss of these repeats (a reduction in telomere length) is associated with CVD. As exercise preserves telomere length and cardiovascular health, the aim of this study was to determine the effects of growth restriction and exercise training on cardiac telomere length and telomeric genes...
September 7, 2018: Physiological Genomics
Cigir Biray Avci, Fatma Dogan, Neslihan Pinar Ozates Ay, Bakiye Goker Bagca, Zeka Abbaszadeh, Cumhur Gunduz
Telomerase has a critical role in cell proliferation, tumor maintaining, and therapy resistance, which act by modifying many signaling pathways. 2-[(E)-3-Naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532) is one of the most studied telomerase inhibitors, and it targets telomerase components TERC and TERT. In this novel study, we aimed to investigate the epigenetic effects of BIBR1532 on both hematologic malignancies and solid tumors. K-562 human chronic myeloid leukemia cell line and U87MG glioblastoma cell line were compared with control groups without BIBR1532 treatment...
August 26, 2018: Journal of Cellular Biochemistry
Rory M Shallis, Rami Ahmad, Amer M Zeidan
Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen-driven and likely autoimmune dysregulated T-cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease...
December 2018: European Journal of Haematology
Abhishek A Mangaonkar, Alejandro Ferrer, Filippo Pinto E Vairo, Margot A Cousin, Ryan J Kuisle, Eric W Klee, Cassie C Kennedy, Steve G Peters, J P Scott, James P Utz, Misbah Baqir, Hiroshi Sekiguchi, Shakila P Khan, Vilmarie Rodriguez, Douglas A Simonetto, Patrick S Kamath, Roshini S Abraham, Mark E Wylam, Mrinal M Patnaik
Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype...
July 2018: Mayo Clinic Proceedings
Amy Dressen, Alexander R Abbas, Christopher Cabanski, Janina Reeder, Thirumalai R Ramalingam, Margaret Neighbors, Tushar R Bhangale, Matthew J Brauer, Julie Hunkapiller, Jens Reeder, Kiran Mukhyala, Karen Cuenco, Jennifer Tom, Amy Cowgill, Jan Vogel, William F Forrest, Harold R Collard, Paul J Wolters, Jonathan A Kropski, Lisa H Lancaster, Timothy S Blackwell, Joseph R Arron, Brian L Yaspan
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) risk has a strong genetic component. Studies have implicated variations at several loci, including TERT, surfactant genes, and a single nucleotide polymorphism at chr11p15 (rs35705950) in the intergenic region between TOLLIP and MUC5B. Patients with IPF who have risk alleles at rs35705950 have longer survival from the time of IPF diagnosis than do patients homozygous for the non-risk allele, whereas patients with shorter telomeres have shorter survival times...
August 2018: Lancet Respiratory Medicine
Hao Tang, Hu Wang, Xiaolei Cheng, Xiuqin Fan, Fan Yang, Mengmeng Zhang, Yanlian Chen, Yuyang Tian, Cihang Liu, Dongxing Shao, Bin Jiang, Yali Dou, Yusheng Cong, Junyue Xing, Xiaotian Zhang, Xia Yi, Zhou Songyang, Wenbin Ma, Yong Zhao, Xian Wang, Jinbiao Ma, Myriam Gorospe, Zhenyu Ju, Wengong Wang
Telomerase consists of the catalytic protein TERT and the RNA TERC. Mutations in TERC are linked to human diseases, but the underlying mechanisms are poorly understood. Here we report that the RNA-binding protein HuR associates with TERC and promotes the assembly of the TERC/TERT complex by facilitating TERC C106 methylation. Dyskeratosis congenita (DC)-related TERC U100A mutation impair the association of HuR with TERC, thereby reducing C106 methylation. Two other TERC mutations linked to aplastic anemia and autosomal dominant DC, G107U, and GC107/108AG, likewise disrupt methylation at C106...
June 7, 2018: Nature Communications
Abhishek A Mangaonkar, Mrinal M Patnaik
Short telomere syndromes (STSs) are accelerated aging syndromes often caused by inheritable gene mutations resulting in decreased telomere lengths. Consequently, organ systems with increased cell turnover, such as the skin, bone marrow, lungs, and gastrointestinal tract, are commonly affected. Owing to diverse clinical presentations, STSs pose a diagnostic challenge, with bone marrow failure and idiopathic pulmonary fibrosis being frequent manifestations, occurring in association with gene mutations involving DKC1 (for expansion of gene symbols, use search tool at www...
July 2018: Mayo Clinic Proceedings
D Hassoun, S Dirou, P P Arrigoni, C Durant, M Hamidou, A Néel, C Agard
BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a very rare interstitial lung disease (ILD) characterized by progressive fibrotic lesions of the visceral pleura and the sub-pleural parenchyma, affecting predominantly the upper lobes. PPFE may occur in different contextes like bone marrow or lung transplantations, but also in the context of telomeropathy with mutations of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC) or regulator of telomere elongation helicase 1 (RTEL1) genes...
May 18, 2018: BMC Pulmonary Medicine
Tiago Bordeira Gaspar, Ana Sá, José Manuel Lopes, Manuel Sobrinho-Simões, Paula Soares, João Vinagre
Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance...
May 3, 2018: Genes
Hongchun Du, Yubiao Guo, Di Ma, Kejing Tang, Decheng Cai, Yifeng Luo, Canmao Xie
RATIONALE: Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear...
May 2018: Medicine (Baltimore)
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