Modeling and biological evaluation of pegmolesatide, a novel and potent erythropoiesis-stimulating agent.

Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.

Untargeted metabolomics reveal the metabolic profile of normal pulmonary circulation.

BACKGROUND: As an important place of material exchange, the homeostasis of the pulmonary circulation environment and function lays an essential foundation for the normal execution of various physiological functions of the body. Small metabolic molecules in the circulation can reflect the corresponding state of the pulmonary circulation. METHODS: We enrolled patients with Patent Foramen Ovale and obtained blood from the pulmonary arteries and veins through heart catheterization. UPLC-MS based untargeted metabolomics was used to compare the changes and metabolic differences of plasma between pulmonary vein and pulmonary artery. RESULTS: The plasma metabolomics revealed that pulmonary artery had a different metabolomic profile compared to venous. 1060 metabolites were identified, and 61 metabolites were differential metabolites. Purine, Amino acids, Nicotinamide, Tetradecanedioic acid and Bile acid were the most markedly. CONCLUSION: The differential metabolites are mostly related to immune inflammation and damage repaired. It is suggested that the pulmonary circulation is always in a steady state of injury and repair while pathological changes may be triggered when the homeostasis is broken. These changes play an important role in revealing the development process and etiology of lung homeostasis and related diseases. Relevant metabolites can be used as potential targets for further study of pulmonary circulation homeostasis.

Sulfuric acid leaching of ball-milling activated FePO4 residue after lithium extraction from spent lithium iron phosphate cathode powder.

A mechanical-chemical process is proposed to recover the iron phosphate residue(IPR)of spent lithium iron phosphate(LFP)after lithium extraction. In this process, the IPR was pretreated by ball-milling and leached with the sulfuric acid solution. The results showed that, under the optimized ball-milling conditions (a mass ratio of the stainless-steel-ball to material to water of 2:1:2.5, a milling time of 20 min), the maximum particle size of IPR decreased from 34.265 um to 13.102 um, the specific surface increased from 11.41 m2/g to 13.74 m2/g, and the cell volume distortion rate could reach 0.331 %. Under the optimized leaching conditions (a temperature of 333 K, a concentrated acid-to-material ratio of 0.46 mL/g, a liquid-to-solid ratio of 5:1 mL/g, and a stirring speed of 600 rpm), the leaching efficiency of iron phosphate could reach 98 %. The kinetic study indicated that the leaching was controlled by diffusion and chemical reaction with the apparent activation energy of 29 kJ/mol. The dissolution-precipitation phase transition of IPR was also found at high temperatures. This study illustrates that such a mechanical-chemical process is an effective way to improve the leaching efficiency of IPR with a lower sulfuric acid dosage, which has great potential in industrial applications.

Airway acidification impaired host defense against Pseudomonas aeruginosa infection by promoting type 1 interferon ß response.

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonß (IFN-ß) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-ß signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.

Total knee arthroplasty in Ranawat II valgus deformity with enlarged femoral valgus cut angle: A new technique to achieve balanced gap.

BACKGROUND: Nearly 10% of patients undergoing primary total knee arthroplasty (TKA) have valgus deformity (VD) of the knee. For severe VD of the knee, a more lateral structural release is needed to achieve balance between medial and lateral space and neutral femorotibial mechanical axis (FTMA), which is challenging and technical. AIM: To introduce a new surgical technique of resection, soft tissue release, and FTMA for Ranawat type-II VD with a 5-year follow-up. METHODS: A retrospective study was conducted on patients who underwent TKA from December 2011 to December 2014. Hip-knee-ankle (HKA), range of motion (ROM), Oxford knee score (OKS), and knee society score (KSS) were used to assess the joint activity of patients in the new theory TKA group (NT-TKA) and were compared with those of the conventional TKA group (C-TKA). RESULTS: A total of 103 people (103 knees) were included in this study, including 42 patients with an average follow-up period of 83 mo in the C-TKA group and 61 patients with an average follow-up period of 76 mo in the NT-TKA group. Six patients had constrained prosthesis, one had common peroneal nerve injury, and two had joint instability in the C-TKA group, but none of these occurred in the NT-TKA group. There were significant statistical differences in constrained prosthesis usage and complications between the groups (P = 0.002 and P = 0.034, respectively). The KSS at 1 mo post-operation for the C-TKA and NT-TKA groups were 11.2 ± 3.8 and 13.3 ± 2.9, respectively, with a significant difference (P = 0.007). However, the data of HKA, ROM, OKS KSS, and prosthesis survival rate were insignificant (P > 0.05) in both the preoperative and follow-up periods. CONCLUSION: Adopting 5°-7° valgus cut angle for VD and sacrificing 2° neutral FTMA for severe VD which cannot be completely corrected during TKA can reduce the need for soft tissue release, maintain early joint stability, reduce the use of constrained prostheses, and minimize postoperative complications.

Text Mining-Based Drug Discovery for Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: The current medical treatments for connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) do not show favorable efficiency for all patients, and identification of novel drugs is desired. Methods: Text mining was performed to obtain CTD- and PAH-related gene sets, and the intersection of the two gene sets was analyzed for functional enrichment through DAVID. The protein-protein interaction network of the overlapping genes and the significant gene modules were determined using STRING. The enriched candidate genes were further analyzed by Drug Gene Interaction database to identify drugs with potential therapeutic effects on CTD-PAH. Results: Based on text mining analysis, 179 genes related to CTD and PAH were identified. Through enrichment analysis of the genes, 20 genes representing six pathways were obtained. To further narrow the scope of potential existing drugs, we selected targeted drugs with a Query Score ≥5 and Interaction Score ≥1. Finally, 13 drugs targeting the six genes were selected as candidate drugs, which were divided into four drug-gene interaction types, and 12 of them had initial drug indications approved by the FDA. The potential gene targets of the drugs on this list are IL-6 (one drug) and IL-1ß (two drugs), MMP9 (one drug), VEGFA (three drugs), TGFB1 (one drug), and EGFR (five drugs). These drugs might be used to treat CTD-PAH. Conclusion: We identified 13 drugs targeting six genes that may have potential therapeutic effects on CTD-PAH.

Attenuation of cartilage pathogenesis in osteoarthritis by blocking the phosphorylation of tyrosine kinase Fyn to ß-catenin, AZD0530.

OBJECTIVE: To observe the effect of AZD0530 on the progression of knee OA after blocking ß-catenin phosphorylation and then dormancy of the Wnt/ß pathway by tyrosine kinase Fyn. METHODS: The levels of Fyn, ß-catenin, p-ß-catenin (Tyr142), the chondrocyte positive marker Aggrecan, and the chondrocyte negative marker MMP13 were observed in human knee tibial plateau chondrocytes in vivo and in vitro. Different doses of AZD0530 were used to treat chondrocytes of the human OA tibial plateau chondrocytes in vitro, and the degree of chondrocyte degeneration was observed. Different doses of AZD0530 were intraarticularly injected into OA rats to observe the degree of tibial plateau cartilage degeneration. RESULTS: When OA occurred in human knee, the levels of tyrosine kinase Fyn,ß-catenin and p-ß-catenin (Tyr142) in chondrocytes increased significantly.The level of Aggrecan decreased and MMP13 increased in chondrocytes. The levels of ß-catenin, p-ß-catenin (Tyr142) and MMP13 in chondrocytes decreased, while the level of Aggrecan increased after AZD0530 was used to intervene chondrocytes in vitro, which was positively correlated with the dose of AZD0530. Intra-articular injection of AZD0530 obviously attenuated the degeneration of articular cartilage, which was positively correlated with the dose of AZD0530. CONCLUSION: The level of Fyn in chondrocytes of human knee tibial plateau increased significantly when OA occurred. AZD0530 can inhibit tyrosine kinase Fyn from ß-catenin phosphorylation, a key Wnt/ß pathway protein, and then inhibit Wnt/ß pathway levels in chondrocytes. This finding also suggests that disruption of the Wnt/ß pathway with AZD0530 provides chondral protection in rat posttraumatic OA.

[Research progress of bone marrow edema-like lesions in knee osteoarthritis].

Knee osteoarthritis-associated bone marrow edema-like lesions (KOA-BMLs) is a common MRI imaging feature, which is mainly manifested as abnormal bone marrow hyperintensity in subchondral bone on T2 imaging. The formation of KOA-BMLs may be related to the abnormality of lower limb force line and subchondral bone perfusion, and related histopathological studies showed that the remodeling of bone and bone marrow in these damaged areas was abnormally increased. In KOA patients, the size of BMLs can fluctuate or even disappear in a relatively short period of time, and was closely related to pain, subchondral bone cyst formation, and the progression of KOA. However, the current treatment methods for KOA-BMLs are limited, and there is no uniform guideline or expert consensus, mainly includingmedication, physical therapy and surgical treatment. This article reviews the research progress of the disease characteristics and treatment of KOA-BMLs in order to provide guidance for the clinical diagnosis and treatment of KOA-BMLs.

Loss of Autophagy Causes Increased Apoptosis of Tibial Plateau Chondrocytes in Guinea Pigs with Spontaneous Osteoarthritis.

OBJECTIVE: The goal of the present study was to observe the effect of autophagy in tibial plateau chondrocytes on apoptosis in spontaneous knee osteoarthritis (OA) in guinea pigs. DESIGN: Fifty 2-month-old female Hartley guinea pigs were divided into a normal group (10 animals, all euthanized after 7 months) and an OA group (40 animals, 10 of which were euthanized after 10 months). Immunohistochemistry, RT-qPCR and Western blotting were used to evaluate autophagy levels, intracellular glycogen accumulation and apoptosis in tibial plateau chondrocytes in vivo and in vitro. The remaining 30 guinea pigs in the OA group were divided into 3 groups: a rapamycin group, a normal saline group, and a 3-methyladenine (3-MA) group. Intracellular glycogen accumulation and chondrocyte apoptosis were assessed by altering the level of autophagy in chondrocytes in vivo. RESULTS: When spontaneous OA occurred in guinea pigs, autophagy levels in tibial plateau chondrocytes decreased, while intracellular glycogen accumulation and the rate of chondrocyte apoptosis increased. After enhancing the level of autophagy in tibial plateau chondrocytes in guinea pigs with OA, intracellular glycogen accumulation and the rate of chondrocyte apoptosis decreased, while inhibiting autophagy had the opposite effects. CONCLUSION: The results indicate that the function of autophagy in chondrocytes may at least partly involve the catabolism of glycogen. In guinea pigs with OA, the level of autophagy in tibial plateau chondrocytes decreased, and chondrocytes were unable to degrade intracellular glycogen into glucose, leading to less energy for chondrocytes and increased apoptosis.

Experimental observation of the sequence of tibial plateau chondrocyte and matrix degeneration in spontaneous osteoarthritis in Guinea pigs.

BACKGROUND: To observe the sequence of chondrocyte degeneration and matrix degradation in the superficial surface cartilage of the tibial plateau in guinea pigs with spontaneous knee osteoarthritis (OA). METHODS: Sixty guinea pigs were euthanized at the ages of 8 months (n = 20),10 months (n = 20) and 12 months (n = 20) respectively. The degree of degeneration of the tibial plateau cartilage was evaluated by Osteoarthritis Research Society International (OARSI) score. The levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the chondrocytes were detected by immunohistochemistry (IHC). The serum concentration of CTX-II was measured and compared. Western blot analysis was used to detect the levels of Aggrecan,CollagenX,MMP-13 and Caspase-3 in the cartilage tissue. RESULTS: The OARSI scores both in 8-month-old group and 10-month-old group were lower than that in the 12-month-old group. The levels of Aggrecan in articular chondrocyte were higher both in 8-month-old group and 10-month-old group than that in 12-month-old group. The level of Collagen X increased with the age of guinea pigs. And the levels of MMP-13 and caspase-3 both in 10-month-old group and 12-month-old group were higher than those in 8-month-old group. The concentration of CTX-II in serum increased significantly in 12 months old group. CONCLUSION: The superficial chondrocytes of the tibial plateau first appeared to be hypertrophic and then apoptotic, and the matrix was further degraded when spontaneous knee osteoarthritis occurred in guinea pigs. Changes in the physiological state of chondrocytes are the initiating factors in the pathogenesis of knee OA.

[Progress on femorotibial mechanical axis of total knee arthroplasty].

Femorotibial mechanical axis (FTMA) is one of important factors influencing clinical effect after total knee arthroplasty (TKA). It is generally believed that the range of lower limb alignment after TKA is controlled within neutral FTMA ± 3 °, which has more advantages in improving joint function, prolonging prosthesis survival rate and reducing revision rate, and obtain better clinical results. Therefore, neutral FTMA is also considered to be the gold standard for TKA. However, with the application of computer-assisted surgery and other technologies, the alignment of FTMA is more accurate than before, but the clinical effect after surgery has not significantly improved. Some scholars have begun to question the necessity of neutral alignment of FTMA, and proposed alignment methods such as kinematics and retained residual deformity, which could achieve better clinical effects. In recent years, it has been reported that FTMA might not be the most important factor influencing postoperative clinical effects, and it is suggested that the arrangement and measurement of lower limbs and the effects on adjacent joint functions could affect clinical effect after TKA. The paper reviews neutral FTMA alignment is still an important factor for success of TKA. After a thorough evaluation according to the patient's condition, it should be appropriately applied in the case of neutral FTMA alignment; the operator should explore other factors which affect clinical outcome after TKA, and improve it to achieve the best therapeutic effect.

Rare variants in MTHFR predispose to occurrence and recurrence of pulmonary embolism.

BACKGROUND: Rare genetic variants play a critical role in unprovoked pulmonary embolism (PE). However, the known risk genes only account a small proportion of patients with PE. The objective of this study was to investigate the relationship between the rare variants of gene encoding methylenetetrahydrofolate reductase (MTHFR) and the initiation and long-term clinical outcomes of PE. METHODS: The rare variants of MTHFR were detected by whole exome sequencing of DNA from 258 unprovoked PE cases and 11,451 controls. Correlation of genotype and clinical phenotype and outcome were evaluated at baseline and after follow-up. RESULTS: MTHFR rare variants were found in 15 of 258 cases (5.81%) and 241 of 11,451 controls (2.10%), conferring 2.87-fold greater odds of the PE occurrence (OR = 2.87, 95% CI = 1.68-4.91, P = 5.6 × 10-5, chi-square test). The patients with MTHFR rare variants had higher plasma level of homocysteine than those without. During a follow-up of 3.0 years, a total of 84 events were identified. The recurrent PE (two or more events of PE) were significantly higher in patients carrying MTHFR rare variants (8/15, 53.3%) compared with those without (55/239, 23.0%) (P = 0.023). CONCLUSION: We speculate that MTHFR rare variants may increase the occurrence and recurrence of PE.

Effectiveness of Lifestyle and Drug Intervention on Hypertensive Patients: a Randomized Community Intervention Trial in Rural China.

BACKGROUND: Strict medication guidance and lifestyle interventions to manage blood pressure (BP) in hypertensive patients are typically difficult to follow. OBJECTIVE: To evaluate the 1-year effectiveness of lifestyle and drug intervention in the management of rural hypertensive patients. DESIGN: Randomized community intervention trial. PARTICIPANTS: The control group comprised 967 patients who received standard antihypertensive drug intervention therapy from two communities, whereas the intervention group comprised 1945 patients who received antihypertensive drug and lifestyle intervention therapies from four communities in rural China. MAIN MEASURES: Data on lifestyle behaviors and BP measurements at baseline and 1-year follow-up were collected. A difference-in-difference logistic regression model was used to assess the effect of the intervention. KEY RESULTS: BP control after the 1-year intervention was better than that at baseline in both groups. The within-group change in BP control of 59.3% in the intervention group was much higher than the 25.2% change in the control group (P < 0.001). Along with the duration of the follow-up period, systolic and diastolic BP decreased rapidly in the early stages and then gradually after 6 months in the intervention group (P < 0.001). In the intervention group, drug therapy adherence was increased by 39.5% (from 48.1% at 1 month to 87.6% at 1 year) (P < 0.001), more in women (45.6%) than in men (31.2%; P < 0.001). The net effect of the lifestyle intervention improved the rate of BP control by 56.1% (70.8% for men and 44.7% for women). For all physiological and biochemical factors, such as body mass index, waist circumference, lipid metabolism, and glucose control, improvements were more significant in the behavioral intervention group than those in the control group (all P < 0.001). CONCLUSION: The addition of lifestyle intervention by physicians or nurses helps control BP effectively and lowers BP better than usual care with antihypertensive drug therapy alone.

Observational cohort study of clinical outcome in Epstein-Barr virus associated gastric cancer patients.

BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) has unique clinicopathologic features and our present understanding of its treatment outcome is limited. Here, we investigated the clinical outcomes of resectable and metastatic EBVaGC cases with regards to their respective treatment. METHODS: We retrieved the data of EBVaGC patients treated at our center from October 2014 to June 2019. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) for stage I-III patients, progression-free survival (PFS) and objective response rate (ORR) for stage IV patients. RESULTS: Patients classified as stage I-III accounted for 83.7% of the total 197 cases analyzed. Two patients had mismatched repair-deficiency. The 5-year OS rate of the entire cohort was 63.51% [95% (confidence interval (CI): 52.31-72.76%]. Tumor-node-metastasis (TNM) stage and gastric stump cancer were identified as independent prognostic factors for OS. The 3- and 5-year DFS rate for stage I-III patients were 83.72% (95% CI: 75.86-89.19%) and 73.83% (95% CI: 60.39-83.32%), respectively. TNM stage III, neural invasion, lymphovascular invasion, and baseline plasma EBV-DNA positive were correlated with shorter DFS. The ORR and disease control rate (DCR) for metastatic EBVaGC patients to first-line therapy were 29.0% and 90.3% (median PFS: 9.8 months), respectively, and to second-line therapy were 25.0% and 75.0%, respectively. Seven patients received anti-PD1 therapy and had an ORR of 28.5% and a median PFS of 2.8 months. CONCLUSIONS: EBVaGC patients have few metastases, long DFS, and high DCR. TNM stage and gastric stump cancer were independent prognostic factors for OS.

The features of rare pathogenic BMPR2 variants in pulmonary arterial hypertension: Comparison between patients and reference population.

BACKGROUND: Mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2) are the most common genetic risk factors underlying pulmonary arterial hypertension (PAH). However, the features of PAH-related BMPR2 rare variants remain unclear. We propose that the discrepancy of BMPR2 rare variants landscape between patients with PAH and reference population would be important to address the genetic background of PAH-related variants. METHODS: We genotyped BMPR2 rare variants in 670 Chinese patients with pulmonary arterial hypertension. The BMPR2 rare variants were screened in 10,508 reference people from two exome databases. RESULTS: The prevalence of rare BMPR2 variants in patients with PAH was significantly higher compared to the reference population (21.5%, 144/670 vs 0.87%, 91/10508, p = 1.3 × 10-118). In patients with PAH, 49% of identified BMPR2 rare variants were loss-of-function or splicing. These BMPR2 rare variants were only observed in 1% of the reference population (p = 9.0 × 10-12). Arg491, which is absent in the reference population, represented as hot-spot site (14.6%, 21/144) in PAH patients. BMPR2 missense mutations in PAH patients were more likely distributed in extracellular ligand-binding domain (ECD, 29.7% vs 11.1%, p < 0.001). Compared with Non-PAH-related variations, PAH-related missense variants tend to alter the amino acid electric status (51.4% vs 23.3%, p < 0.001). CONCLUSIONS: BMPR2 variants located in extracellular ligand-binding domain or altered the amino acid electric status are more pathogenic.

Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension.

Importance: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with high heritability; however, the bone morphogenetic protein receptor 2 (BMPR2) gene only accounts for 17% of IPAH. The genetic basis of IPAH needs further investigation. Objective: To identify novel IPAH susceptibility genes other than BMPR2. Design, Setting, and Participants: This 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had no BMPR2 variants and were compared with 968 healthy control participants. Data were collected from January 1, 2000, to July 31, 2015, and analyzed from August 1, 2015, to May 30, 2018. Exposures: PTGIS rare variants. Main Outcomes and Measures: Whole-genome sequencing was performed to identify putative IPAH genes in a discovery cohort, with validation in an independent referral cohort. Correlation of genotype and hemodynamic characteristics was then evaluated at baseline and after pulmonary vasodilator testing. Functional assessments were conducted to analyze the effects of identified genetic variants on transcript splicing, enzymatic activity, and endothelial cell phenotypes. Results: Among 230 patients with IPAH (164 female [71.3%]; mean [SD] age, 34 [18] years), an enrichment of rare variants in a gene encoding prostacyclin synthase (PTGIS) was identified in the discovery cohort. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In the combined data set, PTGIS rare variants were found in 14 of 230 cases (6.1%) and 8 of 968 controls (0.8%) (odds ratio, 7.8; 95% CI, 3.2-18.8; P = 5 × 10-6, logistic regression). Compared with patients without PTGIS variants, inhaled iloprost induced a more significant decrease of pulmonary vascular resistance (difference in the least square mean, -21.7%; 95% CI, -31.4% to -12.0%; P < .001, linear regression model) and an increase of cardiac index (difference in the least square mean, 18.3%; 95% CI, 8.8%-27.8%; P < .001, linear regression model) in patients with PTGIS variants. The minigene assay indicated that the c.521 + 1G>A variant resulted in aberrant messenger RNA transcripts. The functional studies showed that the 2 missense rare variants (R252Q and A447T) resulted in a decrease in prostacyclin production and increased cell death of pulmonary microvascular endothelial cells. Conclusions and Relevance: This study identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation. These findings suggest that PTGIS variants may be involved in the pathogenesis of IPAH.

LiCl-promoted amination of ß-methoxy amides (γ-lactones).

An efficient and mild method has been developed for the amination of ß-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,ß-unsaturated intermediates followed by the Michael addition of amines.

Prospective observation: Clinical utility of plasma Epstein-Barr virus DNA load in EBV-associated gastric carcinoma patients.

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.