The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

OBJECTIVE: Agar dilution method (ADM) was used as the golden standard to evaluate the consistency of Epsilometer test (E-test) in detecting the sensitivity of Helicobacter pylori (H. pylori) to metronidazole. METHODS: From August 2018 to July 2020, patients with H. pylori infection treated for the first time in Peking University Third Hospital for gastroscopy due to dyspepsia were included in this study. Gastric mucosas were taken from the patients with H. pylori infection. H. pylori culture was performed. Both the ADM and E-test were applied to the antibiotic susceptibility of H. pylori to metro-nidazole, and the consistency and correlation between the two methods were validated. RESULTS: In the study, 105 clinical isolates of H. pylori were successfully cultured, and the minimum inhibitory concentration ≥ 8 mg/L was defined as drug resistance. Both ADM and the E-test showed high resistance rates to metronidazole, 64.8% and 62.9%, respectively. Among them, 66 drug-resistant strains were detected by ADM and E-test, and 37 were sensitive strains, so the consistency rate was 98.1%. Two strains were evaluated as drug resistance by ADM, but sensitive by the E-test, with a very major error rate of 1.9%. There was zero strain sensitive according to ADM but assessed as resistant by the E-test, so the major error rate was 0%. Taking ADM as the gold standard, the sensitivity of E-test in the detection of metronidazole susceptibility was 97.1% (95%CI: 0.888-0.995), and the specificity was 100% (95%CI: 0.883-1.000). Cohen's kappa analysis showed substantial agreement, and kappa coefficient was 0.959 (95%CI: 0.902-1.016, P < 0.001). Spearmans correlation analysis confirmed this correlation was significant (r=0.807, P < 0.001). The consistency evaluation of Bland-Altman method indicated that it was good, and there was no measured value outside the consistency interval. In this study, cost analysis, including materials and labor, showed a 32.2% higher cost per analyte for ADM as compared with the E-test (356.6 yuan vs. 269.8 yuan). CONCLUSION The susceptibility test of H. pylori to metronidazole by E-test presents better agreement with ADM. Because it is less expensive, less labor intensive, and more rapid, it is an easy and reliable method for H. pylori susceptibility testing.
Humans ; Metronidazole/therapeutic use* ; Helicobacter pylori ; Agar/therapeutic use* ; Disk Diffusion Antimicrobial Tests ; Microbial Sensitivity Tests ; Helicobacter Infections/drug therapy* ; Anti-Bacterial Agents/therapeutic use*

Digestive system malignant tumor is one of the common malignant tumors in humans,and its high morbidity and low survival rate at advanced stages bring heavy disease burden to patients,families and society.However,current tumor screening technologies are not suitable for screening in large-scale populations and long-term follow-up because of the invasiveness or complexity.Thus,liquid biopsy,which based on biomarkers such as circulating tumor DNA,circulating tumor cells,exosomes and other new biomarkers,has broad prospects for development in tumor screening.Exosome,secreted by living cells,is a type of extracellular vesicle with the lipid bilayer.Compared to other biomarkers,exosome has the advantages of high stability,wide distribution,and high quantity.The various proteins carried by exosome can reflect the characteristics of the origin cells,and exosome has important research value for the early diagnosis of tumors.This article reviews the studies of exosomal proteins as biomarkers for early diagnosis of digestive system malignant tumors in the past five years,and summarizes the characteristics and limitations of the above studies,so as to provide reference for promoting the clinical transformation of exosomal proteins.

Gastric schwannoma is a tumor originating from mesenchymal tissue. The clinical incidence is relatively rare, accounting for 6.3% of all gastric stromal tumors. The tumor is more likely to occur in the body of the stomach and usually originates from the gastric submucosal nerve. Most gastric schwannomas do not have any clinical symptoms. Imaging examination can play a diagnostic role, but the diagnosis still requires pathological examination, especially S-100 protein which is the gold standard for the diagnosis of gastric schwannomas. Gastric schwannoma usually needs to be distinguished from gastrointestinal stromal tumors and gastrointestinal autonomic nerve tumors. In terms of treatment, complete surgical resection is the first choice.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common pathological type of glomerular disease. Kidney biopsy, the gold standard for IgAN diagnosis, has not been routinely applied in hospitals worldwide due to its invasion nature. Thus, we aim to establish a non-invasive diagnostic model and determine markers to evaluate disease severity by analyzing the serological parameters and pathological stages of patients with IgAN. METHODS: A total of 272 biopsy-diagnosed IgAN inpatients and 518 non-IgA nephropathy inpatients from the Department of Nephrology of Chinese People's Liberation Army General Hospital were recruited for this study. Routine blood examination, blood coagulation testing, immunoglobulin-complement testing, and clinical biochemistry testing were conducted and pathological stages were analyzed according to Lee grading system. The serological parameters and pathological stages were analyzed. The receiver operating characteristic (ROC) analysis was performed to estimate the diagnostic value of the clinical factors. Logistic regression was used to establish the diagnostic model. RESULTS: There were 15 significantly different serological parameters between the IgAN and non-IgAN groups (all P < 0.05). The ROC analysis was performed to measure the diagnostic value for IgAN of these parameters and the results showed that the area under the ROC curve (AUC) of total protein (TP), total cholesterol (TC), fibrinogen (FIB), D-dimer (D2), immunoglobulin A (IgA), and immunoglobulin G (IgG) were more than 0.70. The AUC of the "TC + FIB + D2 + IgA + age" combination was 0.86, with a sensitivity of 85.98% and a specificity of 73.85%. Pathological grades of I, II, III, IV, and V accounted for 2.21%, 17.65%, 62.50%, 11.76%, and 5.88%, respectively, with grade III being the most prevalent. The levels of urea nitrogen (UN) (13.57 ± 5.95 vs. 6.06 ± 3.63, 5.92 ± 2.97, 5.41 ± 1.73, and 8.41 ± 3.72 mmol/L, respectively) and creatinine (Cr) (292.19 ± 162.21 vs. 80.42 ± 24.75, 103.79 ± 72.72, 96.41 ± 33.79, and 163.04 ± 47.51 μmol/L, respectively) were significantly higher in grade V than in the other grades, and the levels of TP (64.45 ± 7.56, 67.16 ± 6.94, 63.22 ± 8.56, and 61.41 ± 10.86 vs. 37.47 ± 5.6 mg/d, respectively), direct bilirubin (DB) (2.34 ± 1.23, 2.58 ± 1.40, 1.91 ± 0.97, and 1.81 ± 1.44 vs. 0.74 ± 0.57 μmol/L, respectively), and IgA (310.35 ± 103.78, 318.48 ± 107.54, 292.58 ± 81.85, and 323.29 ± 181.67 vs. 227.17 ± 68.12 g/L, respectively) were significantly increased in grades II-V compared with grade I (all P < 0.05). CONCLUSIONS The established diagnostic model that combined multiple factors (TC, FIB, D2, IgA, and age) might be used for IgAN non-invasive diagnosis. TP, DB, IgA, Cr, and UN have the potential to be used to evaluate IgAN disease severity.
Adult ; Biomarkers ; blood ; Blood Urea Nitrogen ; Cholesterol ; blood ; Creatinine ; blood ; Female ; Fibrinogen ; metabolism ; Glomerulonephritis, IGA ; blood ; diagnosis ; pathology ; Humans ; Immunoglobulin A ; blood ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; ROC Curve

BACKGROUND: Accurate estimation of the glomerular filtration rate (GFR) and staging of chronic kidney disease (CKD) are important. Currently, there is no research on the differences in several estimated GFR equations for staging CKD in a large sample of centenarians. Thus, this study aimed to investigate the differences in CKD staging with the most commonly used equations and to analyze sources of discrepancy. METHODS: A total of 966 centenarians were enrolled in this study from June 2014 to December 2016 in Hainan province, China. The GFR with the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Berlin Initiative Study 1 (BIS1) equations were estimated. Agreement between these equations was investigated with the κ statistic and Bland-Altman plots. Sources of discrepancy were investigated by partial correlation analysis. RESULTS: The κ values of the MDRD and CKD-EPI equations, MDRD and BIS1 equations, and CKD-EPI and BIS1 equations were 0.610, 0.253, and 0.381, respectively. Serum creatinine (Scr) explained 10.96%, 41.60% and 17.06% of the variability in these three comparisons, respectively. Serum uric acid (SUA) explained 3.65% and 5.43% of the variability in the first 2 comparisons, respectively. Gender was associated with significant differences in these 3 comparisons (P < 0.001). CONCLUSIONS The strengths of agreement between the MDRD and CKD-EPI equations were substantial, but those between the MDRD and BIS1 equations and the CKD-EPI and BIS1 equations were fair. The difference in CKD staging of the first 2 comparisons strongly depended on Scr, SUA and gender, and that of CKD-EPI and BIS1 equations strongly depended on Scr and gender. The incidence at various stages of CKD staging was quite different. Thus, a new equation that is more suitable for the elderly needs to be built in the future.
Aged, 80 and over ; Asian Continental Ancestry Group ; Creatinine ; blood ; Cystatin C ; blood ; Female ; Glomerular Filtration Rate ; physiology ; Humans ; Male ; Renal Insufficiency, Chronic ; blood ; physiopathology ; Uric Acid ; blood

Biomarkers ; urine ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2 ; pathology ; urine ; Enzyme-Linked Immunosorbent Assay ; Hepatitis A Virus Cellular Receptor 1 ; metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; urine ; Kidney Diseases ; pathology ; urine ; Lipocalin-2 ; urine ; Membrane Proteins ; urine ; Sialoglycoproteins ; urine ; Tissue Inhibitor of Metalloproteinase-2 ; urine

Background: Type 2 diabetes (T2DM) patients are susceptible to Helicobacter pylori (HP), and it has been reported that the occurrence of proteinuria is associated with HP infection in T2DM patients; however, this view remains controversial. This meta-analysis aimed to explore the association between HP infection and the occurrence of proteinuria in T2DM patients. In addition, we hope to provide some recommendations to readers in clinical or related fields. Methods: Our meta-analysis was conducted with the methodology of the Cochrane Collaboration. Search strategies were formulated by relevant professionals. Case-control studies that compared the occurrence of proteinuria in T2DM patients with and without HP infection were involved in our meta-analysis. Relevant English or Chinese studies were searched on online databases before 2018, including PubMed, the Cochrane library, Medline, Google Scholar, the China National Infrastructure, and Wanfang database. The search strategies were "diabetic proteinuria, diabetic microalbuminuria, diabetic albuminuria, diabetic kidney disease, diabetic renal dysfunction, diabetic renal disease, diabetic nephropathy, diabetic complications, and diabetic mellitus, combined with HP." The quality of these involved articles was separately assessed by two investigators using the Newcastle-Ottawa Scale (NOS). Odds ratios (ORs) and associated 95% confidence intervals (CIs) were extracted and pooled using fixed-effects models. Results: Seven studies involving 1029 participants were included. The quality of these seven articles was all above five stars as assessed by NOS, and there was no significant publication bias in our meta-analysis. We found that T2DM patients with HP infection had a 2.00 times higher risk of the occurrence of proteinuria than patients without HP infection (OR: 2.00, 95% CI: 1.48-2.69). Conclusions Our analysis showed that HP infection was associated with the occurrence of proteinuria in T2DM patients. HP radical surgery might be a therapeutic option for protecting kidney function in patients with T2DM.
Confidence Intervals ; Diabetes Mellitus, Type 2 ; metabolism ; microbiology ; Helicobacter Infections ; metabolism ; microbiology ; Humans ; Kidney ; metabolism ; Proteinuria ; metabolism ; microbiology

Objective To analyze the HbA1c results of double heterozygotes of hemoglobin(Hb) NewYork and β-thalassemia detected by five different HbA1c detection systems,and compare the early-warning abilities of erroneous glycosylated hemoglobin results for Hb NewYork and β-thalassemia heterozygotes.Methods Peripheral blood samples from 40 patients without hemoglobinopathies with different range of HbA1c levels were collected to evaluate the consistency of the detected results.Variant Ⅱ system was used as the reference system which successfully completed NGSP Level Ⅰ laboratory certification.Variant Ⅱ Turbo 2.0 (V Ⅱ-T),Capillary 2 Flex Piercing(2FP),Primus Ultra2 (Ultra2)and Roche Modular PPI(PPI) 800 were used as the comparative systems.The HbA1 c in 2 sera from the patients with compand heterozygotes of Hb NewYork was detected by the above systems.Hemoglobin electrophoresis was performed.Gentypes of á-and β-globin genes were analyzed by GAP-PCR,hybridization and dideoxy chain termination method.Results The HbA1c values in non-hemoglobinophthy samples obtained using V Ⅱ-T 2.0,Ultra2,C2FP and PPI systems were well correlated with that of VⅡ system.The hemoglobin genotypes of the two cases of compand heterozygotes were aa/aa,βIVS-2-654/βNewYork and aa/aa,β41-42/βNewYork,respectively.The proportions of HbA were all 0 while the proportions of Hb NewYork were 93.5％ and 94.0％ respectively.The HbA1c results of the two cases detected were 4.3％ (23 mmol/mol)and 4.5％ (26 mmol/mol)by V Ⅱ,4.5 ％ (26 mmol/mol) and 4.6％ (27 mmol/mol) by VⅡ-T 2.0,no values and no values by C2FP,4.1％ (21 mmol/mol) and 4.3 ％ (23 mmol/mol) by Ultra2 and 4.2％ (22 mmol/mol) and 4.8 ％ (29 mmol/mol) by PPI systems,respectively.All the systems did not send warning for abnormal signs in profiles and results.Conclusion The five systems presented different early-warning ability for the double heterozygotes of Hb NewYork and β-thalassemia.The compand heterozygotes should theoretically not contain HbA1 c,but the systems V Ⅱ,V Ⅱ-T,Ultra2 and PPI showed detectable results of HbA1 c indicating all the four systems were not able to provide with early-warning.C2FP system did not report HbA1c result so it exhibited early-warning ability for the double heterozygote.