CaRLO

Description: Ten-eleven translocation methylcytosine dioxygenase 1 ( Tet1 ) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enhanced fear memories. We confirmed that Tet1 overexpression affected adult neurogenesis with oligodendrocyte differentiation in the hippocampal dentate gyrus of Tet1-TG mice. In addition, Tet1 overexpression induced the elevated expression of immediate early genes, such as Egr1 , c-fos , Arc , and Bdnf , followed by the activation of intracellular calcium signals ( i.e. , CamKII, ERK, and CREB) in prefrontal and hippocampal neurons. The expression of GABA receptor subunits ( Gabra2 and Gabra4 ) fluctuated in the prefrontal cortex and hippocampus. We evaluated the effects of Tet1 overexpression on intracellular calcium-dependent cascades by activating the Egr1 promoter in vitro . Tet1 enhanced Egr1 expression, which may have led to alterations in Gabra2 and Gabra4 expression in neurons. Taken together, we suggest that the Tet1 overexpression in our Tet1-TG mice can be applied as an effective model for studying various stress-related diseases that show hyperactivation of intracellular calcium-dependent cascades in the brain.—Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice.

Description: Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans , HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.

Description: In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC), and less than 20% will survive 5 years. Positron emission tomography avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits proapoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics. EAC cell lines and a Barrett epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably overexpressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following overexpression of TXNIP. Apoptosis and DNA damage were measured by annexin V and H2AX assays. Activation of the intrinsic apoptosis was quantitated with green fluorescence protein-caspase 3 reporter assay. In cultured cells and an esophageal tissue array, TXNIP expression was higher in Barrett epithelia and normal tissue compared with EAC. Constitutive overexpression of TXNIP decreased proliferation, clonogenicity, and tumor xenograft growth. TXNIP overexpression increased, whereas knockdown abrogated, DNA damage and apoptosis following cisplatin treatment. An HDAC inhibitor, entinostat (currently in clinical trials), upregulated TXNIP and synergistically increased cisplatin-mediated DNA damage and apoptosis. TXNIP is a tumor suppressor that is downregulated in EACC. Its reexpression dramatically sensitizes these cells to cisplatin. Our findings support phase I/II evaluation of "priming" strategies to enhance the efficacy of conventional chemotherapeutics in EAC. Mol Cancer Ther; 17(9); 2013–23. ©2018 AACR .

Description: Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8 + T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors. Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8 + T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803. Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR .

Description: Creation of quark–gluon plasma droplets with three distinct geometries Creation of quark–gluon plasma droplets with three distinct geometries, Published online: 10 December 2018; doi:10.1038/s41567-018-0360-0 A quark–gluon plasma is produced in proton–gold, deuteron–gold and helium–gold collisions. Observing elliptic and triangular flow in this nearly inviscid fluid from these different initial geometries provides a unique benchmark for hydrodynamic models.

Description: Background/Aim: This study aimed to determine the effect of different BRCA1 exonal mutations on the clinical course of epithelial ovarian cancer (EOC). Patients and Methods: Clinicopathological variables and survival outcomes were compared among 53 primary EOC patients with pathogenic BRCA1 mutations in exons 1-11 (5’ mutations) and in exons 12-24 (3’ mutations). Results: BRCA1 5’ exonal mutations were found in 35 (66.0%) patients. The median follow-up period was 40 months. Clinicopathological variables remained unchanged between the two groups. Patients with 5’ mutations had a significantly longer progression-free survival than those with C-terminal mutations (p=0.034), better predicting progression-free survival [2.923 (1.402-6.093), p=0.004], but not overall survival in cases of multiple relapses (p=0.497). Conclusion: N-terminal BRCA1 mutations in EOC patients are associated with favourable primary progression-free survival, a trend observed only in primary progression-free survival, not in overall survival.

Description: Background/Aim: Melatonin, an endogenously secreted indoleamine hormone that is produced in the pineal gland, is known to possess antitumor effect via various mechanisms including induction of apoptosis and pro-oxidant effects in various cancer cells, including colorectal cancer (CRC). In our study, we hypothesized that melatonin enhances the anticancer effects via suppression of PrP C and PINK1 levels, thereby increasing superoxide production. Materials and Methods: To investigate the antitumor effects of melatonin in CRC cells, assessing its effects on mitochondrial dysfunction, production of superoxide, induction of endoplasmic reticulum stress, and cellular apoptosis were assessed. Results: Melatonin was found to decrease the expression of PrP C and PINK1, and increase superoxide accumulation in the mitochondria. In addition, PrP C -knockdown potentiated the effects of melatonin resulting further in significantly reduced expression of PINK1 and increased superoxide production in CRC. si-PRNP-transfected CRC cells treated with melatonin increased the production of intracellular superoxide and induced endoplasmic reticulum stress associated protein, and apoptosis. Conclusion: Melatonin induces mitochondria-mediated cellular apoptosis in CRC cancer cells via a PrP C -dependent pathway. PrP C knockdown combined with melatonin amplifies the effects of melatonin, suggesting a novel therapeutic strategy in targeting CRC cells.

Description: Background/Aim: Exosomes, derived from chronic myelogenous leukaemia (CML) cells, can be used as biomarkers and new targets for the detection of the BCR-ABL transcript. This study aimed to identify these possibilities. Materials and Methods: Human CML cell line-derived exosomes and CML-patients-derived exosomes were isolated with a size-exclusion chromatography column and ExoQuick™ exosome precipitation solution, respectively. Isolated exosomes were analysed by nested PCR to detect the BCR-ABL transcript. Results: Exosomes derived from the two human CML cell lines yielded a 250-bp band. RNA sequence analysis revealed 99% sequence homology with the partial mRNA for the human BCR-ABL chimeric protein. This ~250-bp band was also observed in the exosomes derived from patients with CML. However, only patients at the blast and accelerated phases showed the exosomal BCR-ABL transcript. Conclusion: CML-derived exosomes could act as novel targets for the detection of the BCR-ABL transcript.

Description: Objectives Secondhand smoke (SHS) exposure is associated with cardiovascular disease. This study aims to determine the association between SHS exposure estimated by questionnaire and hypertension in Korean never smokers. Setting Korean National Health and Nutrition Examination Survey (KNHANES) V was conducted from 2010 to 2012. Participants We selected the never smokers aged over 20 years who answered the question about the SHS exposure. Primary and secondary measures SHS exposure in both the home and work place was estimated using a self-reporting questionnaire. We investigated the association between SHS exposure and hypertension by using multivariate analysis. And we evaluated the mean systolic and diastolic blood pressure values according to SHS exposure after adjusting for possible confounding factors. All analyses were stratified by women and men. Results There were 10 532 (women 8987 and men 1545) never smokers. We divided the subjects into three groups according to the amount of SHS exposure: none—group I, 〈2 hour/day—group II and ≥2 hour/day—group III. Using multivariate analysis, hypertension was more commonly associated with group III than group I in women (adjusted OR 1.50, 95% CI 1.00 to 2.04, p=0.011). Adjusted mean systolic and diastolic blood pressure values in women who were not taking antihypertensive medication were significantly elevated in group III by 2.3 and 1.7 mm Hg, respectively. Conclusion SHS exposure is significantly associated with hypertension in women never smokers.

Description: Objectives Asthma exacerbation, associated with many risks factors, can reflect management failure. However, little is known about how risk factors are associated with exacerbation, according to asthma severity. We aimed to investigate differences in risk factors in patients with different asthma severity and evaluate whether risk factors differed between frequent exacerbators and patients with single exacerbation. Design Nationwide population-based observational study. Setting Korean National Sample Cohort database. Participants We included 22 130 adults with asthma diagnoses more than twice (ICD-10 (International Classification of Diseases, Tenth revision) codes J45 and J46) and one prescription for asthma medication from 2010 to 2011. Outcome measures Asthma exacerbation was defined as having a corticosteroid (CS) burst characterised by a prescription of high-dose oral CS for ≥3 days or one systemic CS injection, hospitalisation or emergency department visit. Results Among severities, history of CS bursts was significantly associated with exacerbation. In mild and moderate asthma, exacerbation was significantly associated with age ≥45 years, being female, gastro-oesophageal reflux disease and chronic rhinitis. High medication possession ratio (MPR≥50%), compared with low MPR (〈20%) showed adjusted ORs of 0.828 (95% CI 0.707 to 0.971) and 0.362 (0.185 to 0.708) in moderate and severe asthma, respectively. In severe asthma, compared with mild asthma, only allergic rhinitis and history of hospitalisation were strongly associated with exacerbation. When comparing frequent exacerbators to patients with single exacerbation, age ≥45 years, atopic dermatitis, anxiety and history of CS burst were significant risk factors in mild and moderate asthma, whereas no risk factors were significant in severe asthma. Conclusions Different associations between risk factors and asthma exacerbations based on asthma severity suggest that patients with mild asthma require greater attention to their age and comorbidities, whereas those with severe asthma require greater attention to hospitalisation history and drug adherence.