Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo

Background:Chimeric antigen receptor T(CAR-T)cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies.However,there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T(CAR-T)cell therapy,as well as the optimal timing for CAR-T cell infusion post-chemotherapy.Materials and Methods:We employed cell-derived tumor xenograft(CDX)murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment.Furthermore,transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen.Results:Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine,followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy,exerts the most efficacious therapeutic effect in B-cell hematological malignancies.Concurrently,RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism,primarily through the inhibition of key mitochondrial targets,such as C-Jun Kinase enzyme(C-JUN).Conclusion:In summary,the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

RPRD1B/CREPT facilitates the progression of diffuse large B-cell lymphoma by inhibiting apoptosis through the NF-κB signaling pathway

Objective:To investigate the role of RPRD1B in the progression of diffuse large B-cell lymphoma(DLBCL)and its potential as a therapeutic target.Methods:This study analyzed RPRD1B expression in DLBCL and normal tissues using public databases and assessed its prognostic impact through survival analysis.In vitro and in vivo experiments were conducted to explore the mechanisms by which RPRD1B influences tumor growth and apoptosis.Results:RPRD1B expression was significantly elevated in DLBCL compared to normal tissues and was associated with poor prognosis.In vitro and in vivo experiments demonstrated that RPRD1B promoted lymphoma cell proliferation and inhibited apoptosis through the NF-κB signaling pathway.Conclusions:RPRD1B plays a critical role in the progression of DLBCL by modulating apoptosis and cellular proliferation.Targeting RPRD1B may offer a novel therapeutic strategy for DLBCL,suggesting its potential as a prognostic marker and therapeutic target in hematological malignancies.

Identifying relevant factors influencing cancer-related fatigue in patients with diffuse large B-cell lymphoma during chemotherapy

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a rapidly growing malignant tumor,and chemotherapy is one of the treatments used to combat it.Although advancements of science and technology have resulted in more and more patients being able to receive effective treatment,they still face side effects such as fatigue and weakness.It is important to thoroughly investigate the factors that contribute to cancer-related fatigue(CRF)during chemotherapy.AIM To explore the factors related to CRF,anxiety,depression,and mindfulness levels in patients with DLBCL during chemotherapy.METHODS General information was collected from the electronic medical records of eligible patients.Sleep quality and mindfulness level scores in patients with DLBCL during chemotherapy were evaluated by the Pittsburgh Sleep Quality Index and Five Facet Mindfulness Questionnaire-Short Form.The Piper Fatigue Scale was used to evaluate the CRF status.The Self-Rating Anxiety Scale and Self-Rating Depression Scale were used to evaluate anxiety and depression status.Univariate analysis and multivariate regression analysis were used to investigate the factors related to CRF.RESULTS The overall average CRF level in 62 patients with DLBCL during chemotherapy was 5.74±2.51.In 25 patients,the highest rate of mild fatigue was in the cognitive dimension(40.32%),and in 35 patients the highest moderate fatigue rate in the behavioral dimension(56.45%).In the emotional dimension,severe fatigue had the highest rate of occurrence,34 cases or 29.03%.The CRF score was positively correlated with cancer experience(all P<0.01)and negatively correlated with cancer treatment efficacy(all P<0.01).Tumor staging,chemotherapy cycle,self-efficacy level,and anxiety and depression level were related to CRF in patients with DLBCL during chemotherapy.CONCLUSION There was a significant correlation between CRF and perceptual control level in patients.Tumor staging,chemotherapy cycle,self-efficacy level,and anxiety and depression level influenced CRF in patients with DLBCL during chemotherapy.

Primary anaplastic lymphoma kinase-positive large B-cell lymphoma of the left bulbar conjunctiva: A case report

BACKGROUND Anaplastic lymphoma kinase(ALK)-positive large B-cell lymphoma(LBCL)is an aggressive and rare variant of diffuse LBCL.Herein,we report an uncommon case of stage IE extranodal ALK-positive LBCL initially originating in the bulbar con-junctiva.CASE SUMMARY A 63-year-old woman presented with a mass in the left bulbar conjunctiva that had persisted for six months,accompanied by swelling and pain that had per-sisted for 3 d.Eye examination revealed an 8 mm slightly elevated pink mass in the lower conjunctival sac of the left eye.Microscopically,the tumor was com-posed of large immunoblastic and plasmablastic large lymphoid cells with scattered anaplastic or multinucleated large cells.Immunophenotypically,the neoplastic cells were positive for ALK,CD10,CD138,Kappa,MUM1,BOB.1,OCT-2,CD4,CD45,EMA,CD79a,CD38,and AE1/AE3,and negative for CD20,PAX5,Lambda,BCL6,CD30 and all other T-cell antigens.The results of gene rearrangement tests showed monoclonal IGH/IGK/IGL and TCRD rearran-gements.Fluorescence in situ hybridization studies did not reveal any BCL2,BCL6 or MYC rearrangements.Furthermore,Epstein-Barr virus was not detected by in situ hybridization in the lesions.Based on the histopathological and imaging examinations,the neoplasm was classified as stage IE ALK-positive LBCL.No further treatments were administered.At the 6,15,and 21 mo postoperative follow-up visits,the patient was in good condition,without obvious discomfort.This case represents the first example of primary extranodal ALK-positive LBCL presenting as a bulbar conjunctival mass,which is extremely rare and shares morphological and immunohistochemical features with a variety of other neo-plasms that can result in misdiagnosis.CONCLUSION Awareness of the condition presented in this case report is necessary for early and accurate diagnosis and appropriate treatment.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

SENEX-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma

Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.

Transformation of marginal zone lymphoma into high-grade B-cell lymphoma expressing terminal deoxynucleotidyl transferase:A case report

BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and HGBL-not otherwise specific(HGBL-NOS),which are morphologically characteristic of HGBL but lack MYC,BCL-2,or BCL-6 rearrangements.HGBL is partially transformed by follicular lymphoma and other indolent lymphoma,with few cases of marginal zone lymphoma(MZL)transformation.HGBL often has a poor prognosis and intensive therapy is currently mainly advocated,but there is no good treatment for these patients who cannot tolerate chemotherapy.CASE SUMMARY We reported a case of MZL transformed into HGBL-NOS with TP53 mutation and terminal deoxynucleotidyl transferase expression.Gene analysis revealed the gene expression profile was identical in the pre-and post-transformed tissues,suggesting that the two diseases are homologous,not secondary tumors.The chemotherapy was ineffective and the side effect was severe,so we tried combination therapy including venetoclax and obinutuzumab.The patient tolerated treatment well,and reached partial response.The patient had recurrence of hepatocellular carcinoma and died of multifunctional organ failure.He survived for 12 months after diagnosis.CONCLUSION Venetoclax combined with obinutuzumab might improve the survival in some HGBL patients,who are unsuitable for chemotherapy.

Association of overall survival benefit of radiotherapy with progression-free survival after chemotherapy for diffuse large B-cell lymphoma:A systematic review and meta-analysis

Objective:To evaluate whether improved progression-free survival(PFS)from radiotherapy(RT)translates into an overall survival(OS)benefit for diffuse large B-cell lymphoma(DLBCL).Methods:A systematic literature search identified randomized controlled trials(RCTs)and retrospective studies that compared combined-modality therapy(CMT)with chemotherapy(CT)alone.Weighted regression analyses were used to estimate the correlation between OS and PFS benefits.Cohen’s kappa statistic assessed the consis-tency between DLBCL risk-models and PFS patterns.Furthermore,the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio(HR)according to the PFS patterns.Results:For both 7 RCTs and 52 retrospective studies,correlations were found between PFS HR(HRPFS)and OS HR(HROS)at trial level(r=0.639-0.876),and between PFS and OS rates at treatment-arm level,regardless of CT regimens(r=0.882-0.964).Incorporating RT into CT increased about 18%of PFS,and revealed a different OS benefit profile.Patients were stratified into four CT-generated PFS patterns(>80%,>60-80%,>40-60%,and≤40%),which was consistent with risk-stratified subgroups(kappa>0.6).Absolute gain in OS from RT ranged from≤5%at PFS>80%to about 21%at PFS≤40%,with pooled HROS from 0.70(95%CI,0.51-0.97)to 0.48(95%CI,0.36-0.63)after rituximab-based CT.The OS benefit of RT was predominant in intermediate-and high-risk patients with PFS≤80%.Conclusion:We demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

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.

Helicobacter pylori eradication treatment for primary gastric diffuse large B-cell lymphoma:A single-center analysis

BACKGROUND Unlike the already established effect of Helicobacter pylori(H.pylori)eradication on gastric mucosa-associated lymphoid tissue(MALT)lymphoma,its therapeutic effect on primary gastric diffuse large B-cell lymphoma(DLBCL)is still unclear.AIM To clarify the efficacy of H.pylori eradication treatment for primary gastric DLBCL.METHODS We reported on 3 new cases,and added them to 3 previously reported cases.We analyzed the usefulness of H.pylori eradication treatment for gastric DLBCL for a total of 6 cases at our center.RESULTS Of the 6 patients(27-90 years old,3 males and 3 females),all 3 patients with single lesions(one transformed from MALT lymphoma)achieved complete remission(CR)after H.pylori eradication.Regarding the 2 newly reported cases,CR was maintained for more than 6 years with eradication treatment alone.In contrast,none of the 3 patients with 2 lesions achieved CR.In 1 newly reported case,endoscopic CR was achieved in one lesion,while stable disease was obtained in the other lesion.Two patients with progressive disease responded to standard chemo therapy±radiation and remained in CR for more than 6 years.CONCLUSION We believe it is worthwhile to attempt H.pylori eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden.

Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors(BTKis)in the treatment of elderly patients with DLBCL.CASE SUMMARY The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with BTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients,thus providing a new treatment strategy.

Diffuse large B-cell lymphoma successfully treated with amplified natural killer therapy alone: A case report

BACKGROUND The prognosis of patients with advanced diffuse large B-cell lymphoma(DLBCL)is poor,with a 5-year survival rate of approximately 50%.The mainstay of treatment is multidrug combination chemotherapy,which has been associated with serious side effects.Amplified natural killer(ANK)cell therapy amplifies and activates natural killer(NK)cells to attack only malignant tumors.As ANK cells attack programmed death ligand 1(PD-L1)-positive tumor cells,ANK therapy is considered effective against adult T-cell lymphoma and malignant lymphoma.CASE SUMMARY Herein,we report a case of an older patient with advanced DLBCL who was successfully treated with ANK immunotherapy.A 91-year-old female visited our hospital with sudden swelling of the right axillary lymph node in April 2022.The patient was diagnosed with stage II disease,given the absence of splenic involvement or contralateral lymphadenopathy.ANK therapy was administered.Six rounds of lymphocyte sampling were performed on July 28,2022.To reduce the occurrence of side effects,the six samples were diluted by half to obtain 12 samples.Cultured NK cells were administered twice weekly.The treatment efficacy was evaluated by performing computed tomography and serological tests every 1 or 2 mo.The treatment suppressed lesion growth,and the antitumor effect persisted for several months.The patient experienced mild side effects.PD-L1 immunostaining was positive,indicating that the treatment was highly effective.CONCLUSION ANK therapy can be used as a first-line treatment for malignant lymphoma;the PD-L1 positivity rate can predict treatment efficacy.

Diagnostic Efficacy of^(18)F-FDG PET/CT in Detecting Bone Marrow Infiltration in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Objective Diffuse large B-cell lymphoma(DLBCL)is often associated with bone marrow infiltration,and 2-deoxy-2-(18F)fluorodeoxyglucose positron emission tomography/computed tomography(^(18)F-FDG PET/CT)has potential diagnostic significance for bone marrow infiltration in DLBCL.Methods A total of 102 patients diagnosed with DLBCL between September 2019 and August 2022 were included.Bone marrow biopsy and^(18)F-FDG PET/CT examinations were performed at the time of initial diagnosis.Kappa tests were used to evaluate the agreement of^(18)F-FDG PET/CT with the gold standard,and the imaging features of DLBCL bone marrow infiltration on PET/CT were described.Results The total detection rate of bone marrow infiltration was not significantly different between PET/CT and primary bone marrow biopsy(P=0.302)or between the two bone marrow biopsies(P=0.826).The sensitivity,specificity,and Youden index of PET/CT for the diagnosis of DLBCL bone marrow infiltration were 0.923(95%CI,0.759-0.979),0.934(95%CI,0.855-0.972),and 0.857,respectively.Conclusion^(18)F-FDG PET/CT has a comparable efficiency in the diagnosis of DLBCL bone marrow infiltration.PET/CT-guided bone marrow biopsy can reduce the misdiagnosis of DLBCL bone marrow infiltration.

Asian variant intravascular large B-cell lymphoma with highly suspected central nervous system involvement:A case report

BACKGROUND Intravascular large B-cell lymphoma(IVLBCL)is a rare subtype of extranodal lymphoma.In particular,the Asian variant of IVLBCL is characterized by hemophagocytic lymphohistiocytosis along with bone marrow involvement.However,central nervous system(CNS)involvement is uncommon in this variant compared to the Western variant.Here,we report a case of typical Asian variant IVLBCL with highly suspected CNS involvement and discuss the nature of the disease and its genetic aberration.CASE SUMMARY A 67-year-old female patient complained of gradually worsening cognitive impairment.While hospitalized,she developed a high fever and showed marked bicytopenia.Intracranial imaging revealed a suspected leptomeningeal disease.Although no malignant cells were found in the cerebrospinal fluid(CSF),the protein and lactate dehydrogenase levels in CSF were increased.Bone marrow examination revealed an increased number of hemophagocytic histiocytes,and 18F-fluorodeoxyglucose(FDG)positron emission tomography with computerized tomography scan revealed increased FDG uptake in both adrenal glands,the liver,and the right ethmoid sinus.A tissue biopsy showed atypical large lymphoid cells with prominent nucleoli in the vessels,and the tumor cells were positive for CD20,BCL2,BCL6,and IRF4/MUM1.In addition,targeted sequencing identified MYD88,TET2,and PIM1 mutations.Consequently,we diagnosed the patient with the Asian variant of IVLBCL with highly suspected CNS involvement.CONCLUSION Suspicion of IVLBCL and immediate diagnosis lead to timely treatment.Moreover,careful CNS examination at diagnosis is recommended.

Comparative analysis of conventional ultrasound and shear wave elastography features in primary breast diffuse large B-cell lymphoma

BACKGROUND Primary breast diffuse large B-cell lymphoma(PB-DLBCL)is a rare subtype of non-Hodgkin lymphoma that accounts for<3%of extranodal lymphomas and 1%of breast tumors.Its diagnosis and management are challenging because of its rarity,heterogeneity,and aggressive behavior.Conventional ultrasound(US)is the first-line imaging modality for breast lesions;however,it has limited specificity and accuracy for PB-DLBCL.Shear wave elastography(SWE)is a novel US technique that measures tissue stiffness and may reflect the histological characteristics and biological behavior of breast lesions.AIM To compare the conventional US and SWE features of PB-DLBCL and evaluate their diagnostic performance and prognostic value.METHODS We retrospectively reviewed the clinical data and US images of 32 patients with pathologically confirmed PB-DLBCL who underwent conventional US and SWE before treatment.We analyzed conventional US features(shape,margin,orientation,echo,posterior acoustic features,calcification,and vascularity)and SWE features(mean elasticity value,standard deviation,minimum elasticity value,maximum elasticity value,and lesion-to-fat ratio)of the PB-DLBCL lesions.Using receiver operating characteristic curve analysis,we determined the optimal cutoff values and diagnostic performance of conventional US and SWE features.We also performed a survival analysis to assess the prognostic value of conventional US and SWE features.RESULTS The results showed that the PB-DLBCL lesions were mostly irregular in shape(84.4%),microlobulated or spiculated in margins(75%),parallel in orientation(65.6%),hypoechoic in echo(87.5%),and had posterior acoustic enhancement(65.6%).Calcification was rare(6.3%)and vascularity was variable(31.3%avascular,37.5%hypovascular,and 31.3%hypervascular).The mean elasticity value of PB-DLBCL lesions was significantly higher than that of benign breast lesions(113.4±46.9 kPa vs 27.8±16.4 kPa,P<0.001).The optimal cutoff value of the mean elasticity for distinguishing PB-DLBCL from benign breast lesions was 54.5 kPa,with a sensitivity of 93.8%,specificity of 92.9%,positive predictive value of 93.8%,negative predictive value of 92.9%,and accuracy of 93.3%.The mean elasticity value was also significantly correlated with Ki-67 expression level(r=0.612,P<0.001),which is a marker of tumor proliferation and aggressiveness.Survival analysis showed that patients with higher mean elasticity values(>54.5 kPa)had worse overall survival(OS)and progression-free survival(PFS)than those with lower mean elasticity values(<54.5 kPa)(P=0.038 for OS and P=0.027 for PFS).CONCLUSION Conventional US and SWE provide useful information for diagnosing and forecasting PB-DLBCL.SWE excels in distinguishing PB-DLBCL from benign breast lesions,reflects tumor proliferation and aggressiveness,and improves disease management.

Effect of T-regulatory cells and interleukin-35, interleukin-10, and transforming growth factor-beta on diffuse large B-cell lymphoma

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is an aggressive non-Hodgkin lymphoma that affects B lymphocytes.It can develop in the lymph nodes and can be localized or generalized.Despite DLBCL being considered potentially curable,little research has been conducted on the relationship between the body's immune response and DLBCL.AIM To study the expression and significance of T-regulatory cells(Tregs)interleukin(IL)-35,IL-10,and transforming growth factor-beta(TGF-β)in DLBCL.METHODS Data from 82 patients with DLBCL who were initially admitted to The First Affiliated Hospital of Ningbo University(Zhejiang Province,China)between January 2017 and June 2022 and treated with standard first-line regimens were reviewed.Three patients were lost to follow-up;thus,79 patients were included in the statistical analysis and then divided into three groups according to the evaluation of clinical efficacy:Incipient(new-onset and treatment-naïve),effectively treated,and relapsed-refractory.Thirty healthy individuals were included in the control group.The expression of peripheral blood T lymphocytes and their associated factors IL-35,IL-10,and TGF-βin the four groups were observed.RESULTS In contrast to the successfully treated and normal control groups,both the incipient and relapse-refractory groups exhibited greater proportions of CD4-positive(+)Tregs(P<0.05),whereas the proportion of CD8+Tregs did not differ substantially between the groups.Serum levels of IL-35 and IL-10 in the incipient and relapsed-refractory groups were higher than those in the effectively treated and normal control groups(P<0.05).There was no statistically significant distinction in the expression level of TGF-βbetween the groups(P>0.05).The correlation between IL-35 and IL-10 concentrations was significantly positive,with a correlation coefficient of 0.531(P<0.05).The correlation between IL-35 and TGF-βconcentration was significantly positive,with a correlation coefficient of 0.375(P<0.05).The correlation between IL-10 and TGF-βconcentration was significantly positive,with a correlation coefficient of 0.185(P<0.05).The expression concentrations of IL-35,IL-10 and TGF-βwere apparently and positively correlated(P<0.05).CONCLUSION Tregs IL-35,and IL-10 may be closely associated with the occurrence and development of DLBCL and the detection of related indices may be helpful in the analysis of disease prognosis.

Coexistence of diffuse large B-cell lymphoma,acute myeloid leukemia,and untreated lymphoplasmacytic lymphoma/waldenström macroglobulinemia in a same patient:A case report

BACKGROUND The Coexistence of myeloid and lymphoid malignancies is rare.Myeloid leukemia occurs more frequently as a secondary event in patients receiving chemotherapy agents for lymphoid malignancies.Synchronous diagnoses of diffuse large B-cell lymphoma(DLBCL),acute myeloid leukemia(AML),and untreated lymphoplasmacytic lymphoma/Waldenström macroglobulinemia(LPL/WM)in the same patient have not been reported.Here we report one such case.CASE SUMMARY An 89-year-old man had a chest wall mass histopathologically diagnosed as DLBCL.The bone marrow and peripheral blood contained two groups of cells.One group of cells fulfilled the criteria of AML,and the other revealed the features of small B lymphocytic proliferative disorder,which we considered LPL/WM.Multiple chromosomal or genetic changes were detected in bone marrow mononuclear cells,including ATM deletion,CCND1 amplification,mutations of MYD88(L265P)and TP53,WT1 overexpression,and fusion gene of BIRC2-ARAP1,as well as complex chromosomal abnormalities.The patient refused chemotherapy because of old age and died of pneumonia 1 mo after the final diagnosis.CONCLUSION The coexistence of DLBCL,AML,and untreated LPL/WM in the same patient is extremely rare,which probably results from multiple steps of genetic abnormalities.Asymptomatic LPL/WM might have occurred first,then myelodysplastic syndromerelated AML developed,and finally aggressive DLBCL arose.Therefore,medical staff should pay attention to this rare phenomenon to avoid misdiagnoses.

基于免疫B-Cell算法求解可满足性问题的性能分析

可满足性问题(SAT)是计算机科学和人工智能研究中的核心NP-完全问题.构造了两类SAT问题实例,易解和难解实例.从理论上分析了B-Cell算法求解该两个实例的运行时间,并证实了B-Cell算法在某些问题上有效而在一些问题上无效.进一步提出了一个简单的基于免疫的多目标优化算法(IBMO),对于一个双目标的SAT问题,证明了IBMO能够有效地找到整个Pareto前沿.这些分析结果从理论上证实和说明了人工免疫系统的有效性.

Antigen epitopes of animal coronaviruses:a mini-review

Coronaviruses are widespread in nature and can infect mammals and poultry,making them a public health concern.Globally,prevention and control of emerging and re-emerging animal coronaviruses is a great challenge.The mecha-nisms of virus-mediated immune responses have important implications for research on virus prevention and control.The antigenic epitope is a chemical group capable of stimulating the production of antibodies or sensitized lympho-cytes,playing an important role in antiviral immune responses.Thus,it can shed light on the development of diagnos-tic methods and novel vaccines.Here,we have reviewed advances in animal coronavirus antigenic epitope research,aiming to provide a reference for the prevention and control of animal and human coronaviruses.

Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer

Objective Colorectal cancer(CRC),a prevalent malignancy worldwide,has prompted extensive research into anticancer drugs.Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities.This study investigated the effects of Notopterygium incisum,a traditional Chinese medicine named Qianghuo(QH),on CRC cells and the underlying mechanism.Methods The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2.Propidium iodide(PI)staining was utilized to detect cell cycle progression,and PE Annexin V staining to detect apoptosis.Western blotting was conducted to examine the levels of apoptotic proteins,including B-cell lymphoma 2-interacting mediator of cell death(BIM),B-cell lymphoma 2(Bcl-2),Bcl-2-associated X protein(BAX)and cleaved caspase-3,as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide.The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis.The in vivo effects of QH extract on tumor growth were observed using a xenograft model.Lastly,APC^(Min+)mice were used to study the effects of QH extract on primary intestinal tumors.Results QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation,perturbation of cell cycle progression,and induction of apoptosis.Mechanistically,QH extract significantly increased the stability of BIM proteins,which undergo rapid degradation under unstressed conditions.Knockdown of BAX,the downstream effector of BIM,significantly rescued QH-induced apoptosis.Furthermore,the in vitro effect of QH extract was recapitulated in vivo.QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APC^(Min+)mice.Conclusion QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.