Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

BACKGROUND: Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS: Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS: A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
Humans ; Non-alcoholic Fatty Liver Disease/diagnosis* ; Keratin-18 ; Biomarkers ; Biopsy ; Hepatocytes/pathology* ; Apoptosis ; Liver/pathology*

Objective: To investigate the clinicopathological characteristics of occupational lung diseases, to reduce the missed diagnoses and misdiagnoses of the diseases and to help standardize the diagnosis and treatment of these patients. Methods: A total of 4 813 lung biopsy specimens (including 1 935 consultation cases) collected at the Department of Pathology, Nanjing Drum Tower Hospital, Nanjing, China from January 1st, 2017 to December 31th, 2019 were retrospectively analyzed. Among them, 126 cases of occupational lung diseases were confirmed with clinical-radiological-pathological diagnosis. Special staining, PCR and scanning electron microscopy were also used to rule out the major differential diagnoses. Results: The 126 patients with occupational lung diseases included 102 males and 24 females. All of them had a history of exposure to occupational risk factor(s). Morphologically, 68.3% (86/126) of the cases mainly showed pulmonary fibrotic nodules, dust plaque formation or carbon end deposition in pulmonary parenchyma. 16.7% (21/126) of the cases mainly showed welding smoke particle deposition in the alveolar cavity and lung interstitium while 15.1% (19/126) of the cases showed granulomas with fibrous tissue hyperplasia, alveolar protein deposition or giant cell interstitial pneumonia. The qualitative and semi-quantitative analyses of residual dust components in the lung under scanning electron microscope were helpful for the diagnosis of welder's pneumoconiosis and hard metal lung disease. Conclusions: The morphological characteristics of lung biopsy tissue are important reference basis for the clinicopathological diagnosis and differential diagnosis of occupational lung diseases. Recognizing the characteristic morphology and proper use of auxiliary examination are the key to an accurate diagnosis of occupational lung diseases on biopsy specimens.
Male ; Female ; Humans ; Retrospective Studies ; Pneumoconiosis/pathology* ; Lung/pathology* ; Dust ; Pneumonia, Viral/pathology* ; Biopsy

Hearing Loss, High-Frequency ; Hearing Loss, Noise-Induced/epidemiology* ; Humans ; Manufacturing Industry ; Noise, Occupational/adverse effects* ; Occupational Exposure

Hearing ; Hearing Loss, Noise-Induced/etiology* ; Humans ; Male ; Manufacturing Industry ; Noise, Occupational/adverse effects* ; Occupational Exposure/adverse effects* ; Surveys and Questionnaires

Humans ; Interior Design and Furnishings ; Manufacturing Industry ; Noise, Occupational ; Occupational Exposure ; Textile Industry

Objective: To analyze the burden of disease (BOD) on diabetes attributable to high BMI in China from 1990 to 2016. Methods: Data based on population of the 2016 Global Burden of Disease Study for China were used to analyze the attributable fractions (PAF) of BOD for diabetes attributable to high BMI. Measurements for attributable BOD of diabetes included disability adjusted life years (DALY), years of lost life (YLL), years living with disability (YLD), death number and mortality rate. The average world population from 2010 to 2035 was used as a reference. Results: In 2016, death number of diabetes attributable to high BMI was 40 310, which was significantly higher than that in 1990 (15 008). Age-standardized death rate of diabetes attributable to high BMI increased from 2.01/100 000 in 1990 to 2.60/100 000 in 2016, which showed a more significant increasing trend in both males and people aged 15-49 years. DALYs of diabetes attributable to high BMI increased from 1.09 million person years to 3.30 million person years. YLL and YLD also showed increasing trends. The highest increasing rate of YLD was in people aged 15-49 years. High BMI was responsible for 26.01% of the diabetes deaths in 2016 in China, an increase of 39.39% compared with that in 1990 (18.66%). Most provinces in China experienced a sharp increase of DALY of diabetes attributable to high BMI from 1990 to 2016. Inner Mongolia, Xinjiang, Zhejiang, Macao SAR, Sichuan and Qinghai had the most significant increase tendency in terms of DALY rate during this period. Conclusions: There was a rapid increase of the deaths and mortality rate of diabetes attributable to high BMI, causing a heavy disease burden, in China from 1990 to 2016. The BOD varied in both different age and gender groups. More attention should be paid to males and people aged 15-49 years in the prevention and control programs of diabetes.
Adolescent ; Adult ; Body Mass Index ; China/epidemiology* ; Cost of Illness ; Diabetes Mellitus/ethnology* ; Disabled Persons ; Humans ; Macau ; Male ; Middle Aged ; Quality-Adjusted Life Years ; Sickness Impact Profile ; Young Adult

Objective: On whole-genome scale, we tried to explore the correlation between obesity-related traits and DNA methylation sites, based on discordant monozygotic twin pairs. Methods: A total of 90 pairs of 6-17 year-old twins were recruited in Chaoyang district, Yanqing district and Fangshan district in Beijing in 2016. Information on twins was gathered through a self-designed questionnaire and results: from physical examination, including height, weight and waist circumference of the subjects under study. DNA methylation detection was chosen on the Illumina Human Methylation EPIC BeadChip. R 3.3.1 language was used to read the DNA methylation signal under quality control on samples and probes. Ebayes function of empirical Bayes paired moderated t-test was used to identify the differential methylated CpG sites (DMCs). VarFit function of empirical Bayes paired moderated Levene test was used to identify the differentially variables CpG sits (DVCs) in obese and normal groups. Results According to the obesity discordance criteria, we collected 23 pairs of twins (age range 7 to 16 years), including 12 male pairs. A total of 817 471 qualified CpG loci were included in the genome-wide correlation analysis. According to the significance level of FDR set as <0.05, no positive sites would meet this standard. When DMC CpG site cg05684382, with the smallest P value (1.26E-06) as on chromosome 12, the DVC CpG site cg26188191 with the smallest P value (6.44E-06) appeared in CMIP gene on chromosome 16. Conclusions: In this study, we analyzed the genome-wide DNA methylation and its correlation with obesity traits. After multiple testing corrections, no positive sites were found to have associated with obesity. However, results from the correlation analysis demonstrated sites cg05684382 (chr: 12) and cg26188191 (chr: 16) might have played a role in the development of obesity. This study provides a methodologic reference for the studies on discordance twins related problems.
Adolescent ; Bayes Theorem ; Beijing ; Body Weight ; Child ; DNA Methylation/genetics* ; Epigenesis, Genetic ; Female ; Genome-Wide Association Study ; Humans ; Male ; Obesity/genetics* ; Twins, Monozygotic ; Waist Circumference

Objective: To investigate the changes of proportion on both consistent condom use and syphilis infection among low-fee female sex workers aged 35 and above (LFSW), in order to provide evidence for targeted intervention strategies. Methods: A total of six cities-Liuzhou city and Pingnan couty of Guigang city of Guangxi Zhuang Autonomous Region, Jinghong city of Xishuangbanna Dai autonomous prefecture and Dali city of Dali Bai autonomous prefecture of Yunnan province, Zhangjiajie city and Jianghua Yao autonomous county of Yongzhou city Hunan province were involved in this study, with 60 eligible participants needed in each city, estimated through a pre-study. The first cross-sectional survey was completed from October 2012 to January 2013. Face-to-face questionnaire interview was carried out to collect information on socio-demography, work-related information and condom use situation. Blood was collected for syphilis testing. The second cross-sectional survey was carried out from June to September, 2015 under the same procedure. Results: A total of 371 and 403 eligible participants were included in the first and second survey, respectively. When comparing the two surveys, we noticed that the average age showed a slight change, from 42.4 years to 43.8 years old (t=3.537, P<0.001) and the average price for every commercial sex exchange increased from 36.8 RMB to 49.5 RMB (t=11.961, P<0.001). In the first survey, 46.9% (174/371) of the participants had more than two years of experience working as LFSW, compared to 61.3% (247/403) in the second survey (χ(2)=16.125, P<0.001). Also, 46.9% (174/371) of the participants consistently used condoms with clients in the past month in the first survey versus 64.3% (259/403) (χ(2)=23.641, P<0.001) in the second one. Rates of syphilis infection were found from 15.9% (59/371) in the first survey reduced to 7.2% (29/403) in the second survey (χ(2)=14.533, P<0.001). Conclusion: Compared with the first survey, the proportion of consistent condoms use showed an increase. Although the proportion of syphilis infection decreased in the second survey, the scope did not meet the criteria on syphilis, set by the government. Targeted intervention strategies on condom promotion and syphilis control should be implemented consistently in this population.
Adult ; China/epidemiology* ; Condoms/trends* ; Cross-Sectional Studies ; Female ; Humans ; Prevalence ; Risk Factors ; Safe Sex ; Sex Work ; Sex Workers ; Sexually Transmitted Diseases/epidemiology* ; Surveys and Questionnaires ; Syphilis/prevention & control* ; Syphilis Serodiagnosis

Objective: To study the modification effect of age on the association between body mass index and the risk of hypertension. Methods: People age ≥18 years old were selected by clusters, from a rural area of Henan province. In total, 20 194 people were recruited at baseline during 2007 and 2008, and the follow-up study was completed from 2013 to 2014. Logistic regression model was used to assess the risk of incident hypertension by baseline BMI and age-specific BMI. Results: During the 6-year follow-up period, 1 950 hypertensive persons were detected, including 784 men and 1 166 women, with cumulative incidence rates as 19.96%, 20.51%, and 19.61%, respectively. Compared with those whose BMI<22 kg/m(2), the RRs of hypertension were 1.09 (0.93-1.27), 1.17 (1.01-1.37), 1.34 (1.14-1.58) and 1.31 (1.09-1.56) for participants with BMI as 22-, 24-, 26- and ≥28 kg/m(2), respectively. In young and middle-aged populations, the risk of hypertension gradually increased with the rise of BMI (trend P<0.05). However, in the elderly, the increasing trend on the risk of hypertension risk was not as significantly obvious (trend P>0.05). Conclusion: The effect of BMI on the incidence of hypertension seemed to depend on age. Our findings suggested that a weight reduction program would be more effective on young or middle-aged populations, to prevent the development of hypertension.
Adolescent ; Age Factors ; Aged ; Asian People/statistics & numerical data* ; Body Mass Index ; Cohort Studies ; Female ; Follow-Up Studies ; Humans ; Hypertension/ethnology* ; Incidence ; Logistic Models ; Male ; Middle Aged ; Risk Factors ; Rural Population