PurposedNatural Killer cell kinetics and Killer-cell immunoglobulin-like receptors (KIRs) are increasingly recognized for their role during allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the prognostic impact of donor KIR haplotype configurations on patient survival remains controversial. To clarify this relationship, we conducted a systematic review and meta-analysis evaluating the impact of donor KIR haplotypes on the survival of patients undergoing allo-HSCT.MethodsWe systematically searched PubMed, Embase, the Cochrane Library, and CBM. Data were analyzed using RevMan5.4. Pooled hazard ratio (HR) for time-to-event data. Subgroup analyses were performed for sample size, area, donor type, T cell replete or deplete, GVHD prophylaxis, and lymphoid or myeloid.Results17 eligible studies were included, and meta-analysis showed that donor KIR B/X genotype is associated with significantly superior overall survival (HR = 0.68, 95%CI, 0.56-0.82; P<0.0001), reduced relapse incidence (HR = 0.61, 95%CI, 0.44-0.85; P = 0.003), and improved relapse-free survival (HR = 0.61, 95%CI, 0.46-0.81; P = 0.0008).DiscussionThe findings suggest that donor KIR B/X haplotype is associated with favorable survival outcomes in allo-HSCT including HLA-matched sibling, unrelated donor, and haploidentical transplantation, supporting its potential utility as a reference biomarker for donor selection.

Objectives: This study investigated the impact of clinical frailty on short-term outcomes of simultaneous colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) resections. Setting and participants: Data of older patients ≥ 60 years old undergoing simultaneous CRC/CRLM resections between 2005 and 2018 were identified in the United States (US) Nationwide Inpatient Sample (NIS) database. Methods: Frailty was determined using the Hospital Frailty Risk Score (HFRS) according to the International Classification of Diseases Ninth and Tenth (ICD-9 and ICD-10) codes. Study outcomes included mortality, prolonged hospital stay (LOS), non-routine discharge, and complications. Results: Data of 4514 patients were analyzed. Frailty was significantly associated with increased risks of in-hospital mortality (adjusted odds ratio [aOR] = 3.65, 95% confidence interval [CI]: 2.52, 5.28), non-routine discharge (aOR = 2.44, 95% CI: 2.08, 2.87), prolonged LOS (aOR = 3.07, 95% CI: 2.60, 3.61), overall complications (aOR = 3.47, 95% CI: 3.03, 3.97), sepsis (aOR = 13.73, 95% CI: 9.76, 19.31), respiratory failure (aOR = 4.99, 95% CI: 3.80, 6.57), acute kidney injury (AKI) (aOR = 6.42, 95% CI: 4.83, 8.52), and acute liver failure (aOR = 2.10, 95% CI: 1.38, 3.21), as well as 32.69 thousand USD higher total hospital costs (95% CI: 28.41, 36.97) than no frailty. Incorporating frailty with traditional demographic and clinical risk factors improved in-hospital mortality prediction (area under ROC curve [AUC]: 0.765 to 0.799). Conclusions: In older patients aged ≥ 60 years undergoing simultaneous CRC and CRLM resection, HFRS-defined frailty is a significant predictor of adverse in-hospital outcomes. The addition of HFRS-defined frailty to demographic and clinical variables in predictive models improved the AUC for mortality prediction. Incorporating frailty assessment into the preoperative risk stratification and decision-making process for these patients may support surgeons in delivering more personalized and effective care.

This Supplementary information consists of (1) materials and methods of FCM; (2) 1 table and 8 supplementary figures.

Background The Philadelphia (Ph) chromosome is the hallmark chromosome aberration in chronic myeloid leukemia (CML), which confers the cancer phenotype of the disease. However, how the Ph chromosome forms and the genetic clonal evolution structure after targeted Ph treatment are still unclear. Methods In this study, we performed genome sequencing and clonal evolution analyses in a series of bone marrow specimens and skin biopsy from a CML patient who had received hematopoietic stem cell transplantation from her sister, then relapsed (lymphoid blast crisis), and received Ph-targeted therapy. Results The Ph chromosome was the “driver” clonal change in the original CML and the relapse. Both the patient and her sister had micro-deletions in the BCR gene region; however, the patient had a frameshift BRIP1 mutation that may account for the malfunctioning homologous recombination DNA repair of the BCR gene region and formation of the Ph chromosome. Conclusion We found that the BCR-ABL1 translocation was the driving force of the patient’s CML and relapse. The malfunctioning double-strand DNA break repair caused by the BRIP1 mutation could be the cause of Ph chromosome formation in the patient.

Objectives: Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews. Methods: We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence. Results: The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96). Conclusions: These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

Transmembrane TNF-α (tmTNF), a transmembrane form of TNF-α, was reported overexpressed in approximately 84% of triple-negative breast cancer (TNBC) patients and has emerged as a valid candidate biomarker for targeting TNBC. Paclitaxel is a first-line chemotherapeutic agent for the treatment of triple-negative breast cancer, but suffers from low water solubility, resulting in its low bioavailability. To achieve site-specific delivery of the anticancer chemotherapeutic drug (paclitaxel) on TNBC, we developed tmTNF-α monoclonal antibody (mAb)-conjugated paclitaxel (PTX) nanoparticles (NPs) (tmTNF-α mAb-PTX NPs) as potential nanocarriers. This targeted delivery-therapy nanocarriers was conducted by using an emulsification-evaporation method. tmTNF-α mAb-PTX NPs displayed favorable physicochemical properties. Compared with the control groups, tumor growth in human MDA-MB-231 xenograft mice was suppressed significantly by tmTNF-α mAb-PTX NPs. TmTNF-α mAb-PTX NPs exerts anti-tumor effects via promoting apoptosis and regulating mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) cascade, as well as AMP-activated protein kinase (AMPK) and nuclear factor Kappa-B (NF-κB) pathways. Moreover, tmTNF-α mAb-PTX NPs can inhibit the process of epithelial-mesenchymal transition (EMT) in TNBC to suppress tumor progression and metastasis. Together, the novel tmTNF-α mAb-PTX NPs based targeted drug delivery system is a potentially highly effective approach for treating TNBC.

Background:The level of uric acid and serum lipids has been suggested as a possible biomarker of bipolar disorder. We aimed to investigate the differences in clinical features and serum levels of lipids and uric acid in patients with bipolar depression or unipolar depression in order to distinguish them. Methods:The clinical data of 53 patients with unipolar depression (unipolar group) and 61 patients with bipolar depression (bipolar group), who all met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV of the American Psychiatric Association, were compared with each other retrospectively. The serum levels of uric acid and lipids (including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides) were measured after hospital admission. The Statistical Package for the Social Science version 22.0 software was used for statistical analysis, and logistic regression was employed to identify the susceptible factors of bipolar depression. Results:Taking into account confounding factors, logistic regression analysis revealed that the high levels of uric acid (odds ratio = 1.016, P = .001) and low levels of triglycerides (odds ratio = 0.457, P = .025) were significantly correlated with bipolar depression. Conclusion:It has been demonstrated from this study that individuals with bipolar depression have higher serum uric acid levels and lower triglyceride levels than unipolar depression ones. Therefore, serum levels of uric acid and triglycerides might have the potential to be the biomarkers for differential diagnosis between bipolar and unipolar depression.

OBJECTIVE:ABCB1 polymorphisms were previously demonstrated to be associated with the metabolism and resistance of carbamazepine (CBZ) in epilepsy, but the results still remained controversial. Therefore, we performed this meta-analysis to further evaluate the impacts of ABCB1 polymorphisms on CBZ metabolism and resistance.METHODS:The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database and Wan Fang Database were searched for eligible publications up to 5 July 2021. The mean difference (MD), Odds ratio (OR) and 95 % confidence interval (CI) were calculated by Review Manager 5.3 software to assess the strength of the association.RESULTS:Twelve studies involving 2126 epilepsy patients were included in this meta-analysis. We found that the TC genotype (heterozygous model: TC vs. CC) of rs1045642 polymorphism was significantly connected with decreased CBZ concentration. Furthermore, this polymorphism was indicated to be associated with concentrations of carbamazepine-10, 11-epoxide (homozygote model: TT vs. CC; heterozygous model: TC vs CC; dominant model: TT + TC vs. CC; over-dominant model: TC vs. TT + CC) and carbamazepine-10, 11-trans dihydrodiol (heterozygous model: TC vs. CC; dominant model: TT + TC vs. CC). Moreover, the AG genotype of rs2032582 polymorphism was related to increased CBZ concentration in heterozygous (AG vs. GG), dominant (AA + AG vs. GG) and over-dominant (AG vs. AA + GG) models. Additionally, rs1128503 was associated with CBZ resistance in heterozygous model (TC vs. CC).CONCLUSIONS:ABCB1 rs1045642 and rs2032582 polymorphisms were associated with CBZ metabolism for epilepsy, and rs1128503 was related to CBZ resistance. These findings would contribute to improving individualized therapy of epileptic patients.

In recent decades, survival was significantly improved in B cell acute lymphoblastic leukemia (B-ALL) patients. But refractory and relapsed B-ALL still has aggressive clinical behavior and poor prognosis. Especially, the patients with central nervous system infiltration is very difficult to achieve complete remissions with routine treatment. Chimeric antigen receptor-modified T-cell therapy targeting CD-19 has shown to be a beneficial treatment approach in refractory and relapsed B cell acute lymphoblastic leukemia (r/r ALL). However, there are very few studies reporting to treatment of refractory and relapsed B cell ALL with central nervous system infiltration. Here, we reported one single case of a patient diagnosed with relapsed B cell ALL with CNS infiltration who was successfully treated by second generation CAR containing a co-stimulator CD28 or 4-1BB therapy. Long-term proliferation of CAR-T cells in peripheral blood and bone marrow was observed more than 18 months. After CAR-T treatment, the patient got toxicity of grade 1 cytokine release syndrome and achieved significantly 36 months event free survival of follow-up. It is suggested that CD-19 CAR containing CD28 or 4-1BB costimulatory may be an effective therapy in refractory and relapsed B cell ALL with central nervous system infiltration. Its toxicity is mild, and its safety is high. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02349698.

Osteoporosis is now a worldwide public health problem that seriously endangers human health, but its causes have not yet been fully clarified. Recently, increasing evidence suggested that polymorphisms in CYP19A1 gene were associated with osteoporosis risk and bone mineral density (BMD), but results remained conflicting. We herein performed a meta-analysis based on evidence currently available from the literature to make a more precise estimation of these relationships. The PubMed, Embase, Cochrane library, CNKI (China National Knowledge Infrastructure), and Wan Fang databases were searched for eligible studies. Odds ratio (OR), mean difference (MD), and 95% confidence interval (CI) were applied to assess the strength of these relationships. A total of 8 studies involving 2632 subjects were included in our meta-analysis. We observed that the AG genotype of CYP19A1 rs700518 was significantly associated with lower BMD values of lumbar spine and femoral neck (AG vs. GG: p = .001 and.01, respectively). However, this polymorphism had no obvious impacts on osteoporosis risk according to current available data. In conclusion, the present meta-analysis showed that CYP19A1 rs700518 polymorphism may be a potential candidate biomarker for osteoporosis screening, early diagnosis, and treatment, which will help improve individualized therapy of osteoporosis patients in clinics.

Abstract Purpose: Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR T cells, resulting in tumor relapse of patients in complete remission (CR). In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). Patients and Methods: In this one-arm, open-labeled study, we infused the T cells modified with hCAR to patients with r/r ALL. Patients were evaluated with long-term follow-up for response and safety of the treatment. The study was registered at Clinicaltrials.gov (NCT02349698). Results: Ten patients with r/r ALL were recruited for this study. All were response evaluable and all achieved CR; eight patients remained CR, and six were in CR for over 18 months without further treatment. A long-term persistence of hCAR T cells was observed in most of the patients. Among these patients, four of them with high tumor burden and rapidly progressive disease (median, 58%) experienced grade 3–4 cytokine release syndrome (CRS) and neurotoxicity. These severe CRSs were successfully controlled by tocilizumab, glucocorticoid, and plasma exchange. Conclusions: T cells expressing the humanized anti-CD19 scFv CARs exhibited sustained therapeutic efficacy in the treatment of r/r ALL. Low replase rate was associated with the long-term persistence of CAR T cells.

BackgroundS100A8 plays a key role in many cellular processes and is highly expressed in various solid cancers. However, the prognostic role of S100A8 has not been well defined. Therefore, we conducted a quantitative meta-analysis to investigate whether or not S100A8 could be used as a prognostic biomarker in solid tumors.MethodsPubMed, Web of Science, Embase, and Cochrane library were searched to acquire relevant studies that evaluated the association between expression of S100A8 and prognosis of cancer patients. Pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were extracted to evaluate the association between S100A8 overexpression and Overall Survival (OS), Disease-Free Survival (DFS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS). The expression of S100A8 was also validated by Flow cytometry, immunohistochemistry (IHC), and western blot.ResultsA total of 2,817 patients from 13 independent studies, ranging from 43 to 1,117 patients in size, were statistically analyzed. Our results indicated that a high level of S100A8 expression was significantly associated with poor OS, poor DFS, and poor PFS/RFS. In term of clinical pathological characteristics, a high expression level of S100A8 was significantly associated with differentiation grades, lymphatic metastasis, ER statue, and PR statue. The validation studies showed that the expression of S100A8 was at high levels in MDA-MB-231 (79.7%), MDA-MB-453 (89.2%), HTB-9 (70.2%), and T24 (53.3%) cells and it was higher in breast cancer tissue and bladder cancer tissue than their corresponding para-carcinoma tissue.ConclusionsS100A8 overexpression was significantly associated with poor clinical prognosis in cancer patients. S100A8 is potential a prognostic biomarker in breast cancer and bladder cancer. More well-designed studies with adequate prognostic data are needed to confirm the prognostic role of S100A8 revealed in this study.

OBJECTIVES Due to the narrow therapeutic window of valproic acid (VPA), grievous adverse reactions such as hepatotoxicity, nephrotoxicity may occur in patients with epilepsy for a long time. This study aimed to explore the effect of VPA concentration on biochemical and routine blood test related to liver, renal, and hematology in epileptic outpatients treated with VPA alone or combined with other antiepileptic drugs. METHODS A total of 3 194 Chinese epileptic outpatients from Xiangya Hospital, were analyzed in a crude analysis after stratifying through dosage regimens. The plasma VPA concentration was detected by gas chromatography method and then standardized through dosage and body weight. Ten biochemical indexes related to liver, renal, and hematology were evaluated. RESULTS Of all patients, blood urea nitrogen (BUN), serum creatinine (SCr) level, and erythrocyte count (RBC) showed positive correlations with standardized VPA concentration (r=0.494, r=0.157, r=0.596, respectively), while platelet specific volume (PCT) and blood platelet (PLT) showed negative correlations with standardized VPA concentration (r=-5.500, r=-0.086, respectively). After stratifying through dosage regimens, significantly positive associations between SCr and standardized VPA concentration were found in the juvenile patients from the monotherapy group and combination therapy group (r=1.800, r=0.352, respectively). In addition, PLT and leukocyte count (WBC) in the juvenile patients from the combination therapy group were negatively correlated with standardized VPA concentration (r=-1.463, r=-0.079, respectively), while RBC showed a positive association with standardized VPA concentration in the juvenile patients from the monotherapy group (r=0.068). CONCLUSIONS SCr level is significantly associated with plasma VPA concentration. Drug combination and age are important factors leading to hematological disorders. The finding provides potential theoretical guidance for the rational and safe clinical use of VPA.

AbstractBackground and objectiveCYP3A4(rs2242480),CYP3A5(rs776746) andSCN1A(rs3812718 and rs2298771) gene polymorphisms were previously indicated to be associated with carbamazepine (CBZ) metabolism and resistance in epilepsy. However, previous studies regarding the effects of these polymorphisms still remain controversial. Therefore, we performed a meta-analysis to evaluate whether the four polymorphisms are associated with CBZ metabolism and resistance.MethodsThe PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched up to January 2020 for appropriate studies regarding the association of rs2242480, rs776746, rs3812718 and rs2234922 polymorphisms with metabolism and resistance to CBZ. The meta-analysis was conducted by Review Manager 5.3 software.ResultsEighteen studies involving 2574 related epilepsy patients were included. Significant associations betweenCYP3A4rs2242480,CYP3A5rs776746 andSCN1Ars3812718 polymorphisms and plasma concentrations of CBZ were observed. Additionally,SCN1Ars3812718 polymorphism was significantly associated with CBZ resistance. However, no association was observed betweenSCN1Ars2298771 polymorphism and metabolism and resistance to CBZ.ConclusionTheCYP3A4rs2242480,CYP3A5rs776746 andSCN1Ars3812718 polymorphisms may play important roles in metabolism and resistance to CBZ, whileSCN1Ars2298771 polymorphism is not associated with CBZ in epilepsy. These findings would improve the individualized therapy of epileptic patients in clinics.

OBJECTIVE:Fracture is a common consequence of osteoporosis and is associated with high morbidity and mortality. Recently, increasing evidence has suggested that polymorphisms in tumor necrosis factor-α (TNF-α) gene were associated with osteoporosis risk and bone mineral density (BMD), but results remain conflicting. We herein performed a meta-analysis based on evidence currently available from the literature to make a more precise estimation of these relationships.METHODS:The PubMed, EMBASE, Cochrane Library, CNKI (China National Knowledge Infrastructure) and Wan Fang databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed and all available data were accumulated. The pooled odds ratios (ORs) or mean differences (MDs) and corresponding 95% confidence intervals (CIs) were applied to assess the strength of the relationships.RESULTS:A total of 15 studies involving 5273 subjects were included in our meta-analysis. The GG genotype of TNF-α G308A was associated with an increased risk of osteoporosis under a mutant model (GG vs GA+AA: OR = 0.63, 95% CI: 0.51-0.77, P < 0.0001, I2  = 31%). Additionally, we also observed a significant association between G308A polymorphism and BMD of lumbar spine (AA vs GG: P = 0.01, I2  = 53%). However, TNF-α T1031C, C857T and C863A polymorphisms had no obvious impacts on osteoporosis risk.CONCLUSIONS:The present meta-analysis demonstrated that TNF-α G308A polymorphism may act as a potential candidate biomarker for screening, diagnosis, and treatment of osteoporosis, which will help improve individualized therapy of osteoporosis patients in clinics.

Fluorescent in situ hybridization (FISH) is commonly used to determine the ratio of human epidermal growth factor receptor 2 (HER2) to centromere enumeration probe for chromosome 17 (CEP17), which further determines HER2 gene status in breast cancer. However, due to copy number alteration in CEP17, inaccurate diagnoses can occur. The current study was performed to investigate the diagnostic value of an alternative CEP17 reference probe for HER2 status in invasive breast cancer. A higher-order repeat in the centromeric region of chromosome 17 was identified and an alternative probe (SCEP17) was subsequently prepared. Karyotype analysis of peripheral blood was used to detect SCEP17 probe specificity. Using a HER2/CEP17 probe, karyotype analysis revealed two strong green signals at the centromere of chromosome 17 and one weaker signal at the other centromere. However, two strong hybridization signals at the centromere of chromosome 17 were observed when the HER2/SCEP17 probe was used. In the 425 patients with invasive breast cancer, no statistical difference was observed between HER2/SCEP17 and HER2/CEP17 when detecting HER2 gene amplification (P=0.157). However, in terms of copy number, the SCEP17 probe exhibited a reduced number compared with the conventional CEP17 probe (P<0.001). In conclusion, the HER2/SCEP17 probe may lead to increased accuracy HER2 status assessment in invasive breast cancer. However, a further large-scale and prospective clinical trial is required for confirmation of the potential benefits of using the HER2/SCEP17 probe.

BackgroundEPHX1 gene polymorphisms were recently acknowledged as an important source of individual variability in carbamazepine metabolism, but the result of that association still remains controversial. Aim of the review To obtain a more precise estimation of the associations between EPHX1 polymorphisms and carbamazepine metabolism and resistance. Methods The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched for appropriate studies regarding the rs1051740 and rs2234922 polymorphisms of EPHX1 up to September 2019. The meta-analysis was carried out using the Review Manager 5.3 software. The mean difference and 95% confidence interval were applied to assess the strength of the relationship. Results A total of 7 studies involving 1118 related epilepsy patients were included. EPHX1 rs1051740 polymorphism was significantly associated with adjusted concentrations of both carbamazepine (CC vs. TT: P = 0.02; CC vs. CT + TT: P = 0.005) and carbamazepine-10,11-epoxide (CC vs. CT + TT: P = 0.03). Furthermore, EPHX1 rs2234922 polymorphism was also observed to be significantly associated with decreased adjusted concentrations of carbamazepine-10,11-trans dihydrodiol (GG vs. GA + AA: P = 0.04) and CBZD:CBZE ratio (GG vs. AA: P = 0.008; GG vs. GA + AA: P = 0.0008). Nevertheless, the pooled analysis showed that the EPHX1 polymorphisms had no significant effect on CBZ resistance. Conclusion EPHX1 rs1051740 and rs2234922 polymorphisms may affect the carbamazepine metabolism; but carbamazepine resistance was not related to any of the single nucleotide polymorphisms investigated. These findings provided further evidence for individualized therapy of epilepsy patients in clinics.

Background The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. Methods The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. Results Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. Conclusions CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

T cells modified with anti-CD19 chimeric antigen receptor (CAR) containing either CD28 or 4-1BB (also termed TNFRSF9, CD137) costimulatory signalling have shown great potential in the treatment of acute lymphoblastic leukaemia (ALL). However, the difference between CD28 and 4-1BB costimulatory signalling in CAR-T treatment has not been well elucidated in clinical trials. In this study, we treated 10 relapsed or refractory ALL patients with the second generation CD19 CAR-T. The first 5 patients were treated with CD28-CAR and the other 5 patients were treated with 4-1BB CAR-T. All the 10 patients were response-evaluable. Three patients achieved complete remission and 1 patient with extramedullary disease achieved partial response after CD28-CAR-T treatment. In the 4-1BB CAR-T treatment group, 3 patients achieved complete remission. Furthermore, FLT-3 ligand (FLT3LG) was highly correlated with response time and may serve as a prognosis factor. No severe adverse events were observed in these 10 treated patients. Our study showed that both CD28 CAR-T and 4-1BB CAR-T both worked for response but they differed in response pattern (peak reaction time, reaction lasting time and reaction degree), adverse events, cytokine secretion and immune-suppressive factor level.