Association of Lung Cancer Risk With the Presence of Both Lung Nodules and Emphysema in a Lung Cancer Screening Trial.

Background: The coexistence of emphysema and lung nodules could interact with each other and then lead to potential higher lung cancer risk. The study aimed to explore the association between emphysema combined with lung nodules and lung cancer risk. Methods: A total of 21,949 participants from the National Lung Screening Trial (NLST) who underwent low-dose computed tomography (LDCT) examination were included. Participants were categorized into four groups (NENN group (non-emphysema and non-nodules), E group (emphysema without nodules), N group (nodules without emphysema), and E + N group (nodules with emphysema)) according to whether there were lung nodules and emphysema. Multivariable Cox regression and stratified analyses were performed to estimate the association between the four groups and lung cancer risk. Results: Among the 21,949 participants, there were 9,040 (41.2%), 5,819 (26.5%), 4,737 (21.6%), and 2,353 (10.7%) participants in the NENN group, E group, N group, and E + N group. The risk of lung cancer incidence increased in turn in NENN group, E group, N group and E + N group. Compared with NENN group, the age-adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of lung cancer incidence were 2.07 (1.69 - 2.54) for E group, 4.13 (3.47 - 5.05) for N group, and 6.26 (5.14 - 7.62) for E + N group. The association was robust to adjustment for potential confounders (1.83 (1.47 - 2.27) for E group, 3.97 (3.24 - 4.86) for N group, and 5.23 (4.28 - 6.48) for E + N group). Comparable results as the lung cancer incidence were observed for lung cancer mortality, whether in age-adjusted model (E group: 1.85 (1.39 - 2.46), N group: 2.49 (1.89 - 3.29), E + N group: 4.27 (3.21 - 5.68)) or fully adjusted model (E group: 1.56 (1.15 - 2.11), N group: 2.43 (1.81 - 3.26), E + N group: 3.39 (2.50 - 4.61)). However, the trend of all-cause mortality risk among the four groups was somewhat different from that of lung cancer risk, whether in age-adjusted model (1.37 (1.21 - 1.54) for E group, 1.06 (0.92 - 1.21) for N group, and 1.75 (1.51 - 2.02) for E + N group) or fully adjusted model (1.26 (1.10 - 1.44) for E group, 1.09 (0.94 - 1.27) for N group, and 1.52 (1.30 - 1.79) for E + N group). Conclusion: Based on a large-scale lung cancer screening trial in the United States, this study demonstrated that either emphysema or lung nodules can increase lung cancer risk, and lung nodules combined with emphysema can further increase the lung cancer risk and all-cause mortality. The significance of these findings for lung cancer screening should be evaluated.

Ligand-Promoted Iron-Catalyzed Nitrene Transfer for the Synthesis of Hydrazines and Triazanes through N-Amidation of Arylamines.

Herein, we report that bulky alkylphosphines such as PtBu3 can switch the roles from actor to spectator ligands to promote the FeCl2 -catalyzed N-amidation reaction of arylamines with dioxazolones, giving hydrazides in high efficiency and chemoselectivity. Mechanistic studies indicated that the phosphine ligands could facilitate the decarboxylation of dioxazolones on the Fe center, and the hydrogen bonding interactions between the arylamines and the ligands on Fe nitrenoid intermediates might play a role in modulating the delicate interplay between the phosphine ligand, arylamine, and acyl nitrene N, favoring N-N coupling over N-P coupling. The new ligand-promoted N-amidation protocols offer a convenient way to access various challenging triazane compounds via double or sequential N-amidation of primary arylamines.

A new risk stratification strategy for fatty liver disease by incorporating MAFLD and fibrosis score in a large US population.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed definition of fatty liver disease (FLD) independent of excessive alcohol consumption (EAC) and hepatitis viral infection. Evidence on the mortality risk in different types of FLD [nonalcoholic FLD (NAFLD), alcoholic FLD (AFLD), and MAFLD] is sparse, hindering the identification of high-risk populations for preferential clinical surveillance. METHODS: A total of 11,000 participants in the Third National Health and Nutrition Examination Survey were enrolled. Participants were categorized into three groups [FLD( - ), MAFLD( - ), and MAFLD( +)] according to FLD and MAFLD criteria, and further categorized into six groups by EAC. Multivariate Cox proportional hazard model was used to estimate the risk of all-cause, cardiovascular-related, and cancer-related mortality. RESULTS: During a median follow-up of 23.2 years, a total of 3240 deaths were identified. Compared with FLD( - )/EAC( - ) participants, MAFLD( +) individuals had higher all-cause mortality risk [hazard ratio (HR) = 1.28, 95% confidence interval (CI) = 1.18-1.39] regardless of EAC status [MAFLD( +)/NAFLD: HR = 1.22, 95%CI = 1.11-1.34; MAFLD( +)/AFLD: HR = 1.83, 95%CI = 1.46-2.28], while not for MAFLD( - ) individuals. Furthermore, diabetes-driven-MAFLD had higher mortality risk (HR = 2.00, 95%CI = 1.77-2.27) followed by metabolic dysregulation-driven-MAFLD (HR = 1.30, 95%CI = 1.06-1.60) and overweight/obesity-driven-MAFLD (HR = 1.11, 95%CI = 1.00-1.22). Additionally, MAFLD( - ) participants with elevated fibrosis score were also associated with statistically significantly higher mortality risk (HR = 3.23, 95%CI = 1.63-6.40). CONCLUSIONS: Utilizing a representative sample of the US population, we proved the validity of MAFLD subtype and fibrosis score, rather than the traditional definition (NAFLD and AFLD), in the risk stratification of FLD patients. These findings may be applied to guide the determination of surveillance options for FLD patients.

Role of PCSK9 in the Development of Mouse Periodontitis Before and After Treatment: A Double-Edged Sword.

Periodontitis is a highly prevalent infectious disease associated genetically with coronary heart disease (CHD). The effects of proprotein convertase subtilisin/kexin type 9 (PCSK9), a critical regulator of CHD, on periodontitis have not been studied to date. Here, we found that PCSK9 expression was increased in periodontitis patients and Porphyromonas gingivalis (Pg)-infected mice. Loss of PCSK9 attenuated Pg-induced periodontal bone loss in mice. First, PCSK9 deficiency reduced the release of inflammation-associated cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1ß, in vitro and in vivo. Second, its deficiency enhanced Pg and endotoxin clearance during Pg invasion in part by upregulating CD36 and low-density lipoprotein receptor (LDLR), respectively. However, after berberine treatment, periodontal bone regeneration in the PCSK9 knockout group was significantly lower than that in wild-type. This was because PCSK9 overexpression promoted osteogenic differentiation of periodontal ligament stem cells (PDLCs) prechallenged by TNF-α. Furthermore, PCSK9 could rescue PDLC osteogenesis by repressing the NF-κB signaling pathway by interacting with TRAF2. These results suggest that PCSK9 may be a potent drug target for treating periodontitis.

Ddit3 suppresses the differentiation of mouse chondroprogenitor cells.

Endochondral ossification is an essential skeletal development process which is strongly linked to chondrocyte differentiation. DNA damage-inducible transcript 3 (Ddit3), a member of the CCAAT/enhancer-binding protein family of transcription factors, is highly expressed in the cartilage plate. However, the role of DNA damage-inducible transcript 3 in chondrocyte differentiation remains to be investigated. Immunofluorescent staining was used to detect Ddit3 expression in the mouse growth plate and in the mouse chondroprogenitor cell line ATDC5. A lentivirus system was employed to overexpress Ddit3 and silence its endogenous expression in ATDC5 cells. The differentiation abilities of ATDC5 cells were examined through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and chondrogenic and hypertrophic-related staining. Western blot analysis was performed to detect the protein expression of sex-determining region Y-type high-mobility group box 9 and CCAAT/enhancer-binding protein ß. Ddit3 was expressed in the proliferative and hypertrophic zones of the mouse growth plate. Ddit3 knockdown significantly enhanced the expression of chondrogenic and hypertrophic markers, whereas Ddit3 overexpression decreased the expression of these markers. This finding was also evidenced by Alcian blue staining, proteoglycan synthesis and alkaline phosphatase assay. Additionally, Ddit3 down-regulation significantly led to Sox9 up-regulation. These results suggest that Ddit3 suppresses the differentiation of ATDC5 cells. The function of Ddit3 might partially be regulated by Sox9 expression during chondrogenic and hypertrophic differentiation.

Association between the (GT)n polymorphism of the HO-1 gene promoter region and cancer risk: a meta-analysis.

BACKGROUND: Several studies have previously focused on associations between the (GT)n repeat polymorphism of the heme oxygenase-1 (HO-1) gene promoter region and risk of cancers, but results are complex. We conducted the present meta-analysis to integrate relevant findings and evaluate the association between HO-1 (GT)n repeat polymorphism and cancer susceptibility. MATERIALS AND METHODS: Published literature was retrieved from the PubMed/MEDLINE, EMBASE and ISI Web of Science databases before November 2013. For all alleles and genotypes, odds ratios were pooled to assess the strength of the associations using either fixed-effects or random-effects models according to heterogeneity. Subgroup analysis was conducted according to ethnicity and histopathology. RESULTS: A total of 10 studies involving 2,367 cases and 2,870 controls were identified. The results showed there was no association between HO-1 (GT)n repeat polymorphism and the cancer risk both at the allelic and genotypic level. However, in the stratified analysis, we observed an increased risk of squamous cell carcinoma in persons carrying the LL genotype and the LL+LS genotype as compared with those carrying the SS genotype. When the LS and SS genotypes were combined, the odds ratio for squamous cell carcinoma in LL-genotype carriers, were also significantly increased. No publication bias was observed. CONCLUSIONS: The LL genotype and L-allele carrying genotypes (LL+LS) of HO-1 (GT)n repeat polymorphism are potential genetic factors for developing squamous cell carcinoma. More large and well-designed studies are required for further validations.

Effect of insulin on the cognizing function and expression of hippocampal Abeta1-40 of rat with Alzheimer disease.

BACKGROUND: A model of simulated Alzheimer's disease (AD) induced by aggregated amyloid protein (Abeta(1-40)) was built in Wistar rats to observe the behavioral and pathological changes of Abeta(1-40) and the effect of hypodermic insulin injected on the function of study and memory and the expression of Abeta(1-40) from the CA1 area of the hippocampus. METHODS: Experimental groups were as follows: contrast, simulated AD model, contrast of Nacl, and insulin treated. The simulated AD model was built by microinjection of aggregated Abeta(1-40) at the CA1 area of the hippocampus, and was hypodermically injected with 0.9% NaCl (1 ml/kg) and insulin (0.1 U/kg) separately the next day. Two weeks after the modeling, the four groups were tested with water maze about the study and memory function of rats. Three weeks after the injection, the expression of Abeta(1-40) at the CA1 area of the hippocampus was examined by pathological tests (HE, Congo red) and immunohistochemical methods. RESULTS: The study and memory abilities of rats were ameliorated significantly by the place navigation test and the spatial probe test after the application of insulin. Insulin could decrease the expression of Abeta(1-40) at the CA1 area of the hippocampus to reduce the pathological damage of Abeta(1-40) to the hippocampal area of rats. CONCLUSIONS: The injection of aggregated Abeta(1-40) to the hippocampal area could simulate the behavioral and pathological features of AD such as the difficulty of study and memory and the damage to neurons. Insulin is effective to improve the function of study and memory and amend the pathological damage of simulated AD model rats. The results give a experimental proof of insulin in the clinical treatment of AD.

[Protective effects of extract of Ginkgo biloba against ethanol-induced oxidative injury in rat testes].

OBJECTIVE: This study was designed to investigate whether EGB protect against ethanol-induced oxidative injury in rat testes. METHODS: The rats were pretreated with EGB (4.8,9.6 mg/100g bw per day) before 30% ethanol administration (2.37g/kg bw by gastric incubation). Ninety days later, the rats were killed in order to measure the activities of Superoxide Dismutase (SOD), Glutathione Reductase (GST), Glutathione Peroxidase (GSH-Px), Catalase (CAT) and the contents of Glutathione (GSH), Reactive Oxygen Species (ROS), Malondialdehyde (MDA)in rat testes. The microsomal fractions were obtained by the method of differential centrifugation, and HO-1 (Heme Oxygenase-1) activity in testicular microsomal was measured. To examine the expression of HO-1 mRNA by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with ethanol group, ROS, and MDA contents significantly decreased in EGB group testes, respectively (P < 0.05). GST, GSH-Px, CAT, SOD activities, and GSH content in EGB group testes elevated markedly (P <0.05). EGB could enhance HO-1 mRNA expression remarkably. CONCLUSION: It is suggested that EGB as a preventive antioxidant can protect against ethanol-induced testicular injury, which may be associated with HO-1 activity enhancement, free radicals elimination, lipid per-oxidation reaction inhibition.

[Effect of flavonoids of ginkgo biloba on anti-oxidizing system of mice after acute alcohol administration].

OBJECTIVE: To investigate the protective effects of flavonoids of ginkgo biloba on anti-oxidizing system damaged by acute alcohol administration. METHODS: Adult male Kunming mice were employed and divided into randomly flavonoid intervention group, normal control and ethanol control group according to body weight. After pretreated with flavonoids of ginkgo biloba (96mg/kg bw), the mice in flavonoid intervention group ingested alcohol (ethanol 4.8g/kg bw) via i.g. and were decapitated after 0.5, 1, 2, 4, 6, 9, and 15 h of ethanol administration. The same treatment was carried out on ethanol control group except that physiological saline was applied instead of flavonoid of ginkgo biloba. Meanwhile, the normal control group was established. RESULTS: The concentration of glutathione (GSH), malondialdehyde (MDA) and the activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) in the serum and liver were determined. The experiment displays that the content of GSH and the activities of GSH-Px and SOD decreased rapidly after 1 h of treatment with alcohol and dropped to the lowest level at 4h of treatment. After 6h of treatment, these indexes came to the normal level rapidly. The level of MDA of serum and liver increased rapidly after 1 h of treatment and reached the climax at 4h and 6h respectively. It went back to the normal concentration until 15h and 9 h respectively. On a whole, there were similar curves between flavonoids intervention group and alcohol control group on the indexes. However, to some extent, the supplement of flavonoid of ginkgo biloba can prohibit the rise of MDA level and the decline of GSH-Px, SOD, GSH which were induced by acute alcohol intakes. CONCLUSION: Flavonoid of ginkgo biloba have some protective effects on the damage of anti-oxidizing system of mice induced by acute alcohol adminstration.

CYP2E1-dependent hepatotoxicity and oxidative damage after ethanol administration in human primary hepatocytes.

AIM: To observe the relationship between ethanol-induced oxidative damage in human primary cultured hepatocytes and cytochrome P450 2E1 (CYP2E1) activity, in order to address if inhibition of CYP2E1 could attenuate ethanol-induced cellular damage. METHODS: The dose-dependent (25-100 mmol/L) and time-dependent (0-24 h) exposures of primary human cultured hepatocytes to ethanol were carried out. CYP2E1 activity and protein expression were detected by spectrophotometer and Western blot analysis respectively. Hepatotoxicity was investigated by determination of lactate dehydrogenase (LDH) and aspartate transaminase (AST) level in hepatocyte culture supernatants, as well as the intracellular formation of malondialdehyde (MDA). RESULTS: A dose-and time-dependent response between ethanol exposure and CYP2E1 activity in human hepatocytes was demonstrated. Moreover, there was a time-dependent increase of CYP2E1 protein after 100 mmol/L ethanol exposure. Meanwhile, ethanol exposure of hepatocytes caused a time-dependent increase of cellular MDA level, LDH, and AST activities in supernatants. Furthermore, the inhibitor of CYP2E1, diallyl sulfide (DAS) could partly attenuate the increases of MDA, LDH, and AST in human hepatocytes. CONCLUSION: A positive relationship between ethanol-induced oxidative damage in human primary cultured hepatocytes and CYP2E1 activity was exhibited, and the inhibition of CYP2E1 could partly attenuate ethanol-induced oxidative damage.