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1.
Artigo em Inglês | MEDLINE | ID: mdl-32427312

RESUMO

Alcoholism leads to organ injury including mitochondrial defect and apoptosis with evidence favoring a role for autophagy dysregulation in alcoholic damage. Parkin represents an autosomal recessive inherited gene for Parkinson's disease and an important member of selective autophagy for mitochondria. The association between Parkinson's disease and alcoholic injury remains elusive. This study aimed to examine the effect of parkin deficiency on chronic alcohol intake-induced organ injury in brain, liver and skeletal muscle (rectus femoris muscle). Adult parkin-knockout (PRK-/-) and wild-type mice were placed on Liber-De Carli alcohol liquid diet (4%) for 12 weeks prior to assessment of liver enzymes, intraperitoneal glucose tolerance, protein carbonyl content, apoptosis, hematoxylin and eosin morphological staining, and mitochondrial respiration (cytochrome c oxidase, NADH:cytochrome c reductase and succinate:cytochrome c reductase). Autophagy protein markers were monitored by western blot analysis. Our data revealed that chronic alcohol intake imposed liver injury as evidenced by elevated aspartate aminotransferase and alanine transaminase, glucose intolerance, elevated protein carbonyl formation, apoptosis, focal inflammation, necrosis, microvesiculation, autophagy/mitophagy failure and dampened mitochondrial respiration (complex IV, complexes I and III, and complexes II and III) in the brain, liver and rectus femoris skeletal muscle. Although parkin ablation itself did not generate any notable effects on liver enzymes, insulin sensitivity, tissue carbonyl damage, apoptosis, tissue morphology, autophagy or mitochondrial respiration, it accentuated alcohol intake-induced tissue damage, apoptosis, morphological change, autophagy/mitophagy failure and mitochondrial injury without affecting insulin sensitivity. These data suggest that parkin plays an integral role in the preservation against alcohol-induced organ injury, apoptosis and mitochondrial damage.

2.
Biochim Biophys Acta Mol Basis Dis ; : 165836, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32413386

RESUMO

Acetylation belongs to a class of post-translational modification (PTM) processes that epigenetically regulate gene expression and gene transcriptional activity. Reversible histone acetylation on lysine residues governs the interactions between DNA and histones to mediate chromatin remodeling and gene transcription. Non-histone protein acetylation complicates cellular function whereas acetylation of key mitochondrial enzymes regulates bioenergetic metabolism. Acetylation and deacetylation of functional proteins are essential to the delicated homeostatic regulation of embryonic development, postnatal maturation, cardiomyocyte differentiation, cardiac remodeling and onset of various cardiovascular diseases including obesity, diabetes mellitus, cardiometabolic diseases, ischemia-reperfusion injury, cardiac remodeling, hypertension, and arrhythmias. Histone acetyltransferase (HATs) and histone deacetylases (HDACs) are essential enzymes mainly responsible for the regulation of lysine acetylation levels, thus providing possible drugable targets for therapeutic interventions in the management of cardiovascular diseases.

3.
Eur Heart J ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32428930

RESUMO

AIMS: Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS: Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS: ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

4.
J Transl Med ; 18(1): 200, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410622

RESUMO

BACKGROUND: Glioblastoma stem-like cells (GSCs) are hypothesized to contribute to self-renewal and therapeutic resistance in glioblastoma multiforme (GBM) tumors. Constituting only a small percentage of cancer cells, GSCs possess "stem-like", tumor-initiating properties and display resistance to irradiation and chemotherapy. Thus, novel approaches that can be used to suppress GSCs are urgently needed. A new carbon material-graphene oxide (GO), has been reported to show potential for use in tumor therapy. However, the exact effect of GO on GSCs and the inherent mechanism underlying its action are not clear. In this study, we aimed to investigate the usefulness of GO to inhibit the growth and promote the differentiation of GSCs, so as to suppress the malignancy of GBM. METHODS: In vitro effects of GO on sphere-forming ability, cell proliferation and differentiation were evaluated in U87, U251 GSCs and primary GSCs. The changes in cell cycle and the level of epigenetic modification H3K27me3 were examined. GO was also tested in vivo against U87 GSCs in mouse subcutaneous xenograft models by evaluating tumor growth and histological features. RESULTS: We cultured GSCs to explore the effect of GO and the underlying mechanism of its action. We found, for the first time, that GO triggers the inhibition of cell proliferation and induces apoptotic cell death in GSCs. Moreover, GO could promote the differentiation of GSCs by decreasing the expression of stem cell markers (SOX2 and CD133) and increasing the expression of differentiation-related markers (GFAP and ß-III tubulin). Mechanistically, we found that GO had a striking effect on GSCs by inducing cell cycle arrest and epigenetic regulation. GO decreased H3K27me3 levels, which are regulated by EZH2 and associated with transcriptional silencing, in the promoters of the differentiation-related genes GFAP and ß-III tubulin, thereby enhancing GSC differentiation. In addition, compared with untreated GSCs, GO-treated GSCs that were injected into nude mice exhibited decreased tumor growth in vivo. CONCLUSION: These results suggested that GO could promote differentiation and reduce malignancy in GSCs via an unanticipated epigenetic mechanism, which further demonstrated that GO is a potent anti-GBM agent that could be useful for future clinical applications.

5.
Cell Death Dis ; 11(5): 388, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439852

RESUMO

Previous studies indicated that Ca2+/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca2+-regulated protease µ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca2+ flux using ryanodine and thapsigargin failed to prevent Ca2+ paradox-induced heart injury. In contrast, the Ca2+ paradox increased CaMKII auto-phosphorylation at Thr287, while the CaMKII inhibitor KN-62 and the Na+/Ca2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of µ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.

6.
Oxid Med Cell Longev ; 2020: 1535201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411318

RESUMO

Diabetes mellitus, a worldwide health threat, is considered an independent risk factor for cardiovascular diseases. The overall cardiovascular risk of diabetes is similar to the one having one myocardial infarction (MI) attack although the precise impact of diabetes on MI-induced myocardial anomalies remains elusive. Given that mortality following MI is much greater in diabetic patients compared to nondiabetic patients, this study was designed to examine the effect of melatonin on MI injury-induced myocardial dysfunction in diabetes. Adult mice were made diabetic using high-fat feeding and streptozotocin (100 mg/kg body weight) prior to MI and were treated with melatonin (50 mg/kg/d, p.o.) for 4 weeks prior to assessment of cardiac geometry and function. The MI procedure in diabetes displayed overt changes in cardiac geometry (chamber dilation and interstitial fibrosis) and functional anomalies (reduced fractional shortening and cardiomyocyte contractile capacity) in association with elevated c-Jun N-terminal kinase (JNK) phosphorylation and p53 level. Melatonin treatment markedly attenuated cardiac dysfunction and myocardial fibrosis in post-MI diabetic mice. Furthermore, melatonin decreased JNK phosphorylation, reduced p53 levels, and suppressed apoptosis in hearts from the post-MI diabetic group. In vitro findings revealed that melatonin effectively counteracted high-glucose/high fat-hypoxia-induced cardiomyocyte apoptosis and contractile dysfunction through a JNK-mediated mechanism, the effects of which were impaired by the JNK activator anisomycin. In summary, our study suggests that melatonin protects against myocardial injury in post-MI mice with diabetes, which offers a new therapeutic strategy for the management of MI-induced cardiac injury in diabetes.

7.
Pharmacol Res ; : 104828, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32339783

RESUMO

Second hand smoke exposure increases the prevalence of chronic diseases partly attributed to inflammatory responses. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is involved in the pathogenesis of multiple diseases although its role in second hand smoke exposure-induced cardiac anomalies remains elusive. This study evaluated the impact of MIF knockout on side-stream smoke exposure-induced cardiac pathology and underlying mechanisms. Adult WT and MIF knockout (MIFKO) mice were placed in a chamber exposed to cigarette smoke for 1 hr daily for 60 consecutive days. Echocardiographic, cardiomyocyte function and intracellular Ca2+ handling were evaluated. Autophagy, mitophagy and apoptosis were examined using western blot. DHE staining was used to evaluate superoxide anion (O2-) generation. Masson trichrome staining was employed to assess interstitial fibrosis. Our data revealed that MIF knockout accentuated side-stream smoke-induced cardiac anomalies in fractional shortening, cardiomyocyte function, intracellular Ca2+ homeostasis, myocardial ultrastructure and mitochondrial content along with overt apoptosis and O2- generation. In addition, unfavorable effects of side-stream smoke were accompanied by excessive formation of autophagolysosome and elevated TFEB, the effect of which was exacerbated by MIF knockout. Recombinant MIF rescued smoke extract-induced myopathic anomalies through promoting AMPK activation, mitophagy and lysosomal function. Taken together, our data suggest that MIF serves as a protective factor against side-stream smoke exposure-induced myopathic changes through facilitating mitophagy and autophagolysosome formation.

8.
J Interpers Violence ; : 886260520907360, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32338115

RESUMO

This study poses the following research questions: What is the prevalence of bullying in vocational schools in China? What are the differences between different genders and professions? How should individuals, families, and schools do to affect school bullying? What can we do to improve and to respond school bullying, to reduce its occurrence and consequences? This cross-sectional study was conducted in 2018 with 95,873 students from 85 vocational schools. The main outcome indicators were self-reported involvement in bullying (perpetrator, victim, perpetrator-victim, or uninvolved). Multinomial logistic regression analyses were conducted, with personal characteristics, relational characteristics, and school climate as predictors. A total of 30.4% of participants reported being bullied, 2.9% reported bullying others, and 21.7% reported being bullied and bullying others. Majors related to primary and secondary industries are more likely to involvement in bullying than majors related to tertiary industries. Boys were more involved in physical or verbal bullying, whereas girls were more involved in relational bullying and cyberbullying. Sex, history of fighting, and emotional/mental state were the strongest individual factors associated with bullying. Having friends was inversely associated with bullying involvement; moreover, a positive relationship with parents and a good parenting style (warmth, democracy, and mutual concern) protected students from bullying others as well as being bullied. School bullying programs, happiness at school, and insecurity at school were strong negative predictors of bullying. Bullying is prevalent among vocational school students in China. An appropriate response to school bullying requires strengthening student capacity to correctly understand and deal with bullying, identifying victims and vulnerable groups, developing school-based interventions, involving parents in prevention programs, and enhancing students' sense of responsibility in supervision, reporting, and creating a friendly environment.

9.
Acta Pharmacol Sin ; 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317756

RESUMO

In patients with sepsis, lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria triggers cardiac dysfunction and heart failure, but target therapy for septic cardiomyopathy remains unavailable. In this study we evaluated the beneficial effects of cardamonin (CAR), a flavone existing in Alpinia plant, on endotoxemia-induced cardiac dysfunction and the underlying mechanisms with focus on oxidative stress and apoptosis. Adult mice were exposed to LPS (4 mg/kg, i.p. for 6 h) prior to functional or biochemical assessments. CAR (20 mg/kg, p.o.) was administered to mice immediately prior to LPS challenge. We found that LPS challenge compromised cardiac contractile function, evidenced by compromised fractional shortening, peak shortening, maximal velocity of shortening/relengthening, enlarged LV end systolic diameter and prolonged relengthening in echocardiography, and induced apoptosis, overt oxidative stress (O2- production and reduced antioxidant defense) associated with inflammation, phosphorylation of NF-κB and cytosolic translocation of transcriptional factor Nrf2. These deteriorative effects were greatly attenuated or mitigated by CAR administration. However, H&E and Masson's trichrome staining analysis revealed that neither LPS challenge nor CAR administration significantly affected cardiomyocyte cross-sectional area and interstitial fibrosis. Mouse cardiomyocytes were treated with LPS (4 µg/mL) for 6 h in the absence or presence of CAR (10 µM) in vitro. We found that addition of CAR suppressed LPS-induced defect in cardiomyocyte shortening, which was nullified by the Nrf2 inhibitor ML-385 or the NF-κB activator prostratin. Taken together, our results suggest that CAR administration protects against LPS-induced cardiac contractile abnormality, oxidative stress, apoptosis, and inflammation through Nrf2- and NF-κB-dependent mechanism.

10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 572-576, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319398

RESUMO

OBJECTIVE: To compare the efficacy of different thalassemia screening strategies used for the couple of pre-pregnancy. METHODS: A total of 1 159 couples were recruited in Chongqing health center for women and children from January 2019 to June 2019. Routine blood test, hemoglobin test and thalassemia gene test were performed for all the coulpes. The efficacy of thalassemia screening strategies were compared. Strategy 1: Hemoglobin was tested if the woman's MCV <80 fl and/or MCH <27 pg, and test for thalassemia genes was required further according to the result of hemoglobin test. If the woman was a thalassemia carrier, it is recommended that the man would receive the corresponding thalassemia gene test, and if the man carried the same type of thalassemia gene, so it meant positive. Strategy 2: the woman's blood cut-off value was MCV<82 fl and/or MCH<27 pg, and the follow-up procedure was the same as strategy 1. Strategy 3: If both of cople showed MCV (<80 fl) and/or MCH (<27 pg), the couple would be tested for hemoglobin electrophoresis, and if both of the couple showed abnomal result of hemoglobin electrophoresis, the couple would be tested for thalassemia gene. If the couple carried the same thalassemia gene, it meant positive. Strategy 4: If one of the couple or both of them showed MCV (<80 fl) and/or MCH (<27 pg), the couple would be tested for hemoglobin electrophoresis, if the couple showed MCV (<80 fl) and/or MCH (<27 pg) and/or the abnormal result of hemoglobin test, genetic test for thalassemia test were performed. RESULTS: A total of 15 couples were thalassemia positive. According to the ROC curve, the area under the curve of strategy 2 was the largest but the cost was the highest. The area under the curve of strategy 4 was slightly less than that of strategy 2, but the cost was lower. CONCLUSION: Strategy 4 is recommended in the case of high degree of male cooperation and strategy 2 is recommended in the case of low degree of male cooperation.

11.
Anesthesiology ; 132(5): 1197-1211, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32294065

RESUMO

BACKGROUND: Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4ß2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam. METHODS: Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague-Dawley rats. RESULTS: Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam. CONCLUSIONS: Activation of α4ß2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.

12.
Basic Res Cardiol ; 115(3): 25, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32232579

RESUMO

Since the publication of the article, the authors found a small problem with Fig. 7e. Unfortunately, Fig. 7e did not contain the correct images. The correct images are shown below and do not change the conclusions.

13.
Zhongguo Zhong Yao Za Zhi ; 45(3): 513-517, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237507

RESUMO

Cerebral ischemia is also known as ischemic stroke. In recent years, research on neuroprotection after ischemia has became a hot spot as stroke can result in symptoms of nerve damages such as hemiplegia, learning and memory disorders. The key factors that cause the death of cells include excitotoxicity, oxidative damage, nitrosative stress and inflammation. However, there is no effective preparation for the treatment of post-ischemic nerve defects at present, so it is urgent to find and develop effective drugs for the treatment of nerve damages after ischemia. Traditional Chinese medicine has advantages and potentials in the treatment of neurological diseases. Many scholars have carried out related researches on the active ingredients of traditional Chinese medicine and achieved some good results. In this context, the researches on the neuroprotective effects of traditional Chinese medicines such as tetramethylpyrazine, butylphthalide and total saponins of Panax notoginseng were reviewed. The author found that the neuroprotective researches of traditional Chinese medicine mostly focused on anti-apoptosis, anti-inflammatory and anti-oxidative stress, but those effects were not sounique to the nervous system. Furthermore, most ingredients of traditional Chinese medicine showed a poor water-soluble property. In view of the research status and existing problems of traditional Chinese medicine in nerve injury, the suggestions for the research and development of the potent neuroprotective agents were proposed in this study from the perspective of pharmacological mechanism research and preparation theory.

15.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188366, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32339608

RESUMO

Autophagy is an evolutionarily conserved self-cannibalization process commonly found in all eukaryotic cells. Through autophagy, long-lived or damaged organelles, superfluous proteins, and pathogens are sequestered and encapsulated into the double-membrane autophagosomes prior to fusion with lysosomes for ultimate degradation and recycling. Given that autophagy is deemed both protective and detrimental in malignancies, the clinical therapeutic utilization of autophagy modulators in cancer has attracted immense attentions over the past decades. Dependence of tumor cells on autophagy during amino acid insufficiency or deprivation has prompted us to explore the underlying autophagy regulatory mechanisms to inject amino acid degrading enzymes and enzyme-based strategies into therapeutic maneuvers of autophagy in cancer.

16.
Pharmacol Res ; 157: 104846, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32339784

RESUMO

Doxorubicin (DOX) is one of the most effective antineoplastic drugs. However, its clinical application has been greatly limited due to the development of cardiotoxicity with DOX utilization. A number of theories have been postulated for DOX-induced cardiotoxicity with a pivotal contribution from unchecked (excess) mitophagy and mitochondrial fission. Liensinine (LIEN), a newly identified mitophagy inhibitor, strengthens the antineoplastic efficacy of DOX although its action on hearts remains elusive. This study was designed to examine the effect of LIEN on DOX-induced cardiotoxicity and the underlying mechanisms involved with a focus on mitochondrial dynamics. Our data revealed that LIEN alleviated DOX-induced cardiac dysfunction and apoptosis through inhibition of dynamin-related protein 1 (Drp1)-mediated excess (unchecked) mitochondrial fission. LIEN treatment decreased Drp1 phosphorylation at Ser616 site, inhibited mitochondrial fragmentation, mitophagy (assessed by TOM20 and TIM23), oxidative stress, cytochrome C leakage, cardiomyocyte apoptosis, as well as improved mitochondrial function and cardiomyocyte contractile function in DOX-induced cardiac injury. In DOX-challenged neonatal mouse ventricular myocytes (NMVMs), LIEN-suppressed Drp1 phosphorylation, mitochondrial fragmentation, and apoptosis were blunted by Rab7 overexpression, the effect of which was reversed by the ERK inhibitor U0126. Moreover, activation of ERK or Drp1 abolished the protective effects of LIEN on cardiomyocyte mechanical anomalies. These data shed some lights towards understanding the role of LIEN as a new protective agent against DOX-associated cardiotoxicity without compromising its anti-tumor effects.

17.
Epigenomics ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32166971

RESUMO

Aim: To identify methylation-driven genes and establish a novel epigenetic signature for gastrointestinal (GI) pan-adenocarcinomas. Materials & methods: Methylation and RNA-seq data for GI adenocarcinomas were downloaded from the Cancer Genome Atlas database. A methylation-driven gene signature was established by multivariate Cox regression analysis. We developed a prognostic nomogram using a combination of methylation-driven gene risk score and clinicopathological variables. A joint survival analysis based on gene expression and methylation was conducted to further investigate the prognostic role of methylation-driven genes. Results: An epigenetic signature was established based on five methylation-driven genes. We also established a prognostic nomogram based on methylation-driven gene risk score and clinicopathologic factors, with a favorable predictive ability. Joint survival analysis revealed that 28 methylation-driven genes could be independent prognostic factors for overall survival for GI adenocarcinomas. Conclusion: An epigenetic signature was established that effectively predicts the overall survival for GI adenocarcinomas across anatomic boundaries.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32182733

RESUMO

Renal calculi are common, with male predilection and androgen exposure potentially increasing the risk of renal calculi. Systemic effects of androgen deprivation therapy (ADT) have been observed but the influence of ADT on renal calculi in prostate cancer (PCa) patients is not fully understood. We conducted this population-based study to evaluate the impact of ADT on the subsequent risk of renal calculi. We used the National Health Insurance Research Database of Taiwan to analyze the incidences of renal calculi in ADT patients and non-ADT patients from 2001 to 2013. In total, 3309 patients with PCa were selected. After matching with 1:1 propensity-score analysis, 758 ADT patients with 758 matched non-ADT controls were enrolled in the final analysis. Demographic characteristics were analyzed and Cox regression analysis for calculating the hazard ratios (HR) was performed for the subsequent risk of renal calculi. Finally, 186 (186/1516, 12.3%) patients with diagnosed renal calculi were detected. ADT patients had a lower risk of subsequent renal calculi with an adjusted HR of 0.38 (7% vs. 17.5%, 95% confidence interval (CI) 0.28-0.53; p < 0.001) in comparison with the non-ADT group. The Kaplan-Meier curve showed significant differences of cumulative incidences of renal calculi. In conclusion, ADT patients had approximately one-third lower risk of subsequent renal calculi. Further studies are warranted to evaluate the clinical significance.

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