Search

Abstract Background Chimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy. Methods We conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes. Results All patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells. Conclusions Our findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells. Highlights 1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs. Graphical Abstract

Abstract. Background:. Although the treatment of peripheral T-cell lymphoma (PTCL) has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory—particularly for relapsed or refractory (R/R) patients. This phase II trial was designed to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate the standard chemotherapy for a variety of reasons. Methods:. We conducted a multicenter phase II clinical trial in which we combined chidamide (30 mg twice weekly) with prednisone (20 mg daily after breakfast), cyclophosphamide (50 mg daily after lunch), and thalidomide (100 mg daily at bedtime) (the CPCT regimen) for a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. Forty-five patients were ultimately enrolled from August 2016 to April 2021 with respect to Chinese patients at nine centers. Our primary objective was to assess the overall response rate (ORR) after the treatment with CPCT. Results:. Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% (32/45) and 28.9% (13/45), respectively, and after a median follow-up period of 56 months, the median progression-free survival (PFS) and overall survival (OS) were 8.5 months and 17.2 months, respectively. The five-year PFS and OS rates were 21.2% (95% confidence interval [CI], 7.9–34.5%) and 43.8% (95% CI, 28.3–59.3%), respectively. The most common adverse event was neutropenia (20/45, 44.4%), but we observed no treatment-related death. Conclusion:. The all-oral CPCT regimen was an effective and safe regimen for R/R PTCL patients who could not tolerate standard chemotherapy for various reasons. Trial Registration:. ClinicalTrials.gov, NCT02879526.

Abstract Background Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. Methods A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specificity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI). Results The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p

Abstract Background Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma‐associated HLH (LA‐HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA‐HLH in the elderly population. Methods We retrospectively analyzed a multicenter cohort of elderly patients with LA‐HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed. Results A total of 173 elderly patients with LA‐HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B‐cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p 1407 U/L), and a higher creatinine level (>96.8 μmol/L) were independent predictors of decreased overall survival and 60‐day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60‐day survival of elderly patients with LA‐HLH. Conclusions LA‐HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA‐HLH.

Abstract Background Extrachromosomal circular DNAs (eccDNAs), a type of double‐stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B‐cell lymphoma (DLBCL) has not been reported. Methods Circular DNA sequencing (circle‐seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK‐8 and scRNA‐seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA‐related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti‐tumour responses. Results EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs‐induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS‐independent manner. Moreover, inhibition of STING exerted a synergistic anti‐tumour effect with cisplatin. Conclusions EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING. Highlights EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.

Abstract The aim of the study was to evaluate the prognostic impact of minimal residual disease (MRD) in the real-world setting and the interaction between MRD and molecular risk, clinical response and autologous stem-cell transplant (ASCT). A retrospective analysis of 275 newly diagnosed multiple myeloma (NDMM) patients who achieved very good partial remission (VGPR) or better before maintenance were involved. We examined MRD status by multiparameter flow cytometry (MFC). At a median follow-up of 37 months (4–88 months), In patients who achieved ≥ VGPR, those with MRD negativity had significantly longer PFS (51 vs. 26 months; P

ABSTRACT: This study was designed to examine the impact of aspirin eugenol ester (AEE) on the growth performance, serum antioxidant capacity, jejunal barrier function, and cecal microbiota of broilers raised under stressful high density (HD) stocking conditions compared with normal density broilers (ND). A total of 432 one-day-old AA+ male broilers were randomly divided into 4 groups: normal density (ND, 14 broilers /m2), high density (HD, 22 broilers /m2), ND + AEE, and HD + AEE. The results of the study revealed a significant decrease in the growth performance of broiler chickens as a result of HD stress (P < 0.05). The total antioxidant capacity (T-AOC) in serum demonstrated a significant decrease (P < 0.05) at both 28 and 35 d. Conversely, the serum level of malondialdehyde (MDA) exhibited a significant increase (P < 0.05). Dietary supplementation of AEE resulted in a significant elevation (P < 0.05) of serum GSH-PX, SOD and T-AOC activity at both 28 and 35 d. Moreover, exposure to HD stress resulted in a considerable reduction in the height of intestinal villi and mRNA expression of tight junction proteins in the jejunum, along with, a significant elevation in the mRNA expression of inflammatory cytokines (P < 0.05). However, the administration of AEE reversed the adverse effects of HD-induced stress on villus height and suppressed the mRNA expression of the pro-inflammatory genes, COX-2 and mPGES-1. Additionally, the exposure to HD stress resulted in a substantial reduction in the α-diversity of cecal microbiota and disruption in the equilibrium of intestinal microbial composition, with a notable decrease in the relative abundance of Bacteroides and Faecalibacterium (P < 0.05). In contrast, the addition of AEE to the feed resulted in a notable increase in the relative abundance of Phascolarctobacterium and enhanced microbial diversity (P < 0.05). The inclusion of AEE in the diet has been demonstrated to enhance intestinal integrity and growth performance of broilers by effectively mitigating disruptions in gut microbiota induced by HD stress.

AimsThe aim of this study was to investigate the effects of aspirin eugenol ester (AEE) on ileal immune function in broilers under lipopolysaccharide (LPS)-induced immune stress.MethodsTwo hundred and forty one-day-old male Arbor Acres chicks were randomly divided into four groups (saline, LPS, saline + AEE and LPS + AEE) with six replicates of ten broilers each. The saline group and LPS group were fed the normal diet, while the other two groups received normal diet plus 0.1 g/kg AEE. Broilers in the LPS and LPS + AEE groups were injected intraperitoneally with 0.5 mg/kg B.W LPS in saline for seven consecutive days beginning at 14 days of age, while broilers in the saline and saline + AEE groups were injected with saline only.ResultsThe results showed that AEE improved the ileal morphology and increased the ratio of villus height to crypt depth of immune-stressed broilers. LPS-induced immune stress significantly reduced the expression of the genes for the tight junction proteins occludin, zonula occludens-1 (ZO-1), claudin-1 and claudin-2, in the ileum, while AEE significantly up-regulated the expression of these genes. Compared with the saline group, the LPS-treated chickens showed significantly increased mRNA expression of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), cyclooxygenase-2 (COX-2), and microsomal Prostaglandin E Synthesase-1 (mPGES-1) in the ileum, while they were significantly decreased by AEE supplementation. In addition, analysis of the ileal bacterial composition showed that compared with saline and LPS + AEE groups, the proportion of Firmicutes and Lactobacillus in the LPS group was lower, while the proportion of Proteobacteria and Escherichia-Shigella was higher. Similarly, Line Discriminant Analysis Effect Size (LEfSe) analysis showed that compared with the LPS group, Brevibacillus was dominant in the saline group, while the LPS + AEE group was rich in Rhizobium, Lachnoclostridium, Ruminococcaceae, Faecalibacterium, Negativibacillus, Oscillospiraceae, and Flavonifractor.ConclusionThese results indicate that dietary supplementation with 0.1 g/kg AEE could protect the intestinal health by improving the intestinal villus morphology, enhancing the expression of tight junction genes and alleviating inflammation to resist the immune stress caused by LPS stimulation in broilers, and the mechanism may involve COX-2-related signal transduction and improved intestinal microbiota composition.

Abstract Peripheral T‐cell lymphoma (PTCL) is a highly heterogeneous group of mature T‐cell malignancies. The efficacy of current first‐line treatment is dismal, and novel agents are urgently needed to improve patient outcomes. A close association between the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway and tumor promotion exists, revealing prospective therapeutic targets. This study, investigates the role of the cGAS‐STING pathway and its underlying mechanisms in PTCL progression. Single‐cell RNA sequencing showes that the cGAS‐STING pathway is highly expressed and closely associated with PTCL proliferation. cGAS inhibition suppresses tumor growth and impaires DNA damage repair. Moreover, Cdc2‐like kinase 1 (CLK1) is critical for residual tumor cell survival after treatment with cGAS inhibitors, and CLK1 suppression enhances sensitivity to cGAS inhibitors. Single‐cell dynamic transcriptomic analysis indicates reduced proliferation‐associated nascent RNAs as the underlying mechanism. In first‐line therapy, chemotherapy‐triggered DNA damage activates the cGAS‐STING pathway, and cGAS inhibitors can synergize with chemotherapeutic agents to kill tumors. The cGAS‐STING pathway is oncogenic in PTCL, whereas targeting cGAS suppresses tumor growth, and CLK1 may be a sensitivity indicator for cGAS inhibitors. These findings provide a theoretical foundation for optimizing therapeutic strategies for PTCL, especially in patients with relapsed/refractory disease.

Abstract Background Histiocytic necrotizing lymphadenitis (HNL) is a self‐limited inflammatory disease of unknown pathogenesis. A very small fraction of patients with HNL could develop hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder. These patients are diagnosed as HNL with HLH (HNL‐HLH). HNL‐HLH in the pediatric population has been systemically studied, however, the clinical, laboratory, and radiological features and outcomes of adult patients with HNL‐HLH remain to be explored. We aimed to explore the clinical, laboratory, and radiological features and outcomes of adult patients with HNL‐HLH. Methods We collected the clinical data of patients with HNL‐HLH admitted to the First Affiliated Hospital of Nanjing Medical University from October 2010 to June 2015. All the patients underwent lymph node biopsy and have a pathological diagnosis of HNL. The age, gender, clinical presentation, lymph node signs, laboratory findings and imaging data, and pathological findings of the patients were collected. Results In this study, we reported five adult patients with HNL‐HLH. All five patients showed enlarged lymph nodes and prolonged fever. Laboratory findings were consistent with the diagnosis of HLH. 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) showed enlarged lymph nodes with increased FDG uptake and splenic hypermetabolism could be present. All the patients responded well to corticosteroids and had a good prognosis. Two of the five patients were diagnosed with systemic lupus erythematosus during the follow‐up. Conclusions Our study demonstrated that adult patients with HNL‐HLH showed distinct clinical, laboratory, and radiological features. And the prognosis is good and patients could be managed with steroids and supportive care.

This study aimed to analyze the safety and applicability of a 90-min duration of infusion (SDI) of obinutuzumab in patients with B-cell non-Hodgkin's lymphoma (NHL) in a tertiary hospital in China. This exploratory clinical trial was performed at Jiangsu Province Hospital. All patients were treated with the standard infusion regimen for the first infusion. If no grade ≥3 infusion-related reactions (IRRs) occurred, the subsequent infusions were given as SDI. The primary endpoint was the incidence of IRR during the standard infusion (3-4 h) and 90-min SDI regimens. This study enrolled 208 patients and all completed cycle 1. Forty-one patients (19.71%) had IRRs: five (2.40%) with grade 1, twenty-eight (13.46%) with grade 2, and eight (3.85%) with grade 3. The 41 patients had 71 IRRs, mainly fever (40.85%), chest pain/tightness (12.68%), and dyspnea (9.86%). The occurrence of IRRs in the first infusion was significantly lower in patients who received oral acetaminophen prophylaxis than those who did not (10.72% vs 30.21%, P

Abstract Targeted therapy with Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of patients with various B-cell malignancies. BTK inhibitors such as ibrutinib, zanubrutinib, orelabrutinib, and acalabrutinib have shown good clinical efficacy and better safety profiles than those of traditional chemotherapy and chemoimmunotherapy regimens. Multiple studies on new BTK inhibitors are ongoing, which may provide more therapeutic options for the treatment of B-cell malignancies. Considering the unmet need of evidence on BTK inhibitors in all clinical settings and to standardize the use of BTK inhibitors available in mainland China, Taiwan, Hong Kong, and Macau regions, this consensus has been formulated for the treatment of various B-cell malignancies based on the clinical practice and available evidences on the use of BTK inhibitors. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective treatment of B-cell malignancies with BTK inhibitors.

Using traditional algorithms to identify persistent scatterer (PS) points is challenging during bridge construction because of short-term changes at construction sites, such as earthworks, as well as the erection and dismantling of temporary structures. To address this issue, this study proposes a PS point selection method based on statistical theory and Gaussian Mixture Model-Expectation Maximization (GMM-EM) algorithm. This method adopts amplitude information as an incoherence evaluation indicator. Furthermore, the statistical median of the amplitude dispersion index and amplitude mean is screened twice to extract a set of candidate points, including PS points that exhibit stable backscattering over long durations. Temporal coherence is simultaneously used as the coherence evaluation indicator. Another candidate point set is obtained by extracting high-coherence PS points using the GMM-EM algorithm. These sets of candidate points are then combined to obtain a final PS points set. In the experiment, the deformation monitoring of the under-construction Shenzhen-Zhongshan Cross-Sea Bridge in China was selected as a case study, with 28 Sentinel-1A images used as the data source for PS selection and deformation information extraction. The results show that the proposed method enhanced the density and quality of PS points on the under-construction cross-sea bridge compared to existing PS selection methods, thus offering higher reliability. Deformation analysis further revealed fluctuating deformation trends at characteristic points of the Shenzhen-Zhongshan Cross-Sea Bridge, indicating the occurrence of elastic deformation during its construction.

In order to improve wind power utilization efficiency and reduce wind power prediction errors, a combined prediction model of EMD-KPCA-BilSTM-ATT is proposed, which includes a data processing method combining empirical mode decomposition (EMD) and kernel principal component analysis (KPCA), and a prediction model combining bidirectional long short-term memory (BiLSTM) and an attention mechanism (ATT). Firstly, the influencing factors of wind power are analyzed. The quartile method is used to identify and eliminate the original abnormal data of wind power, and the linear interpolation method is used to replace the abnormal data. Secondly, EMD is used to decompose the preprocessed wind power data into Intrinsic Mode Function (IMF) components and residual components, revealing the changes in data signals at different time scales. Subsequently, KPCA is employed to screen the key components as the input of the BiLSTM-ATT prediction model. Finally, a prediction is made taking an actual wind farm in Anhui Province as an example, and the results show that the EMD-KPCAM-BiLSTM-ATT combined model has higher prediction accuracy compared to the comparative model.

Abstract Background Diffuse large B‐cell lymphoma (DLBCL) is the most common histological subtype of non‐Hodgkin lymphoma worldwide. The emergence of multiple primary malignancies (MPMs) has been described as a new prognostic factor in many types of tumors. Methods To investigate the morbidity, incidence, and survival of MPM in DLBCL, we retrospectively reviewed the characteristics of 788 patients with DLBCL. Results Forty‐two patients were diagnosed with MPM, and 22 of them were diagnosed with subsequent primary malignancies (SPM) by pathologic biopsy. The incidence of SPM was associated with older age. Germinal center B‐cell‐like (GCB) subtype and earlier Ann Arbor stage DLBCL patients were more prone to SPM. MPM, age, lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS), Hans classification, and international prognostic index (IPI) score were prognostic risk factors for overall survival (OS). Conclusion These data provide a comprehensive view of MPM in DLBCL. MPM was an independent prognostic factor of DLBCL in univariate analysis.

During bone drilling surgery, the bone drill can generate drilling force and frictional heat, which may lead to mechanical and thermal damage to the bone tissue. This paper presents a finite element (FE) simulation of bone drilling for cortical and cancellous bone, analyzing the influence of drilling parameters on bone drilling force and temperature. The simulation results reveal the change laws of axial force and temperature during different density bone drilling for various parameters. To optimize the bone drilling parameters, the Taguchi method is applied to conduct bone drilling simulation experiments based on the FE simulation model. The optimal values of axial force and temperature are predicted and calculated under the condition of optimal drilling parameters. Furthermore, a robot bone drilling experiment platform is used to verify the bone drilling FE simulation model and the optimal parameters. The research demonstrates that the FE simulation model effectively explores the influence of drilling parameters on bone drilling force and temperature, while the Taguchi method optimizes the drill parameters to minimize the mechanical and thermal damage to the bone tissue.

[This corrects the article DOI: 10.1371/journal.pone.0125429.].

Excessive biofluid around wounds can cause infection and prevent healing. In this study, an anisotropic quaternized chitosan (QC)/sodium alginate (AL)-based aerogel wound dressing was prepared via a directional freeze-drying technique inspired by the channel structure used for water transport in trees. The aligned channels provided the dressing with self-pumping ability, allowing it to rapidly and completely remove biofluids and absorb biofluids up to 1292.5 % of its own weight. To enhance the strength of the dressing, a double cross-linked network was constructed based on the QC-AL electrostatic attraction and AL-Ca2+ chelation interaction. The axial compressive strength of the double cross-linked dressing reached 207.3 kPa (ε = 50 %). In addition, the dressing exhibited strong conductive properties (conductivity = 13.0 S/m), antioxidant activities [reactive oxygen species (ROS) scavenging ability = 88.0 %], and hemostatic characteristics (blood coagulation index = 1.8 %). The dressing also exhibited powerful antibacterial performance, exhibiting over 98.0 % inhibition of E. coli and S. aureus. Experiments on diabetic mouse models revealed that the dressing considerably promoted wound healing. On day 3, the wound healing rate was 96.7 % faster in the QAC group than in the gauze group. Therefore, the developed dressing may have great potential for chronic wound care.

AbstractBackground: Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM).Methods: A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B) and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher’s exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model.Results: Compared to patients without EMDs, patients with EM-E were younger (p = 0.028), and those with EM-B had less renal damage (p

Abstract Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6‐methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL. Herein, an m6A scoring system and an m6A‐related circRNA prognostic signature are established, and circTET2 as a potential prognostic biomarker for CLL is identified. The level of m6A modification is found to affect the transport of circTET2 out of the nucleus. By interacting with the RNA‐binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), circTET2 regulates the stability of CPT1A and participates in the lipid metabolism and proliferation of CLL cells through mTORC1 signaling pathway. The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells. In addition, the biogenesis of circTET2 can be affected by the splicing process and the RBPs RBMX and YTHDC1. CP028, a splicing inhibitor, modulates the expression of circTET2 and shows pronounced inhibitory effects. In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL.

Heat stress (HS) negatively affects the growth, metabolism, reproduction, and productivity of plants and its adversary can be lessened through using exogenous substance (ES). With an extensive and comprehensive review of 136 collective literatures published for last two decades on alleviation of HS in plants through applying 65 ESs, we have proposed and discussed in details six mechanisms that underline their different effects on plant responses and regulations against HS at the structural, biochemical, molecular level through: 1) improving antioxidant pathways in plants; 2) promoting the synthesis of osmotic regulatory substances in cells; 3) enhancing photosynthetic functions in leaves; 4) adjusting the hormone balance, 5) regulating the expression of HS defensive genes and signal transduction; and 6) microbe-involved regulatory processes. More detailed information, research progress, perspectives and potential breakthroughs on using various ESs in alleviating plant HS are outlined to benefit researchers working on the subject to have a more comprehensive understanding of ESs effects and their underlying tolerance against plant HS.

AbstractBackground T-cell large granular lymphocyte leukaemia (T-LGLL) generally has a favourable prognosis, but a small proportion of patients are facing a relatively short survival time. This study aimed to identify clinical factors associated with survival in patients with T-LGLL and develop a predictive model for guiding therapeutic decision-making.Materials and Methods We conducted a retrospective study on 120 patients with T-LGLL. Lasso regression was performed for feature selection followed by univariate and multivariate Cox regression analysis. A decision tree algorithm was employed to construct a model for predicting overall survival (OS) in T-LGLL.Results The median age of diagnosis for the entire cohort was 59 years, and 76.7% of patients reported disease-related symptoms. After a median follow-up of 75 months, the median OS was not reached. The 5-year OS rate was 82.2% and the 10-year OS rate was 63.8%. Multivariate analysis revealed that an Eastern Cooperative Oncology Group performance status over two and a platelet count below 100 × 109/L were independently associated with worse OS, leading to the development of a simplified decision tree model. The model’s performance was adequate when internally validated. The median OS of the high- and intermediate-risk- risk groups was 43 and 100 months respectively, whereas the median OS of the low-risk group was not reached. Furthermore, we found that immunosuppressive agent-based conventional treatment was unsatisfactory for our high-risk patients.Conclusions Our model is an easily applicable clinical scoring system for predicting OS in patients with T-LGLL. However, external validation is essential before implementing it widely.

Abstract Background Although t (8;21) is in fact considered a good risk acute myeloid leukemia (AML), only 60% of the patients live beyond 5 years after diagnosis. Studies have shown that RNA demethylase ALKBH5 promotes leukemogenesis. However, the molecular mechanism and clinical significance of ALKBH5 in t (8;21) AML have not been elucidated. Methods The expression of ALKBH5 was assessed in t (8;21) AML patients via qRT-PCR and western blot. The proliferative activity of these cells was examined through CCK-8 or colony-forming assays, while flow cytometry approaches were used to examine apoptotic cell rates. The in vivo role of ALKBH5 promoting leukemogenesis was assessed using t (8;21) murine model, CDX, and PDX models. RNA sequencing, m6A RNA methylation assay, RNA immunoprecipitation, and luciferase reporter assay were used to explore the molecular mechanism of ALKBH5 in t (8;21) AML. Results ALKBH5 is highly expressed in t (8;21) AML patients. Silencing ALKBH5 suppresses the proliferation and promotes the apoptosis of patient-derived AML cells and Kasumi-1 cells. With integrated transcriptome analysis and wet-lab confirmation, we found that ITPA is a functionally important target of ALKBH5. Mechanistically, ALKBH5 demethylates ITPA mRNA and increases its mRNA stability, leading to enhanced ITPA expression. Furthermore, transcription factor TCF15, specifically expressed in leukemia stem/initiating cells (LSCs/LICs), is responsible for the dysregulated expression of ALKBH5 in t (8;21) AML. Conclusion Our work uncovers a critical function for the TCF15/ALKBH5/ITPA axis and provides insights into the vital roles of m6A methylation in t (8;21) AML.

Abstract To explore the prognostic values of baseline 2‐deoxy‐2‐[18F] fluoro‐D‐glucose (FDG) positron emission tomography/computed tomography (PET/CT) dissemination parameter in angioimmunoblastic T‐cell lymphoma (AITL) and its added values to total metabolic tumour volume (TMTV). Eighty‐one AITL patients with at least two FDG‐avid lesions in baseline PET/CT were retrospectively included. PET parameters including TMTV and the distance between the two lesions that are the furthest apart (Dmax) were obtained. Univariate Cox analysis showed that both Dmax and TMTV were risk factors for progression‐free survival (PFS) and overall survival (OS). Multivariate Cox analysis models of different combinations showed that high Dmax (> 65.7 cm) could independently predict both PFS and OS, while high TMTV (>456.6 cm3) was only significant for OS. A concise PET model based on TMTV and Dmax can effectively risk‐stratify patients. PFS and OS rates were significantly lower in patients with high Dmax and high TMTV than in patients with low Dmax and low TMTV (3‐year PFS rate: 15.0% vs. 48.7%, p = 0.001; 3‐year OS rate: 27.6% vs. 79.0%, p

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). With increasing approval of CAR T-cell products and advances in CAR T cell therapy, CAR T cells are expected to be used in a growing number of cases. However, CAR T-cell-associated toxicities can be severe or even fatal, thus compromising the survival benefit from this therapy. Standardizing and studying the clinical management of these toxicities are imperative. In contrast to other hematological malignancies, such as acute lymphoblastic leukemia and multiple myeloma, anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features, most notably local cytokine-release syndrome (CRS). However, previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL. Consequently, we developed this consensus for the prevention, recognition, and management of these toxicities, on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions. This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management, and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

In this paper, an improved APF-GFARRT* (artificial potential field-guided fuzzy adaptive rapidly exploring random trees) algorithm based on APF (artificial potential field) guided sampling and fuzzy adaptive expansion is proposed to solve the problems of weak orientation and low search success rate when randomly expanding nodes using the RRT (rapidly exploring random trees) algorithm for disinfecting robots in the dense environment of disinfection operation. Considering the inherent randomness of tree growth in the RRT* algorithm, a combination of APF with RRT* is introduced to enhance the purposefulness of the sampling process. In addition, in the context of RRT* facing dense and restricted environments such as narrow passages, adaptive step-size adjustment is implemented using fuzzy control. It accelerates the algorithm’s convergence and improves search efficiency in a specific area. The proposed algorithm is validated and analyzed in a specialized environment designed in MATLAB, and comparisons are made with existing path planning algorithms, including RRT, RRT*, and APF-RRT*. Experimental results show the excellent exploration speed of the improved algorithm, reducing the average initial path search time by about 46.52% compared to the other three algorithms. In addition, the improved algorithm exhibits faster convergence, significantly reducing the average iteration count and the average final path cost by about 10.01%. The algorithm’s enhanced adaptability in unique environments is particularly noteworthy, increasing the chances of successfully finding paths and generating more rational and smoother paths than other algorithms. Experimental results validate the proposed algorithm as a practical and feasible solution for similar problems.

Resveratrol (RSV), a polyphenol, is known to have a wide range of pharmacological properties in vitro. RSV may have therapeutic value for various neurodegenerative diseases via neuroprotective effects. However, it is not yet clear whether RSV can induce intestinal–brain interactions. It is assumed that the intestinal cells may secrete some factors after being stimulated by other substances. These secreted factors may activate nerve cells through gut–brain interaction, such as exosomes. In this study, it was discovered that Caco-2 cells treated with RSV secrete exosomes to activate SH-SY5Y neuronal cells. The results showed that secreted factors from RSV-treated Caco-2 cells activated SH-SY5Y. The exosomes of RSV-treated Caco-2 cells activated SH-SY5Y cells, which was manifested in the lengthening of the nerve filaments of SH-SY5Y cells. The exosomes were characterized using transmission electron microscopy and sequenced using the Illumina NovaSeq 6000 sequencer. The results showed that the miRNA expression profile of exosomes after RSV treatment changed, and twenty-six kinds of miRNAs were identified which expressed differentially between the control group and the RSV-treated group. Among them, three miRNAs were selected as candidate genes for inducing SH-SY5Y neural cell activation. Three miRNA mimics could activate SH-SY5Y neurons. These results suggested that the miRNA in intestinal exocrine cells treated with RSV may play an important role in the activation of SH-SY5Y neurons.

Aspirin eugenol ester (AEE) is a novel medicinal compound synthesized by esterifying aspirin with eugenol using the pro-drug principle. Pharmacological and pharmacodynamic experiments showed that AEE had excellent thromboprophylaxis and inhibition of platelet aggregation. This study aimed to investigate the effect of AEE on the liver of thrombosed rats to reveal its mechanism of thromboprophylaxis. Therefore, a multi-omics approach was used to analyze the liver. Transcriptome results showed 132 differentially expressed genes (DEGs) in the AEE group compared to the model group. Proteome results showed that 159 differentially expressed proteins (DEPs) were identified in the AEE group compared to the model group. Six proteins including fibrinogen alpha chain (Fga), fibrinogen gamma chain (Fgg), fibrinogen beta chain (Fgb), orosomucoid 1 (Orm1), hemopexin (Hpx), and kininogen-2 (Kng2) were selected for parallel reaction monitoring (PRM) analysis. The results showed that the expression of all six proteins was upregulated in the model group compared with the control group. In turn, AEE reversed the upregulation trend of these proteins to some degree. Metabolome results showed that 17 metabolites were upregulated and 38 were downregulated in the model group compared to the control group. AEE could reverse the expression of these metabolites to some degree and make them back to normal levels. The metabolites were mainly involved in metabolic pathways, including linoleic acid metabolism, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. Comprehensive analyses showed that AEE could prevent thrombosis by inhibiting platelet activation, decreasing inflammation, and regulating amino acid and energy metabolism. In conclusion, AEE can have a positive effect on thrombosis-related diseases.

Background SMARTTOUCH SURROUNDFLOW (STSF) catheter is the new generation of SMARTTOUCH (ST) catheter with an upgraded irrigation system for radiofrequency catheter ablation (RFCA) in patients with atrial fibrillation (AF).Methods This systematic literature review searched the major English and Chinese bibliographic databases from 2016 to 2022 for any original clinical studies assessing the STSF catheter for RFCA in AF patients. Meta-analysis with a random effects model was used for evidence synthesis.Results Pooled outcomes from 19 included studies indicated that STSF catheter was associated with a significantly shorter procedure time (weighted mean difference (WMD): −17.4 min, p