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The 2nd CASMS conference was held virtually through Gather. Town platform from October 17 to 21, 2022, with a total of 363 registrants including an outstanding and diverse group of scientists at the forefront of their research fields from both academia and industry worldwide, especially in the United States and China. The conference offered a 5-day agenda with an exciting scientific program consisting of two plenary lectures, 14 parallel symposia, and 4 special sessions in which a total of 97 invited speakers presented technological innovations and their applications in proteomics & biological mass spectrometry and metabo-lipidomics & pharmaceutical mass spectrometry. In addition, 18 invited speakers/panelists presented at 3 research-focused and 2 career development workshops. Moreover, 144 posters, 54 lightning talks, 5 sponsored workshops, and 14 exhibitions were presented, from which 20 posters and 8 lightning talks received presentation awards. Furthermore, the conference featured 1 MCP lectureship and 5 young investigator awardees for the first time to highlight outstanding mid-career and early-career rising stars in mass spectrometry from our society. The conference provided a unique scientific platform for young scientists (i.e., graduate students, postdocs and junior faculty/investigators) to present their research, meet with prominent scientists, and learn about career development and job opportunities (http://casms.org).

Ke Ma,1,* Zhixiang Cheng,2,* Hao Jiang,3,* Zhangya Lin,4,* Chuansheng Liu,5,* Xianguo Liu,6,* Lijuan Lu,7,* Yan Lu,8,* Wei Tao,9,* Suoliang Wang,10,* Xiaoqiu Yang,11,* Qishan Yi,12,* Xiaomei Zhang,13,* Ying Zhang,14,* Yanqing Liu15,* 1Department of Algology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Algology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Algology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 4Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 5Department of Algology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 6Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 7Department of Pain Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 8Department of Algology, Xijing Hospital, The Fourth Military Medical University, Xian, People’s Republic of China; 9Department of Neurosurgery, Shenzhen University General Hospital, Shenzhen, People’s Republic of China; 10Department of Algology, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 11Department of Algology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 12Department of Algology, The Yibin First People’s Hospital Affiliated Chongqing Medical University, Yibin, People’s Republic of China; 13Department of Algology, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 14Department of Algology. Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, People’s Republic of China; 15Department of Algology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke Ma, Department of Algology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University school of medicine, Shanghai, 200092, People’s Republic of China, Tel +86133618792160, Email marke72@163.com Yanqing Liu, Department of Algology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China, Tel +8618601203409, Email lyqttyy@126.comAbstract: Ion channel drugs have been increasing used for chronic pain management with progress in the development of selective calcium channel modulators. Although ion channel drugs have been proven safe and effective in clinical practice, uncertainty remains regarding its use to treat chronic pain. To standardize the clinical practice of ion channel drug for the treatment of chronic pain, the National Health Commission Capacity Building and Continuing Education Center for Pain Diagnosis and Treatment Special Ability Training Project established an expert group to form an expert consensus on the use of ion channel drugs for the treatment of chronic pain after repeated discussions on existing medical evidence combined with the well clinical experience of experts. The consensus provided information on the mechanism of action of ion channel drugs and their recommendations, caution use, contraindications, and precautions for their use in special populations to support doctors in their clinical decision-making.Keywords: chronic pain, ion channel drugs, voltage-gated calcium channels, voltage-gated sodium channel

Simin Min,1,2 Weiting Tao,1 Yuchen Miao,3 Yan Li,4 Tianyu Wu,5 Xiaoyu He,6 Yijing Zhang,7 Bangye Liu,7 Zixin Meng,7 Ke Han,1 Saisai Liu,1 Li Li,1 Jie Chen,1 Shidi Zhao,1 Junjie Zhang,3 Xiaonan Zhang1 1Bengbu Medical College Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 2Suzhou Hospital of Anhui Medical University, Suzhou, Anhui, 234000, People’s Republic of China; 3Department of Chemistry, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 4School of Medicine and Health Engineering, Changzhou University, Changzhou, Jiangsu, 213164, People’s Republic of China; 5School of Public Health, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 6Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 7School of Clinical Medicine, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of ChinaCorrespondence: Xiaonan Zhang, Department of Pathophysiology, Bengbu Medical College, 2600 Donghai Avinue, Longzihu District, Bengbu, Anhui, People’s Republic of China, Tel +86-13609827842, Fax +86-552-3175283, Email zhangxn@bbmc.edu.cn Junjie Zhang, Department of Chemistry, Bengbu Medical College, 2600 Donghai Avinue, Longzihu District, Bengbu, Anhui, People’s Republic of China, Tel +86-16655208659, Fax +86-552-3175257, Email zhangjj@bbmc.edu.cnBackground: The respiratory system is intensely damaged by acute lung injury (ALI). The anti-inflammatory effects of tetramethylpyrazine (TMP) against ALI have been confirmed, but it exhibits a short half-life. miR-194-5p could directly target Rac1, but the internalization rate of miRNA cells was low.Purpose: To explore the potential of the soft mesoporous organic silica nanoplatform (NPs) as carriers for delivery of TMP and miR-194-5p through the tail vein.Methods: NPs@TMP and NPs@PEI@miR-194-5p were added to the HUVEC cell-lines, in vitro, to observe the cell uptake and cytotoxic effects. In vivo experiments were conducted by injecting fluorescently labeled NPs through the tail vein and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically.Results: In vitro study exhibited that NPs have no toxic effect on HUVECs within the experimental parameters and have excellent cellular uptake. The IVIS Spectrum Imaging System shows that NPs accumulate mainly in the lungs. NPs@TMP treatment can improved oxidative stress and inflammation levels in ALI mice and inhibited the TLR4/NLRP3/caspase 1 pathway. NPs@PEI@miR-194-5p can inhibit the Rac1/ZO-1/occludin pathway and improved endothelial cell permeability in ALI mice. The co-treatment of NPs@TMP and NPs@PEI@miR-194-5p can significantly improved the survival rates of the mice, reduced pulmonary capillary permeability and improved pathological injury in ALI mice.Innovation: This study combined traditional Chinese medicine, bioinformatics, cellular molecular biology and nanobiomedicine to study the pathogenesis and treatment of ALI. The rate of cellular internalization was improved by changing the shape and hardness of nanoparticles. NPs@TMP and NPs@PEI@miR-194-5p combined application can significantly improve the survival condition and pathological injury of mice.Conclusion: NPs loaded with TMP and miR-194-5p showed a greater therapeutic effect in ALI mice. Keywords: NPs@TMP, NPs@PEI@miR-194-5p, tight junction, pulmonary capillary, endothelial cells, inflammation, acute lung injury

Tao W, Li Y, Zhu M, Li C, Li P. Onco Targets Ther. 2019;12:8841–8851. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication of the article, concerns were raised about the duplication of images from Figures 4 and 5 with images from an unrelated article. Specifically, The images for Figure 4D, BGC803 and BGC823, Ctrl, have been duplicated with images for Figure 4A, miR-519a mimics NC, 0Gy and Figure 4G, miR-519a mimics+OE-EphA2, 2Gy, respectively, from Gong S, Li Y, Lv L, et al. Restored microRNA-519a enhances the radiosensitivity of non-small cell lung cancer via suppressing EphA2. Gene Ther. 2022;29:588–600. https://doi.org/10.1038/s41434-020-00213-x. The image for Figure 5D, BGC803, pcNORAD+miR-214, has been duplicated with the image for Figure 4G, si-EphA2, 0Gy from Gong S, et al (2022). The corresponding author did not respond to our queries and was unable to provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Yamei Cui,* Ying Yang,* Wenqiang Tao, Wei Peng, Deqiang Luo, Ning Zhao, Shuangyan Li, Kejian Qian, Fen Liu Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fen Liu, Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Dong Lake District, Nanchang, 330000, People’s Republic of China, Tel +86 0791 88692533, Email liufen9934@163.comBackground: Uncontrolled inflammation is a typical feature of sepsis-related lung injury. The key event in the progression of lung injury is Caspase-1-dependent alveolar macrophage (AM) pyroptosis. Similarly, neutrophils are stimulated to release neutrophil extracellular traps (NETs) to participate in the innate immune response. This study aims to illustrate the specific mechanisms by which NETs activate AM at the post-translational level and maintain lung inflammation.Methods: We established a septic lung injury model by caecal ligation and puncture. We found elevated NETs and interleukin-1b (IL-1β) levels in the lung tissues of septic mice. Western blot and immunofluorescence analyses was utilized to determine whether NETs promote AM pyroptosis and whether degrading NETs or targeting the NLRP3 inflammasome had protective effects on AM pyroptosis and lung injury. Flow cytometric and co-immunoprecipitation analyses verified intracellular reactive oxygen species (ROS) levels and the binding of NLRP3 and ubiquitin (UB) molecules, respectively.Results: Increased NETs production and IL-1β release in septic mice were correlated with the degree of lung injury. NETs upregulated the level of NLRP3, followed by NLRP3 inflammasome assembly and caspase-1 activation, leading to AM pyroptosis executed by the activated fragment of full-length gasdermin D (FH-GSDMD). However, the opposite effect was observed in the context of NETs degradation. Furthermore, NETs markedly elicited an increase in ROS, which facilitated the activation of NLRP3 deubiquitination and the subsequent pyroptosis pathway in AM. Removal of ROS could promote the binding of NLRP3 and ubiquitin, inhibit NLRP3 binding to apoptosis-associated spotted proteins (ASC) and further alleviate the inflammatory changes in the lungs.Conclusion: In summary, these findings indicate that NETs prime ROS generation, which promotes NLRP3 inflammasome activation at the post-translational level to mediate AM pyroptosis and sustain lung injury in septic mice.Keywords: sepsis, neutrophil extracellular traps, macrophage pyroptosis, NLRP3 inflammasomes, ubiquitination, oxidative stress

Wang C, Tao W, Ni S, Chen Q. Onco Targets Ther. 2019;12:8085–8094. At the authors request, we, the Editor and Publisher of OncoTargets and Therapy have retracted the published article. Since publication, concerns have been raised to the authors about the integrity of the data in the article, including the duplication of images in Figure 6. Specifically, The flow cytometry images for Figure 6C, T24, circFoxo3(-) miR191(-), circFoxo3(-) miR191(+), circFoxo3(+) miR191(-) and circFoxo3(+) miR191(+) have been duplicated with images for Figure 6C, T82, circFoxo3(-) miR191(-), circFoxo3(-) miR191(+), circFoxo3(+) miR191(-) and circFoxo3(+) miR191(+), respectively. The authors explained they were unable to provide the original data for their study and the results could not be verified. As verifying the validity of the published work is core to the integrity of the scholarly record, the authors requested to retract the article and the editor and Publisher agreed with this decision. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Jian-guo Zhang,1– 3,&ast; Shang-miao Fu,1,&ast; Fen Liu,1 Jian-guo Wan,4 Shu-bing Wu,4 Guang-hui Jiang,4 Wen-qiang Tao,1 Wen Zhou,4 Ke-jian Qian1 1Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Infection, First Affiliated Hospital of Nanchang University, Nanchang, Jianxi, People’s Republic of China; 3Department of Critical Care Medicine, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 4Department of Critical Care Medicine, First Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke-jian Qian, Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, No. 17 YongwaiZheng Street, Nanchang, Jiangxi, 330006, People’s Republic of China, Email 361439919072@email.ncu.edu.cn Wen Zhou, Department of Critical Care Medicine, First Hospital of Nanchang, No. 128 Xiangshan North Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Email doctor20210428@163.comPurpose: To investigate the correlation and prognostic significance of low triiodothyronine (T3) syndrome and norepinephrine dosage in patients with sepsis and septic shock.Methods: This single-center, retrospective, cohort study enrolled 169 patients with sepsis and septic shock that were admitted to the intensive care unit of First Hospital of Nanchang, Nanchang, China from June 2017 to July 2019. All included patients were followed up for 28 days or died, whichever was earlier. Patients with free T3 (FT3) of < 3.1 pmol/L were considered with low T3 syndrome. The correlation and prognostic significance of the FT3 and maximum dosage of norepinephrine (MDN) within 72 h, as well as other clinical indicators, were analyzed by using correlation analysis, principal component analysis, receiver operating characteristic curve, Youden index, and logistic regression.Results: A total of 138 patients were allocated to the low T3 group. FT3 inversely correlated with the Sequential Organ Failure Assessment (SOFA) score within 24 h, fluid resuscitation volume within 24 h, and lactic acid levels, and positively correlated with the mean arterial pressure. The critical values of age, SOFA, and MDN for predicting the 28-day mortality were 79.5 years, 8.5 points, and 0.61 μg/kg/min, respectively. The mortality of the low T3 and normal T3 groups was similar. Considering the MDN of 0.61 μg/kg/min as the cutoff value, the mortality between the two groups was significantly different.Conclusion: Among patients with sepsis and septic shock, FT3 was inversely correlated with the disease severity. An MDN ≥ 0.61 μg/kg/min within 72 h may be an important prognostic indicator.Keywords: euthyroid sick syndromes, low T3 syndrome, non-thyroidal illness syndrome, norepinephrine, sepsis, septic shock

Shifu Li, Wengui Tao, Zheng Huang, Langchao Yan, Bo Chen, Chudai Zeng, Fenghua Chen Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Fenghua Chen, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China, Email xyswcfh@csu.edu.cnBackground: Brain arteriovenous malformations (bAVM) are abnormal vascular lesions characterized by direct connections between arteries and veins without an intervening capillary bed. The primary goal for brain AVM treatment is to prevent rupture and hemorrhage; however, the underlying molecular mechanisms are still unknown.Methods: We constructed venous hypertension (VH) rat model with end-to-end anastomosis of the proximal left common carotid artery and the left distal external jugular vein. Thirty-eight adult rats were randomly assigned to four groups: the 0-week (n=5), the 1-week VH group (n=12), the 3-week VH group (n=9), and the 6-week VH group (n=12). We measured the hemodynamics and diameter of the arterialized veins. An RNA sequencing of arterialized veins was conducted, followed by comprehensive bioinformatics analysis to identify key genes and biological pathways involved in VH progression. The candidate genes from RNA-Seq were validated by RT-qPCR and immunostaining in human tissues.Results: We observed high-flow and low resistance characteristics in VH models. A total of 317 upregulated and 258 downregulated common genes were consistently differentially expressed during VH progression. Thirteen co-expression modules were obtained by WGCNA analysis, and 4 key modules were identified. Thirteen genes: Adamts8, Adamtsl3, Spon2, Adamtsl2, Chad, Itga7, Comp, Itga8, Bmp6, Fst, Smad6, Smad7, Grem1, and Nog with differential expressions were identified using the density of maximum neighborhood component (DMNC) algorithm in Cytohubba. The expression of five potential genes (Adamts8, Adamtsl3, Spon2, Adamtsl2, Itga8) were increased in RT-qPCR, while in human bAVM tissue, the protein levels of Adamtsl2 and Itga8 were significant elevated and Spon2 and Adamtsl3 were decreased.Conclusion: The identified gene networks of Adamtsl3, Spon2, Adamtsl2, and Itga8 provided key genes for further intervention.Graphical Abstarct: Keywords: WGCNA, xCells, focal adhesion, vascular microenvironment, bioinformatics

Yong Cheng,1 Yu-Xi Cheng,1 Xiao-Yu Liu,1 Bing Kang,2 Wei Tao,1 Dong Peng1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Department of Clinical Nutrition, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Dong PengDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaTel +86 23 89011014Email carry_dong@126.comPurpose: The purpose of the current study was to analyze the effect of type 2 diabetes mellitus (T2DM) on the short-term outcomes and prognosis of stage I–III colorectal cancer (CRC) undergoing primary surgery.Methods: Patients who underwent primary CRC surgery were retrospectively collected from Jan 2011 to Jan 2020 in a single clinical center. The short-term outcomes and prognosis were compared between T2DM group and non-T2DM group using propensity score matching (PSM) analysis.Results: A total of 4250 patients were included in this study. There were 521 patients with T2DM and 3729 patients without T2DM. After 1:1 ratio PSM, there were 519 T2DM patients and 519 non-T2DM patients left in this study. No significant difference was found in baseline information after PSM (p> 0.05). T2DM had higher overall complications (p=0.033) after PSM in terms of short-term outcomes. As for prognosis, T2DM group had worse overall survival (OS) in all stages (p=0.044), stage I (p=0.009) and stage II (p=0.021) of CRC and T2DM group had worse disease-free survival (DFS) than non-T2DM group in stage I (p=0.008) of CRC before PSM. However, T2DM did not affect the overall survival (OS) or disease-free survival (DFS) on different stages of CRC after PSM (p> 0.05). Moreover, T2DM was not an independent predictor of OS or DFS (p> 0.05).Conclusion: T2DM increased overall complications after primary CRC surgery. However, T2DM might not affect OS and DFS of stage I–III CRC patients.Keywords: colorectal cancer, type 2 diabetes mellitus, outcomes, prognosis

Yiping Li,1,&ast; Jia Yang,2,&ast; Wenyu Tao,1 Man Yang,1 Xiaoling Wang,1 Tinglian Lu,1,3 Chuanyin Li,2 Ying Yang,1 Yufeng Yao2 1Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China; 2Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming City, People’s Republic of China; 3School of Clinic Medicine, Dali University, Dali City, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying YangDepartment of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming, 650021, Yunnan, People’s Republic of ChinaEmail yangying2072@126.comYufeng YaoInstitute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan, 650118, People’s Republic of ChinaEmail leoyyf@gmail.com; yufeng_yao@imbcams.com.cnBackground: Insulin receptor (INSR), insulin receptor substrate (IRS) and glucose transporter 4 (GLUT4) play important roles in the insulin resistance pathway. The microRNA (miRNA or miR) involved in INSR, IRS or GLUT4 could be associated with the development of type 2 diabetes (T2DM).Methods: The aim of this study was to investigate the association of T2DM with 12 single nucleotide polymorphisms (SNPs) in 7 miRNAs (miR-195, miR-126, miR-144, miR-155, miR-21, miR-93 and miR-222) involved in the insulin resistance pathway. A total of 1593 subjects with T2DM and 1656 nondiabetic subjects were genotyped. Then, the associations of these SNPs with the development of T2DM and individual metabolic traits were evaluated, such as fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1C).Results: Our data showed that the C allele of rs1292037 in miR-21 could increase the risk of developing T2DM (P = 0.002, OR = 1.17; 95% CI: 1.06– 1.29). In addition, the T allele of rs13137 in miR-21 could be a risk factor for T2DM (P = 0.003, OR = 1.16; 95% CI: 1.05– 1.28). According to inheritance mode analysis, compared with the T/T-T/C genotype, the C/C genotype of rs1292037 showed a risk effect in T2DM in the recessive mode (P = 0.001, OR = 1.35; 95% CI: 1.13– 1.63). For rs13137, compared with the A/A-A/T genotype, the T/T genotype also showed a risk effect in T2DM in the recessive mode (P = 0.001, OR = 1.35; 95% CI: 1.13– 1.62). Moreover, in the nondiabetic group, compared with the rs78312845 A/G (FPG = 5.177± 0.488mmol/L; HbA1C = 5.147± 0.293%) and A/A genotypes (FPG = 5.155± 0.486mmol/L; HbA1C = 5.136± 0.299%), the G/G genotype (FPG = 4.887± 0.482mmol/L; HbA1C = 4.960± 0.397%) was associated with lower FPG (P = 0.012 and 0.019) and HbA1C (P = 0.008 and 0.011).Conclusion: Our results revealed that rs1292037 and rs13137 in miR-21 were associated with T2DM susceptibility in a Han Chinese population. Moreover, the rs78312845 in miR-195 contributed to the level of FPG and HbA1C in nondiabetic group in the Han Chinese population.Keywords: polymorphisms, T2DM, insulin resistance, Chinese population, microRNA

Suxing Liu,1 Di Li,1 Jian Liu,2 Huiyun Wang,1 Ivana Horecny,1 Ru Shen,1 Rumin Zhang,1 Heping Wu,2 Qiyue Hu,3 Peng Zhao,2 Fengqi Zhang,2 Yinfa Yan,2 Jun Feng,4 Linghang Zhuang,2 Jing Li,1 Lianshan Zhang,5 Weikang Tao5 1Department of Biology, Eternity Bioscience Inc., Cranbury, NJ, 08512, USA; 2Department of Chemistry, Eternity Bioscience Inc., Cranbury, NJ, 08512, USA; 3Department of Molecular Modeling, Shanghai Hengrui Pharmaceutical Co. Ltd., Shanghai, 200245, People’s Republic of China; 4Department of Process Chemistry, Shanghai Hengrui Pharmaceutical Co. Ltd., Shanghai, 200245, People’s Republic of China; 5R&D Center, Shanghai Hengrui Pharmaceutical Co. Ltd., Shanghai, 200245, People’s Republic of ChinaCorrespondence: Suxing LiuDepartment of Biology, Eternity Bioscience Inc, 6 Cedarbrook Drive, Cranbury, NJ, 08512, USAEmail lius@eternitybioscience.comIntroduction: CD73 and adenosine support growth-promoting neovascularization, metastasis, and survival in cells, and promote anti-PD-1 mAb therapy-induced immune escape. Consequently, developing a CD73 inhibitor as monotherapy and a potential beneficial combination partner with immune-checkpoint inhibitors needs investigation.Methods: CD73 inhibitors were evaluated in vitro with soluble and membrane-bound CD73 enzymes, as well as its PD biomarker responses in human peripheral blood mononuclear cells (PBMC) by flow cytometry and ELISA. The binding modes of the molecules were analyzed via molecular modeling. The anti-tumor activity and synergistic effect of SHR170008 in combination with anti-PD-1 mAb were evaluated in a syngeneic mouse breast cancer model.Results: SHR170008 was discovered during the initial structural modifications on the link between the ribose and the α-phosphate of AMPCP, which significantly improved the stability of the compound confirmed by the metabolite identification study. Further modifications on the adenine base of AMPCP improved the potency due to forming stronger interactions with CD73 protein. It exhibited potent inhibitory activities on soluble and endogenous membrane-bound CD73 enzymes, and induced IFNγ production, reversed AMP-suppressed CD25+ and CD8+/CD25+ expression, and enhanced granzyme B production on CD8+ T cells in human PBMC. SHR170008 showed dose-dependent anti-tumor efficacy with suppression of adenosine in the tumors in EMT6 mouse breast tumor model. The increase of adenosine in tumor tissue by anti-PD-1 mAb alone was suppressed by SHR170008 in the combination groups. Simultaneous inhibition of CD73 and PD-1 neutralization synergistically enhanced antitumor immunity and biomarkers in response, and exposures of SHR170008 were correlated with the efficacy readouts.Conclusion: Our findings suggest that CD73 may serve as an immune checkpoint by generating adenosine, which suppresses the antitumor activity of anti-PD-1 mAb, and inhibition of CD73 may be a potential beneficial combination partner with immune-checkpoint inhibitors to improve their therapeutic outcomes in general.Keywords: small-molecule inhibitor of CD73, adenosine, anti-PD-1 mAb, checkpoint blockade, immunotherapy, combination therapy

Wei Tao,* Yu-Xi Cheng,* Ying-Ying Zou, Dong Peng, Wei Zhang Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong PengDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaTel +86-13370754855Email carry_dong@126.comPurpose: The purpose of the present study was to evaluate whether vascular calcification is a risk factor for anastomotic leakage after gastrectomy in gastric cancer patients.Methods: Patients with confirmed gastric cancer were collected from the database of a single clinical center from January 2013 to January 2019. The calcification score and anastomotic leakage were recorded, and predictors of anastomotic leakage were analyzed.Results: A total of 856 patients were included in this study; 818 patients had no anastomotic leakage, and 38 patients had anastomotic leakage. The ratio of hypertension status (p=0.011), open gastrectomy (p=0.012), postoperative length of stay (p=0.000), aorta calcification score (p=0.000) and celiac axis calcification (p=0.000) were higher in the anastomotic leakage group than in the nonanastomotic leakage group. In multivariate analysis, aorta calcification (p=0.029, odds ratio =2.425, 95% CI=1.095– 5.491) was an independent predictor of the anastomotic leakage.Conclusion: Aorta calcification is an independent risk factor for anastomotic leakage after gastrectomy in gastric cancer patients.Keywords: calcification, leakage, gastrectomy, gastric cancer

Dong Peng,* Ying-Ying Zou,* Yu-Xi Cheng, Wei Tao, Wei Zhang Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ZhangDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaTel +86-13808353353Email cyzhangwei@hotmail.comPurpose: The purpose of the present study was to evaluate the effect of time (season, surgical starting time in the daytime, preoperative waiting time) on patients with gastric cancer.Methods: A retrospective collection of medical records of patients who underwent gastrectomy at a single clinical center from January 2013 to December 2018 was performed. Medical records were collected, and short-term outcomes and long-term survival were analyzed by different time groups.Results: A total of 586 patients were included in this study. In terms of surgical starting time, the midday group had a shorter operation time (p=0.017) but more complications (p=0.048) than the non-midday group. No significant difference was found based on the season of gastrectomy. The long preoperative waiting group had a shorter postoperative hospital stay than the short waiting group (p=0.026). No significant difference was found between the short-waiting group and long-waiting group in overall survival for all clinical stages. Age (p=0.040, HR=1.017, 95% CI=1.001– 1.033), BMI (p< 0.001, HR=0.879, 95% CI=0.844– 0.953) and clinical stage (p< 0.001, HR=2.053, 95% CI=1.619– 2.603) were independent prognostic factors predicting overall survival; however, season of gastrectomy, surgical starting time and preoperative waiting time were not identified as independent prognostic factors.Conclusion: Surgical starting time at the midday could cause more complications, and surgeons should be careful when the surgical starting time is midday.Keywords: gastric cancer, season, waiting time, surgical starting time

Deqiang Luo,1,2 Fen Liu,1 Jianguo Zhang,1 Qiang Shao,1 Wenqiang Tao,1 Rui Xiao,1 Wei Dai,2 Chengzhi Ding,1 Kejian Qian1 1Department of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330000, People’s Republic of China; 2Department of Intensive Care Unit, The Fifth People’s Hospital of Shangrao City, Shangrao, 334000, People’s Republic of ChinaCorrespondence: Kejian QianDepartment of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Dong Lake District, Nanchang, Jiangxi Province, 330000, People’s Republic of ChinaEmail ndyfyicu@email.ncu.edu.cnPurpose: To explore the molecular mechanism and search for candidate lncRNA and mRNA associated with pyroptosis in the gene expression profile of LPS-induced acute lung injury (ALI).Methods: We investigated lncRNA and mRNA expression in lipopolysaccharide (LPS)-induced ALI at an early stage. RNA sequencing (RNA-Seq) was carried out to analyze lncRNA and mRNA expression profiles between the LPS-induced and control groups. We used bioinformatics analysis to predict target genes of early differential lncRNAs among obtained the differential mRNAs.Results: A total of 78 lncRNAs and 248 mRNAs were upregulated at 2 hours and downregulated at 9 hours, and 21 lncRNAs and 107 mRNAs were downregulated at 2 and upregulated at 9 hours in early ALI models. We predicted 7 cis-and trans-regulated target genes of the top 20 lncRNAs. Gene Ontology (GO) analysis indicated that the target genes for the screened lncRNAs were most enriched in three-terms: regulation of protein serine/threonine kinase activity, pertussis, and cellular response to LPS. Additionally, target genes of lncRNAs were the top three enriched in pertussis, osteoclast differentiation, and cAMP signaling pathways with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We also identified vital mRNAs and lncRNAs. Protein-protein interaction (PPI) network analysis suggested that Tnf, Jun, and Atf3 were the top three key genes. Hub lncRNA4344 (NONRATT004344.2) and cis-regulated target mRNA (NLRP3) were validated in vitro. Finally, luciferase assay results confirmed that lncRNA4344 sponged miR‐138-5p to promote pyroptosis in inflammatory responses to LPS‐induced acute lung injury by targeting NLRP3.Conclusion: Based on analysis of lncRNA and mRNA expression profiles by RNA-Seq and experimental verification, this study is the first to reveal that lncRNA4344 sponged miR‐138-5p to promote pyroptosis in inflammatory responses of LPS‐induced acute lung injury by targeting NLRP3. These newly identified lncRNA, miRNA, and mRNA might be novel potential targets for early treatment and prevention in early ALI.Keywords: acute lung injury, alveolar macrophage, ceRNA network long noncoding RNAs, pyroptosis, RNA sequencing

Extracellular vesicles (EVs) in urine are a promising source for developing non-invasive biomarkers. However, urine concentration and content are highly variable and dynamic, and actual urine collection and handling often is nonideal. Furthermore, patients such as those with prostate diseases have challenges in sample collection due to difficulties in holding urine at designated time points. Here, we simulated the actual situation of clinical sample collection to examine the stability of EVs in urine under different circumstances, including urine collection time and temporary storage temperature, as well as daily urine sampling under different diet conditions. EVs were isolated using functionalized EVtrap magnetic beads and characterized by nanoparticle tracking analysis (NTA), western blotting, electron microscopy, and mass spectrometry (MS). EVs in urine remained relatively stable during temporary storage for 6 hours at room temperature and for 12 hours at 4 °C, while significant fluctuations were observed in EV amounts from urine samples collected at different time points from the same individuals, especially under certain diets. Sample normalization with creatinine reduced the coefficient of variation (CV) values among EV samples from 17% to approximately 6% and facilitated downstream MS analyses. Finally, based on the results, we applied them to evaluate potential biomarker panels in prostate cancer by data-independent acquisition (DIA) MS, presenting the recommendation that can facilitate biomarker discovery with nonideal handling conditions. [ABSTRACT FROM AUTHOR]

Chuanyin Li,1,* Keyu Shen,2,* Man Yang,3 Ying Yang,3 Wenyu Tao,3 Siqi He,4 Li Shi,1 Yufeng Yao,1 Yiping Li3 1Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan 650118, People’s Republic of China; 2Department of Medicine, Dentistry and Healthy Science, The University of Melbourne, Melbourne, VIC 3010, Australia; 3Department of Endocrinology and Metabolism, The Second People’s Hospital of Yunnan Province, & the Affiliated Hospital of Yunnan University, Kunming, Yunnan 650021, People’s Republic of China; 4School of Clinical Medicine, Dali University, Dali, Yunnan 671000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yufeng YaoInstitute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118 Yunnan, People’s Republic of ChinaEmail yufeng_yao@imbcams.com.cnYiping LiDepartment of Endocrinology and Metabolism, The Second People’s Hospital of Yunnan Province & the Affiliated Hospital of Yunnan University, Kunming, 650021 Yunnan, People’s Republic of ChinaEmail yyflyp@aliyun.comPurpose: Type 2 diabetes mellitus (T2DM) has a high global prevalence, and the interaction of environmental factors and genetic factors may contribute to the risk of T2DM. We aimed to investigate the association between T2DM and the single nucleotide polymorphisms (SNPs) in genes (CDKAL1 and HHEX) associated with insulin secretion.Subjects and Methods: T2DM (n=1,169) and nondiabetic (NDM) (n=1,277) subjects were enrolled and the eight SNPs in CDKAL1 and HHEX genes associated with insulin secretion were genotyped in a Chinese population using MassARRAY. Then, the association of these SNPs with T2DM was analyzed.Results: Our results revealed that four SNPs (rs4712524, rs10946398, rs7754840 in CDKAL1, and rs5015480 in HHEX) showed significantly different distributions between the T2DM and NDM groups (P< 0.00625). The G allele of rs4712524 (P=0.004, OR=1.184; 95% CI=1.057– 1.327), C allele of rs10946398 (P< 0.001, OR=1.247; 95% CI=1.112– 1.398), and C allele of rs775480 in CDKAL1 (P< 0.001, OR=1.229; 95% CI=1.096– 1.387) functioned as risk alleles of T2DM. The C allele of rs5015480 in HHEX (P< 0.001, OR=1.295; 95% CI=1.124– 1.493) was also the risk factor for T2DM. The haplotype analysis revealed that CDKAL1 haplotype rs4712524G-rs10946398C-rs7754840C-rs9460546G (P=0.001, OR=1.210; 95% CI=1.076– 1.360) and HHEX haplotype rs1111875C-rs5015480C (P< 0.001, OR=1.364; 95% CI=1.180– 1.576) were the risk factors of T2DM.Conclusion: Our results revealed that genetic variations in CDKAL1 and HHEX were associated with T2DM susceptibility in Chinese population.Keywords: association study, single nucleotide polymorphisms, CDKAL1, HHEX, type 2 diabetes, Chinese population