Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies.

BACKGROUND: Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility. METHODS: The antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma. RESULTS: B2M-/TRAC- universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A-/B-/TRAC- novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application. CONCLUSIONS: The nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.

Association between inflammatory bowel disease and cancer risk: evidence triangulation from genetic correlation, Mendelian randomization, and colocalization analyses across East Asian and European populations.

BACKGROUND: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have been inconsistent and may face the bias of confounding and reverse causality. The potential causal relationships between IBD and the risk of cancers remain largely unclear. METHODS: We performed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analyses using summary genome-wide association study (GWAS) data across East Asian and European populations to evaluate the causal relationships between IBD and cancers. Sensitivity analyses for the MR approach were additionally performed to explore the stability of the results. RESULTS: There were no significant genetic correlations between IBD, CD, or UC and cancers (all P values > 0.05) in East Asian or European populations. According to the main MR analysis, no significant causal relationship was observed between IBD and cancers in the East Asian population. There were significant associations between CD and ovarian cancer (odds ratio [OR] = 0.898, 95% CI = 0.844-0.955) and between UC and nonmelanoma skin cancer (OR = 1.002, 95% CI = 1.000-1.004, P = 0.019) in the European population. The multivariable MR analysis did not find any of the above significant associations. There was no shared causal variant to prove the associations of IBD, CD, or UC with cancers in East Asian or European populations using colocalization analysis. CONCLUSIONS: We did not provide robust genetic evidence of causal associations between IBD and cancer risk. Exposure to IBD might not independently contribute to the risk of cancers, and the increased risk of cancers observed in observational studies might be attributed to factors accompanying the diagnosis of IBD.

Contributions of bone marrow monocytes/macrophages in myeloproliferative neoplasms with JAK2V617F mutation.

The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Despite having the same JAK2V617F mutation, the clinical manifestations of these three subtypes of MPN differ significantly, which suggests that the bone marrow (BM) immune microenvironment may also play an important role. In recent years, several studies have shown that peripheral blood monocytes play an important role in promoting MPN. However, to date, the role of BM monocytes/macrophages in MPN and their transcriptomic alterations remain incompletely understood. The purpose of this study was to clarify the role of BM monocytes/macrophages in MPN patients with the JAK2V617F mutation. MPN patients with the JAK2V617F mutation were enrolled in this study. We investigated the roles of monocytes/macrophages in the BM of MPN patients, using flow cytometry, monocyte/macrophage enrichment sorting, cytospins and Giemsa-Wright staining, and RNA-seq. Pearson correlation coefficient analysis was also used to detect the correlation between BM monocytes/macrophages and the MPN phenotype. In the present study, the proportion of CD163+ monocytes/macrophages increased significantly in all three subtypes of MPN. Interestingly, the percentages of CD163+ monocytes/macrophages are positively correlated with HGB in PV patients and PLT in ET patients. In contrast, the percentages of CD163+ monocytes/macrophages are negatively correlated with HGB and PLT in PMF patients. It was also found that CD14+CD16+ monocytes/macrophages increased and correlated with MPN clinical phenotypes. RNA-seq analyses demonstrated that the transcriptional expressions of monocytes/macrophages in MPN patients are relatively distinct. Gene expression profiles of BM monocytes/macrophages suggest a specialized function in support of megakaryopoiesis in ET patients. In contrast, BM monocytes/macrophages yielded a heterogeneous status in the support or inhibition of erythropoiesis. Significantly, BM monocytes/macrophages shaped an inflammatory microenvironment, which, in turn, promotes myelofibrosis. Thus, we characterized the roles of increased monocytes/macrophages in the occurrence and progression of MPNs. Our findings of the comprehensive transcriptomic characterization of BM monocytes/macrophages provide important resources to serve as a basis for future studies and future targets for the treatment of MPN patients.

Change of neck circumference in relation to visceral fat area: a Chinese community-based longitudinal cohort study.

BACKGROUND/OBJECTIVES: Neck circumference (NC) has been positively associated with visceral fat area (VFA) in cross-sectional studies. This study aimed to evaluate the effects of NC changes on VFA in a Chinese community-based longitudinal cohort. SUBJECTS/METHODS: Subjects recruited from Shanghai communities were followed up for 1.1-2.9 years. A total of 1421 subjects (men 578, women 843) were included, aged 24-80 years, with an average age of 57.8 ± 7.1 years. INTERVENTIONS/METHODS: Biochemical and anthropometric measurements, including NC, were obtained from all subjects. VFA was assessed by magnetic resonance imaging. Abdominal obesity was defined as a VFA ≥ 80 cm2. RESULTS: After a mean follow-up of 2.1 years, the NCs for men and women were 38.1 ± 2.3 cm and 33.8 ± 2.0 cm, respectively, and the average value of VFA was 84.55 (59.83-113.50) cm2. After adjusting for age, sex, body mass index, smoking, history of drinking, glycated hemoglobin, blood pressure and blood lipids, individuals who had gained a NC of more than 5% had 1.26 (95% CI: 1.05-1.49) times more visceral adipose tissue at follow-up than NC maintainers (NC change between -2.5% and 2.5%). In the non-abdominal obesity group at baseline (n = 683), after adjusting for confounding factors, changes in NC were associated with abdominal obesity (odd ratio 1.23, 95% CI: 1.09-1.39). CONCLUSIONS: Changes in NC were positively associated with VFA in a Chinese community-based cohort, suggesting that NC measurement is practical for assessing abdominal obesity.

GM-CSF impairs erythropoiesis by disrupting erythroblastic island formation via macrophages.

Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.

Chain structure and ß conformation of poly(9,9-dioctylfluorene) (PFO) with different molecular weights delivering from the solution to the film in a drop-casting process.

Over the last decade, considerable attention has been paid to the formation mechanism of the ordered ß conformation for PFO both in the solution and film to prepare high-efficiency optoelectronic devices. However, the process of solvent evaporation and aggregates transferred from the solution to the film also play key roles in forming ordered structures, which have been neglected. In this study, the influence of molecular weight on the above process was systematically studied using techniques such as SLS/DLS, UV-Vis, PL, and TEM. Five samples with different Mw ranging from 25 100 Da to 117 000 Da were obtained by the precipitation fractionation method. In dilute THF solution, the molecular chains were in α conformation without aggregates. In films, as the molecular weight increased, the content of ß conformation and ordered structure increased first and then decreased. By studying the solvent evaporation process, for the first time, we propose a possible mechanism for the transformation process of chain structure and ß conformation from the solution to the film, which involves three stages. This study reveals the transformation process of the chain structure and ß conformation of PFO from the solution to the film and its relationship with the molecular weight, which provides theoretical and practical versions for in-depth understanding and control of the formation of the ordered structure in high-efficiency films.

The relationship between sex hormones and glycated hemoglobin in a non-diabetic middle-aged and elderly population.

BACKGROUND: Sex hormones are strongly linked to the occurrence and development of diabetes, and influence glycated hemoglobin (HbA1c) levels in diabetic population; but, the relationship between sex hormones and HbA1c in non-diabetic population remains unknown. This study aimed to explore the extent of influence of sex hormones on HbA1c levels in non-diabetic population. METHODS: A total of 1409 non-diabetic subjects, including 601 men and 808 postmenopausal women were recruited from Shanghai community. HbA1c was detected using high performance liquid chromatography, and hemoglobin level was determined by sodium lauryl sulfate colorimetry. Serum estradiol (E2), total testosterone (TT), and sex hormone binding globulin (SHBG) were measured by chemiluminescent microparticle immunoassays. RESULTS: The level of HbA1c was 5.6 (5.4-5.9) % in all subjects, with 5.6 (5.4-5.8) % in men and 5.7 (5.5-5.9) % in postmenopausal women. After adjusting for age, body mass index (BMI), and hemoglobin, E2 was positively correlated with HbA1c in men (r = 0.122, P = .003), and SHBG was inversely correlated with HbA1c (r = - 0.125, P < .001) in women. Other hormones were not correlated with HbA1c (all P > .05). Multivariate linear regression analysis showed that, except for traditional factors, such as age, hemoglobin, and BMI, E2 was another determinant of HbA1c (standardized ß = 0.137, P = .003) in men; besides, in women, SHBG was another determinant of HbA1c (standardized ß = - 0.178, P < .001), except for age and systolic blood pressure. CONCLUSION: After controlling for confounding factors, two sex hormones, as E2 and SHBG could influence HbA1c levels in non-diabetic population.

Neck circumference predicts development of carotid intima-media thickness and carotid plaque: A community-based longitudinal study.

BACKGROUND AND AIMS: Carotid intima-media thickness (C-IMT) is an important index for evaluating subclinical atherosclerosis. Neck circumference (NC), a new anthropometric index of the upper body fat, is closely related to cardiovascular disease (CVD) and CVD risk factors. This study investigated the relationship between NC, C-IMT, and carotid plaque in a community-based cohort. METHODS AND RESULTS: Participants recruited from Shanghai communities were followed up for 1.1-2.9 years. All participants underwent anthropometric and biochemical measurements. Elevated NC was defined as NC ≥ 38.5 cm and NC ≥ 34.5 cm in men and women, respectively. Elevated C-IMT, determined by ultrasound, was defined as a level higher than the 75th percentile in the study population (>0.75 mm). In total, 1189 participants without carotid plaque at baseline were included, with an average age of 59.6 ± 7.3 years. After a mean follow-up of 2.1 ± 0.2 years, 203 participants developed carotid plaques. After adjusting for various atherosclerosis risk factors, the logistic regression showed that the higher NC group had a significantly greater risk of developing carotid plaque than the lower NC group (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.12-2.14; P = 0.008). Of those without carotid plaque at follow-up, 495 participants developed elevated C-IMT. Compared to the lower NC group, the higher NC group had a significantly increased risk of elevated C-IMT (OR, 1.49; 95% CI, 1.14-1.95; P = 0.003). CONCLUSION: Higher NC was significantly positively correlated with the risk of carotid plaque and elevated C-IMT.

Neck circumference for predicting the occurrence of future cardiovascular events: A 7.6-year longitudinal study.

BACKGROUND & AIMS: This study aimed to investigate whether neck circumference (NC) could be used to predict future cardiovascular (CV) events in a community-based Chinese cohort. METHODS AND RESULTS: We enrolled 1435 participants aged 50-80 years (men, 43.62%) from communities in Shanghai. High NC was defined as NC ≥ 38.5 cm in men and NC ≥ 34.5 cm in women. Kaplan-Meier analysis and Cox proportional hazards regression were performed to explore the association between NC and CV events. During a mean follow-up period of 7.6 years, 148 CV events (10.31%) occurred. The incidence of CV events was higher in men than in women (83 (13.26%) vs. 65 (8.03%), P = 0.002). Multivariable-adjusted Cox regression analysis showed that for every 1-SD increase in NC in the whole population, the hazard ratio (HR) of CV events was 1.45 (95% confidence interval [CI], 1.15-1.83). The dose-response association between NC and CV events was significant in men (HR, 1.37, 95% CI, 1.10-1.71) but not in women (HR, 1.19, 95% CI, 0.94-1.52). In comparison with participants showing low baseline NC, those with high baseline NC showed a significantly higher risk of CV events (HR, 1.59, 95% CI, 1.14-2.22). Further stratified by sex, the positive association remained significant in men (HR, 1.90, 95% CI, 1.21-2.98) but not in women (HR, 1.25, 95% CI, 0.75-2.07). CONCLUSION: NC was significantly associated with the risk of future CV events in middle-aged and elderly populations in the community and was a better predictor in men.

Associations between sex hormones and metabolic-associated fatty liver disease in a middle-aged and elderly community.

Metabolic-associated fatty liver disease (MAFLD) was proposed by an international expert consensus to replace non-alcoholic fatty liver disease (NAFLD) in 2020. Previous studies have shown that sex hormones are strongly linked to NAFLD development. This study aims to explore whether sex hormones are associated with MAFLD and liver fat content (LFC) in a middle-aged and elderly community. The study included 732 subjects aged 50-80 years enrolled from communities. MAFLD was diagnosed using the 2020 International Expert Consensus. LFC was calculated using parameters from abdominal ultrasound images. Serum estradiol (E2), total testosterone (TT), sex hormone-binding globulin (SHBG), FSH, and LH were measured by chemiluminescent microparticle immunoassay. MAFLD was diagnosed in 107/304 (35.2%) men and 154/428 (35.2%) women. After adjustments for confounding factors, logistic regression analysis showed that SHBG was negatively correlated with MAFLD in men (OR, 0.95 [0.93-0.97], p < 0.001). In women, SHBG and FSH were negatively correlated with MAFLD (OR, 0.95 [0.94-0.97], p < 0.001; OR, 0.97 [0.96-0.98], p < 0.001). Multivariate linear regression analysis showed that SHBG was a negative factor for LFC in both men (standardized ß = -0.188, p < 0.001) and women (standardized ß = -0.184, p < 0.001). FSH was a negative factor for LFC in women (standardized ß = -0.082, p = 0.046). SHBG was negatively correlated with MAFLD in middle-aged and elderly men and women. Moreover, FSH was negatively correlated, and bioactive testosterone was positively correlated with MAFLD in women. These findings suggest a relationship between sex hormones and MAFLD.

Neck Circumference Predicts the Occurrence and Remission of Metabolic Associated Fatty Liver Disease: A Longitudinal Study of Community-Dwelling Population.

AIM: Neck circumference (NC), a proxy for upper-body subcutaneous fat, is closely related to metabolic dysfunction, independent of other obesity indices. The purpose of this study was to explore the relationship between NC and the incidence and remission of metabolic associated fatty liver disease (MAFLD), a novel concept proposed by an international consensus panel in 2020 through a community-based longitudinal cohort. METHODS: This study included 1,549 community participants and was conducted from 2013 to 2016. MAFLD was diagnosed using the International Expert Consensus (2020) criteria. All participants underwent NC measurement and biochemical measurements. Elevated NC was defined as NC ≥38.5 cm in men and NC ≥34.5 cm in women. RESULTS: A total of 1,549 subjects (638 men and 911 women), with an average age of 59.6 ± 7.3 years, were included. During a mean follow-up of 2.1 years, MAFLD occurred in 146 of the 870 participants without baseline MAFLD and was resolved in 225 of the 679 participants with baseline MAFLD. After adjusting for confounding factors such as age, sex, body mass index, waist circumference, fasting plasma glucose, and liver enzyme levels, multivariable logistic regression showed that higher NC at baseline was positively correlated with MAFLD occurrence (OR 1.96, 95% confidence interval: 1.21-3.31; p = 0.003) and negatively correlated with MAFLD remission (OR 0.57, 95% confidence interval: 0.40-0.80; p < 0.001). CONCLUSION: A higher NC is associated with an increased risk of MAFLD occurrence and a reduced probability of MAFLD remission, making NC measurement a potential predictor in MAFLD management.

Association of suboptimal health status with intestinal microbiota in Chinese youths.

Suboptimal health status (SHS), a physical state between health and disease, is a subclinical and reversible stage of chronic disease. Previous studies have shown alterations in the intestinal microbiota in patients with some chronic diseases. This study aimed to investigate the association between SHS and intestinal microbiota in a case-control study with 50 SHS individuals and 50 matched healthy controls. Intestinal microbiota was analysed by MiSeq 250PE. Alpha diversity of intestinal microbiota in SHS individuals was higher compared with that of healthy controls (Simpson index, W = 2238, P = .048). Beta diversity was different between SHS and healthy controls (P = .018). At the phylum level, the relative abundance of Verrucomicrobia was higher in the SHS group than that in the controls (W = 2201, P = .049). Compared with that of the control group, nine genera were significantly higher and five genera were lower in abundance in the SHS group (all P < .05). The intestinal microbiota, analysed by a random forest model, was able to distinguish individuals with SHS from the controls, with an area under the curve of 0.79 (95% confidence interval: 0.77-0.81). We demonstrated that the alteration of intestinal microbiota occurs with SHS, an early stage of disease, which might shed light on the importance of intestinal microbiota in the primary prevention of noncommunicable chronic diseases.

Association between telomere length in peripheral blood leukocytes and risk of ischemic stroke in a Han Chinese population: a linear and non-linear Mendelian randomization analysis.

BACKGROUND: Many contradictory conclusions pertaining to the telomere length in peripheral leukocyte chromosomes as a potential biomarker for ischemic stroke (IS) risk have been reported by the various observational studies in previous years. This study aims to investigate whether the leukocyte telomere length is associated with an increased IS risk or not, based on the Mendelian randomization (MR) approach. METHODS: Based on the NHGRI-EBI GWAS Catalog database, the Chinese online genetic database as well as the previous published studies, twelve single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 0.05 were selected and the leukocyte telomere length was measured in 431 first-ever IS patients and 304 healthy controls (quantitative polymerase chain reaction). To explore linear and non-linear effect of telomere length on the IS risk, we preformed the linear MR analysis (the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method), and the non-linear MR analysis (semiparametric method with three tests for non-linearity, including the quadratic test, Cochran's Q test, and the fractional polynomial test). RESULTS: Two verified SNPs (rs11125529 and rs412658) were chosen as instrumental variables. In linear MR analysis, the adjusted odds ratios and 95% confidence intervals of IS for genetically predicted telomere lengths, based on the two SNPs, were 1.312 (0.979 to 1.759), 1.326 (0.932 to 1.888) and 1.226 (0.844 to 1.781) for the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method, respectively. Three tests for nonlinearity failed to reject the null exactly, indicating that the relationship between telomere length and IS risk is unlikely to be non-linear. CONCLUSION: This MR study based on individual data does not provide strong evidence for a positive linear or non-linear effect of telomere length on the IS risk.

Tumor suppressor miR-139-5p targets Tspan3 and regulates the progression of acute myeloid leukemia through the PI3K/Akt pathway.

Dysregulation of microRNAs is closely implicated in the initiation and progression of human cancers including acute myeloid leukemia (AML). Though miR-139-5p was reported to be a potent tumor suppressor in adult AML, its underlying molecular mechanism in AML remains to be further defined. Herein, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were conducted to determine the expressions of miR-139-5p and tetraspanin3 (Tspan3) in AML patients and cells. Luciferase reporter assay, qRT-PCR, and Western blot analysis were carried out to detect the interaction between miR-139-5p and Tspan3. Cell proliferation, cell cycle distribution, invasion, and migration were evaluated by cell counting kit-8, flow cytometry, transwell invasion, and migration assays, respectively. Western blot analysis was conducted to determine phosphorylated-protein kinase B (Akt) and Akt levels. We found that a significant reduction in miR-139-5p expression and a prominent increase in Tspan3 expression were observed in AML patients and cells. Tspan3 was confirmed as a direct target of miR-139-5p and was negatively modulated by miR-139-5p. Rescue experiments showed that overexpression of miR-139-5p constrained cell proliferation, invasion and migration capabilities, and induced cell cycle arrest at the S phase in AML cells, which were partially reversed by Tspan3 overexpression. In addition, we found that miR-139-5p suppressed the phosphoinositide 3-kinase (PI3K)/Akt pathway in AML cells by targeting Tspan3. In conclusion, our study concluded that miR-139-5p suppressed the leukemogenesis in AML cells by targeting Tspan3 through inactivation of the PI3K/Akt pathway, providing a better understanding of AML progression.

Ischemic stroke is associated with the pro-inflammatory potential of N-glycosylated immunoglobulin G.

BACKGROUND: Glycosylation significantly affects protein structure and function and thus participates in multiple physiologic and pathologic processes. Studies demonstrated that immunoglobulin G (IgG) N-glycosylation associates with the risk factors of ischemic stroke (IS), such as aging, obesity, dyslipidemia, type 2 diabetes, and hypertension. METHODS: The study aimed to investigate the association between IgG N-glycosylation and IS in a Chinese population. IgG glycome composition in patients with IS (n = 78) and cerebral arterial stenosis (CAS) (n = 75) and controls (n = 77) were analyzed by ultra-performance liquid chromatography. RESULTS: Eleven initial glycans and 10 derived glycans in IgG glycome representing galactosylation, sialylation, and bisecting GlcNAc significantly differed between IS patients and CAS and healthy controls after controlling for gender, age, obesity, diabetes, hypertension, and dyslipidemia. Logistic regression models incorporating IgG glycan traits were able to distinguish IS from CAS (area under receiver-operator characteristic curves (AUC), 0.802; 95% confidence interval (CI), 0.732-0.872) and controls (AUC, 0.740; 95% CI, 0.661-0.819). The canonical correlation analysis indicated that initial N-glycan structures are significantly correlated with inflammation markers (r = 0.566, p < 0.001). CONCLUSION: Our findings indicated that loss of galactose and sialic acid, as well as addition of bisecting GlcNAc, might involve in pro- or anti-inflammatory IgG functionality and further contribute to the pathogenesis of IS. IgG glycan profiles may be developed as clinical useful biomarkers for chronic disease in the future.

DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia.

We aimed to investigate the association between dihydropyrimidine dehydrogenase (DPYD) gene polymorphisms and the risk of pediatric acute lymphoblastic leukemia (ALL) and its prognosis after chemotherapy. A total of 147 pediatric ALL patients diagnosed by our hospital between January 2011 and December 2014 were included in the case group, and 102 healthy people who received a physical examination during the same time frame in our hospital were included in the control group. DNA sequencing was applied for site determination and genotyping of the DPYD 85T > C, 2194G > A, 1156G > T, and IVS14 + 1G > A polymorphisms. The genotype and allele frequencies of the two groups were compared. A significant difference was found in the comparison of the mutant gene and allele frequencies of the 85T > C polymorphism between the case and control groups (P < 0.05). The CT and CC genotypes in the 85T > C polymorphism were associated with the risk of the disease (OR = 1.592, 95 % CI = 1.010-2.509), suggesting that the recessive gene (85C) was more likely to lead to the occurrence of ALL compared with the dominant gene (85T) (P < 0.05). Patients carrying the C allele of the 85T > C polymorphism presented higher damage of their liver functions and higher infection rates compared with patients carrying the non-C allele (P < 0.05). A higher proportion of liver function damage and a higher infection rate were found in patients with the GA genotype in the IVS14 + 1G > A polymorphism compared with the GG genotype (P < 0.05). The complete remission (CR) rate in patients with the GG genotype in the IVS14 + 1G > A polymorphism was higher than in patients with the GA genotype (P = 0.020). After 5-fluorouracil/calcium folinate (5-FU/CF)-based chemotherapy, the event-free survival (EFS) rate of patients with the TT genotype was higher than patients with the CT and CC genotypes (P < 0.05). Our results revealed that the C allele of the 85T > C polymorphism might be associated with susceptibility to pediatric ALL. Patients carrying the C allele may have an increased risk of ALL. Thus, the 85T > C polymorphism may be a predictor of CR for pediatric ALL patients.

Twin Scholarships of Glycomedicine and Precision Medicine in Times of Single-Cell Multiomics.

Systems biology and multiomics research expand the prospects of planetary health innovations. In this context, this mini-review unpacks the twin scholarships of glycomedicine and precision medicine in the current era of single-cell multiomics. A significant growth in glycan research has been observed over the past decade, unveiling and establishing co- and post-translational modifications as dynamic indicators of both pathological and physiological conditions. Systems biology technologies have enabled large-scale and high-throughput glycoprofiling and access to data-intensive biological repositories for global research. These advancements have established glycans as a pivotal third code of life, alongside nucleic acids and amino acids. However, challenges persist, particularly in the simultaneous analysis of the glycome and transcriptome in single cells owing to technical limitations. In addition, holistic views of the complex molecular interactions between glycomics and other omics types remain elusive. We underscore and call for a paradigm shift toward the exploration of integrative glycan platforms and analysis methods for single-cell multiomics research and precision medicine biomarker discovery. The integration of multiple datasets from various single-cell omics levels represents a crucial application of systems biology in understanding complex cellular processes and is essential for advancing the twin scholarships of glycomedicine and precision medicine.

Bispecific antibodies in immunotherapy for adult acute leukemia: latest updates from the 65th American Society of Hematology 2023 Annual Meeting.

Introduction Bispecific antibodies (BsAbs) represent a novel and potentially effective approach in cancer immunotherapy. These antibodies feature two unique binding domains, enabling them to simultaneously attach to two antigens or two epitopes of a single antigen. Recently, a variety of BsAbs targeting distinct B-cell antigens and myeloid lineage-specific surface markers-such as CD19xCD3, CD38xCD3, and CD123xCD3-have demonstrated promising results in heavily pretreated relapsed/refractory acute lymphoblastic leukemia (R/R ALL) and relapsed/refractory acute myeloid leukemia (R/R AML) patients. Areas covered New trail results were reported by different research groups at the 65th annual meeting of the American Society of Hematology (ASH). We provide a summary of the latest progress in BsAbs for immunotherapy in adult acute leukemia. Expert opinion B-ALL is the most favored leukemia for treatment with BsAbs, unlike T-ALL and AML, which are limited in constructs and results. The clinical application of blinatumomab in the first-line setting, combined with other therapies, has clearly benefited these B-ALL patients, especially older adults, due to its lower toxicity. In the B-ALL relapsed/refractory setting, new combinations with blinatumomab are under investigation, such as PD-1 or CTLA-4 inhibitors. We believe that with more clinical trial results, it is possible that blinatumomab will be used in new clinical indications soon. No novel BsAbs developed for B-ALL have yielded better results.

CD7-positive leukemic blasts with DNMT3A mutations predict poor prognosis in patients with acute myeloid leukemia.

Background: DNMT3A mutations can be detected in premalignant hematopoietic stem cells and are primarily associated with clonal hematopoiesis of indeterminate potential; however, current evidence does not support assigning them to a distinct European Leukemia Net (ELN) prognostic risk stratification. CD7 is a lymphoid antigen expressed on blasts in approximately 30% of acute myeloid leukemia (AML), and its role in AML remains unclear and depends on subgroup evaluation. This study investigated the prognostic value of DNMT3A mutation combined with CD7 expression in AML. Methods: We retrospectively analyzed the clinical data of 297 newly diagnosed non-M3 AML patients. According to the DNMT3A mutation and CD7 expression in AML cells, patients were divided into the DNMT3A-mutated/CD7-positive (CD7+), DNMT3A-mutated/CD7-negative (CD7-), DNMT3A-wild-type/CD7+, and DNMT3A-wild-type/CD7- groups. Results: The DNMT3A-mutated/CD7+ group had lower complete remission rates and higher relapse rates. Importantly, these patients had significantly shorter overall survival (OS) and relapse-free survival (RFS). Furthermore, multivariate analysis showed that CD7+ with DNMT3A mutation was an independent risk factor for OS and RFS. Conclusion: CD7+ with DNMT3A mutation predicts a poor prognosis in AML patients, and the immunophenotype combined with molecular genetic markers can help to further refine the current risk stratification of AML.

Rectal culture could predict carbapenem-resistant organism bloodstream infection and reduce the mortality in haematological patients: A retrospective cohort study.

OBJECTIVES: The objective is to explore the correlation between rectal swab culture and the overall 30-d survival of hematologic patients diagnosed with carbapenem-resistant organism (CRO) bloodstream infection. METHODS: A total of 434 haematological patients who were complicated with Gram-negative bacilli (GNB) bloodstream infections (BSIs) caused by Gram-negative bacteria between January 2020 and December 2021 were included in our retrospective study. Based on their drug susceptibility results, we classified patients into CRO BSIs and non-CRO BSIs cases. Through group comparison, to uncover the correlation between the positive screening of rectal swabs and reducing the mortality of CRO BSI in patients with haematological diseases. RESULTS: Among the 434 cases of Gram-negative bacteria bloodstream infection, 96 were identified as carbapenem-resistant bloodstream infection, which consisted of 57 cases of carbapenem-resistant Klebsiella pneumoniae (CR-KP), 19 cases of carbapenem-resistant Pseudomonas aeruginosa (CR-PA), 11 cases of carbapenem-resistant Escherichia coli (CR-CO), 5 cases of carbapenem-resistant Acinetobacter baumannii (CR-AB), and 4 cases of other Enterobacteriaceae. Before the onset of CRO bloodstream infection, rectal swab cultures were conducted on 36 patients, and the positive result rate was 75.0% (27/36), with 20 cases of CR-KP, 6 cases of CR-CO, and one case of carbapenem-resistant Enterobacter cloacae. It was observed that the rectal and blood cultures had matching outcomes in 75.0% of cases. The mortality rate within 30 d for CRO BSIs was 53.1% (51/96), while for carbapenem-resistant Enterobacteriaceae (CRE) BSIs it was 62.5% (45/72). Univariate analysis showed that 30-d mortality was significantly reduced when there were positive rectal culture results preceding bloodstream infection (P < 0.001), as well as preemptive anti-infection treatment (P < 0.001). Multivariate analysis demonstrated that preemptive adjustment to an effective antibiotic regimen, guided by positive rectal culture results, had a significant effect on decreasing 30-d mortality following CRO BSIs (P= 0.002). Furthermore, for the management of CRE BSIs, antibiotic treatments utilising ceftazidime/avibactam (CAV/AVI) may be more beneficial compared to those that use tigecycline (TGC) or polymyxin (PMB). CONCLUSION: CRO BSI, especially CRE BSI, can be life-threatening for those with haematological diseases. Utilising rectal culture can effectively identify CRO strains with high sensitivity and specificity. Adjusting antibiotic treatment based on the preemptive positive rectal culture results may significantly decrease 30-d mortality rates for haematological patients with CRO BSIs.