Sarcoma is a rare tumor derived from the mesenchymal tissue and mainly found in children and adolescents. The outcome for patients with sarcoma is relatively poor compared with that for many other solid malignant tumors. Sarcomas have a highly heterogeneous pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequently observed in sarcomas. The telomere maintenance mechanism (TMM) has recently been considered as a prognostic factor for patients with sarcomas, and alternative lengthening of telomeres (ALT) positivity has been correlated with poor outcomes in patients with several types of sarcomas. Therefore, telomeres and telomerases may be useful targets for treating sarcomas. This review aims to provide an overview of telomere and telomerase biology in sarcomas.

UNASSIGNED: The purpose of this study is to investigate the causal effect and potential mechanisms between telomere length and abdominal aortic aneurysm (AAA).
UNASSIGNED: Summary statistics of telomere length and AAA were derived from IEU open genome-wide association studies and FinnGen R9, respectively. Bi-directional Mendelian randomization (MR) analysis was conducted to reveal the causal relationship between AAA and telomere length. Three transcriptome datasets were retrieved from the Gene Expression Omnibus database and telomere related genes was down-loaded from TelNet. The overlapping genes of AAA related differentially expressed genes (DEGs), module genes, and telomere related genes were used for further investigation. Telomere related diagnostic biomarkers of AAA were selected with machine learning algorisms and validated in datasets and murine AAA model. The correlation between biomarkers and immune infiltration landscape was established.
UNASSIGNED: Telomere length was found to have a suggestive negative associations with AAA [IVW, OR 95%CI = 0.558 (0.317-0.701), P < 0.0001], while AAA showed no suggestive effect on telomere length [IVW, OR 95%CI = 0.997 (0.990-1.004), P = 0.4061]. A total of 40 genes was considered as telomere related DEGs of AAA. PLCH2, PRKCQ, and SMG1 were selected as biomarkers after multiple algorithms and validation. Immune infiltration analysis and single cell mRNA analysis revealed that PLCH2 and PRKCQ were mainly expressed on T cells, while SMG1 predominantly expressed on T cells, B cells, and monocytes. Murine AAA model experiments further validated the elevated expression of biomarkers.
UNASSIGNED: We found a suggestive effect of telomere length on AAA and revealed the potential biomarkers and immune mechanism of telomere length on AAA. This may shed new light for diagnosis and therapeutics on AAA.

Living with chronic pain is associated with substantial suffering and high societal costs. Patient reported outcomes (PROM\'s) and cellular ageing should be considered in pain management. The aim of this study was to explore correlations of PROM\'s and cellular ageing (telomere length [TL] and telomerase activity [TA]) amongst patients with chronic non-malignant pain. This was an explorative pilot study with cross-sectional design and recruitment was done at two pain rehabilitation facilities in Sweden, with inpatient setting/integrative care and outpatient setting/multimodal care, respectively. Eighty-four patients were enrolled by referral to pain rehabilitation in Sweden. The main outcome measures collected after admission in addition to TL and TA were the following PROMs: Numerical Rating Scale (NRS), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), Five Facets Mindfulness Questionnaire (FFMQ), WHO Quality of Life-Spiritual, Religious and Personal Beliefs (WHOQoL-SRPB) and EuroQol 5 Dimensions (EQ-5D). All the PROM\'s showed evidence of poor overall health status among the participants. TL correlated negatively with HADS score (r = -.219, p = .047) and positively with WHOQoL-SRPB (r = .224, p = .052). TL did not correlate with any of the pain measures. TA correlated positively with pain spread (r = .222, p = .049). A mediation of the direct effect of spiritual well-being on TL by anxiety and depression could be shown (b = 0.008; p = .045). The correlations between TL and SRPB and anxiety and depression suggest some importance of emotional and SRPB dimensions in pain management, with implications for cellular aging, which may warrant further study. Trial registration: ClinicalTrials.gov Identifier: NCT02459639.

Shelterin serves critical roles in suppressing superfluous DNA damage repair pathways on telomeres. The junction between double-stranded telomeric tracts (dsTEL) and single-stranded telomeric overhang (ssTEL) is the most accessible region of the telomeric DNA. The shelterin complex contains dsTEL and ssTEL binding proteins and can protect this junction by bridging between the ssTEL and dsTEL tracts. To test this possibility, we monitored shelterin binding to telomeric DNA substrates with varying ssTEL and dsTEL lengths and quantified its impact on telomere accessibility using single-molecule fluorescence microscopy methods in vitro. We identified the first dsTEL repeat nearest to the junction as the preferred binding site for creating the shelterin bridge. Shelterin requires at least two ssTEL repeats while the POT1 subunit of shelterin that binds to ssTEL requires longer ssTEL tracts for stable binding to telomeres and effective protection of the junction region. The ability of POT1 to protect the junction is significantly enhanced by the 5\'-phosphate at the junction. Collectively, our results show that shelterin enhances the binding stability of POT1 to ssTEL and provides more effective protection compared to POT1 alone by bridging single- and double-stranded telomeric tracts.

UNASSIGNED: Alternative lengthening of telomeres (ALT) occurs in sarcomas and ALT cancers share common mechanisms of therapy resistance or sensitivity. Telomeric DNA C-circles are self-primed circular telomeric repeats detected with a PCR assay that provide a sensitive and specific biomarker exclusive to ALT cancers. We have previously shown that 23% of high-risk neuroblastomas are of the ALT phenotype. Here, we investigate the frequency of ALT in Ewing\'s family sarcoma (EFS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) by analyzing DNA from fresh frozen primary tumor samples utilizing the real-time PCR C-circle Assay (CCA).
UNASSIGNED: We reviewed prior publications on ALT detection in pediatric sarcomas. DNA was extracted from fresh frozen primary tumors, fluorometrically quantified, C-circles were selectively enriched by isothermal rolling cycle amplification and detected by real-time PCR.
UNASSIGNED: The sample cohort consisted of DNA from 95 EFS, 191 RMS, and 87 OS primary tumors. One EFS and 4 RMS samples were inevaluable. Using C-circle positive (CC+) cutoffs previously defined for high-risk neuroblastoma, we observed 0 of 94 EFS, 5 of 187 RMS, and 62 of 87 OS CC+ tumors.
UNASSIGNED: Utilizing the ALT-specific CCA we observed ALT in 0% of EFS, 2.7% of RMS, and 71% of OS. These data are comparable to prior studies in EFS and OS using less specific ALT markers. The CCA can provide a robust and sensitive means of identifying ALT in sarcomas and has potential as a companion diagnostic for ALT targeted therapeutics.

Meiotic progression requires coordinated assembly and disassembly of protein complexes involved in chromosome synapsis and meiotic recombination. Mouse TRIP13 and its ortholog Pch2 are instrumental in remodeling HORMA domain proteins. HORMAD proteins are associated with unsynapsed chromosome axes but depleted from the synaptonemal complex (SC) of synapsed homologs. Here we report that TRIP13 localizes to the synapsed SC in early pachytene spermatocytes and to telomeres throughout meiotic prophase I. Loss of TRIP13 leads to meiotic arrest and thus sterility in both sexes. Trip13-null meiocytes exhibit abnormal persistence of HORMAD1 and HOMRAD2 on synapsed SC and chromosome asynapsis that preferentially affects XY and centromeric ends. These major phenotypes are consistent with reported phenotypes of Trip13 hypomorph alleles. Trip13 heterozygous mice exhibit meiotic defects that are less severe than the Trip13-null mice, showing that TRIP13 is a dosage-sensitive regulator of meiosis. Localization of TRIP13 to the synapsed SC is independent of SC axial element proteins such as REC8 and SYCP2/SYCP3. Terminal FLAG-tagged TRIP13 proteins are functional and recapitulate the localization of native TRIP13 to SC and telomeres. Therefore, the evolutionarily conserved localization of TRIP13/Pch2 to the synapsed chromosomes provides an explanation for dissociation of HORMA domain proteins upon synapsis in diverse organisms.

Fluorescence in situ hybridization (FISH) with two different probes, the canonical insect telomeric sequence (TTAGG)n and the sequence (TTAGGGATGG)n, was performed on meiotic chromosomes of two members of the true bug family Cimicidae (Cimicomorpha), the common bed bug Cimex lectularius Linnaeus, 1758 and the tropical bed bug C. hemipterus (Fabricius, 1803), whose telomeric motifs were not known. In both species, there were no hybridization signals with the first probe, but strong signals at chromosomal ends were observed with the second probe, indicating the presence of a telomeric motif (TTAGGGATGG)n. This study represents the first FISH confirmation of the presence of a non-canonical telomeric motif not only for the infraorder Cimicomorpha but also for the suborder Heteroptera (Hemiptera) as a whole. The present finding is of key significance for unraveling the evolutionary shifts in the telomeric sequences in this suborder.

Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10-1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23-3.53, p = 0.007). Additionally, subgroup analysis indicates that adjustments for age, sex, and smoking did not affect the significance of our findings. In conclusion, our meta-analysis found evidence for an association between short TL and HNC risk, which could indicate that TL might act as a potential biomarker for HNC risk, but high-quality prospective studies are imperative to validate our findings.

Glioblastoma (GBM) is a primary CNS tumor that is highly lethal in adults and has limited treatment options. Despite advancements in understanding the GBM biology, the standard treatment for GBM has remained unchanged for more than a decade. Only 6.8% of patients survive beyond five years. Telomerase, particularly the hTERT promoter mutations present in up to 80% of GBM cases, represents a promising therapeutic target due to its role in sustaining telomere length and cancer cell proliferation. This review examines the biology of telomerase in GBM and explores potential telomerase-targeted therapies. We conducted a systematic review following the PRISMA-P guidelines in the MEDLINE/PubMed and Scopus databases, from January 1995 to April 2024. We searched for suitable articles by utilizing the terms \"GBM\", \"high-grade gliomas\", \"hTERT\" and \"telomerase\". We incorporated studies addressing telomerase-targeted therapies into GBM studies, excluding non-English articles, reviews, and meta-analyses. We evaluated a total of 777 records and 46 full texts, including 36 studies in the final review. Several compounds aimed at inhibiting hTERT transcription demonstrated promising preclinical outcomes; however, they were unsuccessful in clinical trials owing to intricate regulatory pathways and inadequate pharmacokinetics. Direct hTERT inhibitors encountered numerous obstacles, including a prolonged latency for telomere shortening and the activation of the alternative lengthening of telomeres (ALT). The G-quadruplex DNA stabilizers appeared to be potential indirect inhibitors, but further clinical studies are required. Imetelstat, the only telomerase inhibitor that has undergone clinical trials, has demonstrated efficacy in various cancers, but its efficacy in GBM has been limited. Telomerase-targeted therapies in GBM is challenging due to complex hTERT regulation and inadequate inhibitor pharmacokinetics. Our study demonstrates that, despite promising preclinical results, no Telomerase inhibitors have been approved for GBM, and clinical trials have been largely unsuccessful. Future strategies may include Telomerase-based vaccines and multi-target inhibitors, which may provide more effective treatments when combined with a better understanding of telomere dynamics and tumor biology. These treatments have the potential to be integrated with existing ones and to improve the outcomes for patients with GBM.

The number of infertile couples undergoing in vitro fertilisation (IVF) has increased significantly. The efficacy of this procedure is contingent upon a multitude of factors, including gamete quality. One factor influencing gamete quality is oxidative stress, which leads to telomere damage and accelerates cellular ageing. Identifying new biomarkers that can predict the success of assisted reproduction techniques is a current relevant area of research. In this review, we discuss the potential role of SIRT1, a protein known to protect against oxidative stress and telomeres, which are responsible for genome stability, as biomarkers of gamete quality and assisted reproduction technique outcomes.