The inflammatory microenvironment in MDS.

Myelodysplastic syndromes (MDS) are a collection of pre-malignancies characterized by impaired proliferation and differentiation of hematopoietic stem cells and a tendency to evolve into leukemia. Among MDS's pathogenic mechanisms are genetic, epigenetic, apoptotic, differentiation, and cytokine milieu abnormalities. Inflammatory changes are a prominent morphologic feature in some cases, with increased populations of plasma cells, mast cells, and lymphocytes in bone marrow aspirates. Accumulating evidence suggests that the bone marrow microenvironment contributes to MDS disease pathology, with microenvironment alterations and abnormality preceding, and facilitating clonal evolution in MDS patients. In this review, we focus on the inflammatory changes involved in the pathology of MDS, with an emphasis on immune dysfunction, stromal microenvironment, and cytokine imbalance in the microenvironment as well as activation of innate immune signaling in MDS patients. A better understanding of the mechanism of MDS pathophysiology will be beneficial to the development of molecular-targeted therapies in the future.

Telomeres and telomerase in T cells of tumor immunity.

Telomeres are specific nucleoprotein structures at the end of a eukaryotic chromosomes characterized by repeats of the sequence TTAGGG and regulated by the enzyme telomerase which prevents their degradation, loss, rearrangement and end-to-end fusion. During activation, T lymphocytes actively divide, albeit through only a finite number of cell divisions due to shortening of telomeres. However, studies have demonstrated that human telomerase reverse transcriptase (hTERT), thought to be the major component regulating telomerase activity, can enhance the proliferation of T cells when overexpressed. There are many treatments for cancers, most of which are targeting the telomere and telomerase of tumor cells. However, the hTERT-transduced T cells improve their potential for proliferation, making them an appropriate cell resource for tumor adoptive immunotherapy, a procedure whereby T cells are isolated from patients, expanded ex vivo and eventually delivered back into the patients, provides a new approach for tumor therapy through improved overall survival rates in cancer patients. In this review, we will focus on the telomerase activity in T cells, the regulation of telomerase activity, and hTERT-transduced T cells used in adoptive immunotherapy for cancer.

Serum lipids mediate the relationship of multiple polyaromatic hydrocarbons on non-alcoholic fatty liver disease: A population-based study.

Polyaromatic hydrocarbons (PAHs) are recognized as organic pollutants with liver toxicity. However, the relationship between PAHs and nonalcoholic fatty liver disease (NAFLD) is unclear in humans. The aim of this study was to investigate the levels of PAHs in the US population and their association with the risk of NAFLD. We investigated urinary levels of nine PAHs in 2436 participants from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2012, including 1-Hydroxynapthalene (1-OHN), 2-Hydroxynapthalene (2-OHN), 3-Hydroxyfluorene (3-OHF), 2-Hydroxyfluorene (2-OHF), 3-Hydroxyphenanthrene (3-OHPhe), 1-Hydroxyphenanthrene (1-OHPhe), 2-Hydroxyphenanthrene (2-OHPhe), 1-Hydroxypyrene (1-OHPyr), 9-Hydroxyfluorene (9-OHF). Logistic regression models were used to estimate the relationship between single PAH and NAFLD. Assessment of the overall effect of multiple PAH mixtures on NAFLD using Bayesian kernel machine regression (BKMR) model. There were 698 participants diagnosed with NAFLD in the study group. After adjusting for related covariates such as sex, age, race, education, marital status, poverty income ratio (PIR), body mass index (BMI), total energy intake, smoking, hypertension, and diabetes, logistic regression analysis showed that compared to the low tertile (T1), the odds ratio of the high tertile (T3) was 1.70 (95%CI: 1.26-2.29, p = 0.001) for total PAHs, 1.50 (95%CI: 1.11-2.03, p = 0.008) for 2-OHN, 1.75 (95%CI: 1.31-2.34, p < 0.001) for 2-OHPhe, 1.59 (95%CI: 1.18-2.14, p = 0.002) for 9-OHF and 0.63 (95%CI: 0.46-0.87, p = 0.004) for 3-OHF. In the BKMR model, we found that the overall effect of the nine PAH mixtures was positively associated with the risk of NAFLD. Mediation analysis showed that HDL and TG mediated the association between PAHs and NAFLD. Our study suggests that multiple PAHs mixtures exposure may induce NAFLD by mediating serum lipids in human metabolism.

Shorter telomere length of T-cells in peripheral blood of patients with lung cancer.

PURPOSE: Telomere shortening occurs in tumor tissues and peripheral blood lymphocytes of many common human malignancies, including lung cancer, but its variation in T-cells has never been investigated. Thus, the aim of this study was to assess telomere length in T-cells and its correlation with the clinical characteristics of patients with lung cancer. PATIENTS AND METHODS: A total of 40 patients with lung cancer but without prior cancer history and 25 healthy individuals were selected. T-cells were isolated and their telomere lengths were measured using quantitative real-time polymerase chain reaction methods. RESULTS: Telomere length in T-cells was significantly shorter in patients with lung cancer than in controls (P<0.001). Shorter telomere length was significantly associated with increased clinical stage (P=0.008) and distant metastasis (P=0.028). Naïve T-cells from patients with lung cancer had significantly decreased telomere length when compared with those from controls (P=0.012). CONCLUSION: The shortened telomere length in T-cells occurred in naïve T-cells and might be related to lung cancer progression.

Telomerase, hTERT and splice variants in patients with myelodysplastic syndromes.

Telomeres are specialized structures maintaining chromosome integrity during cellular division and preventing from premature senescence and apoptosis. The rate-limiting component of telomerase is human telomerase reverse transcriptase (hTERT), for which multiple transcripts exist. The aim of this work was to characterize hTERT splice variants in MDS and its relation to telomerase activity, telomere length and hTERT expression. The telomere length in PBMCs of patients with MDS cases was significantly shorter compared to controls (n=30, p=0.002). MDS patients had significantly higher basal telomerase activity (p=0.022) and higher total hTERT (p=0.007), α+ß+ hTERT variant (p=0.016) and α+ß- hTERT variant expression than control. The ratio of α+ß- transcript to α+ß+ transcript was significantly increased in cases (p=0.039). This study provided a detailed insight into the hTERT transcript pattern in MDS while correlation analysis showed that only telomerase activity was significantly correlated with total hTERT expression in MDS.