Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma.

Sorafenib is one a first-line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib-resistant SMMC-7721 cells compared to parental cells. NFIB knockdown not only sensitized drug-resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib-induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction.

Spatially resolved transcriptomics revealed local invasion-related genes in colorectal cancer.

Objective: Local invasion is the first step of metastasis, the main cause of colorectal cancer (CRC)-related death. Recent studies have revealed extensive intertumoral and intratumoral heterogeneity. Here, we focused on revealing local invasion-related genes in CRC. Methods: We used spatial transcriptomic techniques to study the process of local invasion in four CRC tissues. First, we compared the pre-cancerous, cancer center, and invasive margin in one section (S115) and used pseudo-time analysis to reveal the differentiation trajectories from cancer center to invasive margin. Next, we performed immunohistochemical staining for RPL5, STC1, AKR1B1, CD47, and HLA-A on CRC samples. Moreover, we knocked down AKR1B1 in CRC cell lines and performed CCK-8, wound healing, and transwell assays to assess cell proliferation, migration, and invasion. Results: We demonstrated that 13 genes were overexpressed in invasive clusters, among which the expression of CSTB and TM4SF1 was correlated with poor PFS in CRC patients. The ribosome pathway was increased, while the antigen processing and presentation pathway was decreased along CRC progression. RPL5 was upregulated, while HLA-A was downregulated along cancer invasion in CRC samples. Pseudo-time analysis revealed that STC1, AKR1B1, SIRPA, C4orf3, EDNRA, CES1, PRRX1, EMP1, PPIB, PLTP, SULF2, and EGFL6 were unpregulated along the trajectories. Immunohistochemic3al staining showed the expression of STC1, AKR1B1, and CD47 was increased along cancer invasion in CRC samples. Knockdown of AKR1B1 inhibited CRC cells' proliferation, migration, and invasion. Conclusions: We revealed the spatial heterogeneity within CRC tissues and uncovered some novel genes that were associated with CRC invasion.

[Research on competency building standards of institutions of schistosomiasis prevention and control in Hubei Province I Investigation of institution management].

OBJECTIVE: To investigate the current situation of management of institutions of schistosomiasis prevention and control in Hubei Province, so as to explore the probable competency building standards for these institutions at the county and township levels. METHODS: By using a combination of quantitative and qualitative methods, the institutions of schistosomiasis prevention and control at county and township levels were investigated for the institutional setup, staffing and fulfillment functions since the reform of 2004. RESULTS: Among 63 schistosomiasis endemic counties (cities, districts) of Hubei Province, there were 26 independent schistosomiasis control institutions (41.27%), there were 24 institutions which were incorporated into CDC (38.10%), and there were no institutions in 13 counties (20.63%). Among 518 endemic towns, there were 299 institutions (57.72%). The total staffing size were 1 932, but there were 1 586 (82.09%) people actually working in the post, and therefore there were 346 (17.91%) empty positions. The average rates of carrying out the six functions were 91.48%-71.19%, but only 19.23% of the institutions participated in the comprehensive schistosomiasis control management project and its effect assessment. CONCLUSION: According to the management model for schistosomiasis control institutions under the current institutional mechanisms, we need a rigorous industry standard to constrain, guide and standardize the management and capacity-building of the institutions in different historical periods.

[Research on competency building standards of institutions of schistosomiasis prevention and control in Hubei Province. II. Investigation of human resources].

OBJECTIVE: To understand the human resources of the grassroots institutions of schistosomiasis control and prevention, so as to provide the evidence for formulating the standards of institutional capacity-building. METHODS: By using the combination of quantitative and qualitative methods, the hierarchy of schistosomiasis control institution workers, structural features of workers, and benefits of workers were investigated and the results were analyzed statistically after the 2004 reform. RESULTS: The constituent ratios of personnel ≤ 30 years old, 30 to 45 years old, and ≥ 45 years old were 6.8%, 64.0% and 29.2% respectively, with an average age of 43.1 years. For education levels, 61.35% of the personnel had secondary or high school levels. At the city level, the structural proportion of the senior professional; medium professional and primary professional titles was 1.4 : 5.6 : 3.0, and at the county level, the proportion was 0.5 : 6.1 : 3.4. There was 14 200 yuan per capita at the township schistosomiasis control institutions. CONCLUSION: The technology of the personnel in schistosomiasis institutions of Hubei Province is weak, the average age of personnel is old, and the salary is low.