Screening for lung cancer using thin-slice low-dose computed tomography in southwestern China: a population-based real-world study.

OBJECTIVES: Lung cancer is one of the most common malignant tumors threatening human life and health. At present, low-dose computed tomography (LDCT) screening for the high-risk population to achieve early diagnosis and treatment of lung cancer has become the first choice recommended by many authoritative international medical organizations. To further optimize the lung cancer screening method, we conducted a real-world study of LDCT lung cancer screening in a large sample of a healthy physical examination population, comparing differences in lung nodules and lung cancer detection between thin and thick-slice LDCT scanning. METHODS: A total of 29 296 subjects who underwent low-dose thick-slice CT scanning (5 mm thickness) from January 2015 to December 2015 and 28 058 subjects who underwent low-dose thin-slice CT scanning (1 mm thickness) from January 2018 to December 2018 in West China Hospital were included. The positive detection rate, detection rate of lung cancer, pathological stage of lung cancer, and mortality rate of lung cancer were analyzed and compared between the two groups. RESULTS: The positive rate of LDCT screening in the thin-slice scanning group was significantly higher than that in the thick-slice scanning group (20.1% vs. 14.4%, p < 0.001). In addition, the lung cancer detection rate in the thin-slice LDCT screening positive group was significantly higher than that in the thick-slice scanning group (78.0% vs. 52.9%, p < 0.001). CONCLUSIONS: The screening positive rate of low-dose thin-slice CT scanning is higher and more early-stage lung cancer (IA1 stage) can be detected in the screen-positive group.

LDCT screening results among eligible and ineligible screening candidates in preventive health check-ups population: a real world study in West China.

To compare the LDCT screening results between eligible and ineligible screening candidates in preventive health check-ups population. Using a real-world LDCT screening results among people who took yearly health check-up in health management center of West China Hospital between 2006 and 2017. Objects were classified according to the China National Lung Cancer Screening Guideline with Low-dose Computed Tomography (2018 version) eligibility criteria. Descriptive analysis were performed between eligible and ineligible screening candidates. The proportion of ineligible screening candidates was 64.13% (10,259), and among them there were 4005 (39.04%) subjects with positive screenings, 80 cases had a surgical lung biopsy. Pathology results from lung biopsy revealed 154 cancers (true-positive) and 26 benign results (false-positive), the surgical false-positive biopsy rate was 4.17%, and ineligible group (7.69%) was higher than eligible group (2.47%), P < 0.05. Further, in ineligible screening candidates, the proportion of current smokers was higher among males compared to females (53.85% vs. 4.88%, P < 0.05). Of the 69 lung cancer patients detected in ineligible screening candidates, lung adenocarcinoma accounts for a high proportion of lung cancers both in male (75.00%) and female (85.00%). The proportion of ineligible screening candidates and the surgical false-positive biopsy rate in ineligible candidates were both high in health check-ups population.

Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing.

Lung adenocarcinomas (LUAD) arise from precancerous lesions such as atypical adenomatous hyperplasia, which progress into adenocarcinoma in situ and minimally invasive adenocarcinoma, then finally into invasive adenocarcinoma. The cellular heterogeneity and molecular events underlying this stepwise progression remain unclear. In this study, we perform single-cell RNA sequencing of 268,471 cells collected from 25 patients in four histologic stages of LUAD and compare them to normal cell types. We detect a group of cells closely resembling alveolar type 2 cells (AT2) that emerged during atypical adenomatous hyperplasia and whose transcriptional profile began to diverge from that of AT2 cells as LUAD progressed, taking on feature characteristic of stem-like cells. We identify genes related to energy metabolism and ribosome synthesis that are upregulated in early stages of LUAD and may promote progression. MDK and TIMP1 could be potential biomarkers for understanding LUAD pathogenesis. Our work shed light on the underlying transcriptional signatures of distinct histologic stages of LUAD progression and our findings may facilitate early diagnosis.

Diagnosing sarcopenia and myosteatosis based on chest computed tomography images in healthy Chinese adults.

BACKGROUND: Measuring muscle mass and muscle quality based on chest Computed Tomography (CT) images would facilitate sarcopenia and myosteatosis research. We aimed (1) to measure muscle mass and myosteatosis based on chest CT images at the 12th thoracic vertebra level and compare the relevant indicators with whole-body skeletal muscle mass (BSM) and whole-body fat mass (BFM) measured by bioelectrical impedance analysis; and (2) to determine the cut-off points of these indicators for diagnosing sarcopenia or myosteatosis in healthy Chinese adults. METHODS: Chest CT images were analyzed using a segmentation software. Skeletal muscle area (SMA), skeletal muscle radiodensity (SMD), and intermuscular adiposity tissue (IMAT) were measured. Skeletal muscle indices (SMIs) and IMAT/SMA ratio were calculated. RESULTS: We included 569 participants. SMA, SMA/height2, and SMA/BMI were strongly and positively correlated with BSM (r = 0.90, 0.72, and 0.69, respectively, all p < 0.001); whereas SMA/weight was moderately and positively correlated with BSM (r = 0.38, p < 0.001). IMAT and IMAT/SMA were strongly and positively correlated with BFM (r = 0.67 and 0.58, respectively, both p < 0.001). SMD was moderately and negatively correlated with BFM (r = - 0.40, p < 0.001). We suggest SMA/height2 (< 25.75 cm2/m2 in men and < 20.16 cm2/m2 in women) for diagnosing sarcopenia and SMD (< 37.42 HU in men and < 33.17 HU in women) or IMAT (> 8.72 cm2 in men and > 4.58 cm2 in women) for diagnosing myosteatosis. CONCLUSIONS: Muscle mass indicators (SMA and SMIs) and muscle quality indicators (SMD, IMAT, and IMAT/SMA) measured by chest CT images are valuable for diagnosing sarcopenia and myosteatosis, respectively.

Functional Polymorphism in the NFE2L2 Gene Associated With Tuberculosis Susceptibility.

Background: Nuclear transcription factor erythroid 2 p45-related factor 2 (Nrf2), encoded by NFE2L2, functions as a key transcription factor and regulates expression of antioxidant genes. Our study aimed to investigate the association of single nucleotide polymorphisms of NFE2L2 with tuberculosis (TB) and latent tuberculosis infection (LTBI) and the underlying causal mechanisms. Methods: 1950 unrelated Chinese Han participants were included in our two independent study groups. Five tag polymorphisms were selected and genotyped. The functional effects of the rs13005431 polymorphism were confirmed by dual-luciferase reporter assays and mRNA level comparisons. Results: Rs13005431_C and rs2364723_G were associated with increased TB susceptibility (P = 0.010 and P = 0.041) after adjustment for confounding factors. rs6726395_A was associated with increased risk of active TB (P=0.035) in a comparison with the LTBI group. The frequency of haplotype rs1049751- rs13005431 AC was higher in the TB group (P =0.013), while frequency of haplotype AT was higher in the healthy control group (P =0.025). The luciferase activity of a plasmid with the rs13005431C-promoter was significantly lower than that of the rs13005431T-promoter. In addition, neutrophils with the CC/TC genotypes which were activated by GM-CSF showed a decreased level of NFE2L2 mRNA when compared with the rs13005431 TT genotype. Conclusions: Our study suggests that allele C of rs13005431 might increase the susceptibility to TB by down-regulating the transcriptional activity of NFE2L2.

Current lung cancer screening guidelines may miss high-risk population: a real-world study.

BACKGROUND: Despite much research published on lung cancer screening, China has had no large-scale study on the missed diagnosis of lung cancer in a health examination population. We therefore did a real-world study using the current lung cancer screening guidelines to a health examination population in China to determine the proportion of lung cancer cases that have been missed. METHODS: A real-world cohort study of screening, with the use of low-dose computed tomography, was conducted among people who took yearly health checkup in health management center of West China Hospital between 2006 and 2017. We respectively used current guidelines including lung cancer screening guidelines of the U.S. Preventive Services Task Force (USPSTF) and expert consensus on low dose spiral CT lung cancer screening in China. RESULTS: In a total of 15,996 participants with health examination who completed the baseline screening, 6779 (42.4%) subjects had at least one positive finding, and 142 (2.1%) cases of lung cancer were screened positive. The false positive rate was 97.9%. Of 142 lung cancer cases detected in our study, only 9.2% met the lung cancer screening guidelines proposed by the USPSTF, and 24.4% met that of China. The rates of missed diagnosis were as high as 90.8 and 75.6% respectively. In addition, we did an in-depth analysis by gender. We found that among male patients with lung cancer, the proportion of smokers was 75%, and the proportion of young people under 50 was 23.2%. Among female patients with lung cancer, the proportion of smokers was only 5.8%, and the proportion of young people under 50 was up to 33.3%. CONCLUSIONS: The rate of missed diagnosis was as high as 90.8% applying the current lung cancer screening guidelines to the health examination population in China. Further study to determine screening guidelines for targeted populations, is warranted.

Function of miR-200a in proliferation and apoptosis of non-small cell lung cancer cells.

Lung cancer is the most prevalent type of cancer worldwide and is the leading cause of cancer-associated cases of mortality in the USA and China. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases. microRNAs (miRs) serve multiple roles in the pathogenesis of lung cancer. The current study investigated the lower level of miR-200a in tumor tissues compared with healthy tissue. Overexpression of miR-200a inhibited NSCLC cell proliferation and promoted apoptosis. miR-200a was identified to target Rhophilin Rho GTPase binding protein 2 (RHPN2) and higher levels of RHPN2 were observed in tumor tissues compared with adjacent normal tissues. The current study proposes that miR-200a exhibits a tumor suppressive role in NSCLC and suggests that miR-200a could target RHPN2.

Association between Serum Uric Acid and Nonalcoholic Fatty Liver Disease in Nonobese Postmenopausal Women: A Cross-sectional Study.

This study aimed to determine the association between serum uric acid (sUA) and nonalcoholic fatty liver disease (NAFLD) in nonobese postmenopausal women. A total of 4323 female individuals over 18 years of age participated in this cross-sectional study. The subjects were divided into four groups according to menopause status and body mass index. sUA quartiles in this female population were categorized as follows: Q1 ≤ 230 mmol/L, Q2: 231-270 mmol/L, Q3: 271-310 mmol/L and Q4: ≥ 311 mmol/L. The presence or absence of NAFLD was assessed by abdominal ultrasonography. The prevalence of NAFLD was 38.8% in the general population, and the average age was 46.5 ± 11.3 years. Among nonobese and obese subjects, the prevalence of NAFLD was lower in nonmenopausal subjects than in postmenopausal subjects (nonobese: 20.74% vs 45.26%, respectively, P < 0.0001; obese: 70.51% vs 84.35%, respectively, P < 0.0001). After adjusting for age, current smoking status, current alcohol drinking status, diabetes, hypertension disease and triglyceride, the ORs (95% CIs) for NAFLD among individuals in Q2-Q4 were 1.518 (1.062-2.169), 1.431 (1.010-2.027) and 2.054 (1.442-2.927), respectively, P value for trend <0.0001. Higher sUA levels can be used as a predictive biomarker for NAFLD in nonobese postmenopausal women.

Association of heme oxygenase-1 single nucleotide polymorphisms with susceptibility to tuberculosis in Chinese Han population.

BACKGROUND: Tuberculosis (TB) is an infectious disease, caused by mycobacterium tuberculosis infection, which is associated with oxidative stress and the induction of host antioxidants to counteract this response. The heme oxygenase-1 (HO-1) single nucleotide polymorphisms have been reported to be associated with many critical diseases. Our purpose was to investigate the association of HO-1 single nucleotide polymorphisms with the susceptibility to tuberculosis in Chinese Han population. METHODS: A case-control study was performed on Chinese Han population, and a group of 638 TB patients was compared to 610 healthy controls. Three single nucleotide polymorphisms (SNPs) including rs2071746, rs5995098, and rs8140669 were genotyped using the MassARRAY platform. The genotype frequency was compared between TB patients and healthy controls. The association between the three genetic models of the three SNPs and TB risk was further investigated. RESULTS: The results showed that, in the case of additive model, there was significant difference of the genotype frequencies of SNP rs8140669 between the TB patients and control groups (P = .038). In the case of dominant model, the genotype frequencies of SNP rs8140669 may have difference between the two cohorts (P = .051), while the allele frequency and genotype distribution for other two SNPs showed no significant difference between the two groups (P > .05). CONCLUSION: HO-1 polymorphism was associated with TB susceptibility in Chinese Han population.

Is anti-tuberculosis drug-induced hepatotoxicity due to a change in pharmacokinetics caused by alterations in antioxidant gene expression and polymorphisms in the NFE2L2 gene?
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OBJECTIVE: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a major adverse reaction of tuberculosis (TB) therapy. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcription factor encoded by the NFE2L2 gene. Nrf2 regulates the expression of antioxidant genes which affect the kinetics of drugs and other xenobiotics, and plays a key role in the regulation of cellular redox status. We investigated the potential association of NFE2L2 single-nucleotide polymorphisms (SNPs) with ATDH. MATERIALS AND METHODS: 280 newly diagnosed TB patients were recruited in this prospective study and were followed up for 3 months after initiating anti-TB therapy. Five tagSNPs (rs2001350, rs6726395, rs1962142, rs13001694, and rs2364723) were selected based on a Han Chinese panel in the International HapMap database with a minor allele frequency < 5% and an r2 threshold of 0.8. RESULTS: Of the 280 subjects recruited in this research, there were 24 patients diagnosed with ATDH, 223 subjects without ATDH, and 33 individuals excluded during the follow-up. After adjusting for confounding factors including sex, age, smoking status, and body mass index, there was no statistically significant difference. CONCLUSION: Our results suggest that NFE2L2 variants may not contribute to the pathogenesis of ATDH in a Chinese population. Further large sample studies and various population studies are needed to fully explore the association between ATDH and NFE2L2 polymorphism.

Association of UGT2B7 polymorphisms with risk of induced liver injury by anti-tuberculosis drugs in Chinese Han.

Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform. The associations between tag-SNPs and ATLI risk were analyzed by logistic regression analysis adjusting for confounding factors. In this prospective study, 33 patients were lost to follow-up, and 24 patients were diagnosed with ATLI and considered as the case group. The remaining 223 subjects without ATLI were considered as the control group. No significant association was observed in allele and genotype frequencies of UGT2B7 between the two groups. This study is the first attempt to investigate the association of genetic polymorphisms of UGT2B7 with ATLI in Chinese Han. There is no significant association between UGT2B7 polymorphisms and ATLI in Chinese Han.

Rifampicin-induced antineutrophil cytoplasmic antibody-positive vasculitis: a case report and review of the literature.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a pauci-immune necrotizing vasculitis that involves small vessels. Herein, we report an extremely rare case of rifampicin (RFP)-induced AAV. A 42-yearold female was transferred to the West China Hospital due to cough with phlegm for 3 months, fever for 1 month, and fatigue for 2 weeks. The patient was diagnosed with pulmonary tuberculosis (TB) and received anti-TB treatment with isoniazid, RFP, ethambutol, and pyrazinamide (PZA) at her local hospital. After 5 days of anti-TB treatment, her creatinine level rose to 420.2 µmol/L from a normal level prior to anti-TB treatment. Serum proteinase 3 (PR3)-ANCA was positive. After discontinuing the anti-TB drugs and administering protective renal treatment, her renal function improved, whereas PR3-ANCA remained positive. With RFP rechallenge after transfer to our hospital, the patient developed oliguria. Her urine volume increased gradually after RFP was discontinued 3 days later. Therefore, RFPinduced AAV was suspected. Eventually, the patient received prednisone and anti-TB therapy, including isoniazid, ethambutol, PZA, and moxifloxacin. After 2 months, PZA was discontinued. During 6 months of normal, and PR3-ANCA became negative at 4 months. This outcome is characteristic of RFP-induced AAV.

Genetic Polymorphisms of Glutathione S-Transferase P1 (GSTP1) and the Incidence of Anti-Tuberculosis Drug-Induced Hepatotoxicity.

BACKGROUND: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most common adverse effects associated with tuberculosis (TB) therapy. Animal studies have demonstrated important roles of glutathione S-transferases in the prevention of chemical-induced hepatotoxicity. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of glutathione S-transferase P1 (GSTP1) and ATDH in TB patients. METHODS: We used two independent samples for this genetic association study. In the initial prospective study, 322 newly diagnosed TB patients were followed up for three months after initiating anti-TB therapy. In an independent retrospective study, 115 ATDH patients and 116 patients without ATDH were selected to verify the results of the prospective study. Tag-SNPs of GSTP1 were genotyped either with the MassARRAY platform or the improved multiple ligase detection reaction (iMLDR) method. The associations between SNPs and ATDH were analyzed by logistic regression analysis adjusting for confounding factors. RESULTS: Of the 322 patients recruited in the prospective cohort, 35 were excluded during the 3 months of follow-up, and 30 were diagnosed with ATDH and were considered as the ATDH group. The remaining 257 subjects without ATDH were considered as the non-ATDH group. After correction for potential confounding factors, significant differences were found for rs1695 (A>G) under an allelic model (OR = 3.876, 95%CI: 1.258011.905; P = 0.018). In the retrospective study, rs1695 allele A also had a higher risk of ATDH (OR = 2.10, 95%CI: 1.17-3.76; P = 0.012). We only found rs4147581AA genotype under a dominant model was related to ATDH in the prospective study (OR = 2.578, 95%CI: 1.076-6.173; P = 0.034). CONCLUSIONS: This is the first study to suggest that GSTP1 genotyping can be an important tool for identifying patients who are susceptible to ATDH. This result should be verified in independent large sample studies and also in other ethnic populations.

Analysis of silent information regulator 1 (SIRT1) gene polymorphisms in antituberculosis- drug-induced hepatotoxicity in a prospective cohort study.

OBJECTIVE: Antituberculosisdrug-induced hepatotoxicity (ATDH) is a common and sometimes serious side effect related to tuberculosis (TB) treatment. A number of risk factors and host genetics contribute to the development of ATDH. However, genetic factors of ATDH remain to be identified. Silent Information Regulator 1 (SIRT1), an essential metabolism gene, was proved to be involved in ATDH in mice. The aim of this investigation was to study the association between ATDH and tag-single nucleotide polymorphisms (tag-SNPs) of the SIRT1 gene in a prospective cohort study in patients with TB. METHODS: 280 newly diagnosed TB patients were recruited in this study before starting first line anti-TB treatment and were followed up for 3 months after initiating anti-TB therapy. The tag-SNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese Beijing. Genotyping was performed by polymerase chain reaction (PCR) and the Sequenom MassARRAY iPLEX platform. RESULTS: 24 (9.8%) of the 245 patients included in the final analysis developed hepatotoxicity during the following up period. No significant differences in the allele, genotype, or haplotype frequency distributions of the tag- SNPs (rs7069102, rs2273773, rs4746720) of the SIRT1 gene were identified between the ATDH and non-ATDH groups (all p > 0.05). CONCLUSIONS: The SIRT1 gene may not contribute to the risk for developing hepatotoxicity during anti-TB treatment in the Han Chinese population.

Association of CYBB polymorphisms with tuberculosis susceptibility in the Chinese Han population.

OBJECTIVE: Reactive oxygen species (ROS) play a major role in the nonspecific innate immune response to invading microorganisms, such as Mycobacterium tuberculosis (MTB). Gp91phox, encoded by CYBB, serves as a key functional subunit of the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex, which is pivotal to ROS generation. Therefore, the aim of the study was to investigate the association of CYBB polymorphisms with tuberculosis (TB) susceptibility. METHODS: In total, 636 TB patients and 608 healthy, age and gender matched controls were enrolled in this study. All subjects were unrelated ethnic Han Chinese. Two tagSNPs were selected from the HapMap database and genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry. RESULTS: After adjusting for confounders including age, gender and smoking, rs5917471 allele T showed significant association with decreased risk of TB (OR 0.745, 95% CI 0.556-0.999) and pulmonary TB (OR 0.618, 95% CI 0.410-0.931). However, no difference in allelic distribution was observed for the rs6610650 G/A polymorphism with respect to TB or different clinical types of TB. Further stratified analyses demonstrated the protective effect of allele T of rs5917471 was stronger among males (OR 0.500, 95% CI 0.295-0.846), smokers (OR 0.462, 95% CI 0.239-0.896), and male smokers (OR 0.372, 95% CI 0.182-0.761); the individuals carrying the A allele of rs6610650 exhibited an decreased risk of TB among males, smokers and male smokers, with OR (95% CI) of 0.535 (0.290-0.984), 0.442 (0.198-0.988), and 0.350 (0.145-0.845), respectively. There were no statistically significant differences in haplotype distribution between TB and control groups. Smoking and rs5917471 formed the best gene-environment interaction model with the testing balanced accuracy of 53.29% and cross-validation consistency of 9/10. CONCLUSIONS: This is the first study of the association of CYBB polymorphisms with TB. Our findings suggest that the CYBB polymorphisms are significantly correlated with reduced risk of TB, especially among male smokers. Further studies are needed to verify this association.