KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA.

OBJECTIVE: We aimed to disclose the molecular mechanism of snail1 in liver fibrosis. METHODS: Carbon tetrachloride (CCl4) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC-T6) were irritated with transforming growth factor (TGF)-ß1, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription-quantitative polymerase chain reaction, in addition to α-smooth muscle actin (SMA), anti-collagen type I α1 (COL1A1), vimentin, and E-cadherin. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C-bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation. RESULTS: In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and α-SMA, COL1A1 and VIMENTIN expressions but increased E-cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC-T6 cells exposed to TGF-ß1, ALKBH5 overexpression weakened cell viability and migration, downregulated α-SMA, COL1A1 and VIMENTIN, upregulated E-CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC-T6 cell activation by regulating the ALKBH5/snail1 axis. CONCLUSION: KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.

The global, regional, and national burden of cancer among adolescents and young adults in 204 countries and territories, 1990-2019: a population-based study.

BACKGROUND: Accurate appraisal of burden of adolescents and young adults (AYAs) cancers is crucial to informing resource allocation and policy making. We report on the latest estimates of burden of AYA cancers in 204 countries and territories between 1990 and 2019 in association with socio-demographic index (SDI). PATIENTS AND METHODS: Estimates from the Global Burden of Disease study 2019 were used to analyse incidence, mortality, and disability-adjusted life years (DALYs) due to AYA cancers at global, regional, and national levels by sex. Association between AYA cancer burden and SDI were investigated. Burdens of AYA cancers were contextualized in comparison with childhood and older adult cancers. All estimates are reported as counts and age-standardized rates per 100,000 person-years. RESULTS: In 2019, there were 1.2 million incident cases, 0.4 million deaths, and 23.5 million DALYs due to AYA cancers globally. The highest age-standardized incidence rate occurred in Western Europe (75.3 [Females] and 67.4 [Males] per 100,000 person-years). Age-standardized death (23.2 [Females] and 13.9 [Males] per 100,000 person-years) and DALY (1328.3 [Females] and 1059.2 [Males] per 100,000 person-years) rates were highest in Oceania. Increasing SDI was associated with a higher age-standardized incidence rate. An inverted U-shaped association was identified between SDI and death and DALY rates. AYA cancers collectively is the second leading cause of non-communicable diseases-related deaths globally in 2019. DALYs of AYA cancers ranked the second globally and the first in low and low-middle SDI locations when compared with that of childhood and older adult cancers. CONCLUSION: The global burden of AYA cancers is substantial and disproportionally affect populations in limited-resource settings. Capacity building for AYA cancers is essential in promoting equity and population health worldwide.

Global, regional, and national burden of severe periodontitis, 1990-2019: An analysis of the Global Burden of Disease Study 2019.

AIM: Up-to-date epidemiological studies on the global burden of severe periodontitis is scarce. This study aimed to present the latest estimates for prevalence of severe periodontitis from 1990 to 2019, by region, age, and level of socio-demographic development. MATERIALS AND METHODS: Estimates from the Global Burden of Disease study 2019 were used to investigate burden and trends of prevalence of severe periodontitis and its association with socio-demographic development at global, regional, and national level. Decomposition analysis was performed to explore the contribution of demographic and epidemiological factors to the evolving burden of severe periodontitis. RESULTS: In 2019, there were 1.1 billion (95% uncertainty interval: 0.8-1.4 billion) prevalent cases of severe periodontitis globally. From 1990 to 2019, age-standardized prevalence rate of severe periodontitis increased by 8.44% (6.62%-10.59%) worldwide. Prevalence of severe periodontitis is higher among less developed countries/regions. Global population growth accounted for 67.9% of the increase in the number of prevalent cases of severe periodontitis from 1990 to 2019. CONCLUSIONS: The global burden of severe periodontitis has been substantial and increasing over the past three decades. Upstream policy changes are urgently needed to address the global public health challenge of severe periodontitis.

Trends in the Burden of Untreated Caries of Permanent Teeth in China, 1993-2017: An Age-Period-Cohort Modeling Study.

INTRODUCTION: This study aims to identify the trends in incidence and prevalence of untreated caries in permanent teeth in China during 1993-2017. METHODS: Data representing >31 billion person-years of observation from the Global Burden of Disease study 2017 were analyzed. Age-period-cohort modeling was performed to investigate the trends in untreated caries that may be of value to policymakers. Analyses were conducted in 2019-2020. RESULTS: Prevalence of untreated caries in permanent teeth decreased steadily before 2010; after which, an increasing trend was noted without the signs of plateauing (age-adjusted annual percentage change, 1993-2017: -0.54%, 95% CI= -0.75%, -0.33%; declining period RR, 1993-2017: p=6.33 × 10-9; declining cohort RR, 1993-2017: p=3.46 × 10-6). Although untreated caries prevalence declined overall among multiple age groups (p<0.05), an increase in prevalence after 2010 was noted. This was driven by the deteriorating oral health condition in recent birth cohorts aged <25 years. Estimates of the longitudinal age trend (incidence: -0.013, 95% CI= -0.015, -0.011; prevalence: -0.0038, 95% CI= -0.0060, -0.0015) suggested that the highest untreated caries incidence and prevalence rate were both observed among young adults aged 20-24 years. No differences between incidence and prevalence of untreated caries were observed among adults aged >55 years (p>0.05). CONCLUSIONS: The increased burden of untreated caries in China after 2010 is driven by those aged <25 years. Untreated caries data from the Global Burden of Disease study are a valid complement to the data from the Chinese National Oral Health Epidemiology Surveys.

Effects of seawater immersion on open traumatic brain injury in rabbit model.

We emulated instances of open traumatic brain injuries (TBI) in a maritime disaster. New Zealand rabbit animal models were used to evaluate the pathophysiological changes in open TBI with and without the influence of artificial seawater. New Zealand rabbits were randomly divided into 3 groups. Control group consisted of only normal animals. Animals in TBI and TBI + Seawater groups underwent craniotomy with dura mater incised and brain tissue exposed to free-fall impact. Afterward, only TBI + Seawater group received on-site artificial seawater infusion. Brain water content (BWC) and permeability of blood-brain barrier (BBB) were assessed. Reactive oxygen species levels were measured. Western blotting and immunofluorescence were employed to detect: apoptosis-related factors Caspase-3, Bax and Bcl-2; angiogenesis-related factors CD31 and CD34; astrogliosis-related factor glial fibrillary acidic protein (GFAP); potential neuron injury indicator neuron-specific enolase (NSE). Hematoxylin & eosin, Masson-trichrome and Nissl stainings were performed for pathological observations. Comparing to Control group, TBI group manifested abnormal neuronal morphology; increased BWC; compromised BBB integrity; increased ROS, Bax, CD31, CD34, Caspase-3 and GFAP expressions; decreased Bcl-2 and NSE expression. Seawater immersion caused all changes, except BWC, to become more significant. Seawater immersion worsens the damage inflicted to brain tissue by open TBI. It aggravates hypoxia in brain tissue, upregulates ROS expression, increases neuron sensitivity to apoptosis-inducing factors, and promotes angiogenesis as well as astrogliosis.

[Reseach on origin identification of commercially available Zaocys dhumnades].

Through market investigation, the adulteration of Zaocys dhumnades on markets was found out, and samples of authentic and adulterated Z. dhumnades on markets were collected. The origin and properties of the adulterated Z. dhumnades were studied in order to provide reference for the identification of Z. dhumnades. The counterfeit Z. dhumnades sold on markets were as follows: Ptyas korros, P. mucosus, Najanaja atra, Sinonatrix annularis, Dinodon septentrionalis, etc. It is found that there existed a obvious difference between the traits of the Z. dhumnades and counterfeits. Genuine Z. dhumnades with "sword ridge" "iron tail", strongly ribbed scales and other features, is the key point to identify the difference from adulterants.

Pericardial effusion is correlated with clinical outcome after pulmonary artery denervation for pulmonary arterial hypertension.

OBJECTIVES: Pericardial effusion (PE) is correlated with outcomes in patients with pulmonary arterial hypertension (PAH). Pulmonary artery denervation (PADN) was used for treatment of PAH. The present study aimed to analyze the prognostic value of PE for outcomes after PADN in patients with WHO Group I, Group II and Group IV PAH. RESULTS: PE, frequently seen in patients with connective tissue disease, was featured by fast heart rate, decreased exercise capacity, more syncope, worsening pulmonary arterial hemodynamic and right atrium size. PADN procedure resulted in dramatic reduction of PE. After a median of 376 days follow-up, the rate of PAH-related event, all-cause death and rehospitalization increased over the PE amount and occurred in 29.8%, 19.7% and 25.2% of patients with PE, different to 3.4%, 3.4% and 6.8% of patients without PE (p = 0.034, p = 0.041 and p = 0.039, respectively). The reduction of PE during follow-up was similar among three groups. MATERIALS AND METHODS: Between March 2012 and July 2014, a total of 66 consecutive patients (52 ± 16 years) who underwent PADN were stratified by no PE (n = 20), PE < 10 mm (n = 29) and PE ≥ 10 mm (n = 17) according to baseline echocardiograph. Dynamic change of PE and its correlation with PAH-related event after PADN were measured. CONCLUSIONS: PE is associated with increased PAH-related event after PADN. PADN results in significant similar reduction of PE among patients with Group I, Group II and Group IV PAH.

Stent fracture is associated with a higher mortality in patients with type-2 diabetes treated by implantation of a second-generation drug-eluting stent.

Type 2 diabetes correlates with clinical events after the implantation of a second-generation drug-eluting stent (DES). The rate and prognostic value of stent fracture (SF) in patients with diabetes who underwent DES implantation remain unknown. A total of 1160 patients with- and 2251 without- diabetes, who underwent surveillance angiography at 1 year after DES implantation between June 2004 and August 2014, were prospectively studied. The primary endpoints included the incidence of SF and a composite major adverse cardiac event [MACE, including myocardial infarction (MI), cardiac death, and target-vessel revascularization (TVR)] at 1-year follow-up and at the end of follow-up for overall patients, and target lesion failure [TLF, including cardiac death, target vessel myocardial infarction (TVMI) and target lesion revascularization (TLR)] at the end of study for SF patients. In general, diabetes was associated with a higher rate of MACE at 1-year (18.4 vs. 12.9%) and end of follow-up (24.0 vs. 18.6%, all p < 0.001), compared with those in patients who did not have diabetes. The 1-year SF rate was comparable among patients with diabetes (n = 153, 13.2%) and non-diabetic patients (n = 273, 12.1%, p > 0.05). Diabetic patients with SF had a 2.6-fold increase of SF-related cardiac death at the end of study and threefold increase of re-repeat TLR when compared with non-diabetic patients with SF (5.9 vs. 2.2%, p = 0.040; 6.5 vs. 2.2%, p = 0.032), respectively. Given the fact that diabetes is correlated with increased MACE rate, SF in diabetic patients translates into differences in mortality and re-repeat TLR compared with the non-diabetic group.

Incidence and Clinical Outcomes of Stent Fractures on the Basis of 6,555 Patients and 16,482 Drug-Eluting Stents From 4 Centers.

OBJECTIVES: The present study aimed to analyze the incidence of SF and its correlation with clinical events after DES implantation and the outcome of re-intervention for symptomatic in-stent restenosis (ISR) induced by stent fracture (SF). BACKGROUND: SF is associated with a high rate of clinical events after the implantation of drug-eluting stents (DES). However, the chronological rate of SF and the effect of SF on clinical outcomes from a large patient population remain underreported. METHODS: A total of 6,555 patients with 16482 DES in 10751 diseased vessels and surveillance angiography between November 2003 and January 2014 were prospectively studied. The primary endpoints included the incidence of SF, in-stent restenosis (ISR), target lesion revascularization (TLR), and definite stent thrombosis (ST) at the end of follow-up before and after propensity score matching. Clinical outcomes after TLR were also followed up. RESULTS: The SF rate was detected in 803 (12.3%) patients, 3,630 (22.0%) stents, and 1,852 (17.2%) diseased vessels. SF increased over time. SF was associated with higher unadjusted rates of ISR (42.1%), TLR (24.8%, n = 379), and definite ST (4.6%) compared with stents without fracture (10.7%, 6.6%, and 1.03%, all p < 0.001), and the differences remained significant after propensity score matching (all p < 0.05). There was no significant difference in any-cause or cardiac mortality between patients with and without SF. After 1,523 days of follow-up since the first surveillance angiography, repeat ISR was detected in 90 of 379 (23.8%) stents after reintervention, and 6 (7.5%) stents required repeat TLR. CONCLUSIONS: SF is more frequently observed after DES implantation. TLR was required in almost one-fourth of fractured stents. Increased events in the SF group did not translate into a difference in mortality compared with the non-SF group. Reintervention was associated with acceptable clinical results.

Periprocedural myocardial infarction is associated with increased mortality in patients with coronary artery bifurcation lesions after implantation of a drug-eluting stent.

OBJECTIVES: The present study aimed to investigate the association between periprocedural myocardial infarction (PMI), defined by creatine kinase (CK)-MB or troponin I (TNI) level elevations >5 times the 99 th percentile of the upper reference limit (URL) within 48 hr after implantation of a drug-eluting stent (DES), and one-year mortality in patients with coronary bifurcation. BACKGROUND: PMI is reported to be associated with increased one-year mortality after DES implantation. However, the prevalence and association of PMI with mortality after stenting bifurcation lesions remains unclear. METHODS: We prospectively followed 1,971 patients with true coronary bifurcations who underwent DES implantation as part of the multicenter DEFINITION study. These patients were grouped into categories based on PMI outcome: Non-PMI, CKMB-PMI, TNI-PMI, and CKMB/TNI-PMI. The primary endpoint was the rate of all-cause mortality at one year. RESULTS: PMI occurred in 11.4% of patients by CKMB criteria and 41.3% of patients by TNI criteria. At one-year follow-up, the mortality rate was 2.3% in the entire patient population. However, mortality was significantly higher in the CKMB-PMI (6.4%) and CKMB/TNI-PMI (6.1%) groups compared to the Non-PMI (1.7%) and TNI-PMI (2.1%) groups (all P < 0.05). A 10-fold increase in TNI levels resulted in similar PMI rate (5.2%) and mortality risk (adjusted HR 2.7, 95% CI 3.0-5.2) as a fivefold increase in CKMB levels. CONCLUSIONS: PMI, as defined by CKMB elevations following coronary bifurcation lesion stenting, was associated with increased one-year mortality. Additionally, to attain an equal frequency of PMI, the elevation in TNI levels needed to be twice as high as the elevation in CKMB levels.