Combined transcriptome and metabolome analysis revealed the molecular mechanisms of fruit skin coloration in pink strawberry.

Elucidating the key genes and metabolites responsible for fruit skin color is essential for the breeding of strawberry varieties with beautiful fruit color. Here, transcriptome and metabolome analyses were used to identify the key genes and metabolites associated with fruit skin color in strawberry accessions of red skin (Kaorino), white skin (2012-W02), and the pink skin (Fenyu NO.1, the F1 hybrid of Kaorino and 2012-W02). The metabolomic data showed that the content of anthocyanin-related metabolites, such as p-Coumaroyl quinic acid, 5-Hydroxyconiferyl alcohol and Coumestrol were significantly higher in red-skinned strawberry line Kaorino than in the white-skinned line 2012-W02. The flavonoids and isoflavonoids such as syringetin and 2,7,4'-trihydroxy-isoflavone, were less expressed in the Kaorino than in the other two accessions. Transcriptome analysis revealed that the expression of genes involved in anthocyanin biosynthesis, such as BZ1, F3H, CHS, CHI, DFR, 4CL, PAL, CCR, 4CL, F5H, REF1 and UGT72E, were also significantly upregulated in the red-skinned line Kaorino compared to the white-skinned line 2012-W02, while the HCT, CYP75B1, FG3, HIDH, IF7MAT, I2'H, and VR was downregulated in Kaorino. Combined transcriptome and metabolome analyses revealed that the pathways of isoflavonoid biosynthesis and flavone and flavonol biosynthesis, and the phenylpropanoid biosynthesis pathway essential for anthocyanin synthesis were commonly enriched by DRMs and DEGs. In addition, the metabolites of peonidin 3-O-glucoside, 2'-hydroxydaidzein and daidzin, and the genes of CYP93B2_16 and UGT73C6 were detected and most accumulated in pink-skinned Fenyu NO.1. This result suggested that the main strategy for obtaining a red skin color is to enhance the upstream pathway of anthocyanin biosynthesis, including the phenylpropanoid biosynthesis pathway, and to restrict the downstream steps in the flavonoid biosynthesis pathway, such as the branch pathway of flavone and flavonol biosynthesis and isoflavonoid biosynthesis.

Short-term peritoneal rest reduces peritoneal solute transport rate and increases ultrafiltration in high/high average transport peritoneal dialysis patients: a crossover randomized controlled trial.

Background: The peritoneal solute transport rate (PSTR) tends to increase over time in some patients undergoing peritoneal dialysis (PD), potentially leading to ultrafiltration (UF) failure. Previous case reports have shown a significant decrease in PSTR and subsequent recovery of UF after discontinuing PD for a while. Therefore, we conducted a randomized controlled crossover study to evaluate the impact of short-term peritoneal rest on PSTR. Methods: The study involved 14 continuous ambulatory peritoneal dialysis (CAPD) patients with high/high-average transport rate. Two groups were randomly assigned different treatment sequences: one group underwent daily intermittent peritoneal dialysis (IPD) for 4 weeks followed by CAPD, while the other group initially received CAPD treatment for 4 weeks and then switched to IPD. Peritoneal equilibration tests were performed before and after each treatment to evaluate PSTR and paired t-tests were used to compare the changes. Volume load, serum potassium and other clinical indicators were monitored at the same time. Results: Short-term peritoneal rest (daily IPD) significantly reduced PSTR, with a decrease in the dialysate:plasma creatinine ratio from 0.71 ± 0.05 to 0.65 ± 0.07 (P < .001). Additionally, ultrafiltration significantly increased from 210 ± 165 ml to 407 ± 209 ml (P = .001). But there were no significant changes in interleukin-6 and vascular endothelial growth factor of PD effluent. No serious adverse events such as hypotension or hyperkalaemia occurred. Conclusions: In PD patients with high and high-average transport, a 4-week period of short-term peritoneal rest by switching from CAPD to IPD (without long dwell) can lead to reductions in PSTR and increases in UF volumes, while maintaining clinical safety.

Specificity protein 1/3 regulate T-cell acute lymphoblastic leukemia cell proliferation and apoptosis through ß-catenin by acting as targets of miR-495-3p.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic heterogeneous disease. This study explored the mechanism of specificity protein 1/3 (Sp1/3) in T-ALL cells through ß-catenin by acting as targets of miR-495-3p. Expression levels of miR-495-3p, Sp1, Sp3, and ß-catenin in the serum from T-ALL children patients, healthy controls, and the T-ALL cell lines were measured. The cell proliferation ability and apoptosis rate were detected. Levels of proliferation-related proteins proliferating cell nuclear antigen (PCNA)/cyclinD1 and apoptosis-related proteins B-cell lymphoma-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) were determined. The binding of Sp1/3 and ß-catenin promoter and the targeted relationship between miR-495-3p with Sp1/3 were analyzed. Sp1/3 were upregulated in CD4+ T-cells in T-ALL and were linked with leukocyte count and risk classification. Sp1/3 interference prevented proliferation and promoted apoptosis in T-ALL cells. Sp1/3 transcription factors activated ß-catenin expression. Sp1/3 enhanced T-ALL cell proliferation by facilitating ß-catenin expression. miR-495-3p targeted and repressed Sp1/3 expressions. miR-495-3p overexpression inhibited T-ALL cell proliferation and promoted apoptosis. Conjointly, Sp1/3, as targets of miR-495-3p limit apoptosis and promote proliferation in T-ALL cells by promoting ß-catenin expression.

Fat mass and obesity-associated protein (FTO)-induced upregulation of flotillin-2 (FLOT2) contributes to cancer aggressiveness in diffuse large B-cell lymphoma (DLBCL) via activating the PI3K/Akt/mTOR signal pathway.

The role of fat mass and obesity-associated protein (FTO)-mediated N6-methyladenosine (m6A)-demethylation has been investigated in various types of cancers, but it is still unclear whether FTO participates in the progression of diffuse large B-cell lymphoma (DLBCL). Here, by conducting Real-Time qPCR and Western Blot analysis, we verified that FTO was especially enriched in the DLBCL cells (RCK-8, LY-3, DHL-6 and U2932) compared to normal WIL2S cells. Then, the overexpression and silencing vectors for FTO were delivered into the LY-3 and U2932 cells, and our functional experiments confirmed that silencing of FTO suppressed cell viability and division, and induced apoptotic cell death in the DLBCL cells, whereas FTO-overexpression exerted opposite effects. Further mechanical experiments showed that FTO demethylated m6A modifications in flotillin-2 (FLOT2) mRNA to sustain its stability for FLOT2 upregulation, and elevated FLOT2 subsequently increased the expression levels of phosphorylated PI3K (p-PI3K), p-Akt and p-mTOR to activate the tumor-initiating PI3K/Akt/mTOR signal pathway. Of note, FLOT2 also serve as an oncogene to enhance cancer malignancy in DLBCL, and the rescuing experiments showed that FTO-ablation induced suppressing effects on the malignant phenotypes in DLBCL were all abrogated by overexpressing FLOT2. Taken together, those data hinted that FTO-mediated m6A-demethylation upregulated FLOT2 to activate the downstream PI3K/Akt/mTOR signal pathway, leading to the aggressiveness of DLBCL, which potentially provided diagnostic, therapeutic and prognostic biomarkers for DLBCL.

Efficacy of chidamide maintenance therapy versus autologous stem cell transplantation versus observation as a post-remission choice in the survival of adult patients with peripheral T-cell lymphoma: Post hoc analysis of a prospective, multicenter, phase 2 study in China.

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .

Analysis and Investigation of Bioinformatics and Epigenetics Reveal the Underlying Mechanisms by which FLOT2 Modulates the Progression of Diffuse Large B-cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) poses a significant threat to the quality of life for people worldwide. Regrettably, effective treatment strategies for this disease remain elusive in clinical practice due to the unclear understanding of its molecular mechanisms. Therefore, this study was devised to address these issues and identify novel diagnostic, therapeutic, and prognostic biomarkers for DLBCL. METHODS: Gene expression and clinical data for DLBCL patients were retrieved from The Cancer Genome Atlas (TCGA) database, and relevant clinical data, tumor mutational burden (TMB), and gene expression levels were extracted. Bioinformatics analysis was conducted to screen for differentially expressed genes (DEGs). The prognostic significance of flotillin-2 (FLOT2) was assessed using Kaplan-Meier survival analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses were employed to evaluate mRNA and protein levels of the genes. Cell proliferation, apoptosis, and invasion were assessed using cell counting kit-8 (CCK-8) assay, flow cytometry analysis, and Transwell assay, respectively. RESULTS: Our bioinformatics analysis revealed that FLOT2 was significantly overexpressed in DLBCL tissues compared to normal tissues, a finding corroborated by subsequent immunohistochemistry staining, qRT-PCR, and Western blot analyses. To elucidate its biological functions, shRNAs targeting FLOT2 were transfected into DLBCL cell lines (LY-3 and U2932), resulting in suppressed cell proliferation and invasion, while promoting apoptosis. Furthermore, a positive correlation between TMB and FLOT2 expression in DLBCL was observed. Subsequently, quanTIseq was utilized to calculate the immune score and assess FLOT2 gene expression. In DLBCL, FLOT2 gene expression was found to be associated with T cell CD4+ (non-regulatory) (p < 0.01), monocytes (p < 0.05), and uncharacterized cells (p < 0.05). Regarding immune checkpoint markers, including the cluster of differentiation 274 (CD274), cytotoxic T lymphocyte-associated antigen-4 (CTLA4), hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte activation gene-3 (LAG3), programmed cell death protein 1 (PDCD1), programmed cell death 1 ligand 2 (PDCD1LG2), Siglec-15 (SIGLEC15), and T cell immunoreceptor with Ig and ITIM domains (TIGIT), our analysis indicated that in DLBCL, FLOT2 exhibited a relationship only with TIGIT (p < 0.05). CONCLUSIONS: In summary, FLOT2 functions as an oncogene and is linked to DLBCL prognosis and the tumor microenvironment. Targeting FLOT2 deletion emerges as a novel strategy to impede DLBCL aggressiveness by inhibiting cell proliferation and invasion, ultimately inducing apoptotic cell death.

Influence of academic involution atmosphere on college students' stress response: the chain mediating effect of relative deprivation and academic involution.

BACKGROUND: In recent years, the phenomenon of academic involution atmosphere among college students has gradually attracted the focus of education and social circles. Thus, this study targets college students as the research object and constructs a hypothetical model to explore the relationship between academic involution atmosphere and college students' stress response, as well as the mediating role of relative deprivation and academic involution. METHODS: A survey was conducted on 1090 college students using the Academic Involution Atmosphere Scale, Relative Deprivation Scale, Personal Academic Involution Scale, and Stress Response Scale. RESULTS: The results show that: (1) Academic involution atmosphere, relative deprivation, and academic involution are significantly and positively correlated with stress response; (2) Academic involution atmosphere not only directly predicts college students' stress response, but also indirectly predicts them through relative deprivation and academic involution, respectively; (3) Relative deprivation and academic involution have a chain mediating effect between academic involution atmosphere and stress response. CONCLUSIONS: The findings of this study reveal the influence of academic involution atmosphere on college students' stress response and the mechanism, providing beneficial insights for reducing college students' stress response and maintaining their psychological well-being.

Efficient 3D imaging and pathological analysis of the human lymphoma tumor microenvironment using light-sheet immunofluorescence microscopy.

Rationale: The composition and spatial structure of the lymphoma tumor microenvironment (TME) provide key pathological insights for tumor survival and growth, invasion and metastasis, and resistance to immunotherapy. However, the 3D lymphoma TME has not been well studied owing to the limitations of current imaging techniques. In this work, we take full advantage of a series of new techniques to enable the first 3D TME study in intact lymphoma tissue. Methods: Diverse cell subtypes in lymphoma tissues were tagged using a multiplex immunofluorescence labeling technique. To optically clarify the entire tissue, immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+), clear, unobstructed brain imaging cocktails and computational analysis (CUBIC) and stabilization to harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD) were comprehensively compared with the ultimate dimensional imaging of solvent-cleared organs (uDISCO) approach selected for clearing lymphoma tissues. A Bessel-beam light-sheet fluorescence microscope (B-LSFM) was developed to three-dimensionally image the clarified tissues at high speed and high resolution. A customized MATLAB program was used to quantify the number and colocalization of the cell subtypes based on the acquired multichannel 3D images. By combining these cutting-edge methods, we successfully carried out high-efficiency 3D visualization and high-content cellular analyses of the lymphoma TME. Results: Several antibodies, including CD3, CD8, CD20, CD68, CD163, CD14, CD15, FOXP3 and Ki67, were screened for labeling the TME in lymphoma tumors. The 3D imaging results of the TME from three types of lymphoma, reactive lymphocytic hyperplasia (RLN), diffuse large B-cell lymphoma (DLBCL), and angioimmunoblastic T-cell lymphoma (AITL), were quantitatively analyzed, and their cell number, localization, and spatial correlation were comprehensively revealed. Conclusion: We present an advanced imaging-based method for efficient 3D visualization and high-content cellular analysis of the lymphoma TME, rendering it a valuable tool for tumor pathological diagnosis and other clinical research.

Evaluation of Lipid Oxidation Characteristics in Salmon after Simulation of Cold Chain Interruption Using Rapid Evaporation Ionization Mass Spectrometry.

Temperature fluctuations occurring during the cold chain logistics of salmon contribute to lipid oxidation. This study aimed to simulate cold chain interruption through freeze-thaw operations and evaluate the lipidomics data from salmon samples subjected to different numbers of freeze-thaw cycles by using rapid evaporative ionization mass spectrometry (REIMS) combined with an intelligent surgical knife (iKnife). The results indicated significant differences in the relative abundance of characteristic ions among the samples (p < 0.05). A total of 34 ions with variable importance for the projection values ≥1 were identified as potential biomarkers, including m/z 719.4233 ([PCC36:5-NH(CH3)3]-), m/z 337.3134 ([FAC22:1]-), m/z 720.4666 ([PEC35:6-H]-), m/z 309.2780 ([FAC20:1]-), m/z 777.4985 ([PCC40:4-NH(CH3)3]-), m/z 745.4421 ([PCC38:6-NH(CH3)3]-/[PEC38:6-NH3]-), m/z 747.4665 ([PCC38:5-NH(CH3)3]-/[PEC38:5-NH3]-), etc. The degree of lipid oxidation was found to be associated with the number of freeze-thaw cycles, exhibiting the most significant alterations in the relative abundance of lipid ions in the 8T samples. Additionally, sensory evaluation by the CIE-L*a*b* method and volatile analysis by headspace solid-phase microextraction gas chromatography-mass spectrometry demonstrated significant differences (p < 0.05) in color and odor among the salmon samples, with a correlation to the number of freeze-thaw cycles. The primary compounds responsible for alterations in salmon odor were aldehydes with lower odor thresholds. In summary, the iKnife-REIMS method accurately differentiated salmon muscle tissues based on varying levels of lipid oxidation, thus expanding the application of REIMS.

Assessment and predictive ability of the absolute neutrophil count in peripheral blood for in vivo CAR T cells expansion and CRS.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is an advanced and effective immunotherapy for relapsed or refractory B-cell malignancies. High expansion of CAR T cells in vivo and durable antitumor activity indicate a persistent therapeutic response. However, this treatment is linked to a high frequency of adverse events, such as cytokine release syndrome (CRS), which affects its efficacy and can even be life-threatening. At present, a variety of markers associated with clinical response and treatment toxicity after CAR T cells infusion have been reported. Although these biomarkers can act as effective indicators reflecting CAR T cells expansion as well as CRS, they fail to predict the expansion rate of CAR T cells. Hence, further investigation is urgent to find a new biomarker to fill this void. METHODS: We analyzed the association between the absolute neutrophil count (ANC) and CAR expansion and CRS in 45 patients with B-cell malignancies from two clinical trials. We proposed that ANC could be a practical biomarker for CAR T cells expansion and CRS, and conducted a feasibility analysis on its predictive ability. RESULTS: In this study, 17 B-cell hematological malignancy patients with anti-B-cell maturation antigen CAR-treated and 28 with CAR19/22 T-cell-treated were enrolled and divided into an ANC-absence group and an ANC-presence group. The results showed that ANC absence correlated positively with CAR expansion and the expansion rate. The ANC can be used as a predictive marker for CAR T cells expansion. Moreover, the patients with ANC absence experienced a more severe CRS, and ANC performed a predictive ability for CRS. In addition, the peak serum concentration of several cytokines involved in CRS was higher in patients with ANC absence. CONCLUSION: Thus, we suggest ANC as an evaluative and predictive biomarker for CAR expansion and CRS during CAR T cell therapy, which can help to maximize clinical efficacy, reduce treatment-related toxicity and prolong survival.

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

First-line induction chemotherapy with high-dose methotrexate versus teniposide in patients with newly diagnosed primary central nervous system lymphoma: a retrospective, multicenter cohort study.

BACKGROUND: This study aimed to compare the efficacy and safety of high-dose methotrexate (HD-MTX) versus teniposide (TEN) in patients with newly diagnosed immunocompetent primary central nervous system lymphomas (PCNSLs). METHODS: The study included immunocompetent, adult patients with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The patients received HD-MTX or TEN as first-line induction therapy. The objective response rate, progression-free survival, and overall survival were analyzed for each patient cohort. RESULTS: A total of 96 patients were eligible: 62 received HD-MTX, while 34 received teniposide. The overall response rate was 73.2% and 72.7% in the MTX and the TEN cohorts, respectively (P = 0.627). The median progression-free survival was 28.4 months [95% confidence interval (CI): 13.7-51.2] in the MTX cohort and 24.3 months (95% CI: 16.6-32.1) in the TEN cohort (P = 0.75). The median overall survival was 31 months (95% CI: 26.8-35.2) in the MTX cohort and 32 months (95% CI: 27.6-36.4) in the TEN cohort (P = 0.77). The incidence of any grade of coagulopathy/deep-vein thrombosis and gastrointestinal disorders was significantly higher in the MTX cohort than in the TEN cohort; no significant difference was found in the incidence of other adverse events between the two cohorts. CONCLUSIONS: This was the first multicenter study using TEN as the main agent compared with HD-MTX in newly diagnosed primary CNS lymphoma. The TEN-based regimen was non-inferior to the HD-MTX-based regimen with similar overall responses. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that the teniposide-based regimen was non-inferior to high-dose methotrexate - based regimen with similar overall responses and long-time survival in immunocompetent patients with PCNSL.

Real-world treatment and outcome patterns of patients with mantle cell lymphoma in China: A large, multicenter retrospective analysis.

BACKGROUND: Mantle cell lymphoma (MCL) is an uncommon heterogeneous subtype of B cell non-Hodgkin lymphoma, and clinical features in MCL appear regional characteristics. MCL treatment opinions are not uniform between countries or regions within Asia and China, and Asian patient-specific data for MCL treatment are fewer. The study aims to explore the clinical characteristics, treatment patterns and prognosis of MCL patients in China. METHODS: A total of 805 patients diagnosed with MCL between April 1999 and December 2019 at 19 comprehensive hospitals in China were included in this retrospective analysis. Kaplan-Meier method coupled with the log-rank test was used for univariate analysis, and COX proportional hazards model was used for multivariate analysis (MVA). p < 0.05 was consided statistically significant. All outputs were produced using R version 4.1.0. RESULTS: The median age of the cohort was 60.0 years with a male-to-female ratio of 3.36:1. Five-year progression-free survival (PFS) and overall survival (OS) rates were 30.9% and 65.0%, respectively. High-intermediate/high-risk group according to MIPI-c, without high-dose cytarabine, lack of Auto-SCT as consolidation and maintenance treatment and SD/PD in initial treatment remained statistically relevant to poor PFS on MVA, and ki67 ≥50%, B symptoms, high-intermediate/high risk group according to MIPI-c, without high-dose cytarabine, lack of maintenance treatment, SD/PD in initial treatment and relapse/refractory state were independently associated with poorer OS on MVA. CONCLUSIONS: First-line high dose cytarabine exposure, auto-SCT as consolidation therapy obtained survival benefits in Chinese population. Our study further confirmed the value of maintenance treatment and explored the application of new drug treatment and bendamustine in R/R MCL patients.

Establishment and evaluation of a nomogram for predicting the survival outcomes of patients with diffuse large B-cell lymphoma based on International Prognostic Index scores and clinical indicators.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma, treatment outcomes of patients vary greatly. The current International Prognostic Index (IPI) is not enough to distinguish patients with poor prognosis, and genetic testing is very expensive, so a inexpensive risk prediction tool should be developed for clinicians to quickly identify the poor prognosis of DLBCL patients. Methods: DLBCL patients (n=420; 18-80 years old) who received a combination of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) with or without rituximab (R-CHOP) at our hospital between 2008 and 2017 were included in the study. Potential predictors of survival were determined by univariate and multivariate Cox regression analyses, and significant variables were used to construct predictive nomograms. The new prediction models were assessed using concordance indexes (C-indexes), calibration curves, and their clinical utility was assessed by decision curve analyses (DCAs). Results: The 5-year overall survival (OS) rate was 70.62% and the 5-year progression-free survival (PFS) rate was 59.02%. The multivariate Cox analysis indicated that IPI, Ki-67, the lymphocyte/monocyte ratio, and first-line treatment with rituximab were significantly associated with survival. The C-index results indicated that a predictive model that included these variables had better discriminability for OS (0.73 vs. 0.67) and PFS (0.68 vs. 0.63) than the IPI-based model. The calibration plots showed good agreement with observations and nomogram predictions. The DCAs demonstrated the clinical value of the nomograms. Conclusions: Our study identified prognostic factors in patients who were newly diagnosed with DLBCL to construct an individualized risk prediction model, combined IPI with common clinical indicators. Our model might be a valuable tool that could be used to predict the prognosis of DLBCL patients who receive standard first-line treatment regimens. It enables clinicians to quickly identify some patients with possible poor prognosis and choose more active treatment for patients, such as chimeric antigen receptor T-cell (CART) Immunotherapy and other new drugs therapy, so as to prolong the PFS and OS of patients.

Distributed Acoustic Sensing Based on Microtremor Survey Method for Near-Surface Active Faults Exploration: A Case Study in Datong Basin, China.

Active fault detection has an important significance for seismic disaster prevention and mitigation in urban areas. The high-density station arrays have the potential to provide a microtremor survey solution for shallow seismic investigations. However, the resolution limitation of the nodal seismometer and small-scale lateral velocity being inhomogeneous hinder their application in near-surface active fault exploration. Distributed acoustic sensing (DAS) has been developed rapidly in the past few years; it takes an optical fiber as the sensing medium and signal transmission medium, which can continuously detect vibration over long distances with high spatial resolution and low cost. This paper tried to address the issue of near-surface active fault exploration by using DAS. We selected a normal fault in the southern Datong basin, a graben basin in the Shanxi rift system in north China, to carry out the research. Microtremor surveys across the possible range of the active fault were conducted using DAS and nodal seismometers, so as to obtain a shallow shear wave velocity model. Meanwhile, we applied a Brillouin optical time domain reflectometer (BOTDR) and distributed temperature sensing (DTS) to monitor the real-time fluctuation of ground temperature and strain. Our results show that the resolution of the deep structures of the fault via the microtremor survey based on DAS is lower than that via the seismic reflection; whereas, their fault location is consistent, and the near-surface structure of the fault can be traced in the DAS results. In addition, both the BOTDR and DTS results indicate an apparent consistent change in ground temperature and strain across the fault determined by the DAS result, and the combination of surface monitoring and underground exploration will help to accurately avoid active faults and seismic potential assessment in urban areas.

Relationships Between College Students' Belief in a Just World and Their Learning Satisfaction: The Chain Mediating Effects of Gratitude and Engagement.

Purpose: This paper reveals the mechanism of the influence of belief in a just world on college students' learning satisfaction, and provides reference for further improving the quality of talent training in higher education. Methods: By convenient sampling method, 131,894 college students from 348 undergraduate universities in China were investigated on the belief in a just world scale, gratitude scale, learning engagement scale and learning satisfaction scale. Then, SPSS, AMOS and other software were used to analyze the data. Results: 1) Belief in a just world, gratitude, learning engagement and learning satisfaction are positively correlated. 2) Belief in a just world can not only directly and positively predict college students' learning satisfaction, but also indirectly and positively predict college students' learning satisfaction through gratitude and learning engagement respectively. 3) Gratitude and learning engagement play a chain mediating role between belief in a just world and learning satisfaction. Conclusion: Belief in a just world positively predicts college students' learning satisfaction through gratitude and learning engagement, suggesting that colleges and universities should create a fair learning environment and enhance college students' sense of gratitude, so as to improve college students' belief in a fair world and gratitude level, thus promoting their learning engagement and finally improving their learning satisfaction.

Identification of ATP1B1, a key copy number driver gene in diffuse large B-cell lymphoma and potential target for drugs.

Background: Copy number variations (CNVs) participate in the development and progression of cancer by altering the expression levels of genes. However, it is unclear whether this correlation exists in diffuse large B-cell lymphoma (DLBCL). Methods: Differentially expressed genes (DEGs) were identified from the GSE25638 and GSE56315 datasets. Modules that were highly related to DLBCL prognosis were obtained by Weighted Gene Co-expression Network Analysis (WGCNA). We performed an integrated analysis between CNV and differential gene expression in The Cancer Genome Atlas (TCGA) DLBCL. The DEGs were then overlapped with the module genes and expression-copy number variations-related (Exp-CNV-related) genes to obtain the common key genes. Time-dependent receiver operating characteristic (ROC) analysis was utilized to evaluate the accuracy of the key gene in predicting the prognosis of DLBCL. Next, we conducted a Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to explore the key gene. The potential molecule drugs of the key gene were identified by Connectivity Map (Cmap) analysis. Results: A turquoise module with 160 genes was identified as the signature module. ATP1B1 is overexpressed in DLBCL cell lines, compared to Cluster of Differentiation 19+B (CD19+B) cells. The ROC curve indicated that ATP1B1 could be a biomarker for diagnosing DLBCL, and the forest map suggested that ATP1B1 gene expression levels had a greater impact on the prognosis of patients with DLBCL. The area under curve (AUC) value of the time-dependent ROC curve with values based on the 1-, 3-, and 5-year survivability were 0.576, 0.663, and 0.706, respectively. Pathway analysis demonstrated the relationship between ATP1B1 and focal adhesion, etc. The inhibitory effects of ATP1B1 downregulation on DLBCL cell proliferation, cell migration, invasion, and cell adhesion were also examined. We found out that the higher proliferation ability in ATP1B1-overexpression cells was rescued with roxithromycin. Conclusions: ATP1B1 is a copy number driver gene that could potentially be adopted as a diagnostic biomarker and therapeutic target of DLBCL.

Comparison of Droplet Digital PCR and Metagenomic Next-Generation Sequencing Methods for the Detection of Human Herpesvirus 6B Infection Using Cell-Free DNA from Patients Receiving CAR-T and Hematopoietic Stem Cell Transplantation.

Purpose: The aim of this study was to examine and compare the differences between droplet digital PCR (ddPCR) and metagenomic next-generation sequencing (mNGS) in the detection of human herpesvirus 6B (HHV-6B). Long-term monitoring of HHV-6B viral load in patients receiving chimeric antigen receptor-modified T-cell (CAR-T) therapy and hematopoietic stem cell transplantation (HSCT) can be used to identify immune effector cell-associated neurotoxicity syndrome (ICANS) and guide drug therapy. Methods: Twenty-seven patients with suspected HHV-6B infection who had both mNGS and ddPCR test results were analyzed retrospectively, including 19 patients who received CAR T-cell therapy and 8 who received HSCT. The HHV-6B probe and primers were designed, and the performance of the ddPCR assay was evaluated. Subsequently, ddPCR was performed utilizing blood and urine. Data on clinical information and mNGS investigations were collected. Results: The ddPCR test results correlated significantly with the mNGS test results (P < 0.001, R2 = 0.672). Of the 27 time-paired samples, ddPCR showed positive HHV-6B detection in 20 samples, while mNGS alone showed positive HHV-6B detection in 12 samples. ddPCR detected additional HHV-6B infections in 8 samples that would have been missed if only mNGS were used. In addition, the first HHV-6B infection event was detected at a median of 14 days after CAR T-cell infusion (range, 8 to 19 days). Longitudinal monitoring of HHV-6B by ddPCR was performed to assess the effectiveness of antiviral therapy. The data showed that with antiviral treatment HHV-6B viral load gradually decreased. Conclusion: Our results indicated that ddPCR improved the HHV-6B positive detection ratio and was an effective adjunct to mNGS methods. Furthermore, the longitudinal detection and quantification of HHV-6B viral load in patients undergoing CAR T-cell therapy and HSCT may serve as a guide for drug treatment.

IP-10 enhances the amplification capacity and antitumor activity of CAR-T cells in vitro and could influence positive outcomes in MM patients treated with CAR-T cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy has shown impressive outcomes in haematologic malignancies. However, many patients experience a limited response and tumour relapse because of poor expansion and transport. Fourth-generation CARs address some of the limitations of CAR-T cell therapy, and cytokines are frequently included in fourth-generation CARs due to their importance in T cell development and homeostasis. However, new explorations are still needed to provide more desirable possibilities. Here, we first analysed clinical data from 18 patients with multiple myeloma (MM) who received immunotherapy with BCMA-CAR-T cells. The data showed that the basal serum level of IP-10 was correlated with patient outcomes one year after CAR-T cell therapy and that a higher basal serum level of IP-10 was positively associated with progression-free survival (PFS). Next, we performed in vitro experiments using flow cytometry-based assays, enzyme-linked immunosorbent assays, and cytotoxicity assays. The data verified that IP-10 can effectively stimulate the chemotaxis of CD8+ CAR-T cells. In addition, CAR-T cells cultured in IP-10-supplemented medium had a greater proliferation ability and a more powerful ability to kill tumour cells at a lower effector: target ratio. Thus, our findings demonstrate that IP-10 can enhance the function of CAR-T cells, which has important implications for improving CAR-T cell immunotherapy for haematologic malignancies.

Colletotrichum Spp. Diversity Between Leaf Anthracnose and Crown Rot From the Same Strawberry Plant.

Leaf anthracnose (LA) and anthracnose crown rot (ACR) represent serious fungal diseases that pose significant threats to strawberry production. To characterize the pathogen diversity associated with above diseases, 100 strawberry plants, including varieties of "Hongjia," "Zhangji," and "Tianxianzui," were sampled from Jiande and Zhoushan, the primary plantation regions of Zhejiang province, China. A total of 309 Colletotrichum isolates were isolated from crown (150 isolates) and leaves (159 isolates) of affected samples. Among these, 100 isolates obtained from the plants showing both LA and CR symptoms were selected randomly for further characterization. Based on the morphological observations combined with phylogenetic analysis of multiple genes (ACT, ITS, CAL, GAPDH, and CHS), all the 100 tested isolates were identified as C. gloeosporioides species complex, including 91 isolates of C. siamense, 8 isolates of C. fructicola causing both LA and ACR, and one isolate of C. aenigma causing ACR. The phenotypic characteristics of these isolated species were investigated using the BIOLOG phenotype MicroArray (PM) and a total of 950 different metabolic phenotype were tested, showing the characteristics among these isolates and providing the theoretical basis for pathogenic biochemistry and metabolism. The pathogenicity tests showed that even the same Colletotrichum species isolated from different diseased tissues (leaves or crowns) had significantly different pathogenicity toward strawberry leaves and crown. C. siamense isolated from diseased leaves (CSLA) was more aggressive than C. siamense isolated from rotted crown (CSCR) during the infection on "Zhangji" leaves. Additionally, C. fructicola isolated from affected leaf (CFLA) caused more severe symptoms on the leaves of four strawberry varieties compared to C. fructicola isolated from diseased crown (CFCR). For crown rot, the pathogenicity of CSCR was higher than that of CSLA.