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Most clinical related proteomic studies were aimed to screen potential biomarkers for clinical usage. However, it is known that only a few candidates can be validated in later stages. Besides clinical biomarkers, it is also necessary to identify key proteins to better understand the molecular mechanism of human diseases. Here, we updated the connotations of precision and translational proteomics and proposed a refined research framework for clinical proteomics. We abstracted the framework as a three-tier system: to determine research objectives and approaches for achieving a certain purpose, to choose the appropriate methods for optimal results, and to apply a standardized experimental procedure for reliable and reproducible results. Started from the initial discovery stage, we divided the following proteomics-driven translational studies into two directions: biomarker screening and mechanism investigation. We also discussed possible causes that may lead to high rates of experimental variation and low rates of follow-up validation. Moreover, we pointed out that the main bottlenecks for the identification of effective targets are data interpretation and statistical inference. Finally, we emphasized that the transparency of experimental design and results can help to ensure data quality. Conclusively, the refined framework provides constructive recommendations and comprehensive guides for designing and performing clinical related proteomic studies with the aim of obtaining reliable and reproducible results. It can also help to further promote the standardization and integration of proteomic studies.

Rui Yang,1,* Leilei Wang,2,* Zhifeng Wu,3 Yongxiang Yin,4 Shi-Wen Jiang1 1Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, People’s Republic of China; 2Department of Medical Genetics, Lianyungang Maternal and Child Health Hospital Affiliated to Yangzhou University, Lianyungang, 222000, Jiangsu, People’s Republic of China; 3Department of Ophthalmology, The Affiliated Wuxi Clinical College of Nantong University, Wuxi, 214002, Jiangsu, People’s Republic of China; 4Department of Pathology, The Affiliated Maternity and Child Health Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shi-Wen Jiang, Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, People’s Republic of China, Tel +86-13730975986, Fax +86-510-82725094, Email jiangsw137@163.comAbstract: Accumulated data indicated that many types of cancers have increased protein O-GlcNAcylation at cell surface and inside cells. The aberrant O-GlcNAcylation is considered a potential therapeutic target. Although several types of compounds capable of inhibiting O-GlcNAcylation have been developed, their low solubility, poor permeability and delivery efficiency have impeded the application for in vivo and pre-clinical studies. Nanocarriers have the advantages of controllable drug release and active cancer-targeting capability. Moreover, nanoparticles can improve drug delivery efficiency and reduce the non-specific distribution in normal tissues by the enhanced permeability and retention (EPR) effect in cancer. Taking the advantage of O-GlcNAc-specific antibodies or lectins, nanoparticles could further improve their cancer-targeting capability. Although nanocarriers targeting the canonical N- and O-linked glycosylation have been extensively investigated for cancer detection and therapy, application of nanotechniques for the specific targeting of O-GlcNAcylation has not been actively pursued. This review summarizes the general features of GlcNAcylation and its alterations in cancers. Analyses are focused on the following areas: How the nanocarriers may improve the solubility and/or cell permeability of O-GlcNAc transferase (OGT) inhibitors; The modification of nanocarriers with lectins or antibodies for active targeting of O-GlcNAc; The nanocarriers-mediated co-delivery of OGT inhibitors and conventional drugs, which may lead to synergistic effects. Unsolved issues impeding the research progression on O-GlcNAcylation-targeting scheme are also discussed.Graphical Abstract: Keywords: O-GlcNAcylation, nanocarriers, OGT inhibitor, targeted therapy, lectin, combined therapy

Gestational diabetes mellitus is a progressive and complex pregnancy complication, which threatens both maternal and fetal health. It is urgent to screen for specific biomarkers for early diagnosis and precise treatment, as well as to identify key moleculars to better understand the pathogenic mechanisms. In the present review, we comprehensively summarized recent studies of gestational diabetes using mass spectrometry-based proteomic technologies. Focused on the entire experimental design and proteomic results, we showed that these studies have covered a broad range of research contents in terms of sampling time, sample types, and outcome associations. Although most of the studies only stayed in the stage of initial discovery, several proteins were further verified to be efficient for disease diagnosis. Functional analysis of all the combined significant proteins also showed that a small number of proteins are known to be involved in the regulation of insulin or indirect signaling pathways. However, many factors such as diagnostic criteria, sample processing, proteomic method, and statistical method can greatly affect the identification of reproducible and reliable protein candidates. Thus, we further provided constructive suggestions and recommendations for carrying out proteomic or follow-up studies of gestational diabetes or other pregnancy complications in the future.