HelixADMET: a robust and endpoint extensible ADMET system incorporating self-supervised knowledge transfer.

MOTIVATION: Accurate ADMET (an abbreviation for 'absorption, distribution, metabolism, excretion and toxicity') predictions can efficiently screen out undesirable drug candidates in the early stage of drug discovery. In recent years, multiple comprehensive ADMET systems that adopt advanced machine learning models have been developed, providing services to estimate multiple endpoints. However, those ADMET systems usually suffer from weak extrapolation ability. First, due to the lack of labelled data for each endpoint, typical machine learning models perform frail for the molecules with unobserved scaffolds. Second, most systems only provide fixed built-in endpoints and cannot be customized to satisfy various research requirements. To this end, we develop a robust and endpoint extensible ADMET system, HelixADMET (H-ADMET). H-ADMET incorporates the concept of self-supervised learning to produce a robust pre-trained model. The model is then fine-tuned with a multi-task and multi-stage framework to transfer knowledge between ADMET endpoints, auxiliary tasks and self-supervised tasks. RESULTS: Our results demonstrate that H-ADMET achieves an overall improvement of 4%, compared with existing ADMET systems on comparable endpoints. Additionally, the pre-trained model provided by H-ADMET can be fine-tuned to generate new and customized ADMET endpoints, meeting various demands of drug research and development requirements. AVAILABILITY AND IMPLEMENTATION: H-ADMET is freely accessible at https://paddlehelix.baidu.com/app/drug/admet/train. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Deep Learning with Geometry-Enhanced Molecular Representation for Augmentation of Large-Scale Docking-Based Virtual Screening.

Structure-based virtual screening has been a crucial tool in drug discovery for decades. However, as the chemical space expands, the existing structure-based virtual screening techniques based on molecular docking and scoring struggle to handle billion-entry ultralarge libraries due to the high computational cost. To address this challenge, people have resorted to machine learning techniques to enhance structure-based virtual screening for efficiently exploring the vast chemical space. In those cases, compounds are usually treated as sequential strings or two-dimensional topology graphs, limiting their ability to incorporate three-dimensional structural information for downstream tasks. We herein propose a novel deep learning protocol, GEM-Screen, which utilizes the geometry-enhanced molecular representation of the compounds docking to a specific target and is trained on docking scores of a small fraction of a library through an active learning strategy to approximate the docking outcome for yet nontraining entries. This protocol is applied to virtual screening campaigns against the AmpC and D4 targets, demonstrating that GEM-Screen enriches more than 90% of the hit scaffolds for AmpC in the top 4% of model predictions and more than 80% of the hit scaffolds for D4 in the same top-ranking size of library. GEM-Screen can be used in conjunction with traditional docking programs for docking of only the top-ranked compounds to avoid the exhaustive docking of the whole library, thus allowing for discovering top-scoring compounds from billion-entry libraries in a rapid yet accurate fashion.

EYA1 promotes tumor angiogenesis by activating the PI3K pathway in colorectal cancer.

Blood vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as vascular endothelial growth factor(VEGF) to induce angiogenesis, thereby promoting metastasis. Here, we report that The Drosophila Eyes Absent Homologue 1 (EYA1), which is overexpressed in colorectal tumor cells, can promote colorectal tumor angiogenesis by coordinating with the hypoxia-inducible factor 1 (HIF-1α) to increase the expression of VEGF-A. Moreover, data indicated that the enhancement of HIF-1α expression by Eya1 depended on its ability to activate the phosphatidylinositol 3-kinase (PI3K) signaling pathways to increase the phosphorylation of AKT subunits. Overexpression of Eya1 increased tumor angiogenesis in vivo and in vitro. Our study suggested that Eya1 is essential in regulating cancer cell-mediated angiogenesis and contributes to tumor growth, and that Eya1 provides a potential and specific target for new anti-angiogenesis drug development.

Accurate prediction of CDR-H3 loop structures of antibodies with deep learning.

Accurate prediction of the structurally diverse complementarity determining region heavy chain 3 (CDR-H3) loop structure remains a primary and long-standing challenge for antibody modeling. Here, we present the H3-OPT toolkit for predicting the 3D structures of monoclonal antibodies and nanobodies. H3-OPT combines the strengths of AlphaFold2 with a pre-trained protein language model and provides a 2.24 Å average RMSDCα between predicted and experimentally determined CDR-H3 loops, thus outperforming other current computational methods in our non-redundant high-quality dataset. The model was validated by experimentally solving three structures of anti-VEGF nanobodies predicted by H3-OPT. We examined the potential applications of H3-OPT through analyzing antibody surface properties and antibody-antigen interactions. This structural prediction tool can be used to optimize antibody-antigen binding and engineer therapeutic antibodies with biophysical properties for specialized drug administration route.

Effects of different radical distal gastrectomy on postoperative inflammatory response and nutritional status in patients with gastric cancer.

Objectives: The inflammatory response caused by gastric cancer surgery and the low nutritional status of patients with gastric cancer can cause growth of tumour cells, reduce immunity, and increase tumour burden. We investigated the effects of different surgical methods on postoperative inflammatory response and nutritional status in patients with distal gastric cancer. Methods: Clinical data of 249 patients who underwent radical distal gastrectomy for distal gastric cancer from February 2014 to April 2017 were retrospectively analysed. Patients were divided according to the surgical method (open distal gastrectomy [ODG], laparoscopic-assisted distal gastrectomy [LADG] and total laparoscopic distal gastrectomy [TLDG]). Characteristics of different surgical procedures, including inflammation parameters and nutritional indicators, and different time points (preoperatively, 1 day postoperatively, and 1 week postoperatively) were compared using non-parametric test analysis. Results: At postoperative day 1, white blood cell count [WBC], neutrophil count [N], neutrophil/lymphocyte ratio [NLR], and platelet/lymphocyte ratio [PLR] increased in the three groups, and ΔN and ΔNLR were significant; the smallest change was observed in TLDG (P < 0.05). Albumin [A]and prognostic nutrition index [PNI] significantly decreased; the smallest ΔA and ΔPNI, which were statistically significant, were noted in TLDG. One week postoperatively, WBC, N, NLR, and PLR decreased, and WBC, N, and NLR showed significant difference. A and PNI of the three groups increased after 1 week, and A and PNI showed significant differences. Conclusion: Postoperative inflammatory response and nutritional status of patients with distal gastric cancer are associated with the surgical technique. TLDG has little influence on the inflammatory response and nutritional level compared with LADG and ODG.

The safety and efficacy of laparoscopic gastrectomy for patients with locally advanced gastric cancer following neoadjuvant chemotherapy.

Limited researches focused on the application of laparoscopic gastrectomy (LG) in locally advanced gastric cancer (LAGC) patients following neoadjuvant chemotherapy (NACT). In this study, we aimed at illustrating the surgical and survival outcome of LG in LAGC patients following NACT. We performed a retrospective study of patients with LAGC who received either LG following NACT or upfront LG at Fujian Provincial Hospital between March 2013 and October 2018. Perioperative parameters, short-term and long-term outcomes were compared. The Kaplan-Meier estimator was used to describe the survival curves, and the differences were examined by the log-rank test. In total, 76 consecutive patients were enrolled into the NACT-LG (41 patients) and LG (35 patients) group. The postoperative hospital stay was significantly longer for LG than for NACT-LG (11.0 vs. 12.0 day, P = 0.031). Significant difference was found in Grade ≥ III severe postoperative complications in two groups (0 vs. 17.1%, P = 0.001). No patient died of postoperative complications in the NACT-LG group, and one patient (1/35, 2.9%) died of postoperative complications in the LG group. A forest plot revealed that most subgroups of LG group were at great risks of postoperative complications. Compared with the LG group, the NACT-LG group had a significantly better DFS (14.4% vs. 5.7%, P = 0.0299) and better OS (34.1% vs. 8.6%, P = 0.0061) at 3 years. NACT increased the safety of LG for patients with LAGC and offer better disease-free and overall survival. For patients with LAGC, LG following NACT should be the priority treatment.

Selection of Policy Instruments on Integrated Care in China: Based on Documents Content Analysis.

Facing the aggravating trend of an aging population and a fragmented medical service delivery system, the Chinese Central Government has introduced a series of policies to promote the development of integrated care against the background of the "Healthy China Strategy". The achievement of integrated care depends on the choice of policy instruments. However, few studies have focused on how policy instruments promote the practice of integrated care in China. This article aims to obtain a deeper understanding of the use of policy instruments in the development of integrated care in China. Policy documents are the carriers of policy instruments. National-level integrated care policy documents from 2009 to 2019 were selected. Using the qualitative document analysis method, this paper conducts an analysis of integrated care policy instruments. In order to comprehensively view the integrated care policy instruments, a three-dimensional analytical framework consisting of the policy instruments dimension, stakeholders dimension, and health service supply chains dimension is proposed. The results are as follows. (1) From the perspective of policy instruments, the integrated care policy has adopted supply-side policy instruments, demand-side policy instruments, and environmental policy instruments. Among the three types of policy instruments, environmental policy instruments are used most frequently, supply-side policies are preferred, while demand-side policy instruments are relatively inadequate. (2) As for the stakeholders dimension, the central policy instruments focus on the health service providers, while less attention is paid to the health service demanders. (3) In terms of health service supply chains, the number of policy instruments used in the prevention stage is the highest, followed by the treatment stage, whereas less attention paid to the rehabilitation stage. Finally, suggestions were made for the development of integrated care by better perfecting policy instruments.

Lysine-specific histone demethylase 1B (LSD2/KDM1B) represses p53 expression to promote proliferation and inhibit apoptosis in colorectal cancer through LSD2-mediated H3K4me2 demethylation.

Epigenetic alterations have been reported to play critical roles in the development of colorectal cancer (CRC). However, the biological function of the lysine-specific histone demethylase 1B (LSD2/KDM1B) in CRC is not well understood. Therefore, we investigated the characteristics of LSD2 in CRC. We observed significant upregulation of LSD2 in CRC tissue compared to that in normal colorectal tissue. LSD2 promotes CRC cell proliferation and inhibits cell apoptosis through cell cycle regulation, promoting CRC progression both in vitro and in vivo. We found that LSD2 performs these functions by inhibiting the p53-p21-Rb pathway. Finally, we found that LSD2 directly binds to p53 and represses p53 expression via H3K4me2 demethylation at the p53 promoter. Our results revealed that LSD2 acts as an oncogene by binding and inhibiting p53 activity in CRC. Thus, LSD2 may be a new molecular target for CRC treatment.

Combining Resource, Structure and Institutional Environment: A Configurational Approach to the Mode Selection of the Integrated Healthcare in County.

Integrated healthcare has received considerable attention and has developed into the highly important health policy known as Integrated Healthcare in County (IHC) against the background of the Grading Diagnosis and Treatment System (GDTS) in rural China. However, the causal conditions under which different integrated health-care modes might be selected are poorly understood, particularly in the context of China's authoritarian regime. This study aims to identify these causal conditions, and how they shape the mode selection mechanism for Integrated Healthcare in County (IHC). A theoretical framework consisting of resource heterogeneity, governance structure, and institutional normalization was proposed, and a sample of fifteen IHCs was selected, with data for each IHC being collected from news reports, work reports, government documents and field research for Fuzzy-sets Qualitative Comparative Analysis (fsQCA). This study firstly pointed out that strong governmental control and centralization are necessary conditions for the administration-oriented organization mode (MOA). Additionally, this research found three critical configured paths in the selection of organizational modes. Specifically, we found that the combination of low resource heterogeneity, weak governmental control, centralization, and normalization was sufficient to explain the selection path of the insurance-driven organization mode (MOI); the combination of low resource heterogeneity, strong governmental control, centralization, and normalization was sufficient for selecting MOA; and the combination of weak governmental control, weak centralization, and weak normalization was sufficient for selecting the contractual organization mode (MOC). Our study highlighted the necessity and feasibility of constructing different IHC modes separately and promoting their development gradually, as a result of the complex relationships among the causal conditions described above, thus helping to optimize the distribution of health resources and integrate the healthcare system.

Not all mutations of KRAS predict poor prognosis in patients with colorectal cancer.

The mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) has been reported to be prognostically important in patients with colorectal cancer (CRC). In this study, we investigated whether all KRAS mutations predict poor prognosis in patients with CRC. Our analysis of characteristics of KRAS mutations revealed the mutation rate for codon 12 was 72.7%, of which G12D was the highest (47.5%) followed by G12V (30.6%), and the mutation rate for codon 13 was 22.0%, of which all were G13D. In support of the concept that prognostic value of the KRAS codon-12 mutations is different from the codon-13 mutations, results from our Cox proportional hazard model studies showed that codon-12 mutations correlated with worse overall survival (OS; HR = 2.846, 95% CI: 1.967-4.118, P < 0.001) and progression free survival (PFS; HR = 2.011, 95% CI: 1.450-2.789, P < 0.001). No prognostic significance was revealed for codon-13 mutations. On further analysis, we found that mortality risk was significantly increased with G12D and G12V (G12D: HR = 2.802, 95% CI: 1.793-4.381, P < 0.001; G12V: HR = 2.802, 95% CI: 1.793-4.381, P < 0.001), as was the risk of disease progression (G12D: HR = 2.079, 95% CI: 1.396-3.099, P < 0.001; G12V: HR = 2.408, 95% CI: 1.517-3.822, P < 0.001). To conclude, our results support the concept that codon-12 mutations were predictive for a poor prognosis in Chinese patients with CRC. Specifically, G12D and G12V were independent prognostic factors for worse OS and PFS.

[The enhancement effect of emulsion in flame atomic absorption spectrometry].

A enhancement method of FAAS with emulsion as enhancement agent has been developed. The enhancement effect of emulsion made of three organic solvents (benzene, benzene-propanone, xylene), one organic reagent (dibutyl phthalate) and three emulsifiers (Tween-80, Triton X-100, OP) for iron, nickel, zinc, manganese and lead was studied. The results indicated that the enhancement is satisfactory. The emulsion with maximum enhancement percentage are respectively emulsion of benzene-OP-dibutyl phthalate with 89%, emulsion of xylene-Trition-100-dibutyl phthal with 34%, emulsion of benzene-Trition-100 with 121%, emulsion of benzene-Trition-100-dibutyl phthalate with 38% and 69% in sequence of the above elements.

[Determination of iron and nickel in crude oils by emulsification technique-FAAS method].

The methyl isobutyl ketone-dimethyl benzene solution of sample was emulsified into emulsion by emulsifier Triton X-100. The standard addition method was used to determine with polyisobutylene emulsion as the reference. An analytical method for rapid determination of iron and nickel in crude oils by FAAS had been developed. A principle and method of preparing blank solution had been advanced. Choices of solvent and emulsifier, preparing blank solution were studied. The determination results were consistent with those obtained by ashing method-FAAS.