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Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the "end replication problem," or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans. [ABSTRACT FROM AUTHOR]

Background: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT).Methods: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes.Results: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003).Conclusions: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival of patients with the most common type of kidney cancer (called Clear cell renal cell carcinoma—ccRCC) would dramatically improve if it was diagnosed earlier. Early diagnosis can be achieved using imaging techniques, but they are too expensive and therefore cannot be used to screen the population at risk for ccRCC. A few months ago, we published a study that evaluated the amount of certain small RNAs present in urine and showed that they are present at different levels in the urine of ccRCC patients vs. healthy subjects, and based on this discrepancy, we developed an algorithm that can anticipate the presence of kidney cancer. Such studies, however, can suffer from a technical bias called overfitting, such that the method may seem predictive even when it is not. In the present study, we sought to address this possibility and evaluate the amount of the same small RNAs in the urine of an independent cohort. As a result, we demonstrate that the previously developed algorithm has a sensitivity of 96% and specificity of 65%, thus validating this technique for potential application in the early diagnosis of ccRCC with a noninvasive assay. Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and the absence of symptoms in the early stages makes metastasis more likely and reduces survival. To aid in the early diagnosis of ccRCC, we recently developed a method based on urinary miR-122-5p, miR-1271-5p, and miR-15b-5p levels and three controls. The study here presented aimed to validate the previously published method through its application on an independent cohort. The expression of miRNAs in urine specimens from 28 ccRCC patients and 28 healthy subjects (HSs) of the same sex and age was evaluated by RT-qPCR. Statistical analyses were performed, including the preparation of receiver operating characteristic (ROC) curves. The mean ccRCC diameter in ccRCC patients was 4.2 ± 2.4 mm. Urinary miRNA levels were higher in patients than in HSs. The data were processed using the previously developed algorithm (7p-urinary score), and the area under the curve (AUC) of the algorithm's ROC curve was 0.81 (p-value = 0.0003), with a sensitivity of 96% and specificity of 65%. Therefore, the 7p-urinary score is a potential tool for the early diagnosis of ccRCC. [ABSTRACT FROM AUTHOR]

Objective. CD4+CD25lowGITR+ T lymphocytes expressing FoxP3 and showing regulatory function have been recently described in healthy donors (HD). The objective of the study was to investigate their presence and role in patients with primary SS (pSS).Methods. CD4+CD25lowGITR+ cells circulating in peripheral blood (PB) of patients with pSS were isolated by MACS technique, their phenotype was studied by flow cytometry and real-time PCR, and their function was studied by in vitro co-culture. CD4+CD25lowGITR+ cells infiltrating salivary glands (SGs) were revealed by immunohistochemistry.Results. Results indicated that conventional CD4+CD25high regulatory T cells (Tregs) are decreased, whereas CD4+CD25lowGITR+ cells are expanded in the PB of pSS as compared with HD. Phenotypic analysis demonstrated that CD4+CD25lowGITR+ cells display Treg markers, including FoxP3, TGF-β and IL-10, and functional experiments demonstrated that they exert a strong inhibitory activity against autologous effector cells. CD4+CD25lowGITR+ cells were detectable in great number in the SG inflammatory infiltrate. Interestingly, PB CD4+CD25lowGITR+ cell expansion was evident only in patients with inactive disease, while conventional CD4+CD25high Treg number was not associated with disease activity.Conclusion. The present data demonstrate that circulating CD4+ cells expressing GITR, but with low levels of CD25 (CD4+CD25lowGITR+), are detectable in pSS patients. These cells, displaying Treg phenotype and function, are present in SG inflamed tissues and are expanded in the PB of subjects with inactive disease. Data suggest that the expansion of CD4+CD25lowGITR+ cells in pSS may represent a counter-regulatory attempt against autoimmune-driven inflammation and may provide a new target for future treatment strategies. [ABSTRACT FROM PUBLISHER]