[Association between chronic lung diseases and the risk of lung cancer in UK Biobank: observational and Mendelian randomization analyses].

Objective: To investigate the association between chronic lung diseases and the risk of lung cancer. Methods: Using UK Biobank (UKB) survey data, 472 397 participants who had not previously been diagnosed with cancer and whose self-reported sex was consistent with their genetic sex were studied. Information on the prevalence of previous chronic lung diseases, general demographic characteristics and the prevalence of lung cancer was collected using baseline questionnaires and national health system data. The multivariate Cox proportional risk regression model was used to analyze the association between four previous chronic lung diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and interstitial pulmonary disease) and the risk of lung cancer. A total of 458 526 participants with genotype data in the observational study were selected as research objects, and the closely related and independent genetic loci with four chronic lung diseases were selected as instrumental variables, and the association between four chronic lung diseases and the risk of lung cancer was analyzed by Mendelian randomization (MR). The dose-response relationship between genetic risk score and the risk of lung cancer in different chronic lung diseases was evaluated using a restricted cubic spline function. Results: The age [M (Q1, Q3)] of the subjects was 57 (50, 63) years old, and there were 3 516 new cases of lung cancer (0.74%) during follow-up. The multivariate Cox proportional hazard regression model analysis showed that previous chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis were associated with the risk of lung cancer, about 1.61 (1.49-1.75) and 2.61 (1.24-5.49), respectively. MR Studies showed that genetically predicted chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis were associated with the risk of lung cancer, with HR (95%CI) of 1.10 (1.03-1.19) and 1.04 (1.01-1.08), respectively. The results of restricted cubic spline function analysis showed that the risk of lung cancer increased linearly with the increase of genetic risk scores for chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (P<0.05). Neither observational studies nor Mendelian randomization analysis found an association between previous asthma or interstitial lung disease and the risk of lung cancer (both P values>0.05). Conclusion: Chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis are potential risk factors for lung cancer.

[Mediation effect of smoking and healthy diet score on the association between educational level and the risk of lung cancer incidence].

Objective: To evaluate the possible mediation effect of smoking and healthy diet score on the association between educational level and the risk of lung cancer incidence. Methods: After excluding individuals with missing educational levels and cancer information at baseline, 446 772 participants in the UK Biobank (UKB) prospective cohort study were included. Cox regression models were used to investigate the associations of educational level and smoking and healthy diet score with the incidence of lung cancer. Mediating effect analysis was conducted to analyze the mediating effect of smoking and healthy diet score on the correlation between educational level and lung cancer. Results: During a median follow-up of 7.13 years, 1 994 new- onset lung cancer cases were observed. Per 1 standard deviation (5 years) increase in educational level was associated with a 12% lower risk of lung cancer (HR=0.88, 95%CI: 0.84-0.92). The corresponding level 1-5 in the International Standard Classification for Education (ISCED) were mapped to UKB self-report highest qualification to estimate the educational level. A higher rank means a higher educational level. Compared with level ISCED-1, the HR(95%CI) of level ISCED-2, ISCED-3, ISCED-4 and ISCED-5 were respectively 0.83 (0.72-0.94), 0.67 (0.53-0.85), 0.76 (0.65-0.89) and 0.72 (0.64-0.80) for lung cancer. Education years were negatively correlated with smoking, with ß coefficients (95%CI) being -0.079 (-0.081- -0.077), but positively correlated with healthy diet score (ß=0.042, 95%CI: 0.039-0.045). Analysis of mediating effect indicated that the association of educational level with lung cancer risk was mediated by smoking and healthy diet score, the proportions of mediating effect were 38.952% (95%CI: 31.802%-51.659%) and 1.784% (95%CI: 0.405%-3.713%), respectively. Conclusion: Smoking and healthy diet score might mediate the effect of educational level on the incidence of lung cancer, indicating that improving the level of education can reduce the risk of lung cancer by changing lifestyles such as smoking and diet.

Dracorhodin perchlorate inhibits biofilm formation and virulence factors of Candida albicans.

OBJECTIVE: The aim of this study was to investigate the antifungal activity of dracorhodin perchlorate (DP) against planktonic growth and virulence factors of Candida albicans. METHODS: Microdilution method based on CLSI-M27-A3 was used to test the antifungal susceptibility of DP. The activity of DP against biofilm formation and development of C. albicans was quantified by XTT assay and visualized by confocal laser scanning microscope. The effect of DP on the morphological transition of C. albicans induced by four kinds of hyphal-inducing media at 37°C for 4hours was observed under microscope. The rescue experiment by adding exogenous cAMP analog was performed to investigate the involvement of cAMP in the yeast to hyphal transition and biofilm formation of C. albicans. Egg yolk emulsion agar was used to determine the inhibition of DP on the phospholipase production of C. albicans. Human JEG-3 and HUVEC cell lines, as well as the nematode Caenorhabditis elegans was used to assess the toxicity of DP. RESULTS: The minimum inhibitory concentration (MIC) of DP is 64µM while the antifungal activity was fungistatic. As low as a concentration at 16µM, DP could inhibit the yeast to hyphal transition in liquid RPMI-1640, Spider, GlcNAc and 10% FBS-containing Sabouroud Dextrose medium, as well as on the solid spider agar. Exogenous cAMP analog could rescue part of biofilm viability of C. albicans. DP could inhibit the production of phospholipase. The toxicity of DP against human cells and C. elegans is low. CONCLUSION: DP could inhibit the planktonic growth and virulent factors in multiple stages, such as yeast to hyphal transition, adhesion, biofilm formation and production of phospholipase of C. albicans.

Clinicopathological and prognostic analysis of follicular thyroid carcinoma in a single institute over a 15-year period.

BACKGROUND: This study was to evaluate the clinicopathological and prognostic features of follicular thyroid carcinoma (FTC) in our institute over a 15-year period. METHODS: The clinical features, management and outcome of 134 consecutive patients were analyzed according to the time of diagnosis: Group I (1997-2001), Group II (2002-2006), and Group III (2007-2011). RESULTS: As time advanced, the ratio of FTC to papillary thyroid carcinoma decreased from 8.7% in group I to 4.3% in group III (p = 0.000). The percentage of patients undergoing total thyroidectomy seemed to be more commonly used in the later periods - from 10.5% in group I to 21.8% in group II and 18.9% in group III. The median diameter of tumors in group I was 4.2 cm and it showed a sharp decrease to 2.8 cm in group II and 2.9 cm in group III respectively. There was a trend towards a higher stage in patients from Group I vs. patients from Groups II and III (stage IV, 15.8% vs. 2.2% and 4.3%, p = 0.072). The outcome was improved in terms of disease-free survival (DFS). The 3-year DFS rate improved from 77.8% in group I to 93.7% in group II and 100% in group III (p = 0.008). CONCLUSIONS: The clinical features, management and outcome of FTC patients changed over 15-year period. Patients diagnosed after 2001 had a better prognosis. This improvement was probably related to earlier diagnosis with smaller tumor size and presentation at earlier tumor stage.

CD4+ T-cell loss and delayed expression of modulators of immune responses at mucosal sites of vaccinated macaques following SIV(mac251) infection.

Systemic immunization of macaques with a combination of DNA-poxvirus-based vaccines confers protection from high level of both systemic and mucosal viral replication following rectal exposure to the pathogenic SIV(mac251). Here we investigated early post-infection events in rectal and vaginal tissues, and found that the loss of CCR5+CD4+ T cells was equivalent in vaccinated and control macaques, despite a three logs reduction at mucosal sites of simian immunodeficiency virus (SIV) RNA in the vaccinated group. Even though a normal CD4+ T cell number is not reconstituted at mucosal sites in either group, vaccination appeared to confer a better preservation of the CD4+ CCR5+ T cells that replenish these sites. Analysis of rectal tissues RNA following challenge exposure demonstrated a decreased expression in vaccinated macaques of transforming growth factor-beta, cytotoxic T lymphocyte antigen-4, FoxP3, and indoleamine 2,3-dioxygenase, an immune suppressive enzyme expressed by dendritic cells that converts tryptophan to kynurenine and limits T-cell responses. Accordingly, the ratio of kynurenine and tryptophan in the plasma was significantly reduced in the vaccinated animals respect to the controls. Thus, preexisting adaptive immune responses induced by these vaccine modalities, although they do not protect from CD4+ T-cell depletion, nevertheless, they contain SIV(mac251) replication and delay expression of markers of T-cell activation and/or suppression at mucosal sites.

Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy.

Hepatitis B virus (HBV)-associated nephritis has been reported worldwide. Immune complex deposition has been accepted as its pathogenesis, although the association between the presence of local HBV DNA and viral antigen and the development of nephritis remains controversial. To understand better the roles played by HBV protein expression in the kidney, the global gene expression profile was studied in the kidney tissue of a lineage of HBV transgenic mouse (#59). The mice expressed HBsAg in serum, and HBsAg and HBcAg in liver and kidney, but without virus replication. Full-length HBV genome (adr subtype, C genotype) isolated from a chronic HBV carrier was used to establish the transgenic mice #59. Similarly manipulated mice that did not express HBV viral antigens served as controls. Southern blotting, hybridization with HBV probe, and immuno-histochemical staining were used to study HBV gene expression. mRNA extracted from the kidney tissue was analyzed using Affymetrix microarrays. HBsAg and HBcAg were located mainly in the cytoplasm of tubular epithelium. Altogether 520 genes were "up-regulated" more than twofold and 76 genes "down-regulated" more than twofold in the kidney. The complement activation, blood coagulation, and acute-phase response genes were markedly "up-regulated". Compared to the controls, the level of serum C3 protein was decreased in #59 mice, while the level of C3 protein from kidney extract was increased. Results indicate that expression of HBsAg and HBcAg in tubular epithelial cells of the kidney per se can up-regulate complement-mediated inflammatory gene pathways, in addition to immune complex formation.

Exploiting new potential targets for anti-hepatitis B virus drugs.

Based on the recent studies of HBV strains with different replication efficiency, several new potential targets for anti-HBV replication have been presented. These include the viral and cellular regulatory factors associated with HBV replication and the process for encapsidation of viral genome and budding into endoplasmic reticulum (ER). A putative regulatory domain has been reported at the carboxyl-end of reverse transcriptase (RT) and when serine is substituted for proline at residue 652 of RT, replication efficiency of HBV is decreased. Substitution of proline for threonine at the 2798 nucleotide of the terminal protein (TP) gene, renders the mutant completely replication deficient. Expression of TP blocks the interferon (IFN) pathway and inhibits the responsive state of cells to interferons ( IFN) alpha and gamma. Interference of HBV capsid assembly drastically affects the encapsidation of viral genome, a crucial process for reverse transcription and viral DNA synthesis. Small molecules (bis-ANS) have been reported to act as a "wedge" to misdirect the polymerization of capsid, resulting in inhibition of virus replication. Another new group of compounds (HAP) has been shown to inhibit virus replication and also inhibit the assembly of viral capsid (core particle). Finally the capsids containing HBV genome are enveloped by budding into endoplasmic reticulum and release from virus infected cells, and this morphogenesis and secretion of HBV is dependent on glucosidases in the ER of host cells. Competitive inhibition of these glucosidases has been suggested as strategy against HBV replication.

[Alterations of glial fibrillary acidic protein in rat brain after gamma knife irradiation].

OBJECTIVE: To study glial fibrillary acidic protein (GFAP) immunoreactivity in different time and water content of the rat brain treated with gamma knife radiotherapy and to understand the alteration course of the brain lesion after a single high dose radiosurgical treatment. METHODS: In the brains of the normal rats were irradiated by gamma knife with 160 Gy-high dose. The irradiated rats were then killed on the 1st day, 7th day, 14th day, and 28th day after radiotherapy, respectively. The positive cells of GFAP in brain tissue were detected by immunostaining; the water content of the brain tissue was measured by microgravimetry. The histological study of the irradiated brain tissue was performed with H.E. and examined under light microscope. RESULTS: The numbers of GFAP-positive astrocytes began to increase on the 1st day after gamma knife irradiation. It was enlarged markedly in the number and size of GFAP-stained astrocytes over the irradiated areas. Up to the 28th day, circumscribed necrosis foci (4 mm in diameter) was seen in the central area of the target. In the brain tissue around the necrosis, GFAP-positive astrocytes significantly increased (P < 0.01, compared with the control group). The swelling of cells in irradiated region was observed on the 1st day; after irradiation endothelial cells degenerated and red blood cells escaped from blood vessel on the 7th day; leakage of Evans blue dye was observed in the target region on the 14th day. There was a significant decrease of specific gravity in the irradiated brain tissue the 14th and 28th day after irradiation. CONCLUSION: The results suggest that GFAP can be used as a marker for the radiation-induced brain injury. The brain edema and disruption of brain-blood barrier can be occurred during the acute stage after irradiation.

[Therapeutic effect of gamma-ray stereotactic radiotherapy on brain metastases].

OBJECTIVE: To evaluate the therapeutic effects of gamma-ray stereotactic radiotherapy (SRT) plus whole brain irradiation and radiotherapy alone in brain metastases. METHODS: Forty-three patients with brain metastases were treated by SRT plus whole brain irradiation and 50 patients were treated by routine radiotherapy. SRT was given with the dosage of 15-27 Gy, and whole brain irradiation was given with the dosage of 30-40 Gy. RESULTS: One-year survival rate, median survival period, and tumor local control rate in SRT plus whole brain irradiation group were higher or longer than those in the routine radiotherapy group (P < 0.01). Mortality in SRT plus whole brain irradiation group was lower than that in the routine radiotherapy group (P < 0.05). CONCLUSION: The therapeutic effect of SRT plus whole brain irradiation on brain metastasis of cancer is superior to the routine radiotherapy.

[Early operation with anterior screw-plate system for cervical spine fracture and dislocation].

OBJECTIVE: To evaluate the function of the cervical spine anterior screw-plate system in the early operation of cervical spine fracture and dislocation. METHODS: One hundred and fifteen patients with fracture and dislocation of lower cervical spine treated by cervical anterior decompression, reduction, iliac crest autograft, fixed with cervical anterior locking plate (AO, spine-tech, Orion). RESULTS: All the cases were free from complication except one patient was complicated with infection of the surgical wound and another one with a transient dysfunction of recurrent laryngeal nerve. Symptom of patients were significantly improved in postoperation and no hardware failure. CONCLUSIONS: Early anterior decompression operation for cervical fracture and dislocation can achieve satisfactory clinical outcomes, anterior cervical vertebral screw-plate system is safety, simplicity, rigidity and can provide good conditions for early anterior cervical spine operation.

[Analysis of complication in the spinal pedicle screw internal fixation].

In 1990-1998, five hundred and twenty patients treated with spinal pedicle screw internal fixation were analyzed. The main operative complication was screw misplacement(7.1%), and others such as screw bend and extra-long screw were less seen. The postoperative complications included screw breakage (13.3%) and backache(14.2%). Recently, by making use of RF screw system and X-ray monitor, the complications were significantly decreased.

Human acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) gene organization and evidence that the 4.3-kilobase ACAT-1 mRNA is produced from two different chromosomes.

Acyl-CoA:cholesterol acyltransferase (ACAT) plays important roles in cellular cholesterol homeostasis. Four human ACAT-1 mRNAs (7.0, 4.3, 3.6, and 2.8 kilobases (kb)) share the same short 5'-untranslated region (exon 1) and coding sequence (exons 2-15). The 4.3-kb mRNA contains an additional 5'-untranslated region (1289 nucleotides in length; exons Xa and Xb) immediately upstream from the exon 1 sequence. One ACAT-1 genomic DNA insert covers exons 1-16 and a promoter (the P1 promoter). A separate insert covers exon Xa (1277 base pairs) and a different promoter (the P7 promoter). Gene mapping shows that exons 1-16 and the P1 promoter sequences are located in chromosome 1, while exon Xa and the P7 promoter sequence are located in chromosome 7. RNase protection assays demonstrate three different protected fragments, corresponding to the 4.3-kb mRNA and the two other mRNAs transcribed from the two promoters. These results are consistent with the interpretation that the 4.3-kb mRNA is produced from two different chromosomes, by a novel RNA recombination mechanism involving trans-splicing of two discontinuous precursor RNAs.

Recombinant vaccinia virus expressing Pre-S/S protein of duck hepatitis B virus and its preliminary use for treatment of persistent infection.

The envelope (Pre-S/S) gene of duck hepatitis B virus (DHBV) was amplified by polymerase chain reaction (PCR) and cloned into plasmid pGJP5, under the control of vaccinia virus promoter P(7.5). By recombination in cell culture, and screened in human TK- 143 cells in the presence of 5-bromouracil deoxyriboside (5-BUdR), a recombinant vaccinia virus, bearing the envelope gene of DHBV (pGDHBV-5) which could replicate in cell cultures was constructed. DHBV surface antigen (DHBsAg) was detected in pGDHBV-5-infected cell lysate by dot enzyme immunoassay (EIA). After multiple-site intradermal injections of pGDHBV-5, DHBsAg could be detected in the serum of immunized adult ducks. This indicated that the recombinant virus replicated and expresed DHBsAg in ducks. The recombinant virus was used as a therapeutic vaccine to immunize persistently DHBV-infected ducks. After immunization, a transient significant decrease of serum DHBsAg was observed.

[Rational surgical approaches to the treatment of small primary liver cancer, and the prevention of postoperative recurrence].

From Sep. 1985 to Dec. 1990, surgical treatment was performed in 27 patients with small primary liver cancer (SPLC, < or = 5cm in diameter). Of them, segmentectomy was done in 23 cases and radical local resection in 4 cases with recurrence rate of 66.77% (18/27). Non recurrent lesions were located in the incisal margin. In this group re-resection rate was 55.6% (10/18). (1) Early detection and treatment of recurrent lesions remain a mainstay of prolonging survival. (2) Serum Alpha-fetoprotein (AFP), ultrasonography and X-ray chest film were basic follow-up methods for subclinical recurrence of SPLC. For re-operation cases, digital subtract angiography (DSA) are useful in identifying subclinical lesions. (3) For recurrent liver cancer local hepatectomy was a reasonable approach. (4) For SPLC, radical segmentectomy or radical local resection with a safe margin of 1 to 2cm was the authors' choice.

[Studies on residual antimalarial activity of tripynadine in mice and monkeys].

This paper reports the experiments in which tripynadine free base at a dose 4.5 times that of ED50 was given to mice by intragastric administration. On the 20th day following the administration the mice were inoculated with 1 x 10(7) RBC infected with Plasmodium berghei ANKA strain. The infection rate was zero, implying that all mice had acquired protection. Although the residual activity time of tripynadine phosphate was longer than that of tripynadine free base or piperaquine phosphate, but tripynadine phosphate caused vomiting in monkeys during the medication. The residual antimalarial activity of tripynadine hydroxynaphthoate was less than that of tripynadine phosphate or tripynadine free base. A total dose of 200 mg/kg of tripynadine free base ensured residual antimalarial activity against P. cynomolgi bastianellii for 20 days. However, the residual activity decreased evidently when the total dose was reduced to 100 mg/kg. In short, it seems that the residual antimalarial activity of tripynadine free base is slightly less than that of piperaquine in monkeys.