Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the coronavirus disease, where patients are more susceptible to contract high fever and sore throat.This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression.Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Objective:To learn about the implementation of prevention and control measures in drinking water-borne endemic fluorosis areas and the trend of the disease change in Jiangsu Province.Methods:In March to October 2021, a general survey was carried out in 1 972 villages with drinking water-borne endemic fluorosis in 27 counties (cities and districts) of Jiangsu Province, the operation of water improvement projects in the villages was monitored, and the water fluoride content was determined. The prevalence of dental fluorosis among children aged 8 to 12 years in all the villages was investigated.Results:The 1 972 villages with drinking water-borne endemic fluorosis had completed water improvement, and all water improvement projects were operating normally and the water was qualified. Among them, 1 774 villages in the disease affected areas had achieved the control goal, accounting for 89.96%; and there were 198 villages in the disease affected areas with control measures up to the standard, accounting for 10.04%. A total of 47 water improvement projects were monitored, including 2 small-scale water improvement projects, accounting for 4.26%. There were 45 large-scale water improvement projects, accounting for 95.74%. A total of 125 790 children aged 8 to 12 years were examined, and 12 625 cases of dental fluorosis were detected. The detection rate of dental fluorosis was 10.04%, and the dental fluorosis index was 0.19. The detection rate of dental fluorosis in children aged 8 to 12 years was 9.98% (1 854/18 579), 10.27% (2 704/26 323), 9.48% (2 765/29 152), 9.73% (2 835/29 145) and 10.92% (2 467/22 591), respectively, with statistically significant difference (χ 2 = 10.51, P = 0.015). Among the 198 villages with control measures up to standard, according to the historical water fluoride, the detection rate of dental fluorosis in children in each water fluoride range (1.20-2.00, 2.01-3.00, 3.01-4.00, > 4.00 mg/L) was 37.73% (698/1 850), 43.17% (1 176/2 724), 45.50% (769/1 690) and 55.20% (802/1 453), respectively, with a statistically significant difference (χ 2 = 104.15, P < 0.001). Conclusion:The water improvement measures in drinking water-borne endemic fluorosis areas in Jiangsu Province have achieved significant results, which still need to be further consolidated.

Objective:To dynamically observe the changes in iodine level in residents' drinking water after the change of regional water supply mode (2020) in Jiangsu Province.Methods:The survey of water iodine level was conducted from June to October 2020 in administrative villages of Jiangsu Province with a median water iodine ≥40 μg/L in 2017. The survey mainly covered 1 537 administrative villages in 21 counties (cities and districts) of 5 cities, including Huaian City, Lianyungang City, Suqian City, Yancheng City, and Xuzhou City. Based on the standard of "Definition and Demarcation of Iodine Deficient Areas and Iodine Adequate Areas" (WS/T 669-2020), the administrative villages with a median water iodine of 40 - 100 μg/L were classified as iodine adequate areas. Water iodine testing was conducted using the "Method for Water Iodine Testing in Iodine Deficient and High Iodine Areas" recommended by the National Reference Laboratory for Iodine Deficiency Disorders.Results:Totally 1 498 administrative villages in Jiangsu Province were monitored in 2020, all of which had centralized water supply. The minimum value of water iodine in all administrative villages was 1.2 μg/L and the maximum value was 606.7 μg/L, and the median water iodine was 35.2 μg/L. Among them, 206 administrative villages had median water iodine < 10 μg/L, accounting for 13.75% (206/1 498); 610 administrative villages had median water iodine from 10 to < 40 μg/L, accounting for 40.72% (610/1 498); 635 administrative villages had median water iodine from 40 to 100 μg/L, accounting for 42.39% (635/1 498); and 47 administrative villages with median water iodine > 100 μg/L, accounting for 3.14% (47/1 498). Except for Sucheng District in Suqian City, Xinyi City and Gulou District in Xuzhou City, Qingjiangpu District and Xuyi County in Huaian City, and Guannan County in Lianyungang City, the median water iodine in the administrative villages of the remaining 15 counties (cities and districts) in 2020 decreased significantly compared to 2017, and the differences were statistically significant ( P < 0.05). Conclusion:After change of regional water supply mode in 2020, in most monitored counties (cities and districts) of Jiangsu Province, the water iodine level of administrative villages has decreased significantly compared to 2017.

Objective:To analyze the iodine nutrition status of key populations in water source high iodine areas in Jiangsu Province, providing a reference for scientific prevention and control of water source high iodine hazards.Methods:From May to June 2020, monitoring sites were determined by administrative villages in six high iodine counties (cities, districts) in Jiangsu Province, and drinking water samples were collected from residents to detect the iodine content in the water; 40 non boarding children aged 8 - 10 from one primary school in each village (half male and half female, with an age balance) and 20 pregnant women were selected. Salt samples were taken from children and pregnant women's homes, and urine samples were randomly taken once to detect salt and urine iodine contents. Thyroid volume of children was examined.Results:A total of 36 administrative villages were monitored, with a median of 45.3 μg/L for water iodine, ranging from 8.5 - 372.1 μg/L. A total of 1 422 salt samples were collected, of which 26 were iodized salt, accounting for 1.83%; and 1 396 non iodized salt, with the coverage rate of non iodized salt was 98.17%. A total of 1 365 urine samples were collected from children, with a median urine iodine of 405.6 μg/L. There were statistically significant differences in urine iodine levels among children in different regions, drinking water iodine contents, and age groups ( H = 128.39, 67.81, 39.94, P < 0.001). A total of 57 urine samples were collected from pregnant women, with a median urine iodine of 282.0 μg/L. There were statistically significant differences in urine iodine levels among pregnant women in different regions and drinking water iodine contents groups ( H = 17.54, 18.39, P < 0.001). A total of 1 365 children's thyroid volumes were examined, and 44 cases of thyroid enlargement were detected, with a goiter rate of 3.22%. There were no statistically significant differences in the incidence of thyroid enlargement among children in different regions, drinking water iodine contents, salt types, gender, and age groups ( P > 0.05). Conclusions:The iodine nutrition of children in water source high iodine areas in Jiangsu Province is at an iodine excess level, while the iodine nutrition of pregnant women is at an over optimal level. In areas with high iodine content in water sources, the iodine content in drinking water has a significant impact on the iodine intake of the local population. There is currently no correlation between the iodine content in drinking water, salt type, gender, and age factors and thyroid enlargement in children.

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

ObjectiveTo compare the differences in resistance and structure of skin between acupoints and non-acupoints， and to study the difference in skin permeability characteristics of Corydalis Rhizoma total alkaloid patches （CTTP） after administration at Shenque acupoint and non-acupoint， so as to provide experimental support for its clinical acupoint application to prevent and treat chronic pain. MethodTaking corydaline （CD）， tetrahydropalmatine （THP） and corydalis L （CDL） as evaluation indexes， and the quantitative analysis was carried out by high performance liquid chromatography （HPLC）. The mobile phase was methanol-0.04 mol·L^-1 phosphoric acid aqueous solution （70∶30， pH 6.0 adjusted with triethylamine）， the detection wavelength was 281 nm. In vitro transdermal test in Franz diffusion cell and in vivo transdermal test were used to study the skin permeability characteristics of CTTP through Shenque acupoint and non-acupoint administration. At the same time， the skin resistance between Shenque acupoint and non-acupoint was measured before and after the administration， and the distribution of the drug in each layer of the skin was compared by freezing sectioning， and visual verification was performed with fluorescence inverted microscope. ResultAfter 24 h of administration， the results of in vivo and in vitro experiments showed that the cumulative permeation and retention of CD， THP and CDL at Shenque acupoint skin were higher than those at non-acupoint skin （P<0.05， P<0.01）， the skin resistance of Shenque acupoint was lower than that of non-acupoint at all time points. The fluorescence microscopic observation results showed that the drug content of each layer of the skin was all Shenque acupoint>non-acupoint， indicating that the skin of Shenque acupoint had better effect on drug penetration and storage than non-acupoint. ConclusionThe 24 h cumulative permeation and retention of CTTP in Shenque acupoint skin are higher than those in non-acupoint skin， and the mechanism may be related to the thin skin， low electrical resistance and large number of hair follicle bodies at Shenque acupoint.

Objective:To analyze the detection rate of thyroid nodules and goiter in school-age children in different water iodine regions and investigate the difference of thyroid nodule and goiter in school-age children with different age, gender and body mass index (BMI) in Jiangsu Province.Methods:In 2017, three villages with water iodine values of 8.1, 51.2 and 115.4 μg/L (iodine deficient group, iodine appropriate group and iodine high group) were selected as survey sites in Xuzhou City, Jiangsu Province, where the supply of iodized salt was suspended. One primary school was selected from each village, and children aged 8 to 10 years old (age balance, half male and half female) were selected from each primary school as the survey subjects. Urine sample were collected, urinary iodine level was determined, height and weight were measured, and neck B ultrasound was performed.Results:A total of 131, 140 and 138 school-age children aged 8 to 10 years old were investigated in the iodine deficient group, iodine appropriate group and iodine high group, respectively, with a total of 409 children. The detection rates of thyroid nodules were 6.9% (9/131), 15.0% (21/140) and 16.7% (23/138), respectively, and the detection rates of goiter were 1.5% (2/131), 1.4% (2/140) and 6.5% (9/138) in the three groups, respectively. There were statistically significant differences in the detection rates of thyroid nodules and goiter in different water iodine groups (χ 2 = 6.92, 6.37, P < 0.05). The detection rates of thyroid nodules in different age groups were 9.5% (12/126), 11.3% (16/142) and 17.7% (25/141), the differences were statistically significant (χ 2 = 9.05, P < 0.05). The detection rates of thyroid nodules were 11.6% (24/207), 14.4% (29/202), and 12.5% (39/313), 16.9% (14/83), 0/9 and 0/4 in the subjects of different gender and BMI, the differences were not statistically significant (χ 2 = 0.69, P > 0.05). The detection rates of goiter in the subjects of different gender, age and BMI were 1.4% (3/207), 5.0% (10/202); 2.4% (3/126), 6.3% (9/142), 0.7% (1/141); 1.6% (3/313), 4.8% (4/83), 3/9 and 1/4. The differences were statistically significant (χ 2 = 4.07, 7.66, P < 0.05). Conclusion:The detection rate of thyroid nodules in school-age children in different water iodine regions in Jiangsu Province may have a certain relationship with age, and the detection rate of goiter may have a certain relationship with age, gender and BMI.

Objective:To evaluate the effect of health education on drinking-warter-borne endemic fluorosis in Jiangsu Province.Methods:From 2014 to 2018, a total of 12 counties (districts) with drinking-warter-borne endemic fluorosis were selected to carry out public health education activities, and 3 townships were chosen in each project county (district). School health education activities were carried out in the classes of grade 4 - 6 in the central primary school in each selected twonship. In the meantime, 3 villages were chosen in each selected township where the health education activities in the community were carried out. Before and after the health education activities, questionnaire surveys on knowledge of drinking-warter-borne endemic fluorosis prevention were conducted among 30 students in one class of grade 5 in the central primary school and 15 housewives lived near the central primary school in each township.Results:After the health education activities, the rates of knowledge awareness in the students and the housewives were 94.83% (15 362/16 200) and 95.14% (7 706/8 100), respectively, which were significantly higher than those before the health education activities [63.88% (10 348/16 200) and 65.94% (5 341/8 100)], and the differences were statistically significant (χ 2 = 4 700.00, 2 200.00, P < 0.001). There were no statistical differences in the rates of knowledge awareness in the students and housewives before the health education activities from 2014 to 2018 (χ 2 = 8.43, 0.88, P = 0.077, 0.928). Before the health education activities, the rate of knowledge awareness in the students was lower than that in the housewives, and the difference was statistically significant (χ 2 = 10.03, P = 0.002). After the health education activities, there was no statistical difference between the rate of knowledge awareness in the students and that in the housewives (χ 2 = 1.07, P = 0.301). Conclusions:The rates of knowledge awareness in the students and the housewives are increased significantly after the health education activities. We should expand the coverage of health education. Wide, deep and persistent health education in more ways for different people are needed to consolidate the achievements.

Objective:To investigate the iodine content distribution of drinking water in Jiangsu Province.Methods:In 2017, the iodine content in drinking water of residents in townships (streets, hereinafter referred to as townships) of Jiangsu Province was investigated. Administrative villages (neighborhood committees, hereinafter referred to as administrative villages) of Jiangsu Province were selected as units for the investigation of townships with the median water iodine greater than 10 μg/L. Delimitation criteria: the median iodine content of water < 40 μg/L was iodine deficiency area, 40-100 μg/L was suitable iodine area, and > 100 μg/L was high iodine area.Results:A total of 1 285 townships were surveyed in 101 counties (cities, districts) in 13 cities, and the median water iodine in townships was 7.28 μg/L. Among them, there were 875 townships with median water iodine < 10 μg/L, accounting for 68.09%; 315 townships 10-< 40 μg/L, accounting for 24.51%; 56 townships 40-100 μg/L, accounting for 4.36%; 39 townships > 100 μg/L, accounting for 3.04%. The water iodine survey at the administrative village level was conducted in 5 864 administrative villages in 410 townships in 6 cities. Among them, 769 administrative villages with median water iodine < 10 μg/L, accounting for 13.11%; 3 558 administrative villages 10 - < 40 μg/L, accounting for 60.68%; 613 administrative villages 40 - 100 μg/L, accounting for 10.45%; and 924 administrative villages > 100 μg/L, accounting for 15.76%.Conclusion:According to the water iodine, there are iodine deficiency, suitable iodine and high iodine areas in Jiangsu Province, mainly in iodine deficiency areas.

COVID-19/virology* ; China/epidemiology* ; Disease Outbreaks ; Genetic Linkage ; Humans ; Phylogeny ; Polymorphism, Single Nucleotide ; SARS-CoV-2/isolation & purification*