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Abstract Chimeric antigen receptor T (CAR-T) cell therapy has greatly improved the prognosis of relapsed and refractory patients with large B-cell lymphoma (LBCL). Early identification and intervention of patients who may respond poorly to CAR-T cell therapy will help to improve the efficacy. Ninety patients from a Chinese cohort who received CAR-T cell therapy and underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans at the screening stage (median time to infusion 53.5 days, range 27–176 days), 1 month and 3 months after CAR-T cell infusion were analyzed, with RNA-sequencing conducted on 47 patients at the screening stage. Patients with maximum diameter of the largest lesion (Dmax)

Abstract Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated promising efficacy in early trials for relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, its efficacy in treating primary refractory DLBCL has not been comprehensively investigated, and the underlying resistance mechanisms remain unclear. Here, we report the outcomes of a phase I, open-label, single-arm clinical trial of relmacabtagene autoleucel (relma-cel), a CD19-targeted CAR-T cell product, with safety and efficacy as primary endpoints. Among the 12 enrolled patients, 8 experienced grade 4 hematologic toxicity of treatment-emergent adverse event. No grade ≥3 cytokine release syndrome or neurotoxicity occurred. Single-cell RNA sequencing revealed an increase proportion of C1QB-expressing macrophages in patients with progressive disease before CAR-T cell therapy. Cholesterol efflux from M2 macrophages was found to inhibit CAR-T cells cytotoxicity by inducing an immunosuppressive state in CD8+ T cells, leading to their exhaustion. Possible interactions between macrophages and CD8+ T cells, mediating lipid metabolism (AFR1-FAS), immune checkpoint activation, and T cell exhaustion (LGALS9-HAVCR2, CD86-CTLA4, and NECTIN2-TIGIT) were enhanced during disease progression. These findings suggest that cholesterol efflux from macrophages may trigger CD8+ T cell exhaustion, providing a rationale for metabolic reprogramming to counteract CAR-T treatment failure. Chinadrugtrials.org.cn identifier: CTR20200376.

Abstract Background Epstein–Barr virus (EBV) is a double‐stranded DNA herpesvirus and establishes life‐long infection in 95% of the world's populations. Main body EBV is critically involved in multiple diseases. Aberrant signaling pathways, immune escape, and metabolic reprogramming play essential roles in EBV‐mediated pathogenesis. However, the underlying mechanisms have not yet been fully elucidated. Here we reviewed recent advances on the epigenetic regulation of EBV pathogenesis, which may translate to potential therapeutic strategies in EBV‐associated diseases. Conclusion Growing evidence has suggested that viral infections reconstruct epigenome to modulate gene expression both in the host and the virus levels.

Summary: Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53mut, azacytidine if TET2/KMT2Dmut, tucidinostat if CREBBP/EP300mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12–0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0–26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34–0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28–1.10; p = 0.088). The most common grade 3–4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).

Abstract Background Drawing on the extensive utilization of traditional Chinese medicine (TCM) to combat COVID-19 in Mainland China, experts designed a series of TCM anti-epidemic strategies. This study aims to understand Hong Kong CM practitioners’ application of and opinions on the “Chinese Medicine Anti-epidemic Plans.” Methods Online focus group interviews were conducted, and purposive sampling was employed to invite 22 CM practitioners to voluntarily participate in three interview sessions. The interviews were audio recorded, then transcribed verbatim. The transcripts were analyzed using template analysis. Results Three themes were derived: (1) facilitators of the “Chinese Medicine Anti-epidemic Plans,” (2) barriers of the “Chinese Medicine Anti-epidemic Plans,” and (3) expectations on improving the “Chinese Medicine Anti-epidemic Plans.” The participants could obtain relevant information from various sources, which highlights the value of the plans for TCM medicinal cuisine and non-pharmacologic therapies and guiding junior CM practitioners, supplementing Western medicine interventions, and managing Chinese herb reserves in clinics. However, the barriers included the lack of a specialized platform for timely information release, defective plan content, limited reference value to experienced CM practitioners, and lack of applicability to Hong Kong. The expectations of the CM practitioners for improving the plans were identified based on the barriers. Conclusions To enhance the implementation of the anti-epidemic plans, CM practitioners in Hong Kong expect to utilize a specific CM platform and refine the plans to ensure that they are realistic, focused, comprehensive, and tailored to the local context.

Abstract Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24–74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43–79%) and 68% (95%CI, 47–84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45–83%) and 86% (95%CI, 63–95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

ABSTRACT Plant‐based proteins continue to gain popularity as a sustainable alternative to animal proteins due to their nutritional, functional and health benefits. Dry and wet fractionation methods are increasingly being used for the production of value‐added pulse protein ingredients. The objective of this study was to compare the nutritional properties, protein quality, physicochemical properties and secondary structure of Australian faba bean and yellow pea protein concentrates and protein isolates obtained by dry and wet fractionation. Amino acid scores highlighted that faba bean and yellow pea protein isolates and concentrates were deficient in the sulphur‐containing amino acids, methionine and cysteine and tryptophan. Faba bean (63.7%) and yellow pea protein (63.0%) isolates had higher in vitro protein digestibility‐corrected amino acid scores compared to the protein concentrates, being 50.7% and 54.4%, respectively. Fourier‐transform infrared spectroscopy revealed different secondary structures between protein concentrates and isolates, especially for the amide I region. Faba bean and yellow pea protein concentrates had higher protein solubility (46.2% and 50.1%, respectively) and higher foaming capacity (65% and 59%, respectively) compared to the protein isolates. Water‐holding capacity was higher for faba bean and yellow pea protein isolates, being 4.3% and 4.0 g/g, respectively. These findings demonstrate that faba bean and yellow pea protein concentrates and isolates have unique functional properties that can be exploited for use in a diverse range of new and existing food applications.

The parameter mismatch caused by the parameter uncertainties and unknown disturbances degrades the performance of finite-control-set model predictive control (FCS-MPC). This paper presents a model-free fault-tolerant predictive control (MFFTPC) method based on an extended sliding mode observer (ESMO) for the surface-mounted permanent magnet synchronous motor (SPMSM) drive system. First, considering parameter uncertainties and unknown disturbances, a novel ultra-local model (ULM) is established for the PMSM drive system. Next, a finite-control-set model-free fault-tolerant predictive current controller (FCS-MFFTPCC) is designed in the current loop, and the model-free deadbeat fault-tolerant predictive speed controller (MFDFTPSC) is designed in the speed loop. Then, unknown parts of the novel ULM are estimated by the designed ESMO and compensated for the errors caused by the parameter mismatches. Thus, the presented method reduces the dependence on the precise model and eliminates the effect caused by parameter mismatches on the MPC control performance of the SPMSM drive system.

This paper introduces an enzymatic approach to estimate internal mass-transfer resistances during food digestion studies. Cellulase has been used to degrade starch cell walls (where cellulose is a significant component) and reduce the internal mass-transfer resistance, so that the starch granules are released and hydrolysed by amylase, increasing the starch hydrolysis rates, as a technique for measuring the internal mass-transfer resistance of cell walls. The estimated internal mass-transfer resistances for granular starch hydrolysis in a beaker and stirrer system for simulating the food digestion range from 2.2 × 107 m−1 s at a stirrer speed of 100 rpm to 6.6 × 107 m−1 s at 200 rpm. The reaction rate constants for cellulase-treated starch are about three to eight times as great as those for starch powder. The beaker and stirrer system provides an in vitro model to quantitatively understand external mass-transfer resistance and compare mass-transfer and reaction rate kinetics in starch hydrolysis during food digestion. Particle size analysis indicates that starch cell wall degradation reduces starch granule adhesion (compared with soaked starch samples), though the primary particle sizes are similar, and increases the interfacial surface area, reducing internal mass-transfer resistance and overall mass-transfer resistance. Dimensional analysis (such as the Damköhler numbers, Da, 0.3–0.5) from this in vitro system shows that mass-transfer rates are greater than reaction rates. At the same time, SEM (scanning electron microscopy) images of starch particles indicate significant morphology changes due to the cell wall degradation.

Abstract TP53 mutation (TP53 mut) occurs in 10–20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53 mut remains a significant challenge in DLBCL treatment. Here we assessed TP53 mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53 mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53 mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53 mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53 mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53 mut patient-derived xenograft models and TP53 mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53 mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53 mut-driven cancers.

Abstract Background The current standard of care for non‐bulky diffuse large B‐cell lymphoma (DLBCL) patients with an International Prognostic Index (IPI) of 0 is four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non‐bulky DLBCL patients with an IPI of 1 remains unclear. This study compared four cycles versus six cycles of chemotherapy in non‐bulky low‐risk DLBCL patients with negative interim positron emission tomography with computed tomography (PET‐CT, Deauville 1‐3), irrespective of age and other IPI risk factors (IPI 0‐1). Methods This was an open‐label, randomized, phase III, non‐inferiority trial. Patients aged 14‐75 years with newly diagnosed low‐risk DLBCL, according to IPI, achieving PET‐CT confirmed complete response (CR) after four cycles of R‐CHOP were randomized (1:1) between four cycles of rituximab (4R‐CHOP+4R arm) or two cycles of R‐CHOP plus two cycles of rituximab (6R‐CHOP+2R arm). The primary endpoint was 2‐year progression‐free survival (PFS), conducted in the intention‐to‐treat population. Safety was assessed in patients with at least one cycle of assigned treatment. The non‐inferiority margin was ‐8%. Results A total of 287 patients were included in the intention‐to‐treat analysis, the median follow‐up was 47.3 months, and the 2‐year PFS rate was 95% (95% confidence interval [CI], 92% to 99%) and 94% (95% CI, 91% to 98%) for the 4R‐CHOP+4R and 6R‐CHOP+2R arm. The absolute difference in 2‐year PFS between the two arms was 1% (95% CI, ‐5% to 7%), supporting the non‐inferiority of 4R‐CHOP+4R. Grade 3‐4 neutropenia was lower in the last four cycles of rituximab alone in the 4R‐CHOP+4R arm (16.7% versus 76.9%), with decreased risk of febrile neutropenia (0.0% versus 8.4%) and infection (2.1% versus 14.0%). Conclusions For newly diagnosed low‐risk DLBCL patients, interim PET‐CT after four cycles of R‐CHOP was effective in identifying patients with Deauville 1‐3 who would have a good response and Deauville 4‐5 patients who might have high‐risk biological features or develop resistance. Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low‐risk, non‐bulky DLBCL with interim PET‐CT confirmed CR.

As the main form of improving students’ labor ability level and labor consciousness, labor education is conducive to promoting students’ physical and mental health development, and its content has a high overlap with ideological education. Under this premise, this paper proposes a BOPPPS teaching model that integrates labor ability cultivation and ideological education and constructs an evaluation model of ideological teaching to provide a basis for the validation and analysis of the examples of the BOPPPS teaching model. In the construction of the Civic and Political teaching evaluation model, based on the relevant principles of cluster analysis, an improved NP algorithm is proposed on the basis of K-means clustering algorithm and hierarchical cohesion algorithm, the data matrix is constructed, and the clustering features are introduced to portray the clustering characteristics. The evaluation model of Civics teaching is built based on cluster analysis and combined with hierarchical analysis. The example experiment of the BOPPPS teaching model was launched in University L. The difference between the clusters of Civics teaching evaluation obtained from the experiment and the proportion of the score section of the subject students’ grades is less than 1%, which is basically the same, which verifies the performance of the Civics teaching evaluation model. The mean value of each dimension of labor quality evaluation of the subject students is greater than 4, and the performance of labor quality is excellent.

Abstract Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma (DLBCL). Using whole exome/genome sequencing, RNA-sequencing, and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients, we established a simplified 38-gene algorithm (termed ‘LymphPlex’) based on the information on mutations of 35 genes and rearrangements of three genes (BCL2, BCL6, and MYC), identifying seven distinct genetic subtypes: TP53 Mut (TP53 mutations), MCD-like (MYD88, CD79B, PIM1, MPEG1, BTG1, TBL1XR1, PRDM1, IRF4 mutations), BN2-like (BCL6 fusion, NOTCH2, CD70, DTX1, BTG2, TNFAIP3, CCND3 mutations), N1-like (NOTCH1 mutations), EZB-like (BCL2 fusion, EZH2, TNFRSF14, KMT2D, B2M, FAS, CREBBP, ARID1A, EP300, CIITA, STAT6, GNA13 mutations, with or without MYC rearrangement), and ST2-like (SGK1, TET2, SOCS1, DDX3X, ZFP36L1, DUSP2, STAT3, IRF8 mutations). Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype. TP53 Mut subtype showed poor prognosis, characterized by p53 signaling dysregulation, immune deficiency, and PI3K activation. MCD-like subtype was associated with poor prognosis, activated B-cell (ABC) origin, BCL2/MYC double-expression, and NF-κB activation. BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation. N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell (GCB)-DLBCL, respectively. EZB-like-MYC+ subtype was characterized by an immunosuppressive tumor microenvironment, while EZB-like-MYC- subtype by NOTCH activation. ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation. Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy. Collectively, LymphPlex provided high efficacy and feasibility, representing a step forward to the mechanism-based targeted therapy in DLBCL.

Maintaining physical activity habits is important for long-term health benefits. Many children do not achieve the World Health Organization (WHO) benchmark of 60 min Moderate-to-Vigorous Physical Activity (MVPA) daily. Comprehensive school physical activity programs (CSPAP) target all opportunities at school for children to be physically active. The purpose of this intervention study was to investigate boys’ and girls’ voluntary participation and MVPA in physical activity recess sessions during and after these were connected with the content of physical education.147 (55 girls, 92 boys; mean age = 8 years) second grade children from seven different schools received a 10-lesson parkour unit in physical education and were concurrently offered five parkour recess sessions. After the parkour unit in physical education (i.e., maintenance) another five parkour sessions in which children could voluntarily participate were organized. Systematic observation tools were used to assess children’s MVPA.Overall participation in parkour recess was 64% for both boys and girls. Participation decreased from intervention to maintenance phase for both boys (75% vs 54%; p

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with variable clinical outcomes and prediction of prognosis remains important for long-term remission. We performed serial serum soluble interleukin-2 receptor (sIL-2R) measurement pretreatment and before each cycle of the treatment in 599 patients with de novo DLBCL. Genomic and transcriptomic features were analyzed by 223 DNA- and 227 RNA-sequencing, respectively. Applying the cut-off value to sIL-2R pretreatment and cycle 2 (C2) level, patients were classified into FINE subtype (pretreatment low level) with good prognosis, RES subtype (pretreatment high level and C2 low level) with intermediate prognosis, and RET subtype (pretreatment high level and C2 high level) with poor prognosis, independent of International Prognostic Index. In “others” genetic subtype, dynamic change of sIL-2R showed prognostic significance and genetic features. Compared with FINE subtype, RES subtype had increased ARID1A and MYD88 mutations, and RET subtype had increased KMT2D, LYN and SOCS1 mutations. RES and RET subtypes showed significant enrichment in oncogenic pathways, such as ERK, NF-κB, JAK-STAT, and immune-associated pathways. As for tumor microenvironment, RES subtype exhibited increased recruiting activity of CD8 + T, T helper 1, and natural killer cells, and RET subtype with increased recruiting activity of CD4 + T and regulatory T cells in silico. There was a positive correlation between transcripts of IL-2R and immune checkpoint expressions including PD-1 and CTLA-4. Our findings identified that dynamic change of sIL-2R, with this simple and easy detection method in peripheral blood, had long-term prognostic effect and specific relation to microenvironment alterations in DLBCL.

Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2–4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2–4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was −10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9–93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8–91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, −5.6–10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.

It is highly demanded to steer the charge flow in semiconductor for efficient photocatalytic environmental remediation. Herein, we designed an interfacial contact Ti3C2 MXene/ZnIn2S4 nanosheets (TC/ZISNS) Schottky heterostructure which could greatly enhance photogenerated charge separation of ZnIn2S4 (ZIS). Through TEM and XPS measurement, the strong interface coupling between 2D ZnIn2S4 nanosheets and 2D Ti3C2 MXene were explained, and the formation of Schottky heterostructure was demonstrated by electrochemical method. To investigate the photocatalytic activity of as-prepared samples, the photocatalytic reduction of Cr(VI) and photocatalytic oxidation degradation tetracycline hydrochloride (TC-H) experiments were carried out. The results showed that the Schottky catalyst (10%-TC/ZISNS) possessed the optimum photocatalytic efficiency. Especially, the apparent rate constant of Cr(VI) reduction with 10%-TC/ZISNS was 3.9 times than that of pure ZIS. The photocatalytic performance of 10%-TC/ZISNS toward degradation rate of TC-H was 1.8 times than that of pure ZIS. Finally, a possible mechanism for great enhancement of visible-light driven photocatalytic activity in the TC/ZISNS system was provided. On the whole, this work provided a new insight on 2D/2D contact Schottky heterostructure for enhancing photocatalytic activity.

The relative importance of the physical resistances to mass transfer have been explored by using halved 13 mm diameter apple-pectin tablets containing caffeine, in different external stirring environments within a beaker containing simulated gastric fluid. The effects of different external (outside of the tablets) mass-transfer resistances to the tablets created through two different stirrer types and stirrer speeds, and different internal (inside of the tablets) mass-transfer resistances created through different tablet concentrations and thicknesses, have been studied. These studies enable internal diffusion coefficients of caffeine through the apple pectin matrix to be estimated, as well as estimating the external mass-transfer coefficients from benzoic acid dissolution, which are in the range of 6.5 × 10-6 m/s – 2.4 × 10-5 m/s for the 0.6 mm thick tablets and 4.0 × 10-6 m/s – 1.6 × 10-5 m/s for the 7 mm thick tablets. The diffusion coefficients for different caffeine concentrations in the apple pectin half-tablets have also been calculated in this study. The diffusivity of caffeine in the 7 mm half-tablets with 1% caffeine through 99% pectin was around (1.8 ± 0.5) × 10-10 m2/s. This study points towards the development of multifilm mass-transfer theory for food digestion to create a more fundamentally based understanding of in-vitro digestion systems as an addition to the use of realistic in-vitro food digestion apparatus and give a better correlation between in-vitro and in-vivo digestion tests.

Abstract Background Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. Methods CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. Results We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. Conclusions CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/β-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.

Abstract Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.

Lymphoma cells expressing CD5 (CD5+) confer inferior outcome of diffuse large B-cell lymphoma (DLBCL), especially in non–MYC/BCL2 double expressor (non-DE) patients. In tumor microenvironment, CD5+ non-DE tumor revealed increased proportion of immunosuppressive M2 macrophages and enhanced pathways related to macrophage activation and migration. In accordance to M2 activation, lipid metabolism was upregulated, including fatty acid uptake and fatty acid oxidation, which supplied energy for M2 macrophage polarization and activation. Meanwhile, CD36 expression was upregulated and strongly correlated to the proportion of M2 macrophages in CD5+ non-DE DLBCL. In vitro, a DLBCL cell line (LY10) overexpressing CD5 significantly increased M2 proportion in comparison with control when cocultured with peripheral blood mononuclear cells (PBMCs). The addition of metformin significantly decreased the M2 proportion and the CD36 expression level in the coculture systems, indicating that metformin could target altered lipid metabolism and decrease M2 macrophages in DLBCL, especially in CD5+ non-DE lymphoma. In conclusion, enhanced lipid metabolism and M2 macrophage activation contributed to the immunosuppressive tumor microenvironment and could be potential therapeutic targets in CD5+ non-DE DLBCL.

Abstract Background Setaria italica is the second-most widely planted species of millets in the world and an important model grain crop for the research of C4 photosynthesis and abiotic stress tolerance. Through three genomes assembly and annotation efforts, all genomes were based on next generation sequencing technology, which limited the genome continuity. Results Here we report a high-quality whole-genome of new cultivar Huagu11, using single-molecule real-time sequencing and High-throughput chromosome conformation capture (Hi-C) mapping technologies. The total assembly size of the Huagu11 genome was 408.37 Mb with a scaffold N50 size of 45.89 Mb. Compared with the other three reported millet genomes based on the next generation sequencing technology, the Huagu11 genome had the highest genomic continuity. Intraspecies comparison showed about 94.97 and 94.66% of the Yugu1 and Huagu11 genomes, respectively, were able to be aligned as one-to-one blocks with four chromosome inversion. The Huagu11 genome contained approximately 19.43 Mb Presence/absence Variation (PAV) with 627 protein-coding transcripts, while Yugu1 genomes had 20.53 Mb PAV sequences encoding 737 proteins. Overall, 969,596 Single-nucleotide polymorphism (SNPs) and 156,282 insertion-deletion (InDels) were identified between these two genomes. The genome comparison between Huagu11 and Yugu1 should reflect the genetic identity and variation between the cultivars of foxtail millet to a certain extent. The Ser-626-Aln substitution in acetohydroxy acid synthase (AHAS) was found to be relative to the imazethapyr tolerance in Huagu11. Conclusions A new improved high-quality reference genome sequence of Setaria italica was assembled, and intraspecies genome comparison determined the genetic identity and variation between the cultivars of foxtail millet. Based on the genome sequence, it was inferred that the Ser-626-Aln substitution in AHAS was responsible for the imazethapyr tolerance in Huagu11. The new improved reference genome of Setaria italica will promote the genic and genomic studies of this species and be beneficial for cultivar improvement.

Objective:To determine the factors associated with quality of life of discharged patients with coronavirus disease 2019(COVID-19), so as to provide a basis for optimizing early intervention programs, preventing community from life restriction, and formulating appropriate community rehabilitation measures.Methods:A total of 57 discharged patients with COVID-19 who were cured from Wuhan China resources& Wisco general hospital from March to April 2020. In the"Questionnaire Star"platform from April to May 2020, the 12-item short form health survey version 2(SF-12V2) was used to evaluate life quality of life; the self-rating anxiety scale (SAS) was used to evaluate dyspnea anxiety status; the self-rating depression scale (SDS) was used to evaluate depression status; the modified medical research council dyspnea scores (mMRC) was used to evaluate difficulty of breathing. The quality of life of discharged patients with COVID-19 with different characteristics was compared. The correlation between the quality of life of patients and anxiety, depression and dyspnea and the related factors were analyzed.Results:A total of 57 questionnaires were distributed, and three duplicate and invalid questionnaires were eliminated, 54 valid questionnaires were obtained, with an effective questionnaire of 94.74%.①Quality of life of discharged patients with COVID-19: the physical component summary (PCS) scores and mental component summary (MCS) scores were (37.02±12.32) and (38.46±14.42) respectively; there were 3 cases (5.56%), 45 cases (83.33%), 5 cases (9.26%), and 1 case (1.85%) with dyspnea grade 0 to 3 respectively; 19 cases (35.19%) had an anxiety state (SAS≥50), and 19 cases (35.19%) had an anxiety state (SDS≥53). ②Comparison of quality of life of COVID-19 patients with different characteristics: patients with different disease types showed statistically significant differences in the SF-12V2 PCS(P< 0.05). ③Correlation analysis between quality of life, anxiety, depression and dyspnea: Pearson's correlation indicated that, anxiety (r=-0.34, P=0.011) and dyspnea (r=-0.39, P=0.003) were negatively correlated with the PCS scores, anxiety (r=-0.46, P=0.001) and depression (r=-0.40, P=0.002) were negatively correlated with the MCS scores.④Analysis of influencing factors on the quality of life of COVID-19 patients: multiple linear regression indicated that, sex (β=8.27), depression (β=-0.34) and severity of illness (β=-11.68) were significant predictors of the SF-12V2 PCS scores (P< 0.05). Anxiety (β=-0.62) was a significant predictor of the SF-12V2 MCS scores (P< 0.05).Conclusion:COVID-19 patients discharged from the hospital have problems with dyspnea, anxiety, depression, and the decline of quality of life. Sex, depression, anxiety and severity of illness are important factors for the decline of quality of life in patients with COVID-19. Patients with COVID-19(especially female patients and severe patients) should be screened for depression and anxiety as soon as possible after discharge and intervention should be carried out to reduce patients'negative emotions. Patients should be encouraged to participate in rehabilitation training appropriately to improve respiratory function and improve the quality of life.

Abstract Long noncoding RNAs (lncRNAs) play an essential role in tumor progression. Few researches focused on the clinical and biological relevance of lncRNAs in peripheral T cell lymphoma (PTCL). In this research, a novel lncRNA (ENST00000503502) was identified overexpressed in the main subtypes of PTCL, and designated as T cell lymphoma-associated lncRNA1 (TCLlnc1). Serum TCLlnc1 was associated with extranodal involvement, high-risk International Prognostic Index, and poor prognosis of the patients. Both in vitro and in vivo, overexpression of TCLlnc1 promoted T-lymphoma cell proliferation and migration, both of which were counteracted by the knockdown of TCLlnc1 using small interfering RNAs. As the mechanism of action, TCLlnc1 directly interacted with transcription activator heterogeneous nuclear ribonucleoprotein D (HNRNPD) and Y-box binding protein-1 (YBX1) by acting as a modular scaffold. TCLlnc1/HNRNPD/YBX1 complex upregulated transcription of TGFB2 and TGFBR1 genes, activated the tumor growth factor-β signaling pathway, resulting in lymphoma progression, and might be a potential target in PTCL.

The nature of renewable energy resources (RERs), such as wind energy, makes them highly unstable, unpredictable, and intermittent. As a result, they must be optimized to reduce costs and emissions, increase reliability, and also to find the optimal size and location for RERs and energy storage systems (ESSs). Microgrids (MG) can be modified using ESSs to gradually reduce traditional energy use. In order to integrate RERs in a financially viable scheme, ESSs should be sized and operated optimally. The paper presents an enhanced biogeography-driven optimization algorithm for optimizing the operations and sizes of battery ESSs (BESSs) taking into account MGs that experience wind energy penetration in a way that migration rates are adaptively adjusted based on habitat suitability indexes and differential perturbations added to migration operators. An optimization problem was applied to a BESS to determine its depth of discharge and lifespan. This paper considers three different scenarios in using simulations and compares them to existing optimization methods for the purpose of demonstrating the effectiveness of the offered scheme. Out of all the case studies examined, the optimized BESS-linked case study was the least expensive. We also show that a BESS must be of an optimum size to function both economically and healthily. For economic and efficient functioning of MGs, it has been shown that finding the optimum size of the ESS is important and potentially extends battery lifespan. The IBBOA obtained a more precise size for BESS’s volume, and the final outcomes are compared in this paper with other methods.

Abstract Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.

This paper proposes improved segment direct torque control (DTC) for full speed range in high-power urban rail vehicles engaged in frequent starting and braking. In the mid-speed range, based on a detailed harmonic analysis and comparison, a hybrid method of a rounded hexagon flux for DTC is proposed that can reduce the harmonic distortions in current and voltage. In addition, a circular flux is adopted to eliminate torque ripple in the low-speed range and a hexagon flux is adopted in the high-speed range to eliminate switching frequency. A transition control strategy for different speed segments is presented, and a smooth transition can be achieved. Hence, system stability and security are improved. The operation characteristics and design considerations for the proposed method are also introduced. Finally, a simulation model and a prototype of a full speed range system are built. The simulation and experimental results validate the effectiveness and the advantages of the proposed method.

MicroRNA (miRNA) have been emerged as prognostic biomarkers in diffuse large B‐cell lymphoma (DLBCL). To understand the potential underlying mechanisms and translate these findings into clinical prediction on lymphoma progression, large patient cohorts should be evaluated. Here, using miRNA PCR array, we analyzed the miRNA expression profiles in serum samples of 20 DLBCL patients at diagnosis, remission and relapse. Four candidate miRNA were identified and subsequently evaluated for their ability to predict relapse and survival. A prognostic model based on four circulating miRNA (miR21, miR130b, miR155 and miR28) was established and tested in a training cohort of 279 patients and in a validation cohort of 225 patients (NCT01852435). The prognostic value of the 4‐circulating miRNA model was assessed by univariate and multivariate analyses. The novel 4‐circulating miRNA prognostic model significantly predicted clinical outcome of DLBCL, independent of International Prognostic Index in the training cohort [hazard ratio (HR) = 2.83, 95% CI 2.14–3.51, P

A facile and efficient approach to manufacturing optical devices with a plane graphene-coupled microfiber structure is proposed—attaching the optical microfiber onto a monolayer graphene-coated polydimethylsiloxane substrate. Such devices exhibit strong light–graphene interaction via the evanescent fields of the guided light in microfibers and show evident optical polarization and polarization-dependent saturable absorption effect. When the monolayer graphene with propagation distance is 2.5 mm, and the microfiber diameter is 3.9 μm, the polarization extinction ratio can reach up to 31.0 dB with the light wavelength at 1550 nm. The transmission in TM modes could be increased continuously by increasing the input power of light at 980 nm. The transmission with 3 and 10 dB modulation depths in TM modes could be achieved via 980 nm pump power of 15.1 and 66.1 mW, respectively, which is advantageous over unpolarized graphene-coupled microfiber devices. The proposed microfiber on graphene structure could efficiently integrate optical waveguides with two-dimensional materials, with great potential applications in optical polarizers, all-optical modulators, mode-locked fiber lasers, and sensors, especially for all-fiber systems.

The incidence of diffuse large B-cell lymphoma (DLBCL) increases by age and older DLBCL are commonly related to poor prognosis. However, the clinical and biological features of older DLBCL patients remain to be determined. A total of 2,445 patients with newly diagnosed DLBCL were enrolled for clinical data analysis according to age at diagnosis, with tumor samples of 1,150 patients assessed by DNA sequencing and 385 patients by RNA sequencing. Older DLBCL presented advanced disease stage, elevated serum lactate dehydrogenase, poor performance status, multiple extranodal involvement, high percentage of double expressor subtype, and adverse clinical outcome. According to molecular features, age was positively correlated with the oncogenic mutations of PIM1, MYD88, BTG2, CD79B, TET2, BTG1, CREBBP, TBL1XR1, and with the MYD88-like genetic subtype. These oncogenic mutations were involved in B-cell receptor/NF-κB signaling, B-cell differentiation, and histone acetylation based on biological functions. Older DLBCL also manifested reduction in CD4+ naïve T and CD8+ naïve T cells, and also increased recruitment of exhausted T cells and macrophages, leading to immunosuppressive tumor microenvironment. Our work thus contributes to the understanding of aging-related oncogenic mutations and tumor microenvironment alterations in lymphoma progression, and may provide new insights to mechanism-based targeted therapy in DLBCL.

Terpene cyclases catalyze the formation of diverse hydrocarbon scaffolds found in terpenoids. Here, the authors report the cryptic function of class I terpene cyclases as aromatic prenyltransferases and the universality of this cryptic feature is confirmed using enzymes from different sources.

Abstract Tree peony (Paeonia Sect. Moutan) is a famous ornamental plant, with huge historical, cultural, and economic significance worldwide. In this study, we reported the ~13.79 Gb draft genome of a wide‐grown Paeonia suffruticosa cultivar “Luo shen xiao chun,” representing the largest sequenced genome in dicots to date. Phylogenetic analyses based on genome sequences demonstrated that P. suffruticosa was placed as sister to Vitales, and they together formed a clade that was sister to Rosids, weakly supporting a relationship of ((Saxifragales and Vitales) and Rosids). The identification and expression analysis of MADS‐box genes based on the genome assembly and de novo transcriptome assembly of P. suffruticosa revealed that the function of C class genes was restricted in flower development, which might be responsible for the stamen petalody in tree peony cultivars. Overall, the first sequenced genome in the family Paeoniaceae provides an important resource for the origin, domestication, and evolutionary study as well as cultivar breeding in tree peony.

Floccularia luteovirens, also known as “Yellow mushroom”, is an edible ectomycorrhizal fungus widely distributed in the Qinghai-Tibet Plateau alpine meadow. So far, little genomic information is known about F. luteovirens, which is not conductive to the protection and utilization of it. In this manuscript, we present a first draft genome assembly and annotation of F. luteovirens. The fruiting body of F. luteovirens was sequenced with PacBio Sequel and Illumina Hiseq 2500 system. The assembled genome size was 28.8 Mb, and comprising 183 contigs with a N50 contig size of 571 kb. A total of 8,333 protein-coding genes were predicted and 7,999 genes were further assigned to different public protein databases. Besides, 400 CAZymes were identified in F. luteovirens. Phylogenetic analysis suggested that F. luteovirens should belong to the Agaricaceae family. Time tree result showed that the speciation of F. luteovirens happened approximately 170 Million years ago. Furthermore, 357 species-specific gene families were annotated against KEGG and GO database. This genome assembly and annotation should be an essential genomic foundation for understanding the phylogenetic, metabolic and symbiotic traits of F. luteovirens.

Abstract Background Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. Methods PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m2, epirubicin 70 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and prednisone 60 mg/m2 [maximum 100 mg] on days 1–5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m2 on days 1–3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1–3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1–3, and dexamethasone 40 mg on days 1–4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor samples to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis. Results Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS; 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS; 24.3 months vs. 21.9 months, p = 0.178). Grade 3–4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D, KMT2A, SETD2, EP300, and CREBBP. Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p

Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress (PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation (days 8–14 and 15–21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light (6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early- and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China (approval No. KMMU2019074) in January 2019.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma and related to autoimmune diseases (AIDs). Primary B-cell receptor-mediated AIDs are associated with poor clinical outcome of DLBCL. To further determine the role of immunological alterations on disease progression, our study integrated genomic and transcriptomic analyses on DLBCL with multiple abnormal immunologic markers.MethodsThe clinical data of 1,792 patients with newly diagnosed DLBCL were collected, with DNA- and RNA-sequencing conducted for 164 and 127 patients, respectively. Frequent gene mutations and the involved dysregulated pathways, along with gene expression pattern and tumor microenvironment alternations, were analyzed and compared based on the immune status of the patients.ResultsDLBCL with multiple abnormal immunologic markers demonstrated a variety of characteristics including elevated serum lactic dehydrogenase level, inferior prognosis, and dysregulated cell cycle and immune response, as well as activated oxidative phosphorylation pathway and increased Th1/Th2 and Th17/Treg ratios, which were highly similar as those that occur in AIDs.ConclusionsWe piloted the description of the clinical and genetic features of DLBCL with multiple abnormal immunologic markers, illustrated possible mechanisms of disease progression, and provided a clinical rationale of mechanism-based targeted therapy in this subset of DLBCL.

Background: Metabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment. Methods: To understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models. Findings: In NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens. Interpretation: SLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL. Funding: This study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.

The clinical and molecular characteristics of localized diffuse large B-cell lymphoma (DLBCL) with single nodal (SN) or single extranodal (SE) involvement remain largely elusive in the rituximab era. The clinical data of 181 patients from a retrospective cohort and 108 patients from a phase 3 randomized trial NHL-001 (NCT01852435) were reviewed. Meanwhile, genetic aberrations, gene expression pattern, and tumor immunophenotype profile were revealed by DNA and RNA sequencing of 116 and 53 patients, respectively. SE patients showed similar clinicopathological features as SN patients, except for an increased percentage of low-intermediate risk in the National Comprehensive Cancer Network–International Prognostic Index. According to the molecular features, increased MPEG1 mutations were observed in SN patients, while SE patients were associated with upregulation of TGF-β signaling pathway and downregulation of T-cell receptor signaling pathway. SE patients also presented immunosuppressive status with lower activity of killing of cancer cells and recruiting dendritic cells. Extranodal involvement had no influence on progression-free survival (PFS) or overall survival (OS) in localized DLBCL. Serum lactate dehydrogenase >3 upper limit of normal was an independent adverse prognostic factor for OS, and ATM mutations were related to inferior PFS. Although the overall prognosis is satisfactory, specific clinical, genetic, and microenvironmental factors should be considered for future personalized treatment in localized DLBCL.